Circulation on the Run

This week, please join author Prakriti Gaba as she discusses the article "Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Left Main Disease With and  Without Diabetes: Findings From a Pooled Analysis of 4 Randomized Clinical Trials."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240422.957293

This week, please join author Gilles Montalescot as he discusses the article "Postprocedural Anticoagulation After Primary Percutaneous Coronary Intervention for ST-Segment−Elevation Myocardial Infarction: A Multicenter, Randomized, Double-Blind Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240412.432949

This week, please join author Hanjoong Jo, editorialist M. Luisa Iruela-Arispe, and Associate Editor Charles Lowenstein as they discuss the article "HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells," as well as the Editorial "Hemodynamic Forces and Atherosclerosis: HEG1 at the Center of the Jigsaw Puzzle."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20240408.470208

This week, please join author Nicholas Mills as he discusses the article "Machine Learning for Myocardial Infarction Compared With Guideline Recommended Diagnostic Pathways.

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20240329.877789

This week, please join author William McIntyre, Editorialist Christian Ruff, and Associate Editor Shinya Goto as they discuss the article "Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240322.70604

This week, please join author John Triedman and Associate Editor Gerald Greil as they discuss the article "Pediatric ECG-Based Deep Learning to Predict Left Ventricular Dysfunction and Remodeling."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240315.583656

This week, please join author Kieran Docherty and Associate Editor Justin Grodin as they discuss the article "Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240306.916294

This week, please join author Samir Kapadia and Editorialist Neil Kleiman as they discuss the article "Concomitant Left Atrial Appendage Occlusion and Transcatheter Aortic Valve Replacement Among Patients With Atrial Fibrillation."

For the episode transcript: https://www.ahajournals.org/do/10.1161/podcast.20240301.133854

This week, please join author Josep Rodés-Cabau and Associate Editor Dharam Kumbhani as they discuss the article "Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Small Aortic Annulus: A Randomized Clinical Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240226.780348 

This week's podcast features a panel discussion. Please join authors Masahiro Natsuaki, Myeong-Ki Hong, and Robert Storey, as well as Associate Editor Stefan James as they discuss the Original Research Articles "An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial" and "Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial" and the Editorial "Antiplatelet Therapy After PCI: The Art and Science of De-Escalation."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240220.712469

This week is Circulation's annual Go Red for Women issue. Please join Special Issue Editors Sana Al-Khatib and Mercedes R. Carnethon as they discuss the issue. Then they interview authors Jaime Kitt and Shanshan Sheehy as they discuss the articles "Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Substudy" and "Perceived Interpersonal Racism in Relation to Incident Coronary Heart Disease Among Black Women."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240212.130685

This week, please join author Brendon Neuen and Editor Sandeep Das as they discuss the original research article "Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240205.184727

We have a panel discussion with authors Albert Wiegman and Frederick Raal and Editorialist Raul Santos as they discuss the original research articles "Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia" and "Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/110.1161/podcast.20240129.812328

This week, please join author Geert-Jan Geersing he discusses the article "Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240122.313687

This week, please join author Mikhail Kosiborod and Associate Editor Brendan Everett as they discuss the article "Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20240116.96740

This week, please join author Kimberly Harmon and Associate Editor Mark Link as they discuss the article "Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240108.684387

This week, please join author Colin Berry and Associate Editor Emmanouil Brilakis as they discuss the article "Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240102.447846

This week, the Social Media Editors of Circulation interview the recipients for the 2023 Loscalzo and Willerson Awards. Please join Maryjane Farr, Susmita Sahoo, Shirin Doroudgar, Pishoy Gouda and Peter Kennel as they talk with authors Zihan Ma, Chenfeng Mao, and Alexander Sandhu.

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231222.991468

This week, please join author Cristina Basso and Associate Editor Mark Link as they discuss the Research Letter, "Rate and Cause of Sudden Cardiac Death in the Young During the COVID-19 Pandemic and Vaccination."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231218.67540

This week, please join author Jennifer Rymer and Editorialist Alexander Chaitoff as they discuss the article "Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights from VOYAGER PAD."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231211.181332

This week, please join author Ahamed Idris as he discusses the article "Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Cardiac Arrest: A Multicenter Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231204.859686

This week, please join author Jan Vincent Beltran and Associate Editor Charles Lowenstein as they discuss the article "Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers."

For episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231127.335747

This week, please join author Peter Henriksen and Guest Editor Ileana Piña as they discuss the article "A Multicenter, Prospective, Randomized Controlled Trial of High Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231120.338829

This week, please join author Sameed Ahmed Khatana and Associate Editor Mark Link as they discuss "Projected Change in the Burden of Excess Cardiovascular Deaths Associated with Extreme Heat by Midcentury (2036–2065) in the Contiguous United States."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231113.953480

This week, please join author Jung-Im Shin and Senior Associate Editor Sana Al-Khatib as they discuss "Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231106.465546

This week, please join author Daniel Jones and Associate Editor Dharam Kumbhani as they discuss "Computed Tomography Cardiac Angiography Before Invasive Coronary Angiography in Patients With Previous Bypass Surgery: The BYPASS-CTCA Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231030.705281

This week is a very special podcast: please join Circulation's Executive Editor James de Lemos and Associate Editor Marc Ruel as they discuss the articles in this year's Surgery Issue.

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231023.446837

This week, please join author Sebastian Reinstadler and Senior Associate Editor Victoria Delgado as they discuss "Cardiac Magnetic Resonance Imaging Versus Computed Tomography to Guide Transcatheter Aortic Valve Replacement: A Randomized, Open-Label, Noninferiority Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231016.898440

This week, please join senior author Nathaniel Smilowitz and Associate Editor Joshua Beckman as they discuss the article "Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES)."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/10.1161/podcast.20231009.345628

This week, please join author Karen Joynt Maddox and Associate Editor Sandeep Das as they discuss the article "Changes in Cardiovascular Spending, Care Utilization, and Clinical Outcomes Associated With Participation in Bundled Payments for Care Improvement−Advanced."

For the episode transcript, visit: https://www.ahajournals.org/do10.1161/podcast.20231002.799650

This week, please join author Milton Packer and Associate Editor Brendan Everett as they discuss the article "Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230925.181139

This week, please join authors Robert Yeh, Rahul Aggarwal, as well as Associate Editor Mark Link as they discuss the article "Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230918.938511

This week, please join author Mark Hofmeyer and Guest Editor Mauro Giacca as they discuss the article "Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230911.59229

This week, please join Guest Host Pishoy Gouda, author Kiran Khush, and Associate Editor Maryjane Farr as they discuss the article "Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230905.6639

This week, please join Carolyn Lam and author Frans Van de Werf as they discuss the article "STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment−Elevation Myocardial Infarction: A Randomized, Open-Label Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230828.941314

This week, please join author Jason Glotzbach and Associate Editor Wendy Post as they discuss the article "Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230821.396745

This week, please join Guest Host Pishoy Gouda, author Xin Du, and Guest Editor Walter Paulus as they discuss the article "The Effect of Frailty on the Efficacy and Safety of Intensive Blood Pressure Control: A Post Hoc Analysis of SPRINT Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230813.441244

This week, please join author Joe-Elie Salem and Guest Editor Allan Jaffe as they discuss the article "Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis."

For the episode transcript, visit:

https://www.ahajournals.org/do/10.1161/podcast.20230807.753501

This week, please join author Susmita Sahoo and Associate Editor Thomas Eschenhagen as they discuss the article "Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230731.330982

This week, please author Markus Schlaich as he discusses the Research Letter "Effect of Initial Treatment With a Single Pill Containing Quadruple Combination of Quarter Doses of Blood Pressure Medicines Versus Standard Dose Monotherapy in Patients With Hypertension on Ambulatory Blood Pressure Indices: Results From the QUARTET Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230724.155005

This week, please join our very special panel discussion to accompany Circulation's 2023 Disparities Issue. Please join Guest Host Mercedes Carnethon as she leads a discussion of equity, diversity, and inclusion in scientific research with panelists Karol Watson, Rishi Wadhera, and author Ambarish Pandey.

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.293635

This week, please join author Douglas Johns and Associate Editor Thomas Eschenhagen as they discuss the article "An Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor."

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.411427

This week, please join author Vivek Reddy and Associate Editor Mark Link as they discuss the article "Safety and Effectiveness of Pulsed Field Ablation to Treat Atrial Fibrillation: One-Year Outcomes From the MANIFEST-PF Registry."

For the episode transcript, visit: https://ahajournals.org/do10.1161/podcast.20230630.576031

This week, Digital Strategies Editor Maryjane Farr welcomes two guests, Joshua Beckman and Esther Kim, as they discuss vascular medicine, the current state of vascular medicine research, and two recently published vascular medicine articles in Circulation.

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230626.231366

This week, please join author Aidin Rawshani and Guest Editor Todd Brown as they discuss the article "Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study."

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230619.624297

This week, please join authors Emmy Okello and Andrea Beaton as they discuss the articles "Rheumatic Heart Disease Research Collaborative in Uganda" and "Refining Risk Stratification Among Children With Latent Rheumatic Heart Disease."

For the episode transcript, visit: 

https://ahajournals.org/do/10.1161/podcast.20230612.642952

This week, please join author Leslie Gordon and Associate Editor Torbjørn Omland as they discuss the article "Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230601.394643

This week, please join author Ewa Jankowska and Associate Editor Justin Ezekowitz as they discuss the article "Association Between Hemoglobin Level and the Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230526.118098

This week, please join author David Cohen and Associate Editor Stefan James as they discuss the article "Economic Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Low Surgical Risk: Results From the PARTNER 3 Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230519.961111

This week, please join author Braden Manns and Associate Editor and Editorialist Sandeep Das as they discuss 2 articles: "Self-Management Support Using Advertising Principles for Older Low Income Adults at High Cardiovascular Risk: A Randomized Controlled Trial" and "Eliminating Medication Copayments for Low-Income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230515.95172

This week, Carolyn, Greg, and Peder welcome podcast hosts Laxmi Mehta and Eva Rocha of The Journal of the American Heart Association's new podast "Aha! With JAHA."

Then, please join author Leopoldo Pérez de Isla and Associate Editor Stefan James as they discuss the article "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study. 

For the episode transcript, visit:

https://www.ahajournals.org/do/10.1161/podcast.20230508.620091

This week, please join author Hyo-Soo Kim and Associate Editor Stefan James as they discuss the article "Comparison of 3- to 6-Month Versus 12-Month Dual Antiplatelet Therapy After Coronary Intervention Using the Contemporary Drug-Eluting Stents With Ultrathin Struts: The HOST-IDEA Randomized Clinical Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230428.322841

This week on Circulation: On the Run, please join author Charles Hong and Associate Editor Gabriele Schiattarella as they discuss the article "Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230421.342161

This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE."

Dr Greg Hundley:

Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo.

Dr Greg Hundley:

Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?

Dr Peder Myhre:

Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles.

Dr Greg Hundley:

Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings?

Dr Peder Myhre:

So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure.

Dr Greg Hundley:

Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually.

Dr Peder Myhre:

Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find?

Dr Greg Hundley:

Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide.

Dr Peder Myhre:

Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article “Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.”

Dr Greg Hundley:

Great Peder, and also Professor Perera has a Frontiers article entitled “Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?” and then finally there's a Research Letter from Professor Verma entitled “Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study.” Well Peder, how about we jump to that feature discussion?

Dr Peder Myhre:

Can't wait.

Dr Greg Hundley:

Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Marc Sabatine:

Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events.

And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol.

Dr Greg Hundley:

Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population?

Dr. Prakriti Gaba (PK):

Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier.

Dr Greg Hundley:

Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please?

Dr. Prakriti Gaba (PK):

Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events.

Dr Greg Hundley:

Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender?

Dr. Prakriti Gaba (PK):

That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question.

Dr Greg Hundley:

Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol?

Dr. Amit Khera:

Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see.

So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT.

There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible.

I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms.

I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters.

Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing.

Dr Greg Hundley:

Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly?

Dr. Marc Sabatine:

Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results.

Dr Greg Hundley:

Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial?

Dr. Marc Sabatine:

Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen.

Dr Greg Hundley:

Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research?

Dr. Prakriti Gaba (PK):

I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available.

Dr Greg Hundley:

Very nice. And Marc?

Dr. Marc Sabatine:

Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER.

Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up.

Dr Greg Hundley:

Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target?

Dr. Amit Khera:

The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes.

I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment.

I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it.

Dr Greg Hundley:

Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events.

Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Kavita Sharma and Associate Editor Svati Shah as they discuss the article "Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction."

Dr. Greg Hundley:

Welcome listeners, to this April 11th issue of Circulation on the Run. And I am one of your cohosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital, and the University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, wow. This week's feature discussion, very interesting. We spend a lot of time, especially with our colleague, Dr. Carolyn Lam, on heart failure preserved ejection fraction. But this week's feature discussion, it's going to focus on some of the myocardial metabolomics in this condition. But before we get to that, how about we grab a cup of coffee, and jump into some of the other articles in the issue? How about if I go first?

Dr. Peder Myhre:

Let's go, Greg.

Dr. Greg Hundley:

Okay. So Peder, some believe that cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. And so, the American Heart Association, as you know, recently released an updated algorithm for evaluating cardiovascular health. Life's Essential 8, and it has a very nice score. So these authors, led by Dr. Lu Qi, from Tulane University, aimed to quantify the associations of the Life Essential 8 scores with life expectancy in a nationally representative sample of US adults. And the team included 23,000 non-pregnant non- institutionalized participants who were age 20 to 79 years, who participated in the National Health and Nutrition Examination survey, or NHANES, from 2005 to 2018. And whose mortality was identified through linkage to the National Death Index, from the period extending through December of 2019.

Dr. Peder Myhre:

Oh wow. So really, a validation of the Life's Essential 8. Greg, that's so interesting. What did they find?

Dr. Greg Hundley:

Right Peder, as you say, very interesting. So here are some of the data, and let's itemize them. So, during a median of 7.8 years of follow up, 1,359 total deaths occurred. Now, the estimated life expectancy at age 50 was 27.3 years, 32.9 years, and 36.2 years, in participants with low Life's Essential 8 scores, less than 50. Moderate, so Life's Essential 8 scores of greater than or equal to 50, but less than 80. And then, high scores, greater than 80. Okay? So equivalently, participants with high Life's Essential 8 scores had an average of 8.9 more years of life expectancy at age 50, compared to those with low scores.

Next, on average, 42.6% of the gained life expectancy at age 50, from adhering to sort of that cardiovascular health, those recommendations, was attributable to reduced cardiovascular death.

Next, significant associations with the Life's Essential 8 score and life expectancy were observed in both men and women.

Next, similarly significant associations of cardiovascular health, Life's Essential 8, with life expectancy were observed in non-Hispanic Whites and non-Hispanic Blacks, but not in those originating from the country of Mexico.

So Peder, finally, in summarizing all of this, adhering to the cardiovascular health lifestyle, defined by the Life's Essential 8 score, it was related to a considerably increased life expectancy. However, because of the findings from the individuals from the country of Mexico, more research is needed to be done in some of these minority groups, and particularly, those of Hispanic ethnicity, and perhaps other races.

Dr. Peder Myhre:

Oh, wow. Very interesting. And I would love to learn more about this subgroup analysis in future studies.

So Greg, the next paper is about the hospitalization for heart failure measures. Because contemporary measures of hospital performance for heart failure hospitalization, the 30-day risk standardized readmission and mortality rate, are estimated using the same risk adjusted model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial ethnic groups, and may not adequately represent the hospital performance for patients of Black or other races. And in this study, led by co-corresponding authors, Mentias from Cleveland Clinic and Pandey from University of Texas Southwestern Medical Center, the authors used fee for service Medicare beneficiaries from 2014 to 2019 hospitalized with heart failure, in hospital level 30 day risk standardized remission and mortality rates were estimated using traditional race agnostic models and the race specific approach, with measures derived separately for each race ethnicity group.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what did they find from this study?

Dr. Peder Myhre:

So the study included more than 1.9 million patients, comprising of 75% White patients, 15% Black patients, and 10% patients of other races, with heart failure from 1,860 hospitals. And compared with the race agnostic model, composite race-specific metrics for all patients demonstrated stronger correlation with 30 days readmissions. And that is correlation coefficient 0.78 versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black patients. In concordance in hospital performance was for all patients and patients of Black race was also higher with race specific as compared to race agnostic metrics.

So Greg, the authors conclude that among patients hospitalized with heart failure race specific 30 day risk standardized remission and mortality rates are more equitable in representing hospital performance for patients of Black and other races.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful summary in a very elegant study. Peder, myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlining molecular mechanisms for this relationship remain unclear. Now, recent studies demonstrate, that the diabetic heart is resistant to several cardioprotective interventions, including adiponectin and pre-conditioning. The universal quote, unquote, resistance to multiple therapeutic interventions suggest, impairment of the requisite molecule, or molecules, involved in broad pro survival signaling cascades. Now caveolin is a scaffolding protein coordinating trans-membrane signaling transduction. However, the role of caveolin-3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. And so these investigators, led by Dr. Xinliang Ma, from Thomas Jefferson University, studied mice fed a normal diet or high fat diet for two to 12 weeks, and subjected them to myocardial ischemia and reperfusion.

Dr. Peder Myhre:

Oh wow. What an interesting preclinical science paper, Greg. What did they find?

Dr. Greg Hundley:

Right. So the authors found that nitration of caveolin-3 at tyrosine 73 and resulted signal complex dissociation was responsible for cardiac insulin adiponectin resistance in the pre-diabetic heart. And this contributed to ischemic heart failure progression. Now, early interventions preserving caveolin-3 centered signal zone integrity was found to be an effective novel strategy against diabetic exacerbation of ischemic heart failure. And Peder, I think these very exciting results suggest that this is a new area of research and further experiments are warranted.

And there's a very nice editorial by Professor Heidenreich, entitled “Pursuing Equity in Performance Measurement.

Well Peder, there's some other articles in this issue, and we'll dip in this week to the mail bag, for a Research Letter from Professor Hibbert, entitled “Utility of a Smartphone Application in Assessing Palmar Circulation Prior to Radial Artery Harvesting for Coronary Artery Bypass Grafting.”

Dr. Peder Myhre:

That is so cool. And we also have a Letter from Dr. Kim, regarding the article entitled, “Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study.”

Dr. Greg Hundley:

Very nice. Well, how about we get along to one of Carolyn's favorite topics, heart failure with preserved ejection fraction, and learn more about myocardial metabolomics?

Dr. Peder Myhre:

Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is on my favorite topic, heart failure with preserved ejection fraction, or HFpEF. But today, what we're focusing on is truly novel. We are looking at the myocardial metabolomics of human HFpEF, very, very valuable data and insights. We're so pleased to have with us the corresponding author of today's feature paper, Dr. Kavita Sharma, who's from the Johns Hopkins University School of Medicine, and our associate editor, Dr. Svati Shah, who's, of course, from Duke University School of Medicine.

So welcome Kavita and Svati. Kavita, if I could start by, please put us and bring us all to the same level of knowledge, by perhaps explaining in simple terms, what is metabolomics? And what is normal versus perhaps abnormal metabolomics, in a known condition, like systolic heart failure or heart failure with reduced ejection fraction?

Dr. Kavita Sharma:

Sure. Well thank you, Carolyn, for the opportunity to chat around this topic. And it's great to be with you and Svati this morning. Metabolomics is a broad general study of essentially, all the chemical processes involving metabolites, or small molecule substrates, their intermediates, and even the products of cellular metabolism. This can be studied in really, any organ system, in any organ. What is really unique, I think, to this particular paper in our project is that, it has yet to have been defined or described in human HFpEF from the myocardial tissue. We call this heart failure with preserved ejection fraction, and inherent to that name in this complicated syndrome is that, there is something probably wrong with the heart, yet we have not really had much insight to what that might be from direct myocardial tissue.

We are also still learning about what metabolomics looks like in, for example, the heart failure with reduced ejection fraction state. Though, there is more published in this space than in HFpEF. From the limited knowledge that we have, it does appear that heart failure with reduced ejection fraction hearts, and this is certainly seen in the plasma, which is where most of metabolomic studies have generated from, those hearts tend to utilize various forms of energy banks, if you will. Whether that's fatty acid oxidation, whether that is glucose utilization or intermediates and so on. And our primary interest was to understand, how do the preserved EF parts in patients fare in comparison?

Dr. Carolyn Lam:

Oh, thank you so much, Kavita. That was beautifully explained. And indeed, what's so special about your paper is, it's not just circulating metabolites but myocardial metabolites. And you have the control groups that are so important to study at the same time. So patients with HFpEF, but also those with HFrEF and versus controls. And thank you for establishing too, that if I'm not wrong, fatty acid metabolism accounts for the majority of ATP generation in the normal heart. Whereas, this declines a little in the HFrEF heart. And now, I think we're about to find out what happens in the HFpEF heart. So if you could explain what you did and what you find.

Dr. Kavita Sharma:

Yes, absolutely. So we examined, again, tissue and plasma metabolomics from 38 subjects with HFpEF. These are patients referred to the Hopkins HFpEF Clinic. And so they have been essentially, clinically evaluated, and have what we define as HFpEF, based on hemodynamic testing. So a right heart catheterization, often with exercise, that meets criteria for diagnosis of the syndrome.

As you stated, we compared our HFpEF patient tissue and plasma samples to samples coming from patients with HFrEF, dilated cardiomyopathy, and non-failing controls. And the latter two sources were a tissue bank from the University of Pennsylvania, that is long-standing, where patients with endstage dilated cardiomyopathy are able to have tissue banked at the University of Pennsylvania at the time of explant prior to transplant. So albeit, we are comparing to fairly advanced end stage dilated cardiomyopathy, and control tissue comes from unused donor hearts, essentially. So presumably, normal heart function patients, likely in a brain death state, who for whatever reason, the hearts were not utilized for transplantation. Again, not an entirely perfect controlled state, but again, given the nature of the work, the fact that it's myocardial tissue, the closest that we have found we've been able to come to for a control comparison.

We started out performing what we call quantitative targeted metabolomics. We measured organic acids, amino acids, and acylcarnitines in the myocardium. And that was totaling around 72 metabolites. And we did the same in plasma, so close to 69 metabolites. And our metabolomics work was actually completed at the University of Pennsylvania. And so, I wish to credit Dr. Zoltan Arany and Dr. Dan Kelly for their great collaboration in this study.

Dr. Carolyn Lam:

That's wonderful. Kavita, if you could tell us a little bit more about the patients with HFpEF. We understand it was end stage dilated cardiomyopathy, HFrEF, and donor hearts as the controls, but the patients with HFpEF, in relation to obesity, diabetes, and how that may impact the interpretation of the results.

Dr. Kavita Sharma:

Sure. So these are HFpEF patients that are in an ambulatory state outpatient setting. They have many of the comorbidities we know are intrinsic today to HFpEF. Out of our HFpEF population, the majority were women. So 71%, that's 27 out of the 38 we serve. And we're very fortunate to serve a African-American enriched population in Baltimore that's intrinsic to our center. And so, over half of our patients were Black. The remaining Caucasian, one non-Caucasian. Over half had been hospitalized, for example, in the prior one year. So these are certainly symptomatic patients. And all had NYHA II or greater symptoms.

We do have a rather obese cohort at Hopkins. And so, our median BMI, for example, was 39, our mean is very similar. And the majority have, as we see often in HFpEF, the majority with hypertension, over half with diabetes. In fact, it was actually 70% or so. Rather few with coronary disease, and this is a trend we're seeing in general in HFpEF in the present day kind of common phenotypes, and about a third with atrial fibrillation. So really, representative, I think, of this kind of cardiometabolic as we call it, phenotype of HFpEF, that is the predominant phenotype we're seeing, at least in North America.

Dr. Carolyn Lam:

Oh, that's perfect. And then, maybe just a few words about the results before I bring Svati in for her thoughts. Thanks.

Dr. Kavita Sharma:

Sure, absolutely. So we conducted this study in a couple different stages. We first started with performing a principal component analysis and hierarchical clustering analysis, to see whether the myocardial metabolites and the plasma metabolites, respectively, would they distinguish these three patient groups? So HFpEF from HFrEF and controls. And interestingly, in the myocardial tissue, our PCA analysis and our hierarchical clustering analysis show that actually, in fact, as few as 70 metabolites in the myocardium really distinctly differentiate these three subgroups. The top contributors that separated HF from controls, for example, and HFrEF, were mostly related to amino acids, including branched chain amino acids and their catabolites, as well as medium and long chain acylcarnitines, which are byproducts of fatty acid oxidation.

When it came to the plasma metabolome, on the other hand, there was far less distinguishing between the groups, and significant overlap, both in PCA and hierarchal clustering. And really, the take home there is that, the myocardial tissue and the plasma were really quite distinct for the overall metabolite analysis. But then, even as we broke it down by fatty acid oxidation, by glucose metabolism, and even branched chain amino acids, we saw this trend continue, that the plasma was quite distinct from the myocardial tissue.

Now, which of the two is more representative of the disease state? Which is the one that we should be paying more attention to? I think that remains to be fully understood further. And of course, it would be really nice to replicate these findings in another cohort. But that is something that, I think, is a first, that certainly, that we have seen and important for the community.

Dr. Carolyn Lam:

Indeed. Oh, Kavita, we could go on talking forever, but I'd really love Svati's thoughts. Why was this paper so special? What does it tell us clinically with any implications?

Dr. Svati Shah:

Yeah. I just want to commend Dr. Hahn, Dr. Sharma, on this incredible work. If you can just imagine how much painstaking work this took for Dr. Sharma and Dr. Hahn. It's a very careful phenotyping of HFpEF. These are true HFpEF patients. The ability to get tissue, and to pair the tissue to the plasma, so that we can really understand. When we measure things in the circulation, and we think they're telling us about the heart, are they actually telling us about the heart? So I really want to commend this incredible work.

And Carolyn, I love talking about cardiac metabolism, because the heart is an incredible organ, right? The heart is a metabolic omnivore. It'll eat many different kinds of fuels, and a lot of different things determine which fuels it uses. And as you nicely outlined, Carolyn, earlier, in the normal heart, the heart prefers to use fatty acids.

But what we are not completely certain of is, what happens in HFpEF? So in HFrEF, we know that the heart switches to glucose, which is not a great fuel, actually. It's actually, a metabolically inefficient fuel. And so we know in HFrEF, that the heart has this metabolic inflexibility. All of a sudden, it's not an omnivore, and it's kind of stuck with certain fuels, which are not very healthy for it.

But what Dr. Sharma and Dr. Hahn have shown, for the first time really, is what happens in HFpEF? And so, I think it's really cool that, actually, it just highlights how complex HFpEF is as a disease. So they were able to show that in some ways, HFpEF is similar to HFrEF, including that there's impairments in use of these fatty acids, which is what the normal heart does.

But, they also show that HFpEF may be different than HFrEF in many ways, including, because of these branched chain amino acids. And that may be because of some of the clinical differences that we know exist in patients with HFpEF, including the obesity and diabetes, that Dr. Sharma nicely outlined. Although, I want to point out, they were very careful about trying to take these clinical factors into account when they looked at differences in the metabolites.

So really incredible work, highlighting that the HFpEF heart also has this metabolic inflexibility. It also is not a metabolic omnivore like the normal heart is, but highlighting important differences, potentially, between HFpEF and HFrEF.

Dr. Carolyn Lam:

Oh, Svati, thank you for putting that so clearly.

Dr. Kavita Sharma:

No, I think that was a really elegant summary of the findings, Svati. And thank you for your kind words and support in allowing us to share our work through Circulation. I really couldn't say it better, but that's exactly what we seem to find is that, when we look at various sort of stores or banks of energy resource, what we really found is that these HFpEF hearts are energy inflexible, as Svati said, that begins with fatty acid metabolism. And so, when we look at, for example, medium and launching acylcarnitines, what we find is that these are markedly reduced in HFpEF myocardial tissue, quite similar to HFrEF. Again, both of them reduced compared to controls. And again, these are byproducts of fatty acid oxidation, and that is really responsible for almost 80% of generally what we think of energy metabolism in the normal state.

In the plasma, however, again, back to that theme where we don't see that reproduced in the plasma, we find that HFpEF is actually not too dissimilar from controls for certain medium and long chain acylcarnitines, and then closer to HFrEF in some cases. And interestingly, we compared our metabolomics study to our prior report of our RNA sequencing paper, that was also published in Circulation now two years ago. And what we found is that, there is reduced gene expression of many of the proteins involved with fatty acid uptake and oxidation, when we compare them to control states. So the story is sort of, fits with what we have seen previously, and when we focus in on this group of genes.

Our analysis of glucose metabolism though, did not include glycolysis or glucose oxidation intermediates. We still found that, majority of the TCA cycle intermediate, so succinate, for example, fumarate, malate, were all reduced in HFpEF versus control. It was really only pyruvate in isolation that was increased in HFpEF myocardium, compared to controls. And again, a number of genes implicated in glucose metabolism in general, we found to be lower in HFpEF versus control, including gluten 1, or SLC2A1, which is involved in glucose uptake.

So again, this theme of, we have patients with significant obesity, many in the diabetic state, we would think that these hearts would utilize these energy stores, but they don't seem to be. And finally, we see distinct differences in the tissue and branched chain amino acid pathways as well. There appears to be some sort of a block between the branched chain amino acids, and then sort of byproducts, as you continue down through ketoacids and further. And we don't fully understand where those blocks are, but that was certainly notable.

And then lastly, I'll say, one interest that we've had, and really, what led to much of this work in the tissue, is to pursue what we call deep phenotyping. Can these molecular signatures, whether it's gene expression, or metabolomics, or what we're working on now, which is proteomics, can these really help us identify unique subgroups within HFpEF? And so, we've tried to do that with the metabolomics, and we found that, using various sort of clustering analytical methods, in fact, there is significant overlap, as it turns out, within HFpEF, when it comes to the metabolomic signatures. And we only found, really, two subgroups within HFpEF. And even these two really did not have much that distinguished them, beyond branched chain amino acids.

And so, this is the first time, at least that our group has seen, at a tissue level, that there is actually a fair bit of homogeneity now in the metabolomic signatures, compared to our RNA sequencing work. And that may be reflective of now, this increasingly cardiometabolic phenotype of HFpEF. And now, we may be seeing signs of that at the clinical and at the treatment level, where we have therapies like SGLT2 inhibitors, that are showing benefit to what seems to be a much broader spectrum of HFpEF, compared to prior therapies. So a lot of questions that have been generated from the work, and we're looking forward to exploring much of this in more detail.

Dr. Carolyn Lam:

And Svati, may I give you the last word? Where do you think this field is headed next?

Dr. Svati Shah:

I think there's so much to do, and I think Dr. Sharma and Dr. Hahn have highlighted how much work there is to do in this space. We're brushing the surface and understanding cardiac metabolism with this really important paper. But Carolyn, as you pointed out, we really need to understand what happens to these patients over time? What happens to, not just cardiac metabolism, but molecular biology more broadly, in patients with HFpEF with these various treatments? Including now, thank goodness, we have SGLT2 inhibitors as a therapeutic intervention for patients with HFpEF. And in fact, we published in Circulation a few months ago, a paper led by a very talented junior faculty, Senthil Selvaraj, where we actually showed that these acetylcarnitine levels that reflect fatty acid oxidation actually are changed by SGLT2 inhibitors, and are associated with changes in clinical outcomes in HFpEF. So we really need larger sample sizes, being able to look at these patients in a longitudinal fashion. But really, doing what Dr. Sharma and Dr Hahn have done, which is careful, careful phenotyping and multidisciplinary teams, so that we can understand the molecular biology, as well as the clinical implications.

Dr. Carolyn Lam:

Oh, wow. Thank you so much, Kavita and Svati, for this incredible interview. I learned so much, and enjoyed it so thoroughly, as I'm sure our listeners did as well.

Well, listeners, you've been listening to Circulation on the Run. Thank you for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is Copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Tatsuhiko Naito and Kosuke Inoue as well as Associate Editor Wendy Post as they discuss the article "Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Study."

Dr. Greg Hundley:

Welcome listeners, to this April 4th discussion of Circulation on the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and the University of Oslo in Norway. So Greg, today we have the feature paper, discussing the genetic risk of primary aldosteronism and its contribution to hypertension. So this is such an interesting topic and av very important cost on hypertension. And in this paper, they use cross-ancestry meta-analysis from GWAS studies to assess this very interesting discussion.

But first, Greg, I have a paper that comes to us from the DELIVER trial, and it is about dapagliflozin to patients with HFpEF, and assessing the association with the duration of the heart failure.

So Greg, it is important to understand how the effects of new treatments vary by the duration of heart failure. Because on one hand, physicians may think that a patient who has longer standing heart failure represents a stable survivor where new treatment is unnecessary. On the other hand, the view has been expressed that patients with long-standing heart failure may have more advanced disease, and there may come a point where they no longer respond to or tolerate the addition of new therapies, particularly because of hypotension, kidney dysfunctional and electrolyte abnormality. So the investigators from the DELIVER trial, led by corresponding all author John McMurray from University of Glasgow, therefore, aimed to assess the efficacy and safety of the SGLT2 inhibitor dapagliflozin, according to the duration of heart failure with EF above 40%. So that is mildly reduced or preserved.

Dr. Greg Hundley:

Wow, Peder, very timely, very timely article. So what did they find?

Dr. Peder Myhre:

So Greg, the authors categorized patients by duration of heart failure, one category less than six months, and then six to 12 months, and then one to two years, two to five years, and finally, more than five years. And longer duration heart failure patients were older, and more comorbid with worse symptoms, and the rate of the primary outcome increased with heart failure duration. And so, the benefit of dapagliflozin was consistent across heart failure duration categories with hazard ratios 0.67, 0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of 0.41. So the absolute benefit was therefore since there was no P4 interaction, greatest among those with highest risk, and that it was the longest duration heart failure. So there was a number needed to create for heart failure above five years of 24, versus 32 for those with the shortest duration of heart failure. And the authors therefore conclude, that even in patients with long-standing heart failure and generally mild symptoms cannot be considered stable, and it is not too late for such patients to benefit from an SGLT2 inhibitor.

Dr. Greg Hundley:

Ah, very practical information, Peder, beautiful description. Well Peder, this next paper comes to us evaluating low density lipoprotein cholesterol. And as you know, low density lipoprotein cholesterol is an important causal risk factor for atherosclerotic cardiovascular disease. However, a sizable proportion of middle-aged individuals have not developed coronary atherosclerosis as assessed by the presence of coronary artery calcification. Now whether the presence of coronary artery calcification modifies the association of LDL cholesterol with atherosclerotic cardiovascular disease risk, well, that's unknown. So these authors, led by the corresponding author of Martin Mortensen from Aarhus University Hospital, evaluated the association of LDL cholesterol with future atherosclerotic cardiovascular disease events, in patients with and without coronary artery calcium, from 23,132 consecutive symptomatic patients evaluated for coronary artery disease, using coronary commuted tomography angiography, or CTA, that were included in the Western Denmark Heart Registry, which is a semi-national multi-center based registry with longitudinal registration of both patient and procedural data.

Dr. Peder Myhre:

Oh, that is so important, Greg. So we're looking at LDL cholesterol and the association with ASCVD in patients with and without coronary artery calcification. So what did they find?

Dr. Greg Hundley:

Right, Peder. So during a median follow up of 4.3 years, 552 patients experienced a first cardiovascular disease event. In the overall population, LDL cholesterol per 38.7 milligrams per deciliter increase, was associated with cardiovascular disease events during the follow-up period. Now, when stratified by the presence or absence of a baseline coronary artery calcium score, LDL cholesterol was only associated with a cardiovascular disease event in the 47% of patients with a coronary CAC score greater than zero. While no association was observed in the 53% of individuals with a coronary artery calcium score equal to zero.

Now similarly, very high LDL cholesterol, so greater than 193 milligrams per deciliter, versus an LDL cholesterol of less than 116 milligrams per deciliter, was associated with a cardiovascular disease event in patients with a CAC score greater than zero, but not in those without coronary artery calcium. Next, Peder, in patients with coronary artery calcium equal to zero, diabetes, current smoking, and low HDL cholesterol levels, were associated with future cardiovascular disease events. This principle finding was replicated in the multiethnic study of atherosclerosis.

And so, Peder, LDL cholesterol appears almost exclusively associated with a cardiovascular disease event over the ensuing five years of follow-up in middle-aged patients with versus without evidence of coronary atherosclerosis, as identified by coronary artery calcium scores. This information is quite valuable for individualized risk assessment among middle-aged patients.

Dr. Peder Myhre:

Oh, that is so important, Greg. So really, LDL seems to be more predictive of atherosclerotic cardiovascular disease than those with calcium in their coronaries, while there was no association in those with no calcium in their coronaries. Very interesting.

Dr. Greg Hundley:

Absolutely. And there's a very nice editorial by Professor Sniderman entitled, “Cholesterol Coronary Calcification and Cardiovascular Prevention: Lessons We Can Learn from the Western Denmark Heart Registry.”

Dr. Peder Myhre:

Thank you, Greg, that was a beautiful summary. And we are going to stay in clinical science, but we're going to move to aortic disease and look at gut microbiota. Now, Greg, large scale human and mechanistic mouse studies indicate a strong relationship between the microbiome dependent metabolyte, Trimethylamine-N-oxide, abbreviated TMAO, and several cardiometabolic diseases. And in this study, which comes to us from corresponding author Philip Owens from University of Cincinnati, the investigators aim to assess TMAO's role in the pathogenesis of AAA and targeting its parent microbes as a potential pharmacologic intervention.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what methodology did they use?

Dr. Peder Myhre:

So Greg, this is one of those fantastic studies combining clinical and preclinical science. And the investigator measured TMAO in two independent patient cohorts, with a total of 2,129. And in addition, they used the murine AAA model, and fed the mice a high choline diet, which is a diet that markedly augment plasma levels of TMAO. And these mice were then treated with broad spectrum antibiotics, targeted inhibition of a gut microbial enzyme with fluorometer chloroquine, called FMC, or utilizing mice genetically deficient of Fmo3.

Dr. Greg Hundley:

Very nice. So what did they find, Peder?

Dr. Peder Myhre:

So the authors found that elevated TMAO was associated with increased AAA incidence and growth in both patient cohort studies. And dietary colon supplementations augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad spectrum antibiotics. In treatment with FMC ablated TMAO production attenuated colon augmented aneurysm in the initiation, and halted progression of an established aneurysm model. And additionally, the Fmo3 knockout mice had reduced plasma TMAO, aortic diameters, and were protected from AAA rupture compared to wild type mice.

So Greg, in conclusion, this study defined a role for gut microbiota generated TMAO in AAA formation, and additionally, increased microbiome derived TMAO may serve as a novel therapeutic approach for AAA treatment where non currently exists.

Dr. Greg Hundley:

Beautifully described, Peder. And another one of their articles in Circulation that, as you indicated, very nicely complying the world of preclinical and clinical science.

Well, we've got some other articles in the issue, and how about we jump into some of those? So first, there's a very nice Letter to the Editor from Professor Wong entitled, “Frailty and Age Correlation in Clinical Trials.” And there is another reply to a prior Letter to the Editor from Professor McMurray entitled, “Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure, a Pre-specified Analysis of the DELIVER Trial.” And then next, Peder, Michelle A. Albert has a very nice synopsis of the American Heart Association Presidential Address, entitled, “Economic Adversity and Healthcare.”

Dr. Peder Myhre:

Nice. And finally, there's a Research Letter from Dr. Baggish entitled, “Association Between Concussion Burden During Professional American-style Football and Post-career Hypertension.”

Dr. Greg Hundley:

Very good, Peder. Well, what a packed issue we have this week, and how about we jump next to that feature discussion with our colleague Carolyn? Ah.

Dr. Peder Myhre:

Let's go.

Dr. Carolyn Lam:

Primary aldosteronism, or, we're going to say PA for this discussion, is one of the most common causes of secondary hypertension, and it is also a particularly morbid form of secondary hypertension. So identifying this subgroup of hypertensive patients with primary aldosteronism, again PA, would allow us to perhaps, direct more aggressive management to their cardiometabolic risk. Now, is a genetic approach the way to do it? Well, we're about to find out in today's very special paper.

We're very honored to have the first author, Dr. Tatsuhiko Naito, from Osaka University Graduate School of Medicine, and his second and co-author Dr. Kosuke Inoue, from the Graduate School of Medicine in Kyoto University, as well as our associate editor, Dr. Wendy Post, from Johns Hopkins University School of Medicine, here to discuss this very important paper. Perhaps I could start with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a little bit about what made you do this study, what you did, and what you found?

Dr. Tatsuhiko Naito:

I would like to thank you for inviting us to present the information from our paper. In terms of genetic, germline genetic factors behind the development of PA has not been isolated. And in addition, the PA is the cause of hypertension, but the genetic relationship between hypertension and PA has not been discussed previously. That is why we conducted a genome-wide association study, GWAS, of PA here. Our GWAS consisted of three defined cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our Japanese cohort, we collected samples in Hiroshima University, and we used controls from Biobank Japan, which is the largest Japanese biobank. And we also used two publicly available biobanks, UK Biobank and FinnGen. So they can be used upon registration. By utilizing these resources, we conducted a cross-ancestry, meta-analysis of GWAS.

Dr. Carolyn Lam:

Thank you. And the results, please?

Dr. Tatsuhiko Naito:

In the meta-analysis, we identified five genetic loci that were significantly associated with the risk of PA satisfied in the genome world significant threshold. The strongest association was observed at WNT2B, which is located in chromosome 1. And in addition, we identified one near the genome-wide association locus CYP11B1 and B2, which is located on chromosome 8. So CYP11B2 is the key enzyme that acts in producing aldosterone in the adrenal gland, thus, we consider that resource. This locus would be also our PA risk associated locus with a high probability.

Of interest, these loci were reported to be associated with hypertension, but we thought this results is resemble, because PA occupies around five to 10% of causes of hypertension. Does the PA associated loci could be reported as hypertension associated loci in previous GWAS with large sample size?

So to support our assumption, we compared the risk effect of these genetic loci between PA and hypertension. So if there are risk effects who are coming from PA, these loci should present higher effect on PA than on hypertension. And expectedly, these loci presented significantly higher effect on PA here.

And lastly, inspired by these results, we hypothesized that some of other loci, that had been reported to be associated with hypertension, might come from the primary effects on PA. To investigate this, we picked up blood pressure rated genetic loci from previous GWAS of blood pressure, and compared their risk effects between PA and hypertension. The result was that, 66.7% presented a higher risk effect for PA than for hypertension. And two strictly demonstrates the result. We also performed the adjustment of blood pressure values, and even in this adjustment, 61.9% showed a higher effect on PA than on hypertension. So considering the prevalence of PA among hypertensive individuals, this result is little bit surprising, we think. So PA may explain an unexpectedly large amount of genetic background of hypertension, we think.

Dr. Carolyn Lam:

Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence for genetic predisposition to PA susceptibility, and then, revealing that two thirds of previously established BP associated variants were in fact a higher risk effect for PA than for hypertension. Wow. So Wendy, could you help us put these findings into perspective, please?

Dr. Wendy Post:

Thank you, Carolyn. Congratulations to the authors. This was a really interesting paper that we enjoyed discussing in our meetings. We were especially interested in the clinical potential, clinical implications of your study. We all see patients with hypertension, whether we're cardiologists, or endocrinologists, or primary care physicians. And so, trying to understand more about what is potentially the underlying causes for hypertension, from a biological standpoint, that might help us to identify and treat our patients appropriately, is really so important. And so, I was wondering, Kosuke, if you could tell us, from your perspective as an endocrinologist and a researcher, how you interpret these studies in a way that our readers might be able to use these results to think about the next patient we're seeing in our clinic with hypertension?

Dr. Kosuke Inoue:

Yeah. Thank you very much for asking this important point, Wendy. We're, first of all, I'm very pleased that our research is published in Circulation, and thank you very much for your consideration. And I think there are two major implications of our findings, treatment and a diagnosis.

First of all, for treatment, well, our findings advance our current state of knowledge about PA pathogenesis. Like Wendy said, what is the causes? And what is the genetic causes of primary aldosteronism ? And particularly, it'll be helpful for better precision medicine in the future. And therapy involving genetic information, this may not be the clinical practice tomorrow, but this would advance our clinical practice in the future.

And the second point is diagnosis. Well, primary aldosteronism is really important to diagnose, because treating only blood pressure, or hypertension, is not enough for patients with primary aldosteronism. Like Tatsu said, aldosteronism itself has a direct effect on organ damage beyond blood pressure, elevated blood pressure. So diagnosis of primary aldosteronism is critical, and our findings showed 10%, the current percentage of 10% primary aldosteronism, may not be fully diagnosed patients, given that 67% of PA associated variants presented higher alteration for the PA. So I think, we needed to be more careful about diagnosing primary aldosteronism. So for those who have a resistant hypertension, or who are suspected to have primary aldosteronism, we needed to screen more for such patients.

Dr. Wendy Post:

Thank you, that was really helpful. Can I ask you a little bit more about what you recommend in clinical practice? I've been asking around, we actually just had our American College of Cardiology meeting in New Orleans, and I knew this paper had just been published online, and the editorial is about to come out. And so, I noticed that there's a lot of variability in practice, as to whether we screen for PA, or just treat with aldosterone blocking medications, such as spironalactone. So can you tell me a little bit more about what you recommend? And maybe your practice is different as an endocrinologist, but should we just presume people have primary aldo, and aldosteronism, and treat them for that? Or should we be searching for aldosterone producing adenomas, and surgically removing them? If you could, tell us a little bit more about what you recommend.

Dr. Kosuke Inoue:

Thank you very much for asking this, Wendy. So to be honest, I don't think we can conclude something only from our result, of course. But what I can recommend is, from our findings, it is better to always thinking about primary aldosteronism when treating patients with hypertension. So those may have and those may not have that. I think thinking about primary aldosteronism is important, and if there's a possibility they have, or if their clinicians have trouble treating hypertension, then I would recommend screening for such patients about primary aldosteronism.

Dr. Wendy Post:

In order to find an adenoma, is that the purpose of the screening?

Dr. Kosuke Inoue:

I think, whether they have an adenoma or, there are two types of primary aldosteronism, aldosteronism producing adenoma, and BAH bilateral adrenal hypocardia. And rather does not have adenoma itself, but they have a hyper aldosteronism in their blood. So we cannot tell whether they have a PA or BAH. But anyway, we needed to think about whether they have excess level of aldosterone, and if they have, we needed to think about the proper treatment, such as medication therapy or surgical treatment.

Dr. Wendy Post:

Thank you. So if they have bilateral adrenal hyperplasia, then medical therapy.

Dr. Kosuke Inoue:

Yes.

Dr. Wendy Post:

If they had an adenoma, you might consider surgical excision.

Dr. Kosuke Inoue:

Generally, yes.

Dr. Wendy Post:

Thank you.

Dr. Carolyn Lam:

Wendy, I love that clinical focus, because much as PA is a highly morbid cause of secondary hypertension, it's also sometimes seen as potentially curable, or at least targetable with specific medical therapy. And thank you for inviting that beautiful editorial, I'd love to quote from it. Because the final sentence of it really does say that this paper really reminds everyone treating hypertension, to maintain a high clinical suspicion for PA, and hopefully, such a high clinical suspicion will lower the threshold for biochemical testing. Will motivate the pursuit of localization studies, to determine if a surgical cure is possible. And at minimum, allow for early initiation of mineralocorticoid-receptor blockade. How beautifully put, huh?

So thank you for inviting that editorial. And if I may, are there any final take home messages from anyone? May I start with Dr. Tatsuhiko? Any take home messages or next steps you'd like to mention?

Dr. Tatsuhiko Naito:

Okay. Yeah. I think the future advances in this study first, as Kosuke said, of PA is mainly classified into aldosterone producing adenoma and bilateral adrenal hyperplasia. However, we couldn't identify subtype specific risk associated loci, due to the lack of statistical power. And specifically, we know that histopathological features of aldosterone producing adenoma are reported, vary depending on the causative somatic mutations. So further insights may be obtained by investigating the genetic risk of aldosterone producing adenoma, according to the causative somatic mutations. But anyways, we are happy to present the genome-wide association genetic loci that associated with PA in the cross-ancestry cohort for the first time. Thank you.

Dr. Carolyn Lam:

Thank you. Kosuke?

Kosuke Inoue:

Sure. So I totally agree with what Tatshu said, and also, aldosterone is a nasty hormone. So as a clinician, I would recommend, for all clinicians who treat patients with hypertension, please always consider aldosterone, and whether their aldosterone should be treated or not. And thank you.

Dr. Carolyn Lam:

Wendy?

Dr. Wendy Post:

I also wanted to get back to your statements, Kosuke, about precision medicine. And this was a genetic study, and you did mention how this could potentially lead to precision medicine, practical approaches to identifying patients who might be treated with specific therapies, based on their genetics. And of course, we're not there yet, but thanks for helping us to get closer to that vision in the future.

Dr. Carolyn Lam:

Indeed, thank you so much for publishing this very important paper in Circulation, and for coming online to discuss it today.

You've been listening to Circulation on the Run. Thank you listeners for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study."

Dr. Gregory Hundley:

Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion.

Dr. Gregory Hundley:

Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966.

Dr. Peder Myhre:

Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery.

Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race.

So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients.

Dr. Peder Myhre:

Well, that is really interesting, Greg. Are you ready for the next paper?

Dr. Gregory Hundley:

Absolutely.

Dr. Peder Myhre:

So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events.

Dr. Gregory Hundley:

Interesting, Peder. So what did they find?

Dr. Peder Myhre:

So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits.

Dr. Gregory Hundley:

Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses.

Dr. Peder Myhre:

Oh, this is really interesting, Greg. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction.

So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.

Dr. Peder Myhre:

Oh wow. That was really impressive.

Dr. Gregory Hundley:

Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled “A Mouse Model of Atrial Fibrillation in Sepsis.” And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled “Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure.” And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled “Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes.” And that particular paper is published in Nature.

Dr. Peder Myhre:

That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by Bertram Pitt entitled “Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension.” Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes.

Dr. Gregory Hundley:

Very good. Let's go.

Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Vincent Aengevaeren:

So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis.

And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density.

Dr. Gregory Hundley:

Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here?

Dr. Vincent Aengevaeren:

The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics.

So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise.

Dr. Gregory Hundley:

Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here.

Dr. Vincent Aengevaeren:

So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes.

Dr. Gregory Hundley:

Very nice. So Vince, describe for us your study results.

Dr. Vincent Aengevaeren:

During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings.

Dr. Gregory Hundley:

And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples.

Dr. Vincent Aengevaeren:

So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well.

Dr. Gregory Hundley:

When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year?

Dr. Vincent Aengevaeren:

That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity.

Dr. Gregory Hundley:

Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity?

Dr. Jarett Berry:

Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels.

I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it.

The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two.

And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume.

And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here.

And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think.

But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold.

Dr. Gregory Hundley:

Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research?

Dr. Vincent Aengevaeren:

For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me.

Dr. Gregory Hundley:

Very nice. And Jarett?

Dr. Jarett Berry:

Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings.

Dr. Gregory Hundley:

Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression.

Well, on behalf of Peder and Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age."

Dr. Greg Hundley:

Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?

Dr. Peder Myhre:

I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts.

Dr. Greg Hundley:

Wow, Peder, so a very large gene-wide association study. So what did they find?

Dr. Peder Myhre:

So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease.

Dr. Greg Hundley:

Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development.

Dr. Peder Myhre:

Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.

So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects.

Dr. Peder Myhre:

Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first?

Dr. Greg Hundley:

Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study."

Dr. Peder Myhre:

And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions.

And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century."

And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that?

Dr. Greg Hundley:

Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion?

Dr. Peder Myhre:

Let's go.

Dr. Mercedes Carnethon:

Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found.

Professor Mikael Dellborg:

Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor.

Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD.

Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline.

So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed.

Dr. Mercedes Carnethon:

Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you?

Professor Mikael Dellborg:

What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age.

Dr. Mercedes Carnethon:

Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation?

Dr. Gerald Greil:

Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future?

Professor Mikael Dellborg:

Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years.

The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet.

It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers.

We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper.

Dr. Gerald Greil:

Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients?

Professor Mikael Dellborg:

I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure.

And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69.

And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today.

Dr. Mercedes Carnethon:

That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease?

Professor Mikael Dellborg:

Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera.

You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today.

And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that.

Dr. Mercedes Carnethon:

I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area.

Dr. Gerald Greil:

Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please.

Dr. Mercedes Carnethon:

Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights.

Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

 Dr. Carolyn Lam:

Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first.

I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs.

Dr. Greg Hundley:

Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study.

 Dr. Carolyn Lam:

Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination.

 Dr. Carolyn Lam:

Wow. Wow. Important question. Everyone's interested in the results. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis.

Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science.

 Dr. Carolyn Lam:

Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, “Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction.” That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we?

Dr. Greg Hundley:

Absolutely.

Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address?

Dr. Milind Desai:

Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers.

So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today.

Dr. Greg Hundley:

Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll?

Dr. Milind Desai:

Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients.

Dr. Greg Hundley:

Very nice. So Milind, what were your study results?

Dr. Milind Desai:

Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers.

But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT.

Dr. Greg Hundley:

And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex?

Dr. Milind Desai:

No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders.

Dr. Greg Hundley:

And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there?

Dr. Milind Desai:

There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity.

Dr. Greg Hundley:

And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles?

Dr. Milind Desai:

The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy?

Dr. Mark Link:

Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper.

Dr. Greg Hundley:

Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research?

Dr. Milind Desai:

Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out.

Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging.

Dr. Greg Hundley:

Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about?

Dr. Milind Desai:

So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about.

Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient.

Dr. Greg Hundley:

Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space?

Dr. Mark Link:

Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely.

Dr. Greg Hundley:

Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy.

Well, on behalf of Petter, Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume.

Dr. Greg Hundley:

Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform?

Dr. Carolyn Lam:

So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment.

Dr. Greg Hundley:

Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative.

Dr. Carolyn Lam:

Oh wow. So a new gene variant. So what was the relationship?

Dr. Greg Hundley:

Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials.

And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling.

Dr. Carolyn Lam:

Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go.

So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes.

Dr. Greg Hundley:

Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find?

Dr. Carolyn Lam:

They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar.

In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration.

So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more.

Dr. Greg Hundley:

Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals."

Dr. Carolyn Lam:

There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare.

Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion?

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine.

I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us.

Dr. Xuerong Wen:

Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone.

Dr. Mercedes Carnethon:

Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth.

Dr. Sandeep Das:

Thanks Mercedes. It's great to be with you.

Dr. Mercedes Carnethon:

Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found?

Dr. Xuerong Wen:

So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population.

So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results.

Dr. Mercedes Carnethon:

Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team?

Dr. Xuerong Wen:

That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population.

Dr. Mercedes Carnethon:

Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation?

Dr. Sandeep Das:

Yeah, absolutely. Thanks for the question.

So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question.

Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello.

Dr. Mercedes Carnethon:

Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well.

Dr. Sandeep Das:

Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients?

Dr. Xuerong Wen:

I would say yes. Okay.

Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced.

And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist.

And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease.

Dr. Sandeep Das:

Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice.

Dr. Mercedes Carnethon:

I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular?

Dr. Xuerong Wen:

That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that.

Dr. Mercedes Carnethon:

Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions?

Dr. Sandeep Das:

No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing.

Dr. Mercedes Carnethon:

Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work?

Dr. Xuerong Wen:

Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical.

Dr. Mercedes Carnethon:

Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen.

Dr. Xuerong Wen:

Thanks for this great opportunity to disseminate my study with us, thank you.

Dr. Sandeep Das:

Thanks Mercedes.

Dr. Mercedes Carnethon:

Thank you for joining us for this episode of Circulation on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start?

Dr. Carolyn Lam:

I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction.

Dr. Greg Hundley:

Wow. Pray tell.

Dr. Carolyn Lam:

I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury.

Dr. Greg Hundley:

Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models.

Dr. Carolyn Lam:

Oh, wow. So a vaccine against atherosclerosis? Cool.

Dr. Greg Hundley:

Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler.

Dr. Carolyn Lam:

Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months.

Dr. Greg Hundley:

Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find?

Dr. Carolyn Lam:

Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar.

Dr. Greg Hundley:

Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe.

Dr. Carolyn Lam:

Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on “Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?” There's a Research Letter by Dr. Soehnlein on “Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice.” There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine.

The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy?

Dr. Carolyn Lam:

So important. Let's go.

Dr. Greg Hundley:

Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Jennifer Conway:

Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults.

Dr. Greg Hundley:

And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population?

Dr. Jennifer Conway:

This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at.

Dr. Greg Hundley:

And in the study population, I know it's a pediatric population, what was the age range?

Dr. Jennifer Conway:

The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients.

Dr. Greg Hundley:

And of these pediatric populations, what percentage were, I guess, boys versus girls?

Dr. Jennifer Conway:

Yeah, so just over 75% were males within this study population.

Dr. Greg Hundley:

Okay. And then now Jennifer, can you describe for us your study results?

Dr. Jennifer Conway:

Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events.

So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event.

Dr. Greg Hundley:

Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter?

Dr. Jennifer Conway:

Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance.

Dr. Greg Hundley:

Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward?

Dr. Jennifer Conway:

I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers.

We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important.

Another study that I'm doing that's not part of this is looking at the cardiovascular health of children with hypertrophic cardiomyopathy across Canada. And we are finding that there's a high level of obesity, sedentary lifestyle, high lipid profiles for instance, all of which put people at risk for cardiovascular disease as adults. And so I think as we're getting more comfortable potentially with looking at exercise prescriptions for hypertrophic cardiomyopathy patients and understanding risks a bit better, then exercise testings going to be a key in trying to design maybe some of that programming for patients.

Dr. Greg Hundley:

Wow, Jennifer, just a beautiful explanation of where we need to move with your research results in the future. One thing that kind of caught my attention as you were speaking, really safety. So for all our listeners, in terms of exercising children with this condition or young adults, would you recommend a specialized center or what would you describe in that, at least in terms of safety precautions?

Dr. Jennifer Conway:

Well, if you look at all the... There's not a lot of studies that have been published, but the ones that have, they're in a lab that commonly exercises children. They have protocols of who they will exercise and who they won't and when you would stop an exercise test. For instance, the paper from CHOP nicely describes how they approach the exercise in hypertrophic cardiomyopathy, and they have clear guidelines of when they stop testing. So in their 140 patients, for instance, they stop testing in two patients, one who had, I think ST segment changes and the other one who developed some ventricular ectopy. I think it needs to be in a controlled environment where you have safety measures in place and you have guidelines to direct you in terms of if this happens, this is the response to that. I think that's all very important when you're kind of thinking about exercising what has been deemed as higher risk patients.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta for sharing with us these really interesting results, highlighting that exercise abnormalities are common in childhood hypertrophic cardiomyopathy, and an abnormal exercise test was independently associated with lower transplant free survival especially in those with ischemic or abnormal blood pressure responses during that exercise testing.

Well, on behalf of Peter, Carolyn and myself, we want to wish you a great week, and we will catch you next week on The Run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis?

Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion.

Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address?

Dr. Carolyn Lam:

Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine.

And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan.

However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials.

Dr. Greg Hundley:

Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find?

Dr. Carolyn Lam:

In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure.

Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña.

Dr. Greg Hundley:

Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis.

So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition.

And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage.

So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression.

Dr. Carolyn Lam:

Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex.

They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models.

So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression.

Dr. Carolyn Lam:

Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension.

So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence.

Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development.

As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age.

So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results.

Dr. Greg Hundley:

Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models?

Dr. Carolyn Lam:

Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension.

The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration."

So lots of translational implications of this paper.

Dr. Greg Hundley:

Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe.

Dr. Carolyn Lam:

Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants."

There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea."

In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature.

Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity.

There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study.

Dr. Greg Hundley:

Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Let's go. Thanks.

Dr. Greg Hundley:

Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen.

Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Amil Shah:

Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today.

So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality.

Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes.

Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation.

Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction.

And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals.

But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults.

And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease.

To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life.

Dr. Greg Hundley:

So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population?

Dr. Amil Shah:

Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota.

Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age.

We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally.

And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion.

Dr. Greg Hundley:

Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results?

Dr. Amil Shah:

So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair.

And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort.

And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes.

Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest.

Dr. Greg Hundley:

Now, did you find similar results for men and for women?

Dr. Amil Shah:

So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar.

Dr. Greg Hundley:

And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions?

Dr. Amil Shah:

Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages.

So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly.

So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings.

For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that.

Dr. Greg Hundley:

Very nice. Well, thank you so much, Amil.

And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper?

Dr. Ntobeko Ntusi:

Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle.

And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms.

We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex.

And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution.

The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease.

And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations.

So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg.

Dr. Greg Hundley:

Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research?

Dr. Amil Shah:

So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life.

And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in.

I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients.

Dr. Greg Hundley:

Very nice. Ntobeko, do you have anything to add?

Dr. Ntobeko Ntusi:

Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward.

The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease.

Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time.

And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events.

Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal.

Dr. Sana Al-Khatib:

Hello and welcome to the Special Circulation on the Run podcast focused on the seventh Go Red for Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I had the pleasure of co-leading this issue with a colleague and friend, Dr.

Dr. Mercedes Carnethon:

Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going.

Dr. Sana Al-Khatib:

Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it.

The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think?

Dr. Mercedes Carnethon:

Absolutely. This is such an important issue, particularly for survivors of breast cancer.

Dr. Sana Al-Khatib:

Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain.

And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training.

Dr. Mercedes Carnethon:

That is so exciting to hear, especially with the potential to intervene for better outcomes.

Dr. Sana Al-Khatib:

Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci.

Dr. Mercedes Carnethon:

That is such great news. What did the authors have to say about these findings?

Dr. Sana Al-Khatib:

Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising.

Dr. Mercedes Carnethon:

I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer.

Dr. Sana Al-Khatib:

Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles.

Dr. Mercedes Carnethon:

Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause.

However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution.

And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it.

Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool?

Dr. Sana Al-Khatib:

Wow. How interesting. Absolutely.

Dr. Mercedes Carnethon:

Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes.

Dr. Sana Al-Khatib:

Wow. Well, I can't wait to hear the results.

Dr. Mercedes Carnethon:

So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births.

Dr. Sana Al-Khatib:

That's a very large study.

Dr. Mercedes Carnethon:

Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35.

So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Very important implications here, Merci. I agree.

Dr. Mercedes Carnethon:

Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here.

Dr. Sana Al-Khatib:

Yes, please.

Dr. Mercedes Carnethon:

In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women.

Dr. Sana Al-Khatib:

A very important topic. Yeah, I agree, Merci.

Dr. Mercedes Carnethon:

Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications.

And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events.

Dr. Sana Al-Khatib:

That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful.

Dr. Mercedes Carnethon:

It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode.

Dr. Sana Al-Khatib:

Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you.

So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion.

And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks.

And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation.

And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males.

And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients.

Dr. Mercedes Carnethon:

Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an excellent study that I hope people will find extremely useful.

Dr. Sana Al-Khatib:

Well, thank you very much, and I really want to give a lot of credit to the first author, Dr. Zeitler, who has been mentee of mine for many years and has done a great job and really a lot of credit to the rest of the co-authors.

Dr. Mercedes Carnethon:

Well, that's fantastic. I'm glad that I chose the ordering that I did because the final study that I'd like to talk about is in fact a randomized trial. And I think similar to the one that you just described, this is another study that's comparing sex differences. So this particular study led by Coughlan and colleagues describes sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents. And given the positive impact that drug-eluting stents have had on improving coronary artery disease, I think it's critically important for us to find out whether or not there are any disparities by sex and the types of outcomes that occur following percutaneous coronary intervention. And so in order to address this question, what the authors did was to carry out a pooled analysis of five individual patient data from trials of drug-eluting stints that had at least 10 years of follow up.

And the objective here was to really address the controversy in the field about whether the outcomes were worse for women, which was observed in some studies versus in other studies where there was no difference. And the benefit of using this pool design, again, this sample size, I'm an epidemiologist, I love big samples for what can be done. And in the 9,700 patients that were included in this trial, 24% of them were women. So really it required this type of a meta analytic design in order to have enough women to answer these questions. So the outcomes of interest here included death from all causes, death from cardiovascular disease, MI, stent thrombosis, and revascularization of the target lesion, the target vessel, and the non-target vessel.

So one of the challenges in interpreting findings from prior studies of this question are the concerns that the clinical characteristics of men versus women who underwent PCI were different.

And in fact, in this particular pooled analysis, men were more likely than women to have three vessel disease, and they had a lower, lower mean ejection fraction coming in the characteristics following angiogram and the procedure also showed some differences by sex groups, namely that women had smaller vessel reference diameters before PCI and a smaller minimal luminal diameter after PCI. But men had a longer total stinted length as compared with women. So I'm sure you want to know what ended up happening.

Dr. Sana Al-Khatib:

Please.

Dr. Mercedes Carnethon:

Yes. So when the authors tested their primary hypothesis of sex differences in tenure outcomes, they found that some of the very minor differences in the proportion of women versus men who experience the outcomes of interest were eliminated following adjustment for relevant characteristics, or in fact that women were slightly less likely to experience the outcomes of interest. Specifically women were less likely to experience death from any cause over 10 years, but there was no difference in cardiovascular death as compared with men.

Women though were significantly less likely than men to require repeat revascularization of the target legion, the target vessel, and the non-target vessels over 10 years. But unfortunately, the findings weren't all good. A notable exception was that when the offers examined the one-year event rates, women had a significantly increased likelihood of MI in the first 30 days after PCI. And I'm not sure why this is, but the authors did advance numerous hypotheses to explain their findings. One was that baseline and procedural characteristics varied markedly between men and women, and that the age was a primary confounder of these findings. And this was because they carried out a series of sensitivity analyses where they didn't account for age and when they didn't account for age, women had an increased risk of cardiovascular death through the entire 10 years of follow up. And it's curious why this would happen.

And the observation was thought to be attributable either to women developing CAD later than men in life, or because they're diagnosed later because of decreased physician awareness among women. And that's shocking to hear since we all know that cardiovascular disease is the leading cause of death among women. So I really think that the observations in this large pooled analysis do warrant further study and investigation. And a point that I think we discussed earlier is that the representation of women in clinical trials, we have to have more women in these trials and this was an argument that the authors advanced because then without more women in these trials, we don't have adequate power to investigate these sex differences and to explore reasons behind these sex differences. And so I hope that investigators will really heed these calls so that we can generate the best possible science to inform treatment options for women so that we can maximize our health outcomes.

Dr. Sana Al-Khatib:

No, absolutely. Those are excellent points, Merci, that you make. And we certainly need to make sure that we have more women participating in clinical trials and that to the extent that we can, that patients enrolled in clinical trials are representative of patients that we see in clinical practice. You bring up excellent points. Thank you for that great summary.

Dr. Mercedes Carnethon:

Thank you so much, and thank you really for letting me join you in this special issue. I'm so excited about all of our pieces, not just these original research pieces, but as well our research letters and the rest of our content. I think there's just a lot for our readers to dig into here.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Merci, it's been a pleasure for me to co-lead this issue with you and I agree while we focus this podcast on the original research articles, the other articles are equally interesting and impactful. So a lot for our readers to enjoy here. So in closing, we want to wholeheartedly thank Dr. Joe Hill, the editor-in-chief for Circulation, Dr. James De Lemos, the executive editor of the Journal and all authors who submitted the research for this issue. We also want to thank the Circulation associate editors and staff who worked so hard to deliver what you are about to experience. We're very excited about this issue and know you will find it very informative and interesting.

This concludes our Go Red for Women issue Circulation on the Run podcast. Thank you so much for listening.

Dr. Mercedes Carnethon:

Thank you.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting?

Dr. Carolyn Lam:

Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee.

Dr. Peder Myhre:

Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content.

Dr. Carolyn Lam:

It's true. That's a very interesting question. And will you tell us more?

Dr. Peder Myhre:

Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention.

Dr. Carolyn Lam:

Okay, that's deep investigation. And what did they find?

Dr. Peder Myhre:

So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging.

Dr. Carolyn Lam:

Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins.

And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans.

Dr. Peder Myhre:

Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings?

Dr. Carolyn Lam:

Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management.

Dr. Peder Myhre:

Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries.

Dr. Carolyn Lam:

Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications?

Dr. Peder Myhre:

So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis.

Dr. Carolyn Lam:

Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart?

Dr. Peder Myhre:

Oh, that's interesting. We also have some cardiology news by our own ‪Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications.” And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled “Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from Stanford University School of Medicine.

Dr. Carolyn Lam:

While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go.

Dr. Greg Hundley:

Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address?

Dr. Petr Ostadal:

According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes.

Dr. Greg Hundley:

Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis?

Dr. Petr Ostadal:

We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis.

The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock.

Dr. Greg Hundley:

Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial?

Dr. Petr Ostadal:

The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm.

Dr. Greg Hundley:

Sounds great Petr. And then tell us and describe your study results.

Dr. Petr Ostadal:

The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm.

Dr. Greg Hundley:

Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously?

Dr. Dharam Kumbhani:

Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized.

So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm.

Dr. Petr Ostadal:

Thank you for this question. The situation is maybe a little bit more simple in the Czech Republic here, the cardiologist are responsible for the acute cardiac care, usually competent and experience not only for the diagnosis and examinations and monitoring of patients in cardiogenic shock, but also experience in insertion and management of the mechanical circulatory support. So here this attending cardiologist competent to manage this patient from different sites from the manage not only the conservative therapy but also the mechanical circulatory support therapy in these patients. So in this respect, this is more simple situation in the Czech Republic.

Dr. Dharam Kumbhani:

I just had a very quick question about, and I don't know if you want to include this, but Petr, I was curious, were patients with cardiac arrest, I know you mentioned sky shocks in were patients with cardiac arrest on the field or in the hospital included?

Dr. Petr Ostadal:

Thank you for this excellent question. And in comparison, with other trials comparing the or focusing on patients with cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors were excluded. And the reason was that the brain damage, which is the major cause of death in these patients cannot be influenced by ECMO insertion. And second, in majority of patients after cardiac arrest, if there is a presence of shock, there is frequently combined shock with important peripheral component. And again, it cannot be assumed that this peripheral component can be reversed by ECMO implantation. So in the ECMO-CS trial, the cardiac arrest survivors were excluded from that enrollment.

Dr. Greg Hundley:

Well, thank you so much Petr. Petr, what do you think is the next study to be performed really in this area of research?

Dr. Petr Ostadal:

I think that we are happy because several other clinical trials focusing on the mechanical circulatory support in patients with cardiogenic shock underway. And there are other trials focused on ECMO and trials a bit focused on combination of ECMO with balloon pump and trials focused on Impella. So I think in the very close time we will be able to see the results of these current running trials1.

Dr. Greg Hundley:

And Dharam, do you have anything to add?

Dr. Dharam Kumbhani:

No, I agree completely with Petr. I think this is a very exciting field. I know there's a lot of interest in doing well conducted clinical trials in this space. And so certainly, I think the future is bright for investigation in this field.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Petr Ostadal from Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study highlighting that immediate implementation of VA-ECMO in patients with rapidly deteriorating, or severe cardiogenic shock did not improve clinical outcomes compared to an early conservative strategy that permitted downstream use of VA-ECMO in the case when the patient's hemodynamic status worsened.

Well, on behalf of Carolyn, and Peder, and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join Guest Host Maryjane Farr, authors Sarah Franklin and Stavros G. Drakos, as well as Associate Editor Hesham Sadek as they discuss the article "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo.

Dr. Carolyn Lam:

Peder, today's featured paper is very, very important in the heart failure world. It is such a deep dive into the transcriptomic and proteomic profile that specifies heart failure and the potential of myocardial recovery with mechanical unloading and circulatory support.

Dr. Peder Myhre:

Can't wait for that feature discussion today, Carolyn.

Dr. Carolyn Lam:

But you have to wait because I insist on telling you about yet another really important paper, of course in my favorite subject, heart failure with preserved ejection fraction or HFpEF. Now you know that exercise intolerance is a defining characteristic of HFpEF and a marked rise in pulmonary capillary wedge pressure during exertion is pethepneumonic for HFpEF and it's thought to be a key cause of the exercise intolerance. Now if that is true, acutely lowering the wedge pressure should improve exercise capacity, right? Well, don't assume this because to test this hypothesis, authors led by corresponding author Dr. Ben Levine from UT Southwestern evaluated peak exercise capacity with and without nitroglycerin, which was used to acutely lower pulmonary capillary wedge pressure during exercise in patients with HFpEF.

Dr. Peder Myhre:

Oh, that's so cool. What an amazing research question and Carolyn, you're the best to summarize this. Please tell us what did they find?

Dr. Carolyn Lam:

Well, they studied 30 patients with HFpEF and get this. They underwent two bouts of upright seated cycle exercise dosed with sublingual nitroglycerin or a placebo every 15 minutes in a single blind randomized crossover design. So really well done. Wedge pressure, VO2 and cardiac output were assessed at rest with 20 watts exercise and at peak exercise during both the placebo and nitroglycerin conditions and the principle finding of the study (singing) acutely lowering pulmonary capillary wedge pressure during upright exercise with nitroglycerin in HFpEF did not improve peak exercise performance. So peak VO2 was practically identical with a 1% difference despite a 17% drop in peak wedge pressure. Peak cardiac output and peak peripheral oxygen extraction were unchanged, again, despite the drop in peak wedge pressure suggesting that oxygen delivery and utilization were unaffected. Exercise performance variables including peak wattage, peak ventilation and peak RER were unchanged, suggesting that again, reductions in peak wedge were insufficient to improve exercise tolerance.

All these results suggest acute reductions in wedge pressure are insufficient to improve exercise capacity and provide convincing evidence that a high wedge during exercise by itself is an epiphenomenon perhaps rather than a primary limiting factor for exercise performance in patients with HFpEF. Now of course this is incredibly interesting contrary to hypothesis and so please read the paper. The discussion is very rich.

Dr. Peder Myhre:

Oh wow, Carolyn. That is such a great paper. I can't wait to pick it up and read it from start to finish and now Carolyn, we're going to look into research within cardiovascular disease from COVID-19 and we have learned so much and so quickly about COVID-19 and its effects on the heart and we have really come a long way from the first case reports reported in the beginning of the pandemic and this paper, which comes to us from corresponding author Professor JP Greenwood, really adds important knowledge to this field. The COVID heart study was a prospective longitudinal multi-center observational cohort study of patients hospitalized with COVID-19 and at elevated serum troponin levels across 25 hospitals in the UK and these investigators aim to characterize myocardial injury, its association and sequela in convalescent patients following hospitalization with COVID-19 utilizing appropriately matched contemporary controls.

Dr. Carolyn Lam:

Ooh, important stuff. So what did they find?

Dr. Peder Myhre:

So these authors included in total 519 patients comprising 342 patients with COVID-19 and an elevated troponin, 64 patients with COVID-19 and a normal troponin and 113 age and comorbidity matched controls without COVID-19 and the frequency of any heart abnormality defined as left or right ventricular impairment, scar or pericardial disease was two full greater in patients with COVID positive and troponin positive, so 61% compared to the control groups and that is 36% for COVID positive and troponin negative and 31% for COVID negative and comorbidity positive and the myocardial injury pattern was different for these patients with COVID and an elevated troponin more likely than controls to have infarction and micro infarction. But there was no difference in non-ischemic scar and using the late MRI criteria, the prevalence of probable recent myocarditis was almost 7% for those with COVID and elevated troponin compared to only 2% for the controls without COVID-19 and myocardial scar is but not prior COVID-19 infection or troponin was an independent predictor of MACE.

So Carolyn, these authors discussed their findings in light of previously reported studies and these authors identified a lower prevalence of probable recent myocarditis than previously described and a higher proportion of myocardial infarction and this newly described pattern of micro infarction following COVID-19 and Carolyn, there is a brilliant editorial really summarizing this by Dr. Stuber and Baggish entitled "Acute Myocardial Injury in the COVID Heart Study Emphasizing Scars While Reassuring Scarce." I really recommend everyone to pick this up and read the editorial as well.

Dr. Carolyn Lam:

Very clever title. Thank you. For the last original paper in today's issue, it focuses on the crosstalk between sterile metabolism and inflammatory pathways, which have been demonstrated to significantly impact the development of atherosclerosis. Authors today are featuring and focusing on 25 hydroxy cholesterol, which is produced as an oxidation product of cholesterol and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. So these authors with co-corresponding authors, Dr. Suárez and Fernández-Hernando from Yale University School of Medicine, they showed beautifully that first, 25 hydroxy cholesterol accumulates in human coronary atherosclerosis. Next, that 25 hydroxy cholesterol produced by macrophages accelerated atherosclerosis progression and promoted plaque instability by promoting the inflammatory response in macrophages and also via paracrine actions on smooth muscle cell migratory responses.

Dr. Peder Myhre:

Wow, that is so interesting, Carolyn. What are the therapeutic implications of these findings?

Dr. Carolyn Lam:

Yes, I'm glad you asked because it was summarizing a lot of work in those findings with the very important implications that inhibition of 25 hydroxy cholesterol production might therefore delay atherosclerosis progression and promote plaque stability. So this study actually opens a door to explore the role of 25 hydroxy cholesterol as a target to control inflammation and plaque stability in human atherosclerosis.

Dr. Peder Myhre:

Oh, that is so important. Thank you so much and there is more in this issue as well, Carolyn. We have another issue of Circulation Global Rounds and this time we're going to France in a paper written by Dr. Danchin and Bouleti. We also have an exchange of letters by Dr. Yang and Dr. Schultze regarding the article, "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation" and an ECG Challenge by Drs. Manickavasagam, Dar and Jacob entitled "Syncope After Transcatheter Aortic Valve Implantation: Pace or Not."

Dr. Carolyn Lam:

Interesting. There's a Frontiers paper also by Dr. Dimopoulos on “Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus,” a Research Letter by Dr. Kimenai on the impact of patient selection on performance of an early rule out pathway for myocardial infarction from research to the real world. Nice. Well let's carry on to that feature discussion on heart failure, transcriptomics and proteomic, shall we?

Dr. Peder Myhre:

Can't wait.

Dr. Maryjane Farr:

Welcome everybody to Circulation on the Run. We are so pleased to be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from the University of Utah. My name is Maryjane Farr and I am the heart failure section chief at UT Southwestern and Digital Strategies editor for circulation. Myself and Hesham Sadek will be talking with them about their new paper and circulation called "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients with Potential of Myocardial Recovery Upon Mechanical Unloading and Circulatory Support." Just briefly, Dr. Stavros Drakos is the director of cardiovascular research for the division of cardiology at Utah and co-director of the Heart Failure Mechanical Circulatory Support and Heart Transplant Program. Dr. Sarah Franklin is associate professor of medicine at the University of Utah whose lab has a specific expertise in the applications of proteomics to heart disease. Welcome, Stavros and Sarah.

Dr. Sarah Franklin:

Thank you.

Dr. Stavros Drakos:

Thank you. Thank you for having us.

Dr. Maryjane Farr:

This paper is exciting for clinicians. It's exciting for translational scientists. Hesham, why don't you start digging into this paper and tell us one or then the other of you tell us what this paper is about, what's the background and let's get into the science. Let's go there and then we'll pull back and look at some of the big picture stuff. Hesham.

Hesham Sadek:

Well, thank you. So I've been fascinated by the field of cardiac recovery for some time now and obviously Stavros is as an expert and one of the leaders of that field and what struck me about this is that we are starting to see some distinct molecular signature of patients that can experience recovery as opposed to patients undergoing the same procedures with the same profile that do not manifest evidence of myocardial recovery and specifically, the study was conducted very rigorously and the signature was very clear in that they saw primarily interest for someone like me who's interested in cardiac regeneration, a signature of cell cycle in the patients that experience recovery as well as ECM signature which could suggest reverse remodeling and also there's some evidence that ECM might impact cardiomyocyte and myocardial regeneration. So my interest in this for selfish reasons is primarily that this supports the hypothesis that perhaps there is a molecular signature of regeneration that occurs in patients that experience myocardial recovery with LVAD.

Dr. Maryjane Farr:

So Stavros, let's start with you. Give us the reason why to do this study. You mentioned some of the background. It'd be great to sort of talk for a moment about re-stage heart failure and then how it brought you to this study.

Dr. Stavros Drakos:

Thank you, Jane. So again, thank you for the opportunity to talk about the findings and the implications of this study. I like the way you are asking us to look a little bit at what led to this study and as you mentioned, the re-stage is a multi-center study that was performed in six US sites which showed in a reproducible fashion now given that we had single center studies from all over the world suggesting that, advanced heart failure is not an irreversible process that has to lead to end stage, an irreversible disease and what a re-stage demonstrated was that there is a subset of patients which if you select them based on clinical characteristics that we derived from other studies that were performed previously, you can achieve reverse remodeling, essentially a bad heart looking much better by every clinical, functional, structural characteristic in up to 50% of the selected patients. That's what re-stage showed.

So having this finding now in a multicenter study, what made this study very timely was to be able to understand what drives this remarkable response. What are some of the mechanisms, as Hesham said, that we can if uncover take advantage of and expand this paradigm and enhance it and achieve reverse remodeling and recovery of even more patients and even go earlier in the disease process. So that's kind of how I would link the clinical findings that preceded this study with the motivation to perform the study and the implications of these findings for the ongoing translational and basic science research.

Hesham Sadek:

I'd like to ask a question here. So Stavros, do you think it's too early to sort of redefine the term reverse remodeling in this context to include perhaps some evidence of regeneration? Is there evidence of regeneration in this field or that's too premature to say?

Dr. Stavros Drakos:

I think the data are directing us towards the direction you just mentioned. I think that we can begin talking about it and planting the seed. We do have other evidence from work that you and others have performed indicating that this indeed is one of the mechanisms that drives this phenomenon and I think that the findings, especially in the cell cycle that we identified add to and contribute even more to that body of work that you and others have done. At this point, I will turn it to Sarah who can talk a little bit more about the findings related to the cell cycle that we identified in our study and I think that these may complete the answer to you, Hesham.

Dr. Sarah Franklin:

Yeah, I would love to comment. I think it's a really interesting phenomenon and really in these patient samples we were trying to understand molecularly what the difference is between individuals that respond positively to therapy and individuals that receive the same exact therapy and do not respond positively. So these are termed responders and non-responders and in our analysis we combined two platforms where we could molecularly interrogate what's different in these two tissues and try to see what is differentiating these populations. So what's consistent and reproducible different in responders and non-responders on a molecular level and in both the transcriptomic data and the phospho proteomic data, we saw clear patterns with cell cycle regulation and extracellular matrix or focal adhesion molecules and the interesting thing about cell cycle is cardiomyocytes have typically been thought to exit the cell cycle not long after birth and we see some interesting phenomenon either in humans or mice where we can have nuclei that have either multiple sets of chromosomes or multiple nuclei and there's some differences that have been observed in the nucleus with regards to disease, so hypertrophy, heart failure.

So the molecules that we've identified, we saw a large difference in proteins involved in cell cycle regulation. Now the interesting thing is not all of those molecules are increasing or decreasing. We see a combination of molecules that are increasing or decreasing. But I think the other thing that's interesting is that these molecules, even though we are seeing changes in expression or changes in phosphorylation, exactly how that contributes to either cell cycle or cell cycle reentry or just nuclear function and transcription of proteins or genes or DNA regions is still what we need to continue to study. So exactly how these changes in proteins or transcripts related to the cell cycle, how they are exactly contributing to the physiological improvements that we're seeing is something that still needs to be investigated but is really important that that is a highlight of this study and as Stavros mentioned of previous work.

Dr. Maryjane Farr:

Stavros, tell us the design of the study.

Dr. Stavros Drakos:

Okay. So this study was performed in 93 patients that were prospectively enrolled in the Utah transplant affiliated hospitals here in Salt Lake City between the University of Utah, Intermountain Medical Center and the VA and these people came from all over the mountain west, the surrounding states of Utah and through our VA, through the state, from all over the west and south, from Alaska and Hawaii to Texas and we think it's a very representative population of our country's patient population and then we followed prospectively these people with serial echocardiograms so we can tell who will respond as Sarah said before, which essentially means which hearts are going to get better by echocardiographic criteria functionally and structurally, the dimensions of the heart shrinking and the ejection fraction improving to more than 40% and the dimension shrinking to normal range and then we compare these people, the subset of patients that have responded to the majority of patients actually that they have not responded. As we know these are advanced end stage patients and there is only a subset of those that they will favor respondents.

As we said earlier, these subset can increase if you go selectively and pick these patients based on baseline characteristics. So then we analyze the tissue we got from these people when the LVAD went in, which is the core of the apex of the heart and compare that to the tissue we receive when the patients got transplanted and we got the whole heart. So in the meantime, as we just discussed, we phenotyped these people so we knew who were responders and non-responders and then we went back in the lab and tried to marry two basic processes, analyzing the transcriptome and the proteome and by doing that we were able to see some overlapping changes between the transcriptome and the proteome and we felt that by doing this overlapping analysis, we will increase the likelihood that what we are seeing, exponential mechanistic drivers will be the real mechanism and not just associations that you can frequently find when you do studies in humans and that's kind of a rough, brief summary of the design. Sarah, would you add something to that?

Dr. Sarah Franklin:

No, I think that's a great overview of it. I think what excites me about it is that this was first clinically observed that these patients were recovering and so I think the exciting part is the hypothesis was that there was some molecular underpinnings that could molecularly define these patients that were responding or not responding and so with that hypothesis we then carried out these analyses hoping that we would see a difference and we're very excited. It's very successful in that we found very clear, molecular differences that are reproducible between these patient populations.

Dr. Maryjane Farr:

So obviously there's lots of implications. Let me start with one very simple clinical one and that is, so based on some of the differences in the signatures and pathways that you saw for the next patient who needs LVAD therapy and you're trying to predict in some way whether they may be a responder or a non-responder, could you look at a biopsy sample and try to make some sort of prediction based on some of your findings so that they can choose a VAD over a transplant? That's a very clinical question and then I guess the second question is would it have to be a left ventricular myocardial sample? So are the differences? What do you think about that question? Or it's just too much too, far beyond? This is obviously a mechanistic study. But I'm just asking.

Dr. Stavros Drakos:

No, that's a great question and I'll start and Sarah can add later. So obviously it will be great if we can have a practical way to predict before the intervention who are the people that they will respond and that's one of the motivations for this study. It was not just to find the mechanism so we can make this phenomenon better and enhance it and find the mechanism, create new therapies. It was also the practical approach that you suggested, Jane, and I think that yes, this adds to the clinical predictors that we have already identified from other studies and yes, we could theoretically take the tissue and do this analysis. Is this the most practical thing we can say to the patient to biopsy the heart, right? It would've been better to be able to identify a biomarker in the plaque and we've done that. We started in other studies, identifying what's going on in the tissue and then going targeted in the blood and that's how we identified two cytokines and a two cytokines model, interferon gamma and TNF alpha being predictive as circulating biome.

In this study we identify changes that can also inform future studies of biomarkers in the blood. But if we had a way to easily get the tissue and analyze the genes, yes, we could have done that as a predictor as well. The practical issue is that asking a patient for a biopsy just to predict the response to therapy may be something that most patients and most clinicians will consider way too advanced and complicated, right?that's why more work should and could be done to identify circulating biomarkers or other modalities that can help us interrogate what's going on in the heart related with these findings. But not that we cannot also do what you said. It's just more complicated. I don't know if Sarah would like to add to this.

Dr. Sarah Franklin:

I'd love to. I think that's a great overview. I think the only thing that I would add is that there are a number of conditions whether in the heart or otherwise in the body that you can use a single biomarker and it can be very predictive of conditions. Heart failure is so complex that often individual biomarkers are not sufficient enough to cover an entire population and all the nuances that can go into heart failure symptoms or syndromes and I think the exciting part about this study is it is one of the largest cohorts of patients that have been examined in this manner, which is exciting, but also that we have a multi-factor panel that is made up of multiple biomarkers that with the number of individuals that we examined is completely predictive of all of these patients.

So these biomarkers are consistent and reproducible across all of these patients between responders and non-responders regardless of some of the nuances in the heart failure that they have and so it's very exciting because it's possible that a multifactorial panel could be much more applicable and last the test of time more so than an individual biomarker. I think the one other thing that is exciting like Stavros mentioned is that we did initially identify these in the left ventricle and it will be really exciting to see how far these biomarkers can be used if they can be used in potentially other aspects of the heart or blood, which obviously is less invasive and so that's not something that we've applied this panel to yet, but I think is a really wonderful extension of now saying, can we also identify some of these biomarkers in the blood which would be less invasive even if it's a fraction of them. That would still be wonderful.

Dr. Maryjane Farr:

I have so many clinical questions. But Hesham, what questions do you have?

Hesham Sadek:

Yeah, so the elephant in the room here obviously is that the variable is that these patients have an unloaded heart and there is evidence that unloading can reverse some of the changes that occur after birth with increasing ventricular load and initiate cascade of molecular events that may allow myocytes to proliferate. So this begs the question, is there a difference in how these ventricles of patients that recover versus those that do not recover see load? Are we able to measure load appropriately and is there a difference in load between these patients and if so, can this be improved or detection or measuring unloading or the degree of unloading clinically, can this be improved?

Dr. Stavros Drakos:

No, that's a great question and it provides the opportunity to talk about some of the things we can do on the clinical arena to further enhance this phenomenon. Yes, there are ways that we can use to tailor the mechanical unloading that we can provide in order to enhance this phenomenon. One way, and that's a study that we are proposing, is to use sensors, pressure sensors that can guide the way you function the machines, the devices, right? The way you remove part of the load and these sensors, some of them are clinically approved like cardioments and then without doing invasive procedures you can follow chronically how these patients are being unloaded and how the heart is responding to this unloading. We know that a lot of LVAD patients, despite doing clinically well, we know this from snapshot evaluations in right-heart cath studies, they are not optimally unloaded. They are feeling pressures left and right are not always optimized and so by doing this kind of prospective assessment of the mechanical unloading, you can tailor what you offer and the hypothesis generated is that by doing that you may be able to recover even more people.

You can do this as we said, with approved sensors like cardioments or with other sensors that they are under investigation. You can also do more invasive stuff like PV loops. Of course these will require cathing these patients, which is a little bit more complicated. But it will provide more accurate assessment and it will also interrogate how the heart is improving and provide to you in-depth investigation and in-depth insights on also how the recovery process and the reverse remodeling process is being, I would say, digested by the heart and translated to functional response instead of just looking at it with an echocardiogram or the findings of a right-heart cath and these are studies that others have performed and have published and we know that they can give you a real good look into the systolic and diastolic function of the heart and how this is changing and improving down the road. So yes, that's the short answer. We can do that and we can tailor the unloading and potentially that's the hypothesis, maximize the effect that we saw here.

Hesham Sadek:

So this begs the question, maybe two questions here. One, is there evidence that patients who recover not from this study only but from other studies, is there evidence that patients who recover are more unloaded than patients that do not recover and the second question is: is it time to standardize assessment of mechanical load in patients with LVAD, especially those that will undergo or would be considered for recovery?

Dr. Stavros Drakos:

Yes. So that's a great opportunity to share with our audience what we know and what we don't know in this field in relation to your question about whether we know what is the optimum degree of unloading and the answer I think is that we need to know and understand more. What do I mean by that? There's this idea that the heart as every other organ after being unloaded and not working for some time may it lazy, may get atrophic and may need some rehab like the skeletal muscle when we put it in the cast and get atrophic and we need to rehab it when we remove the cast. So you can imagine that the LVAD and the unloading that provides, which in many cases may take over a significant part of the function of the heart may need gradual reloading as a second phase after the first phase of unloading and that's something that we've done. We have an ongoing study on this and also others have published that it may be beneficial.

Of course, it needs to be validated and investigated further and to discuss about the degree of unloading in the first phase and what is the optimum degree of unloading, I would say even there, there is room for us to understand better what's going on and I think that we can investigate with ongoing studies right now whether full unloading versus partial unloading and measure the pressures using these sensors can translate to better changes functionally and structurally. I think that's something that is very doable and it would be very beneficial. What was the second part of your question, Hesham?

Hesham Sadek:

I was asking whether it's time to start standardizing some measure of unloading if these patients are planned for recovery?

Dr. Stavros Drakos:

Yes, and that's what we are doing. In all of these people, we report from the get-go what is their recovery score based on the intermixed ICARS derived score and when we have patients that they have high likelihood of recovery, we monitor them very closely and clinically what we do is just looking at the echo and whenever we do a right heart cath for clinical reasons. But in a prospective research study we could do more than just looking at the echo and occasional right heart cath and using the sensors we just discussed previously, you can tailor the unloading and begin prospectively unloading them in a more I would say well monitored wave. Yes.

Hesham Sadek:

So this is unloading or device specific parameters. Now are there patient specific parameters with regards to type of heart failure? So we talked initially about whether there's an element of regeneration specifically when it comes to cell cycle. But many patients with non-ischemic cardiomyopathy for example, don't have large scars and don't have lot of myocytes as the underlying cause of cardiomyopathy. Would you foresee that there is different mechanisms, for example, in these patients that don't have myocyte loss, that perhaps maybe it's not cardio myocyte proliferation and not regeneration?

Dr. Stavros Drakos:

Yes. So I think that the differential responses we get based on the heart failure theology warrant further investigation. Sarah and I have discussed that and actually we are following on our findings with larger number of patients so we can tease out these and I'll let Sarah talk a little bit more about it in a minute. But to answer the clinical part of this question, we don't know yet whether different parts of heart failure should be prescribed different modes of unloading. But the way you described it of course invites the hypothesis that of course different substrates, different injuries of the heart, as you said, it's a completely different failing heart if you have a big scar there versus a patient who has a mode of heart failure, another type of injury and would this be treated better and more effectively in terms of reverse remodeling by applying a different mode of unloading? That's things that we need to investigate further. But Sarah, would you like to comment on the potential on the effect of the different heart failure theologies on some of the findings we saw?

Dr. Sarah Franklin:

Yeah, definitely. So I think it's a really interesting question and in this analysis we included ischemic and non-ischemic samples in the patient populations and really we're just stratifying them based on responders and non-responders. When we start layering additional levels onto that, then we're effectively kind of reducing the potential numbers. So if we have 25 responders and we start breaking that down into ischemic and non-ischemic to see if there's another layer of biomarkers there, we actually did that we did not include it in this study. It's something that we're working on to add that. But we do reduce the number overall of patients in those two populations. So it would be fine to share that we were seeing stratification between ischemic and non-ischemic. But we did not feel like the numbers might be high enough within the responder and non-responder categories that warrant including that in this manuscript. So it's very intriguing that just responders and non-responders alone stratify as well as they do.

They separate based on these biomarkers and it looks like it will also be possible in the future for us to even separate these samples further based on similar or additional biomarkers based on more specific factors in the etiology. So I think that will be another really exciting next step for future research.

Hesham Sadek:

My final question would be maybe a little bit broader than LVAD population, but definitely informed by this study. The term non-ischemic cardiomyopathy, do you think it's too broad and too vague for us to use in this setting because this encompasses many different types of cardiomyopathy that really are not nuanced enough by this definition.

Dr. Stavros Drakos:

Well, Jane was smiling while you were asking this question because we all as heart failure clinicians need to accept that it was not a good idea to name all of these different diseases non-ischemic cardiomyopathy when we did it or when this happened many moons ago. As you said, Hesham, and I couldn't agree more, these are completely different diseases. We need to understand them better and I think that the way we treat nowadays, chronic heart failure, many years down the road when people will look back, they will consider it a little bit, I would say, surprising that we were treating all of these the same way.

We need more studies like the one we just did, that they will have enough numbers and that's when the issue becomes that you need enough numbers to be able to tell the differences between all of these non-ischemic cardiomyopathy types, theologies and if you go upstream, motivated and inspired by findings like this, we hope that we will be able to identify how to go and do a root cause analysis and treat these diseases, not down, down, downstream the same way, but going upstream, finding what really went wrong and treating them earlier in the molecular or other pathophysiological mechanism pathway that led to the heart failure and so yes, it was a bad idea to do that. But of course sometimes we do things because we don't understand it better, right? As one of our keynote speakers here in the recovery symposium said a few years ago, Jay Khan, the founder of Heart Failure Strata of America, some things look complicated until you understand them. Then when you understand them, they look simple.

So here we don't really understand non-ischemic cardiomyopathy and how all these theologies lead there and I think studies like these can help us really inform the field better. But we will need, as Sarah said, more numbers.

Dr. Maryjane Farr:

So that was a great conversation. I wanted to just raise one last thing and that is what's so interesting about this cohort relative to re-stage heart failure is these were older patients and for re-stage heart failure, I think the average age was 35. So you would imagine there might have been one etiology for cardiomyopathy, uncontrolled hypertension or peripartum. But for cohorts in their fifties, there's probably an accumulation of different insults over many years time and so I thought that was particularly interesting from the point of view of that you were probably dealing with, again, a mixed bag of pressure overload, volume overload, maybe a genetic underpinning, whatever the life trajectory of some of these patients were and then lastly, the decision to try to go to recovery rather than to transplant, which would be the real world experience of why this wet pathway than the other. These are people truly in their fifties where they may have one or two surgeries in their lifetime left and so it's the relevant population that you're studying and so I'll leave it at that. That's a comment rather than a question, I think.

But I think for heart failure clinicians, this is why the bench to bedside piece is so relevant to understanding this because it actually does change clinical practice, even if the mechanistic pathways may take still many more years to truly understand. It helps understand what's possible from an accrued clinical decision-making level.

Dr. Sarah Franklin:

Jane, if I might just comment on that, I actually think that's one of the most exciting parts about this dataset is that, as you mentioned, these patients have complex diseases. They are older. But yet we are still able to see consistent and reproducible differences between the patient populations that respond and don't respond and to me that suggests that at the end of the day there are consistent differences or reproducible or consistent molecular changes in cardiac tissue and in response to stress and I think that that gives us hope that we could potentially not only predict who would respond or not respond, but that as we get better at understanding the differences, that there could be potential therapeutic targets or therapies that would still be beneficial regardless of the complexity of the heart failure.

Dr. Maryjane Farr:

Okay. So Sarah, Stavros, thank you so much for spending time with Hesham and myself and look forward to EUCORS--I'm allowed to say that.

Dr. Stavros Drakos:

Of course.

Dr. Maryjane Farr:

Thanks so much. Bye.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway.

Dr. Carolyn Lam:

Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question.

Dr. Peder Myhre:

That is so interesting, Carolyn. I can't wait to hear this discussion.

Dr. Carolyn Lam:

Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis.

Dr. Peder Myhre:

Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn.

Dr. Carolyn Lam:

Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157.

How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis.

Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed.

Dr. Peder Myhre:

Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP.

Dr. Carolyn Lam:

Cool. That's interesting. So how did they do this, and what did they find?

Dr. Peder Myhre:

So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm.

And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies.

Dr. Carolyn Lam:

Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction.

Dr. Peder Myhre:

Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain.

Dr. Carolyn Lam:

I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study.

This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload.

So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh?

Dr. Peder Myhre:

Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury.

Dr. Carolyn Lam:

Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find?

Dr. Peder Myhre:

Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study.

Dr. Carolyn Lam:

Indeed.

Dr. Peder Myhre:

And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury.

Dr. Carolyn Lam:

Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature.

Dr. Peder Myhre:

And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles."

And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy."

Dr. Carolyn Lam:

Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we?

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Subodh Verma:

First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes.

Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described.

Dr. Greg Hundley:

Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population?

Dr. Subodh Verma:

So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity.

Dr. Greg Hundley:

And how many subjects did you randomize?

Dr. Subodh Verma:

So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups.

Dr. Greg Hundley:

Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results?

Dr. Subodh Verma:

So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%.

Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant.

Dr. Greg Hundley:

And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age?

Dr. Subodh Verma:

Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se.

Dr. Greg Hundley:

Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes?

Dr. Christopher Granger:

Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes.

But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure.

And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research?

Dr. Subodh Verma:

Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working.

And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further.

So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards.

Dr. Greg Hundley:

Very nice. And Chris, do you have anything to add?

Dr. Christopher Granger:

Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months.

Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial."

Dr. Greg Hundley:

Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think?

Dr. Greg Hundley:

Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that?

Dr. Peder Myhre:

Let's do preclinical science, Greg.

Dr. Greg Hundley:

Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence?

And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined.

Dr. Peder Myhre:

Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications.

Dr. Greg Hundley:

Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow.

And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes.

Dr. Peder Myhre:

That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose.

Dr. Greg Hundley:

Wow, really interesting, Peder. So what did they find here?

Dr. Peder Myhre:

So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study.

Dr. Peder Myhre:

So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find?

Dr. Greg Hundley:

Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow.

Dr. Peder Myhre:

Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting?

Dr. Greg Hundley:

Yes.

Dr. Peder Myhre:

And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy.

Dr. Greg Hundley:

Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results?

Dr. Peder Myhre:

So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5.

And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94.

And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding.

So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events.

Dr. Greg Hundley:

Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.”

Dr. Peder Myhre:

And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions.

Dr. Greg Hundley:

Fantastic, Peder. Well, how about we get off to that feature discussion?

Dr. Peder Myhre:

Let's go.

Dr. Mercedes Carnethon:

Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens.

Dr. Pieter Martens:

Thank you for having me. It's a pleasure to be here today.

Dr. Mercedes Carnethon:

Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found.

Dr. Pieter Martens:

So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients.

Dr. Mercedes Carnethon:

Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you?

Dr. Pieter Martens:

All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion.

And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction.

Dr. Mercedes Carnethon:

Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation?

Dr. Justin Grodin:

Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else."

And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum?

Dr. Mercedes Carnethon:

Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens.

Dr. Justin Grodin:

Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction.

Dr. Pieter Martens:

Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction.

Dr. Justin Grodin:

And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed.

Dr. Pieter Martens:

Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction.

But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure.

Dr. Mercedes Carnethon:

Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice?

Dr. Pieter Martens:

That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice.

Dr. Mercedes Carnethon:

Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today.

Dr. Pieter Martens:

Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction,

Dr. Mercedes Carnethon:

Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run.

Dr. Justin Grodin:

Thank you.

Dr. Pieter Martens:

Thank you for having me.

Dr. Mercedes Carnethon:

I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join authors Loren Field and Sean Reuter, as well as Associate Editor Thomas Eschenhagen as they discuss the article "Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity But Not Cardiomyocyte Proliferation."

Dr. Greg Hundley:

Welcome listeners, to this January 10th issue of Circulation on the Run, and I am Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, listeners, this week's feature discussion delves into the world of preclinical science and evaluates cardiac troponin I and its impact on S phase activity in cardiomyocytes, and does that relate to cardiomyocyte proliferation. But before we get to that, how about we grab a cup of coffee and Peder and I will work through some of the other articles in the issue. Peder, how about this week I go first?

Dr. Peder Myhre:

Go ahead, Greg.

Dr. Greg Hundley:

Right. So Peder, this first study evaluated whether the burden of positive coronary artery calcification on cardiovascular disease differed by multidimensional individual characteristics, and so the investigators led by Dr. Kosuke Inoue from Kyoto University sought to investigate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease. And so Peder, to examine this question, the authors implemented a cohort study design that included adults aged greater than 45 years, free of cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis, or MESA, and after propensity score matching in a one-to-one ratio, they applied a machine learning causal forest model to, first, evaluate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease and then, second, to predict the increase in cardiovascular disease risk at 10 years when the coronary artery calcium score was greater than zero, so versus is it zero at all at the individual level?

Dr. Peder Myhre:

Oh, Greg, that is so cool, so using machine learning for coronary artery calcium and risk prediction, I'm very excited. What did they find?

Dr. Greg Hundley:

Right, Peder, so the expected increases in cardiovascular disease risk when the coronary artery calcium score was greater than zero were heterogeneous across individuals. Moreover, nearly 70% of people with low atherosclerotic cardiovascular disease risk showed a large increase in cardiovascular disease risk when the coronary calcium score was greater than zero, highlighting the need for coronary artery calcium screening among such low-risk individuals. And Peder, future studies are really needed to assess whether targeting individuals for coronary artery calcium measurements based on not only the absolute ASCVD risk, but also the expected increase in CVD risk when a CAC score is greater than zero and whether that improves overall assessment of cardiovascular outcomes.

Dr. Peder Myhre:

Wow, that is so clinically relevant and very interesting. And we're actually going to stay clinically relevant with the next paper which is about anti-platelet therapy after PCI. And this paper describes the long-term results of the HOST-EXAM trial. To remind you, Greg, the HOST-EXAM trial was an investigator-initiated prospective, randomized, open label, multicenter trial done at 37 sites in Korea. They enrolled patients who had undergone PCI with DES and maintained dual anti-platelet therapy without any clinical event for a mean 12 months and then they were randomized one to-one to either clopidogrel, 75 milligrams once daily, or aspirin, 100 milligram once daily. The primary results of this trial was published in Lancet in 2021 and showed superiority of clopidogrel over aspirin in prevention of the composite of MACE and major bleeding during 24 months of followup. And then, through the current paper, this describes the results of the post trial extended followup of about five years.

Dr. Greg Hundley:

Very nice, Peder, so aspirin versus clopidogrel and looking at the maintenance of that monotherapy and cardiovascular outcomes. Wow, so what did they find?

Dr. Peder Myhre:

Yeah, Greg. They, in this extended followup study, had a total of 5.8 years median followup, and the primary endpoint occurred in 12.8% in the clopidogrel group versus 16.9% in the aspirin group, and that has a range of 0.74 with a 95% conference interval ranging from 0.63 to 0.86. So also the clopidogrel group had lower risk of the secondary thrombotic endpoint and the secondary bleeding endpoint while there was no significant difference in the incident on all caused death. So Greg, to conclude, these very interesting results from the primary analysis of the HOST-EXAM trial was consistent through the longer followup, and this support the use of clopidogrel over aspirin monotherapy from 12 months onwards after PCI.

Dr. Greg Hundley:

Very nice Peder, beautiful description and sounds like long-term clopidogrel use over aspirin was quite beneficial. Well, the next study comes to us from the world of preclinical science, and it is from the investigative group led by Dr. Yunzeng Zou from Shanghai Institute of Cardiovascular Diseases and the Zhongshan Hospital and Fudan University. Peder, the study pertains to diabetes. So diabetic heart dysfunction is a common complication of diabetes mellitus and cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise intervening time of particular cell death type remained largely unknown in diabetic hearts. And so, Peder, this study aimed to identify the particular cell death type that is responsible for diabetic heart dysfunction and propose a promising therapeutic strategy by intervening in this cell death pathway.

Dr. Peder Myhre:

Wow, Greg, that is really interesting. Heart dysfunction in diabetes is something that we really have to learn more about and I'm so excited to hear what these authors found, Greg.

Dr. Greg Hundley:

Right. So first, Peder, the authors identified necroptosis as the predominant cell death type at later stages in the diabetic heart. And then second, Peder, the CB2 receptor, and we'll call that CB2-R, recruits transcription factor Bach2 to repress necroptosis and protects against diabetic heart injury while hyperglycemia and MLKL in turn phosphorylates CB2-R to promote ubiquitous dependent degradation of CB2-R, thus forming a CB2-R centric feedback loop of necroptosis. And finally, Peder, cardiac CB2-R or Bach2 expression negatively correlates with both MLKL 10 expression and the extent of diabetic heart injuries in humans. And so the clinical implications of these findings, Peder, are that the CB2-R centric necrotic loop represents a promising target for the clinical treatment of diabetic heart injuries.

Dr. Peder Myhre:

So Greg, this paper that comes to us from corresponding author Amanda Paluch from University of Massachusetts Amherst, is a meta-analysis of eight prospective studies with device measured steps including more than 20,000 adults who were followed for CVD events. And the mean age of participants in this study was 63 years and 52% were women. And the participants were followed for a median of 6.2 years and 1,523 cardiovascular events occurred.

So first, Greg, there was a significant difference in the association of steps per day in cardiovascular disease between older, that is greater or equal to 60 years, and younger, that is less than 60 years adults. So for older adults that has the ratio for cardiovascular disease using Q1 as reference was 0.80 for Q2, 0.62 for Q3, and 0.51 for Q4. And for younger adults that has ratio for cardiovascular disease using Q1 as reference was 0.79 for Q2, 0.90 for Q3, and 0.95 for Q4. And in the paper, Greg, there are some beautiful, restricted cubic lines that really illustrate the association between daily steps and the risk of cardiovascular disease among older adults and in younger adults.

So the authors conclude that for older adults taking more daily steps is associated with a progressively lower risk of cardiovascular disease. And monitoring and promoting steps per day is a simple metric for clinician patient communication and population health to reduce the risk of cardiovascular disease.

Dr. Greg Hundley:

Well, Peder, we've got some other very interesting articles in this issue and how about we dive into that mail bag and discuss a few of those. So I'll go first. The first is a Perspective piece by Professor Powell-Wiley entitled “Centering Patient Voices through Community Engagement in Cardiovascular Research.” A very important topic where can those in the community actually help us design meaningful outcomes for our research initiatives? And next Peder, there is a Research Letter from Professor Evans entitled “Increasing Mononuclear deployed Cardiomyocytes by Loss of E2F7/8, and does that fail to improve cardiac regeneration post myocardial infarction?”

Dr. Peder Myhre:

Thanks, Greg. We also have an ECG Challenge by Dr. Li entitled, “What Is The Truth Behind Abnormal ECG Changes?” And this is describing a very rare and interesting cause of ST segment elevation. I recommend everyone to read that case. We also have our own Nick Murphy who gives us the Highlights from the Circulation Family of Journals where he summarizes five papers from the Circulation subspecialty journals. First, the experience with a novel visually assisted ablation catheter is reported in circulation A and E. The impact of various exercise training approaches on skeletal muscle in heart failure with preserved the F is presented in circulation heart failure. Gaps in heart failure treatment over a decade are reported in circulation cardiovascular quality and outcomes, and the associations of machine learning approaches to plaque morphology from coronary CTA with ischemia are reported in circulation cardiovascular imaging. And finally, Greg, an observational study of left main PCI at sites with and without surgical backup is reported in circulation cardiovascular interventions. Let's go on to the feature paper today describing the cardiac troponin I interacting kinase and the impact on cardiomyocyte S phase activity.

Dr. Greg Hundley:

Great, let's go.

Welcome listeners to this January 10th feature discussion. Very interesting today as we are going to delve into the world of preclinical science. And we have with us today Dr. Loren Field and Dr. Sean Reuter from University of Indiana in Indianapolis, Indiana. And our own associate editor, Dr. Thomas Eschenhagen from University Medical Center of Hamburg in Hamburg, Germany. Welcome gentlemen. Well, Loren, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Loren Field:

Sure. This study actually came about in a rather roundabout fashion. We were doing a study with Kai Wollert in Hanover, Germany, where we were looking at the impact of a CXCR4 antagonist, which is used to mobilize stem cells from the bone marrow. And we had sent our mice over to Kai's lab and we have a mouse model that allows us to track S phase activity in cardiac myocytes, so these are cells are starting to replicate. And Kai crossed them into a different genetic background. And when he sent the mice back to us to analyze the hearts, we observed that we saw things that we never saw before in our experiments here.

His injury model was different than ours and now the mouse also had a genetic background, so we had to spend about a year to figure out if it was the injury model or the background. It turned out to be the genetic background, and the phenotype was these mice had about a 15-fold elevated level of cell cycle reentry. So then it became a relatively simple genetics game where we took the progenitor mice, made F1 animals, looked for the phenotype, did backcross animals, and basically identified the gene responsible for the phenotype.

Dr. Greg Hundley:

Very nice. And so in this study moving forward, what hypothesis did you want to address?

Dr. Loren Field:

Well, the main hypothesis was to figure out what the gene was and then secondarily to figure out the degree of cell cycle progression. When the cell is proliferating, the first task is to replicate its genome, which is S phase activity that's followed by the nuclei dividing and then finally by the cell itself becoming two cells. So our task was to identify, first, the gene and secondly, how far through the cell cycles the cells progressed.

Dr. Greg Hundley:

Very nice. And how did you construct your experiment?

Dr. Loren Field:

It was, again, very straightforward. It was simply setting up the appropriate genetic crosses to produce the animals. For the past 10, 15 years, we've been developing a computer assisted assay that allows us to identify the anatomical position of S phase positive cardiac myocytes in sections of the heart. And basically, we apply that program to the different genetic backgrounds and after that it's a ball of mapping studies, QTL mapping.

Dr. Greg Hundley:

So really mechanistic understanding. Well listeners, we're next going to turn to Sean, and Sean, can you describe for us your study results?

Dr. Sean Reuter:

Yes, as Loren stated, we saw a 15-fold increase in the S phase activity within the remote zone. Now we partition the heart in three different zones after injury, so the scar, the border zone, and then the remote zone or injury. And as Loren stated, we saw a 15-fold increase in the S phase activity, cell cycle activity, in the remote zone. And it's only because we have this system in hand that we can anatomically map the S phase activity within the heart that we were able to detect and also quantify this. And I think that's the reason we discovered this particular phenotype. But in addition to that, we performed RNA-seq or Exome sequencing and discovered that TNNI3K was the responsible gene for elevated S phase activity within the remote zone and border zone, but interestingly not in the scar.

Dr. Greg Hundley:

Very interesting, Sean, and so describe for us the importance of the TNNI3K and its relationship to this S phase.

Dr. Sean Reuter:

Sure. This particular gene was first discovered around 2000, and it's been studied for a while now, but the targets of this kinase specifically expressed in the heart, and it does get elevated after injury, but the actual targets are not well described or well known. It's believed that it phosphorylates some mild filament fibers and structural proteins, but the actual mechanism and the consequence of this is not known. So when we saw this in the remote zone, the elevated S phase, our current theory is that we believe that it's probably increasing oxidative stress that would basically further out from the at-risk zone or the border zone and then it now is in the remote zone. So we think it's just causing the heart, a pathological area of the heart, basically to expand. And so that's our current theory. Other groups have published on the oxidative stress in over expression of TNNI3K as well.

Dr. Greg Hundley:

Very nice. Well listeners, next we are going to turn to our associate editor, Thomas many articles come your way and come across your desk. What attracted you to this particular article, and how do we put its results really in the context of cardiac regeneration?

Dr. Thomas Eschenhagen:

Indeed, there were several arguments. It's a cool paper and the whole field is still very important. As probably most of you know, the field have a rough ride over the last 20 years, went up and down, lots of bad findings. And in the end it turns out that we are there where we have been 20 years ago, the mammalian heart essentially doesn't regenerate. So anything which would improve that would be of very major importance. Why is it a good paper? Because it starts from a very clear finding, one mouse, which looks like strongly regenerating after MI, another mouse line, which doesn't. And so by applying, let's say, classical genetic, very stringent methodology, Loren Field and his group identified this troponin I kinase to be the culprit. And they also proved it, because putting it back in the strain with a low, so-called, regeneration brought it back to the other level. So it's a very clear, nice methodology.

And finally, it's also a bit provocative because others in a very prominent paper, actually, have shown that this kinase... Or they concluded more or less just the opposite. The reason for the discrepancy is not quite clear and I was very happy to learn that the two groups actually discussed about it. So it's not just a bad controversy, but something which brings forward science.

And finally, I think something we didn't talk about yet today, what I particularly liked, maybe the most, on this paper is that this group didn't stop at the point of DNA synthesis. Everybody else would've probably said, "Okay, here we are, one regenerate the other doesn't." But in the very important extra finding of this paper is that this is just increased DNA synthesis and not more myocytes. And this distinction is so critical to the field because people forget that adult mammalian cardiomyocytes often have several nuclei and individual nuclei have more than one set of chromosomes, so this polyploid. And so if you see DNA synthesis like in this paper, it doesn't necessarily mean more myocytes. And actually here it was shown that it is not more myocytes but more polyploidization and making this difference so clear, I think it's a very important contribution to the field.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn back to each of our guests today and we'll start with you Loren. Based on your results, what do you see as the next study moving forward in this sphere of research?

Dr. Loren Field:

I think these results made me appreciate for the first time that the intrinsic level of cell cycle reentry, that's just the S phase, not the cell division, is actually much higher than I had thought previously. And this was because we just fortuitously, or I guess anti-fortuitously, we're using a strain that had low levels of S phase induction. If you calculate the turnover, if every nucleus that it synthesized DNA actually went on to have that cell divide, you could replace a 50% loss of myocytes over the course of about 550 days, give or take. And to me, that's actually telling me that if we could push those cells from just being polypoid, as Thomas was saying, to actually go through cytokinesis, there would be enough intrinsic activity to go forward. So this really tells me that what we should be focusing on is now not trying to induce cell cycle, but to allow the cells that are entering the cell cycle to actually progress through it.

Dr. Greg Hundley:

Very nice. And Sean?

Dr. Sean Reuter:

Yes, well, echoing Loren's point there, it's really not necessarily cell cycle induction, it's cell cycle completion to the cytokinetic fate. And that's the key. If we can get to that point, if we can figure out the mechanism to get to that point, then we have a wonderful discovery. However, we're not quite there yet, but we hope to be.

Dr. Greg Hundley:

And Thomas.

Dr. Thomas Eschenhagen:

Well, nothing to add really from my side, except that I would like to know what this Troponin I kinase does, because that is somehow still a missing link. How does this kinase lead to more DNA synthesis or the initiation of cell cycling? That would be an important finding and I'm sure there will be more research going on. Particularly also, to solve this discrepancy, I mean, there must be something in it and we don't quite yet know how, but I think we are in a good way. I'm sure there will be papers showing that soon. So I think that's, again, a very good start for this discussion.

Dr. Greg Hundley:

Well, listeners, we want to thank Dr. Loren Field, Dr. Sean Reuter and Dr. Thomas Eschenhagen for bringing us this really informative study in mammalian myocellular regeneration, highlighting that the level of cardiomyocyte cell cycle reentry in hearts expressing TNNI3 kinase would lead to significant regenerative growth if each cardiomyocyte exhibiting S phase activity was able to progress through cytokinesis. And this in turn suggests that identification of factors which facilitate cardiomyocyte cell cycle progression beyond S phase will be key to unlocking the intrinsic regenerative capacity of the heart.

Well, on behalf of Carolyn, Peder and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.”

Dr. Greg Hundley:

Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo.

Dr. Greg Hundley:

Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first?

Dr. Peder Myhre:

Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019.

Dr. Greg Hundley:

Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find?

Dr. Peder Myhre:

So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality.

And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe.

Dr. Greg Hundley:

Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative.

Dr. Peder Myhre:

Yes, indeed very impressive.

Dr. Greg Hundley:

Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes.

Dr. Peder Myhre:

Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find?

Dr. Greg Hundley:

Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products.

And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve.

Dr. Peder Myhre:

All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study.

Dr. Greg Hundley:

Oh, very nice Peder. So, what did they find?

Dr. Peder Myhre:

So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts.

Dr. Greg Hundley:

Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo.

So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice.

Dr. Peder Myhre:

Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg?

Dr. Greg Hundley:

Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy.

And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation.

Dr. Peder Myhre:

That was an excellent explanation of a very difficult topic. Thank you, Greg.

Dr. Greg Hundley:

Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled."

Dr. Peder Myhre:

Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time."

Dr. Greg Hundley:

All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease?

Dr. Mercedes Carnethon:

Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings.

Dr. Judith Hochman:

It's a pleasure to be here.

Dr. Mercedes Carnethon:

Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial?

Dr. Judith Hochman:

Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups.

So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years.

And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026.

Dr. Mercedes Carnethon:

This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me.

Dr. Judith Hochman:

I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0.

Dr. Mercedes Carnethon:

Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings.

Dr. Steven Bradley:

Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism.

So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now.

Dr. Mercedes Carnethon:

Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information?

Dr. Judith Hochman:

That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID.

Dr. Mercedes Carnethon:

Tell me more.

Dr. Judith Hochman:

Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria.

Dr. Mercedes Carnethon:

Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you-

Dr. Judith Hochman:

If they take their guideline-directed medical therapy.

Dr. Mercedes Carnethon:

Thank you for pointing that out.

Dr. Judith Hochman:

It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications.

Dr. Mercedes Carnethon:

No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be?

Dr. Steven Bradley:

Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful.

Dr. Judith Hochman:

Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy.

Dr. Mercedes Carnethon:

That's really interesting.

Dr. Judith Hochman:

To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy.

So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point.

Dr. Mercedes Carnethon:

I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast.

Dr. Judith Hochman:

You're very welcome.

Dr. Steven Bradley:

My pleasure.

Dr. Mercedes Carnethon:

I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run.

Please tune in next week where we will have more exciting discussions like this one. Thank you.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

In this week’s Circulation on the Run podcast, we turn the show over to Circulation’s Social Media Editors Dr. Pishoy Gouda and Dr. Peder Myhre. They interview the 2022 recipients of the Joseph Loscalzo Award for Best Basic Science Article, and the 2022 recipients of the James T. Willerson Award for Best Clinical Article.

Dr. Maryjane Farr:

Welcome everybody to Circulation on the Run. My name is Maryjane Farr, and I'm the digital strategies editor at Circulation. Carolyn and Greg are on break this week. And as part of the Circulation tradition, we turn the stage over to two of our social media editors, Dr. Peder Myhre from Oslo and Dr. Pishoy Gouda from Edmonton. They're going to be interviewing the 2022 winners of the Loscalzo Award and the Willerson Award. Take it away, Peter and Pishoy.

Dr. Peder Myhre:

Today. Pishoy, we have a very exciting issue of Circulation on the Run. We are going-

Dr. Pishoy Gouda:

We certainly do.

Dr. Peder Myhre:

Yeah. We're going to discuss two amazing papers that are award-winning and we're going to talk to the first authors who really know these papers and conducted the amazing work that we're going to display here today.

Dr. Pishoy Gouda:

Yeah, I'm excited.

Peter. And with us today, we'll start talking about the recipients of the Loscalzo Award. So I wanted to start off by introducing Dr. Leo and Dr. Suvorava, who are the very proud recipients of the Loscalzo Award for their paper entitled Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure. So welcome Doctors Leo and Suvorava. How are you guys doing today?

Dr. Francesca Leo:

Hi, thank you for the introduction and pretty well, I'm currently in Italy for my winter Christmas holidays, but I'm really excited and happy to be here today with you.

Dr. Pishoy Gouda:

Excellent.

Dr. Suvorava:

Hello. I'm also very happy to be here today. Thank you for your invitation and for your congratulations. It's a privilege and honor for me to be a recipient of this Dr. Loscalzo Award. Thank you.

Dr. Pishoy Gouda:

Well, I just wanted to start off by taking another second here to congratulate you both on this award. We all know the sheer amount of work and dedications to get these projects going, so congratulations. And I'm going to start off with a really easy question for you guys. When you found out that you were a recipient of the Loscalzo Award, who is the first person that you told?

Dr. Francesca Leo:

As I mentioned, I'm Italian and as a good Italian I need to say that. Of course, the first people I told were my parents because we all know that Italian and parents are just one thing. So they were the first ones. And then all of course, my partner and friends came second, parents first, family first.

Dr. Pishoy Gouda:

Very good. What about yourself, Tatsiana?

Dr. Tatsiana Suvorava:

Hi. Yeah. I had to think back like seven years ago and I very good remember one day when I was really excited about the results, what we found, I was in the lab, I was developing a western blood to check the functional ability of our models and it showed that it was very successful that we couldn't knock out our protein of interest almost completely. And at that day exactly, we had a lab meeting. So I directly pulled this image on my USB stick and then showed it on the lab meeting. So actually these were my colleagues who first hear about this.

Dr. Pishoy Gouda:

That's awesome. That's lovely. Well, after I got married, sometimes my parents get bumped to the second phone call and they weren't very happy about that and they let me know very clearly. But let's switch gears a little bit and tell us a little bit about how you made the decision to pursue academics. It's such a daunting career and a daunting topic sometimes. And how did you get interested in research and how did you find yourself coming into this research project?

Dr. Francesca Leo:

If I can start first. Well, I decided to pursue an academical career at the beginning following my master thesis that I did at the University of Pisa here. And I've always wanted to go abroad and gain experience, get to know different realities apart from Italy. And I was actually really lucky that I got the opportunity to work in the laboratory Professor Cortese-Krott because that gave me the opportunity to grow a lot, both personally and professionally, of course. I learned new techniques and together with our great team, we managed to achieve many goals. In particular, this paper, I must say that was my last satisfaction before my doctoral exam. So I think the feeling that you get after any also small achievement is something that you can really, I cannot find it hard to explain to people that are not in research or not in science in general.

Dr. Pishoy Gouda:

No, I totally agree. When I get a new data set, I get so excited and my wife is telling me, what are you doing is I just got new data and I'm like a little child on Christmas day. She doesn't understand it, but she appreciates that some people like that. What about yourself? What about yourself?

Dr. Tatsiana Suvorava:

Yeah, well my decision to pursue academic career started with as probably for many researchers, started from intense fascination from one discovery. I was at the beginning of my bachelors' science studies and then the Nobel Prize was given for the discovery of nitric oxide as a signaling molecule in a cardiovascular system. And I was so fascinated that the gaseous molecule so simple has so lots of responsibility in the body. And since that time, that was always in the focus of my research and this is for me, a lifelong journey. I'm still on the way.

Dr. Pishoy Gouda:

That's amazing, Tatsiana. And that sort of sets us up nicely. And as you guys know, I'm a interventional cardiologist. Basic science is a little bit farther from my memory. So I'll start off by admitting that my basic science research is not where it should be. But with that in mind, I was wondering if you could just tell our listeners a little bit about your research and why this question is so important and explain it to you like you were lowly clinicians that don't really understand basic science.

Dr. Francesca Leo:

I always take over Tanya, but yes, I have less to say than you. I must admit.

Dr. Tatsiana Suvorava:

Okay so let’s start. No problem.

Dr. Pishoy Gouda:

It's a team effort. It's a team effort.

Dr. Tatsiana Suvorava:

Its a team effort and yeah. Ok.

Dr. Francesca Leo:

It's been a really teamwork, I must say from the really, really, really beginning. So this paper was, as I said, the central focus of my doctoral thesis. I just take two small part of it, of course, in particular, what is really important on the paper, I think that is we use really new mice models that Tanya and my Professor Cortese-Krott really and highly characterized at the really beginning, so developed completely from new, and they are mice that are expressing or not eNOS this protein that is responsible for nitric oxide production in the endothelium or in red blood cells. So the importance of this research was to demonstrate the role or pivotal role of eNOS expressed in the red blood cells in the modulation of blood pressure as well as circulating nitric oxide metabolites. And we actually did it with this paper. And considering that cardiovascular disease are one of the major causes of death nowadays, this results can really have important clinical and therapeutical implications for future research and real life, let's say.

Dr. Tatsiana Suvorava:

Yeah, maybe I could add to Francesca.

Dr. Francesca Leo:

Sure,

Dr. Tatsiana Suvorava:

Yeah.

Dr. Pishoy Gouda:

Of course.

Dr. Tatsiana Suvorava:

I think our research was especially important because it's identified the existence of previously unrecognized and actually non-canonical pathway, how the red blood cells can regulate blood pressure. And it was so exciting about this.

Dr. Pishoy Gouda:

Right. So trying to find out if the red blood cell, nitric oxide synthase can actually regulate blood pressure. And this has obviously lots of clinical implications. So in practice, how did you guys set up your experiments? How did you try to test the significance of the Enos red blood cells effects?

Dr. Francesca Leo:

Just if I can add something, what was really important. So what is known is that Enos expressing the endothelium plays an important role in the modulation of blood pressure. What we actually found out is that the one in the red blood cells also is involved and played a role that seems to be independent from the one played from the eNOS expressed in the endothelium. For answering your question, I also, I need to say I'm not the right candidate because this is a huge project that started about 10 years ago. So I was really, I repeated and I will always repeat it, I was really lucky to take part to this project and to get the opportunity to take part to this journey because it was really a journey and it gave me the opportunity to work with very different people and get in touch with very different realities, academical realities.

And I can say that this project started from my previous boss and Tanya that they had this idea and started this whole project together with, of course Tanya is the one that is involved since the really beginning. So she can definitely better answer to this question.

Dr. Tatsiana Suvorava:

Yeah, thank you, Francesca. It's a long way actually what we did, and actually I started this particular project on the level of postdoc and eNOS and hypertension have been already in a center of my research interest for several years. And in a previous project what I had, I also had a transgenic mice, which were generated by conventional genetic approach by micro injection of D N a. And at that time we observed a significant contribution of external endothelial component into the blood pressure regulated. However, at that time we were not able to identify the exact extracellular allocation of this component. There were several candidates which were suggested, and one of them there were red blood cells. And everyone was kind of skeptical about this because the level of eNOS protein in red blood cells is extremely low. And furthermore, there were a lot of doubts how eNOS activity can be exported from the red blood cells because it's red blood cells are full of heme, which is a scavenger of nitric oxide.

Furthermore, actually it was not clear how they transported and how it is released this activity. But now if we think that red blood cells are the largest component contributor to overall cell number in the body, so maybe then we can more critically think and then think that the total amount of red blood cells maybe compensate for this very low eNOS protein expression. And actually because they have a high density and their shape is erase high, so they provide a very sufficient release of this inactivity from red blood cells. But this idea was doubted for many years, although there it was reported that eNOS is expressed in red blood cells in 2006 was a paper.

Dr. Pishoy Gouda:

Well that's very exciting. So what we really learned is that eNOS system in both red blood cells and endothelial cells contribute to blood pressure regulation. Now I might direct this to you, Francesca. Well what does that mean for the clinicians in our audience? Well, what does that mean for a hypertension patients?

Dr. Francesca Leo:

So for clinicians, so, I must say these findings may have really important pathophysiological implication in the understanding of the interrelationships between hematologic and cardiovascular disease and may reveal the really novel therapeutic approaches to improve tissue perfusion. Moreover, our data and models may also help in understanding how red blood cells eNOS signaling can really affect red blood cells function, the scavenging of nitric oxide, as Tanya had previously said, as well as the crosstalk between nitric oxide and the sulfides that are of highly present in the bloodstream and in the body as well as oxygen transport. And may also enable us to refine the criteria for blood banking transfusion and to also try to develop new strategies or therapies for many diseases and pathologies where red blood cells are involved.

For example, coronary artery disease, chronic kidney disease that normally are pathologists that show a decrease in the expression of eNOS expressed in the red blood cells or hematologic disease hemoglobinopathies, which are normally characterized by a systemic decrease in nitric oxide bioavailability or one of the most common diseases, sickle cell disease. Cause of course the shape of red blood cells is definitely also responsible of their functioning. And it can also determine, of course, an impairment or more alteration in the release of nitric oxide in the body.

Dr. Tatsiana Suvorava:

Yeah, maybe I'll just add few words. So actually that's open as a perspective that impairment of red blood cells, eNOS may contribute to the pathogenesis of hypertension. So this is the most important thing I think here in clinician point of view.

Dr. Pishoy Gouda:

Yeah, absolutely. Lots of different ways that this research might be heading. And like you were saying earlier, Tatiana research is really a longitudinal process. You started this almost a decade ago and I'm sure that there's more projects and plans that you have with this for the future. What are you working on now?

Dr. Tatsiana Suvorava:

Well, I'm still in academia and I'm still doing academic career, actually. We continued our study and we also studied pathophysiological significance of red blood cells eNOS for cardio protection. For example, in regulation of coronary blood flow, myocardial performance in myocardial infarction, acute myocardial infarction in vivo. We recently published this and here we could also see involvement of red blood cells eNOS, which limit infarct size in acute myocardial infarction. In a pipeline is also a manuscript about red blood cells and endothelial cells eNOS in exercise induced cardio protection and of course the other focus would be the role of red blood cells eNOS in other disease conditions and a chronicle kidney disease for example. It will be also investigated. So we are full of plans, however, I changed department, but I'm still having eNOS in focus and hypertension as well.

Dr. Pishoy Gouda:

Well that's really exciting stuff and yes, I just wanted to congratulate you both again Dr. Leo and Suvorava and thank you for taking the time to share with us your very clear passion for this topic and I wish you guys both the best of luck. Congratulations again.

Dr. Francesca Leo:

Thank you so much.

Dr. Tatsiana Suvorava:

Thank you so much.

Dr. Pishoy Gouda:

Well congratulations again to our award recipients and Peter, why don't you tell us a little bit about what article we're going to be talking about next?

Dr. Peder Myhre:

Yes, thank you so much Pishoy. And first, I must say it was so much fun to listen to you guys discuss the paper. You can really feel the passion for the science coming through the microphone. And that was for me as a clinician as well. I learned a lot. And now we're going to actually take a step and move over back to clinical science and we are going to talk to the winners of the James T. Willerson Award. So welcome doctors, Jeanne du Fey and Dr. Alexandra Prepoudis.

Dr. Jeanna du Fay de Lavallaz:

Thank you very much for having us on the podcast. It's a pleasure to be here and we're also very happy to be able to discuss this paper with you. And of course we were extremely glad to receive this award, so we're excited about the discussion.

Dr. Peder Myhre:

And so for the listeners who are not familiar with the Willerson Award, this award recognizes the best clinical paper published in circulation in the preceding 12 months. And this award honors Dr. Willerson, who was a major leader within American Heart Association. And among his roles, he served for over a decade as the editor-in-chief of circulation. And during his tenure, the journal transitioned away from a once monthly format, vastly expanded its international footprints and rose substantially in stature and impact. And speaking of international footprint, today we have authors from all over the world and I know both of you, Jeanne and Alexandra are from the amazing biomarker group in Basel led by Christian Mueller. So Alexandra, if we can start with you, I just want to learn a little bit more about you. Where do you work, where are you in your career and your areas of interest?

Dr. Alexandra Prepoudis:

Good evening and thank you for the introduction. My name is Alexandra Prepoudis and I'm currently a cardiology fellow at the University Hospital of Basel in Switzerland. I have always been very interested in clinical research, so I decided to join the group of Professor Christian Mueller in Basel for a year prior my residency in internal medicine. And that's how I met Jeanne and the whole study team.

Dr. Peder Myhre:

Very nice. And Jeanne, what about you?

Dr. Jeanna du Fay de Lavallaz:

So my name is Jeanne du Fey and I'm currently also a cardiology fellow at the hospital in Zurich. I moved a little bit, but my main research is still based in Basel. You don't leave Professor Mueller's group once you're in it. So I sticked around. So I am undertook physician scientist track after med school and for my MD PhD I was very lucky to integrate Dr. Mueller's group into the paper we are going to discuss tonight is actually the very first study that I designed during my PhD of course with a lot of help from the whole group of Professor Mueller, professor Mueller himself and of course Alexandra who joined a little bit later and really helped us tackle quite a big piece of the biomarker research that I'm very excited to talk about.

Dr. Peder Myhre:

So that is amazing. So this is the first paper you designed and what a wonderful debut because today we're going to discuss this award-winning paper and it is entitled Skeletal Muscle Disorder and Non-Cardiac Source of Cardiac Troponin T. And of course we are within the field of troponin and I must admit Jeanne and Alexandra that I myself is a troponin nerd myself. I love research and learning more about troponin and for me this paper was really something I was eager to learn more about because we've all been questioning what is the impact of skeletal muscle disease on troponin. So perhaps Jeanne, if you could start to explain the background for this study, and what was the research question?

Dr. Jeanna du Fay de Lavallaz:

So in the past years, I think there were quite a few reports. These were mostly case series of what you have just mentioned. So it's this observation that skeletal muscle disease might actually have an impact on some troponin measurements and we were not exactly sure which. So there are these two main isophones of troponin, the troponin T and the troponin I. Depending on the hospital, depending on the country, one of both might be measured either the troponin I or the troponin T. And then for troponin T we have only one essay and then for troponin I there are several of them. So there is kind of a big mix up there of what is possibly obtainable to assess cardiovascular health and basically also more coronary health, well cardiovascular health in patients that we see every day in the clinic.

And well, as you just mentioned, we had noticed in the past that sometimes it's troponin T was behaving in weird way in patients that were also suffering of some muscle skeletal muscle disease. So Prof. Mueller is leading a very large group biomarkers on troponin research and this is something that we decide to tackle in a very structured way in order to be able to rehab an answer and bring something to the field that might be maybe a little bit more consistent than this, however very interesting case series, but that were maybe a little bit done on very specific disease and a little bit all over the place.

Dr. Peder Myhre:

Exactly, and this is exactly what really made this paper so amazing is that first of all, you structured the clinical part of it with a prospective cohort. You did multiple essays on the patients and you even included some translational work on top of that, which is truly amazing. So I was wondering, Alexandra, if you perhaps could start with explaining the clinical part of the study, the patient cohort, the mythology use, et cetera. So please, Alexandra.

Dr. Alexandra Prepoudis:

We enrolled patients with muscle complaints. So for example, muscle pain, weakness, stiffness or fasciculations. And we enrolled them at four sites in two countries, most of them during ambulatory visits. And from each patient we collected a blood sample and we measured four different high sensitivity cardiac troponin assays. So one for troponin T and three for troponin I. Then patients underwent the cardiac workup including E C T, echo cardiography and cardiac M R I depending on the clinical indication. As a control group, we used patients from a prior study where patients who presented to the emergency department with the leading symptom of chest pain were enrolled. So of these we analyzed patients without skeletal muscle disease in whom a cardiac cause of chest pain could be excluded.

Dr. Peder Myhre:

Great. So really a big and well pheno typed group of patients. And before we go to the results, we're going to also learn a little bit about the experimental part of the study that you conducted. So Jeanne, if you would just explain what was, this was something with the gene expression in the muscles, right.

Dr. Jeanna du Fay de Lavallaz:

So we decided to be a little bit original and to bring it back to the bench instead of bringing it to the bedside as we usually do. And-

Dr. Peder Myhre:

I love it.

Dr. Jeanna du Fay de Lavallaz:

We will soon. We were also very lucky to have amazing collaborators because that allowed us to collaborate with a rheumatologist with neurologists. And these doctors might have in the past collected some muscle tissue for completely different muscle analysis. So in order to phenotype the diseases that the patients were actually suffering of and we're also lucky enough so that there was sometimes some of this muscle tissue is still available and we basically extracted mRNA from these skeletal muscle samples. And what we looked at was the mRNA of the different troponin genes that we could find in there. So as you probably know, there is some genes coding for skeletal troponin and there are some genes coding for cardiac troponin. And what we could see that was, we might come to that in the results, but basically our goal was to look at the expression of the different skeletal or cardiac troponin in these skeletal muscle samples.

Dr. Peder Myhre:

Exactly. And the next question is going to be difficult because I want you to summarize the findings and there are so many findings to supplement. This is really, it's like pressure. But please Alexandra, can you try to summarize the primary results of this paper?

Dr. Alexandra Prepoudis:

Yes, of course. I will try my best. So maybe first about half of the cohort showed the cardiac disease IE the coronary heart disease, atrial fibrillation, or chronic heart failure. So cardiomyocyte injury resulting from cardiac disease was a major contributor to elevated troponin T and I concentrations even in these patients with skeletal muscle disorders. But troponin T concentrations were above the upper limit of normal in about 55% and the concentrations were significantly higher compared with control subs checked. While troponin I concentrations were elevated to a significantly lower percentage, which were also comparable to the concentrations in the control group. Also, we found that the elevated troponin T concentrations were restricted largely to patients with non-inflammatory myosis and myositis. And maybe one thing to the gene expression regarding the gene expression analysis, we found the eightfold up regulation for the gene and coding for cardiac troponin T in skeletal muscle compared with controls without skeletal muscle disease.

Dr. Peder Myhre:

Wow, that is so great. So please let me try to summarize these important findings to the listeners. So you actually found in patients with skeletal muscle disease, a much higher level of troponin T compared to healthy controls or at least controls without myocardial infarction. And for troponin, these differences were not that pronounced. So that means gene, that troponin T in patients with certain types of skeletal muscle disease may be falsely positive. Is that correct? And how would you put these findings in relation to previous studies in the field and also perhaps some clinical implications of the findings?

Dr. Jeanna du Fay de Lavallaz:

So yeah, I think we can say that in the patient where that was the case, this is actually falsely positive because when we talk about cardiac troponin T, cardiac troponin, we expect it coming from the heart, certainly not from the muscle of the patients or at least it's what cardiologists have been trying to not diagnose in the past years by refining also the assays that we were using so that it doesn't cross-react with anything coming from a skeletal muscle. And I think regarding previous studies in the field, so we tackled, I believe several aspect with this paper that hadn't really been well investigated before. And our study design helped with that a lot. So first we included patients based on their complaints that was not a specific cohort with a certain type of disease. We really enrolled them if they presented with some muscle complaints, so not a specific already diagnosed disease.

So this was the first point. And then second also, we investigated several troponin I assays, which also allowed us to have a broader observation of how this assay are actually interacting also with each other or how they relate to this troponin T assay, which is the only one existing. And then finally, I think this translational part with the MRN analysis really helped us to go back to the primary hypothesis, how does that work? Why is this the case at all? And finding this re-expression of the cardiac troponin T in the skeletal muscle really tells us that this might actually not be a problem with the assay itself but might really be that we have some cardiac troponin T circling in the blood and being measured by a perfectly well working assay, which is a totally different mechanism than for instance, cross reaction that we might sometimes observe for instance, with troponin I assays.

Dr. Peder Myhre:

Exactly. And the findings were so consistent across the 3 troponin I assays and supported by the biopsy findings, I think they were so robust. And you know, we're talking about how this might impact adjudication of a suspected myocardial infarction, but also troponin is a very strong prognostic marker within chronic conditions and in ambulatory patients. And even there it may really impact the utility of troponin as a risk marker. Alexandra, don't you think so?

Dr. Alexandra Prepoudis:

So, to come back to the first part of your question, what about patients with myocardial infarction? Our study did not directly investigate the impact of these unexpected troponin T concentrations on the diagnosis of myocardial infarction. But we believe that it's reasonable to say that if patients with a known chronic skeletal muscle disease present with chest pain to for example the emergency department and the first troponin T comes back elevated, the clinician should be aware that the skeletal muscle can be a possible source of this biomarker. So if possible, a troponin I should be obtained in these patients.

Dr. Peder Myhre:

Excellent. And that brings us to the last question of today, I think Jeanne, and that is the future direction of this field. We now know, I think for certain that some skeletal muscle disease have an elevated cardiac troponin T, or perhaps not cardiac, but at least troponin T. So what do we need to learn more about this? And is there any way we can improve the assays? Please, Jeanne, let me know your thoughts about the future.

Dr. Jeanna du Fay de Lavallaz:

So that's a complex question. I think already we are kind of running into troubles when we already just see the current situation with these assays. Depending on the countries, depending on the hospitals, depending on the laboratory background that all the laboratory measurement system that we might have. Some hospitals have a total different approach on which troponin to measure and what's troponin to make available for their physicians. But I think these biomarkers haven't finished to surprise us and also most likely to bring us some very good prognostic tools. And I believe once we can really refine the exact origin of which elevation in which patient and what this does imply for their prognosis, we might also be able to just predict much better where with our patients are going, what kind of diagnostic or treatments that we need to use in order to improve their life on the short and long term. So I have quite a lot of hope for these different assays to be better understood in the coming years.

Dr. Peder Myhre:

What a wonderful way to finalize this podcast. Jeanne and Alexandra, thank you so much for participating and for sharing your knowledge in the field and to learn about your current situation with work and your choices of career. And also a big thank you to Francesca and Tanya for the winners of the LOSCALZO Award for sharing their research. So on behalf of Pishoy and myself, I want to thank everyone for listening and thank you to the amazing authors and winners of the awards. This is Peter Myra, and on behalf of myself and Pishoy Gouda, we thank you for listening.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Mads Liisberg and Guest Host Mercedes Carnethon as they discuss the article "Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study from 1996 to 2016."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke, National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is about aortic dissections and it's the first nationwide population based study investigating the clinical characteristic, incidents, and mortality based on validated diagnosis of aortic dissection in a national patient registry. You want to hear more? Well, you have to just keep listening. Let's go on though first to discuss the other really important papers in today's issue, shall we?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

You know what, Greg? I'm going to start while you grab a coffee. I want to talk about high sensitivity cardiac troponins and how they have allowed the use of strategies in the emergency department, for example, to rapidly rule out acute MI within one to three hours and potentially facilitate early discharge of low-risk patients. Now, the ability to rapidly rule out MI of course depends on the turnaround time of these high sensitivity cardiac troponin results from the central laboratory, which is often delayed due to specimen transport and handling and all these things.

So, point-of-care assays can reduce this turnaround time by even 40 minutes, and early studies have actually used frozen plasma bio banks to assess these point-of-care assays... But no study has evaluated these point-of-care assays with fresh whole blood to safely rule out MI in the emergency department. That is until today's paper. So in today's study led by corresponding other Doctor Fred Apple from Hennepin Medical Center in Minneapolis, Minnesota and his team, they aimed to derive and validate an optimal high sensitivity cardiac troponin threshold concentration using whole blood point-of-care troponin eye assay on a single sample at presentation in the emergency department to identify patients at low risk of index MI for potential early discharge.

Dr. Greg Hundley:

Fascinating study Carolyn. So point-of-care testing, high sensitivity troponin from whole blood in the ED. So what did they find?

Dr. Carolyn Lam:

Among consecutive emergency department patients from two prospective observational studies with suspected acute coronary syndrome, a point-of-care, whole blood, high sensitivity cardiac troponin eye assay, the Atellica VTli provided a sensitivity of 98.9% and a negative predictive value of 99.5% for ruling out MI. A single measurement using a cutoff of less than four nanograms per liter for whole blood was successful in rapidly identifying patients at low risk of MI cardiac and all cause death and unplanned revascularization at 30 days.

Dr. Greg Hundley:

Very nice Carolyn, and could be quite practical. So Carolyn, my next paper comes to us from the world of preclinical science and it pertains to cardiac regeneration. So cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes. However, certain animals readily regenerate lost myocardium via process involving dedifferentiation, which unlocks their proliferative capacities. So inspired by this concept, these investigators led by Professor Patrick Hsieh from Academic Sinica, generated mice with inducible cardiomyocyte specific expression of the Yamanaka factors enabling adult cardiomyocyte reprogramming and dedifferentiation in vivo.

Dr. Carolyn Lam:

Wow. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So two days following induction, adult cardiomyocytes presented with a dedifferentiated phenotype, an increase proliferation in vivo. Microarray analysis revealed that the up-regulation of ketogenesis was central to this process. Now adenovirus driven HMGCS2 over-expression induced ketogenesis in adult cardiomyocytes and recapitulated cardiomyocyte dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue. And HMGCS2 knockout mice showed impaired cardiac function and response to injury, and so in summary, Carolyn, these data demonstrated the importance of HMGCS2 induced ketogenesis as a means to regulate metabolic response to cardiomyocyte injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

Dr. Carolyn Lam:

Wow, that's so cool. From cell regeneration to autoimmunity in this next paper. Now autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. However, the functional features of cardiac autoimmunity in humans remain undefined due to the challenge of studying immune responses in situ. Now, these authors previously described a subset of c-Met expressing memory T lymphocytes, which preferentially migrate to cardiac tissue in mice and humans. In today's study, these authors led by co-corresponding authors, Dr. Federica Marielli-Berg and Saidi Mohidden from William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, and Queen Mary University of London, and their colleagues performed in-depth phenotyping of peripheral blood T cells in groups of patients with inflammatory and non-inflammatory cardiomyopathies, patients with non-cardiac autoimmunity and healthy controls... And they found that c-Met positive T cells were selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies.

The phenotype and function of c-Met positive T-cells were distinct from c-Met negative T cells, including preferential proliferation to cardiac myosin and co-production of multiple cytokines. Further, circulating c-Met positive T cell subpopulations in different heart muscle diseases identified distinct and overlapping mechanisms of heart inflammation. Furthermore, validation studies in experimental autoimmune myocarditis showed that elevations of auto-antigens specific c-Met positive T cells in peripheral blood, marked the loss of immune tolerance to the heart. Importantly, disease development could be halted by pharmacologic c-Met inhibition indicating a positive role for these c-Met positive T cells.

Dr. Greg Hundley:

All right, Carolyn, as you always ask me. So what's the take home message here?

Dr. Carolyn Lam:

This study demonstrates that the detection of circulating c-Met positive T cells may have utility in the diagnosis and monitoring of adaptive cardiac inflammation and additionally defined new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury... And this is discussed in an editorial by doctors at Abplanalp, Merten, and Dimmeler.

Dr. Greg Hundley:

Very nice, Carolyn. Wow. More fantastic preclinical science. Well, in the mail of the bag today, there is a Research Letter by Professor Burr entitled “Cannabis Inhalation Acutely Reduces Muscle Sympathetic Nerve Activity in Humans.”

Dr. Carolyn Lam:

There's an ECG Challenge by Dr. Reddy entitled “Shortness of Breath and Near Syncope During Exertion In a Child, When Patient Worry Syndrome.” There's also a Perspective by Dr. Weitz on what is the future of Factor 11 inhibitors.

Dr. Greg Hundley:

Well Carolyn, I'm looking forward to learning more about aortic dissections and that large Danish population-based study. Wow.

Dr. Carolyn Lam:

That's great. Let's go Greg.

Dr. Mercedes Carnethon:

Well, welcome to this episode of Circulation on the Run. My name is Mercedes Carnethon, an Associate Editor of Circulation, and Professor and Vice Chair of Preventive Medicine at Northwestern University. I'm really excited today to be here with the senior author of a really exciting paper that we're featuring on clinical characteristics, incidences and mortality rates for aortic dissections type A and B, a nationwide Danish population-based cohort study, and we have with us today Mads Liisberg. So welcome today.

Dr. Mads Liisberg:

Thank you.

Dr. Mercedes Carnethon:

So thank you so much for joining us and really thank you for sharing your important research with Circulation. This topic is so critically important, particularly given the high mortality rates associated with aortic dissections. Can you tell us a little bit about the work that you and your co-authors did in this important space?

Dr. Mads Liisberg:

Yes. Well actually the work originated when I started my PhD thesis and we got a registry data dump from the Danish medical registries and we found that almost none of our patients in the registry were registered with a specific aortic dissection code.

So we did a validation study on the same time period from 1999 to 2006 where we went through all these medical records to ensure that we had the right aortic dissection TC 10 codes on population. Then we went a bit further and looked at the clinical characteristics of this patient, 'cause that's one of the really major things about Danish medical registries in our country, is that we have access to not only every patient's specific in hospital contacts, but also their medicine abuse, their drug use based on a TC code. So we can go really deep into each and everyone's drug history. When we did this study, we wanted to find out if the incidence rates during this timeframe had changed, which we find that it did, but also looking at mortality rates because, as you said, it's really high risk disease to be diagnosed with. So that's more the rationale for this study.

Dr. Mercedes Carnethon:

Thank you so much for sharing that. Certainly we know that the mortality rates from this are very high. I note that you report some changes over time between 1996 and 2016 in the incidents of these types of aortic dissections. So what did you find about the patterns of change in type A aortic dissections?

Dr. Mads Liisberg:

We found that it almost doubled from the beginning of our time period to the last, and the question is why is this? 'Cause that's one of the thing that the data doesn't reveal. We are only able to see that the incidence actually rises, but is it because that they are underdiagnosed in the beginning? Or is it because that we are better diagnosing in the end of the study that really are progressed?

Dr. Mercedes Carnethon:

That's a good question. I noted that when you studied the correlates of aortic dissection, you identified a number of characteristics and what stood out to me was the finding about the strong association of hypertension. I'm less aware of patterns of hypertension in the Danish population. Do you think that the changes in the prevalence of hypertension in the population contributed at all to these findings?

Dr. Mads Liisberg:

Well, most certainly, 'cause when you look at the prevalence of hypertension throughout any person's lifespan, the older they get the more likely they are to suffer from hypertension, and the Danish population has aged quite a lot in recent years. So I think that's one of the main reasons we find this, and also that most of our arctic dissection patients are actually quite old, which would correlate with hypertension as well.

Dr. Mercedes Carnethon:

One thing I really like, and you pointed this out, is really the richness of the data that you have in your health system, and I wonder, just going even a little deeper on the hypertension question, given that it is the most common medical diagnosis worldwide, were you able to study characteristics of hypertension that would be more strongly associated with aortic dissection? So for example, duration of hypertension, severity, prevalence of hypertension control?

Dr. Mads Liisberg:

That's actually a funny question 'cause the last study of my thesis, which hasn't been published yet or even submitted for that fact, examines the correlation between use and the risk of arctic dissection. On a very specific level, the way that hypertension is treated mostly in Denmark is with your general practitioner. So the way that we examine in studies like these, is that we look at prescription drug use. So if we find that an individual has a TC codes corresponding with anti-hypertensive drugs, then we are able to code them as hypertensive patients.

Dr. Mercedes Carnethon:

Okay, thank you for that. I always... I'm an epidemiologist myself, so I really love to see great population science studies and this registry is large, you have long-term follow up and you've got a great deal of data, but those people who feel as though it's obviously not appropriate to make causal conclusions around epidemiology and that perhaps epidemiologic findings shouldn't be driving clinical decision-making. In response to that, I think I would pose the question to you, which is how do you see clinicians and providers using this information from your observational study?

Dr. Mads Liisberg:

I think that's rather difficult. One of the findings that we present is to pose it over mortality for type B dissections when we exclude the 30-day mortality, but then we show that type A dissections have almost a corresponding mortality rate compared to a hypertensive cohort... And this finding is difficult to draw any clinical conclusions from, but there's actually a Danish randomized controlled trial just starting up in the next year. I think it's called the Sunday trial, where they will include all uncomplicated type B dissections and randomize them for treatment or no treatment, and the issue here is that you'll probably be over-treating some patients and under-treating others, but this discussion with the uncomplicated type B dissection has been ongoing for so many years. So it's difficult for me to just give one golden answer.

Dr. Mercedes Carnethon:

Certainly, and I appreciate the caution as we certainly don't want to overstep our findings. You did make a recommendation in the conclusion that it might be beneficial to treat type B aortic dissections more aggressively. Is this what you're alluding to, based on the other study that you're referencing?

Dr. Mads Liisberg:

Yes, yes, definitely. We see some clinicians being more cautious treating type B dissections with a TIVA or a surgery. So it's a difficult thing when they're uncomplicated, why treat them? But they can't be or become complicated quite easily and fast and then it's a difficult thing, because should you have treated them earlier? Or do you need to treat them now in their acute phase? Or wait for a chronic phase? It's a really good question.

Dr. Mercedes Carnethon:

No, I appreciate that and what I really love are the types of research studies that leave you with many more questions and next steps, and so I would like to really sort of bring us to a close with the big picture question, which is what do you see as the next steps in this line of research, given really what we all agree on is a very significant clinical problem.

Dr. Mads Liisberg:

We would really like to expand our database with even more clinical data as of now and include any image diagnostics for our cohort. So we're might be able to see any trends in our modulation before the dissection occurs. If any of our patients have any diagnostics done prior to being diagnosed.

Dr. Mercedes Carnethon:

I really want to thank you today for spending time talking with us. I know that our readers rarely have an opportunity to hear from everybody behind the scenes views on what the rationale was for carrying out a paper and really how the authors themselves hope that the paper will be used. So I really thank you for sharing that with us today, Matts, on behalf of your co-authors, this has been really a wonderful conversation, and thank you again for sharing your research with the journal, Circulation.

Dr. Mads Liisberg:

Oh, thank you for having me in for accepting our paper.

Dr. Mercedes Carnethon:

So thank you so much to our listeners for listening to us on this episode of Circulation on the Run. Please tune in next week as we will have more exciting insights.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy.

But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?

Dr. Carolyn Lam:

Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more.

But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation.

However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries.

Dr. Greg Hundley:

Wow, Carolyn, this is a really interesting question. So what did they find?

Dr. Carolyn Lam:

In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous.

And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba.

Dr. Greg Hundley:

Very nice Carolyn. Very important research in this area using that particular methodology.

Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension.

So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia.

Dr. Carolyn Lam:

Another one of those excellent translational pieces, isn't it Greg? So what did they find?

Dr. Greg Hundley:

Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy.

And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease.

Dr. Carolyn Lam:

Aw, thanks Greg for explaining that so well.

The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction?

Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes.

Dr. Greg Hundley:

Oh wow. So Carolyn, important study. So what did they find?

Dr. Carolyn Lam:

Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis.

So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR.

Dr. Greg Hundley:

Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science.

Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.”

And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.”

Dr. Carolyn Lam:

Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.”

Now, let's go onto the feature discussion of all things MRI, shall we?

Dr. Greg Hundley:

You bet. More on manganese.

Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland.

Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Trisha Singh:

Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought.

In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term.

Dr. Greg Hundley:

Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide?

Dr. Trisha Singh:

So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would.

And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other.

And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis.

Dr. Greg Hundley:

Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically.

Well, with that description, can you describe for us now, your study population and your study design?

Dr. Trisha Singh:

Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography.

Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients.

So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan.

Dr. Greg Hundley:

Very good. So two exams separated longitudinally over time. What were your study results?

Dr. Trisha Singh:

Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome.

Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content.

And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find.

Dr. Greg Hundley:

Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome?

Dr. Trisha Singh:

For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve.

And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population.

Dr. Greg Hundley:

Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study?

Dr. Trisha Singh:

So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that.

Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well.

Dr. Greg Hundley:

Very nice.

And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred?

Dr. Trisha Singh:

Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart.

Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak.

Dr. Greg Hundley:

Very good.

Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo?

Dr. Trisha Singh:

So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture.

And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so.

Dr. Greg Hundley:

Very nice.

Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome.

Well, on behalf of Carolyn and myself, we want to wish you a great week. And we will catch you next week on the run.

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ajjournals.org.

This week, please join author Sean Pokorney and Associate Editor Shinya Goto as they discuss the article "Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial."

Dr Carolyn Lam:              

Welcome to Circulation on the Run, your weekly podcast summary and Backstage Pass of the journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:           

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting topic. In patients that have end stage renal disease that require dialysis, questions emerged should we anticoagulate them to prevent stroke, but of course, there's a risk of excess bleeding. Well, this feature discussion today is a study comparing apixaban and warfarin for anticoagulation in exactly this patient population. But before we get to those results, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?

Dr Carolyn Lam:              

Absolutely, Greg. So my first paper is a pre-specified analysis of the Paradise MI trial and knowing you'll likely ask me what that was about, Greg, at least to summarize for everyone, the Paradise MI trial compared sacubitril/valsartan with ramipril and its effect on reducing heart failure events after an MI in more than 5,600 patients with an acute myocardial infarction complicated by LV systolic dysfunction, pulmonary congestion, or both. Now in today's paper, what Dr. Mehran and colleagues found was that among patients with a recent AMI and LV systolic dysfunction, heart failure are both, sacubitril/valsartan decreased the risk of coronary related events by 14% as compared with ramipril over a median follow-up of 22 months. The reduction in coronary events occurred with a favorable safety profile.

Dr Greg Hundley:           

Wow, Carolyn, very interesting. Another indication perhaps for sacubitril/valsartan, especially relative to ACE inhibitors. So what does this mean for us clinically?

Dr Carolyn Lam:              

Well, the results really cause us to consider if in addition to antiplatelets and lipid lowering therapies, sacubitril/valsartan may be explored as a potential agent to mitigate the residual risk in survivors of AMI. Of course, dedicated studies are necessary to confirm this finding and elucidate its mechanism.

Dr Greg Hundley:           

Oh, very nice, Carolyn. Well, my first paper comes to us from the World of Preclinical Science and Carolyn, this study evaluated the scavenger receptors stabilin-1 and stabilin-2, proteins that are preferentially expressed by liver sinusoidal endothelial cells. Now, they mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. And studies suggest that stabilin-1 and stabilin-2 may impact atherosclerosis. So in this study, the investigative team led by Professor Cyrill Géraud from the University Medical Center and Medical Faculty in Mannheim, Heidelberg comprehensively studied how targeting stabilin-1 and stabilin-2 affects atherosclerosis.

Dr Carolyn Lam:              

Huh. All right, nicely explained. And so what did they find, Greg?

Dr Greg Hundley:           

Right, Carolyn. So inhibition of evolutionary conserved class H scavenger receptors, stabilin-1 and stabilin-2, reduced aortic plaque burden in preclinical models and athero protection was mediated likely through down regulation on transcriptional factor ERG1 in monocytes by multifaceted plasma protein changes. And then finally, Carolyn transforming growth factor beta induced periostin, reelin, and they are novel ligands of stabilin-1 and stabilin-2 and are implicated in the development of atherosclerosis.

Dr Carolyn Lam:              

Okay. Wow. Could you give us a take home message, please Greg?

Dr Greg Hundley:           

Right. Carolyn, I knew you had asked me this. So here we go. Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies provide a novel approach for the future treatment of atherosclerosis. And in the future, perhaps the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients.

Dr Carolyn Lam:              

Wow. Thanks Greg. My next paper is a true story of discovery. Now I could ask you what you know about the condition hypertension with brachydactyly type E... Greg, I love that expression. I wouldn't be able to answer that too. So let me tell you the story. So hypertension with brachydactyly type E is an autosomal dominant Mendelian disease resembling essential hypertension. Untreated patients die of stroke by the age of 50 years. Now, these authors had previously demonstrated a gain of function phosphodiesterase 3A gene mutations that caused the condition by increasing peripheral vascular resistance.

They studied a large family with the condition earlier and were puzzled that cardiac hypertrophy and heart failure did not occur despite the decades of hypertension. And so they hypothesized that in the heart, this phosphodiesterase 3A or PDE3A mutations could be protective. Isn't that neat? And so corresponding authors, Doctors Bader, Klussmann, Bähring and Hübner, all from the Max Delbruck Center for Molecular Medicine in Berlin, Germany. So they studied new patients as well as CRISPR-Cas9 engineered rat models of this condition of hypertension with brachydactyly type E. And they comprehensively phenotyped all of them with the human induced pluripotent stem cells carrying these PDE3A mutations as well. So analyzing all of this from cells to new patients to CRISPR-Cas9 models.

Dr Greg Hundley:           

Wow, Carolyn, what an interesting story. So what did they find?

Dr Carolyn Lam:              

So while in vascular smooth muscle, the PDE3A mutations caused hypertension, in the hearts, they conferred protection against hypertension-induced cardiac damage, hypertrophy and heart failure. The mechanism involved long-term adaptations of mRNA and protein expression as well as calcium cycling. Non-selective PDE3A inhibition was a final short term option in heart failure treatment to increase cardiac cyclic AMP and improve contractility. So the data argued that mimicking the effect of PDE3A mutations in the heart rather than non-selective PDE3 inhibition was cardioprotective in the long term. And these findings could indeed facilitate the search for new treatments to prevent hypertension-induced cardiac damage. This is discussed in a really lovely editorial by Dr. Chiong, Houslay, and Lavandero.

Dr Greg Hundley:           

Very nice, Carolyn. Wow. What another... we have such great articles from the World of Preclinical Science. Beautiful description as well. Well, we have some other articles in the issue, particularly from the Mailbag. And we have a Research Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI in a pre-participation cohort of Young Asian males with T-Wave inversion.”

Dr Carolyn Lam:              

Interesting. There's an exchange of letters between Dr. Xu and Huang regarding the article associations of dietary cholesterol, serum cholesterol and egg consumption with overall and cause-specific mortality with a systematic review and updated meta-analysis. There is a Perspective piece by Dr. Marcus on Smart watch detected atrial fibrillation, the value in positive predictive value. Isn't that interesting? And now onto that very, very important question of anticoagulation in patients with kidney disease. Can't wait. Let's go, shall we?

Dr Greg Hundley:           

You bet. Carolyn. Welcome listeners to our December 6th feature discussion. And we have with us today Dr. Sean Pokorney from Duke University in Durham, North Carolina, and our associate editor, Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome gentlemen. Well, Sean, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Sean Pokorney:        

Yeah, absolutely. Thanks for having me to discuss the renal AF trial. And so I would say that the background information to the study was that we know that atrial fibrillation is an incredibly common condition in patients with chronic kidney disease. And the decision of anticoagulation in patients with end-stage kidney disease, on hemodialysis is really quite complex because these patients are at high risk for stroke and they're at high risk for bleeding. There are concerns with warfarin around calcific uremic arteriolopathy or calciphylaxis and there have been some data including from the original Aristotle trial that apixaban was even more favorable in terms of bleeding reduction relative to warfarin in patients with more advanced chronic kidney disease.

Although patients with creatinine clearance less than 25 were excluded from Aristotle and really all patients with endstage kidney disease on hemodialysis have been excluded from all trials of atrial fibrillation in the past. And so we really wanted to evaluate the safety of apixaban versus warfarin in patients with end-stage kidney disease, on hemodialysis. And the hypothesis was that apixaban was going to be non-inferior to warfarin with respect to safety in terms of major or clinically relevant, non-major bleeding in these patients with atrial fibrillation and end stage kidney disease on hemodialysis.

Dr Greg Hundley:           

Thanks so much, Sean. And you've mentioned the renal AF trial. So could you describe for us, for your, I guess, substudy, what was the study population? Who did you include and describe for us also your study design?

Dr. Sean Pokorney:        

Yeah, absolutely. So the trial included patients who had end-stage kidney disease, and/or on hemodialysis, as well as having concomitant atrial fibrillation. And the patients had to have a CHA-VASc score greater than equal to two. All of the patients had to be on hemodialysis for at least three months. So these were chronic hemodialysis patients. And the study design was an open label randomized trial that was 1:1 randomization between apixaban and warfarin with blinded outcome evaluation. And again, the primary endpoint of the study was major or clinically relevant non-major bleeding based on ISTH definitions. And there were secondary endpoints looking at stroke, systemic embolism, death, medication adherence, and I think a really important sub-study looking at PK data. And the goal was to have 50 patients where we included PK data that was going to more represent what chronic apixaban dosing data would look like in these patients with end-stage kidney disease on hemodialysis.

And originally the goal of the trial was to include over 700 patients. Originally we were trying to include 762 patients based on our initial power calculations to achieve true non-inferiority. Unfortunately, the trial enrollment was low and so the trial was ultimately stopped prematurely at 154 patients, although we were able to include the original targeted 50 patients in the PK substudy. The dosing that we used in the renal AF trial was 5 mg of apixaban twice daily unless patients had a second dose-reduction criteria in addition to chronic kidney disease. So the fact that they had end-stage kidney disease and were on hemodialysis counted as one dose reduction criteria and patients that were under 60 kilograms or less were 80 years of age or older, who had then a second dose-reduction criteria were treated with the 2.5 mg twice daily dosage. And this was important to note because this is different than the dosage that was used in the AXADIA-AFNET trial.

Dr Greg Hundley:           

Very nice. And so Sean, what did you find?

Dr. Sean Pokorney:        

Yeah. So again, a lot of this data is really exploratory because of the limited sample size, we weren't really able to definitively conclude anything about the major or clinically relevant non-major bleeding rates. I would say that some of the key findings that we saw was that there were high rates of major or clinically relevant non-major bleeding in both arms of the trial and one year bleeding event rates were 25% in the warfarin arm and 31% in the apixaban arm. And again, there was no statistically significant difference, although again, this is really exploratory. I would say that some of the other interesting findings that we saw was that there were very low rates of ischemic and hemorrhagic stroke in this patient population. Again, there were 82 patients randomized to apixaban, 72 patients randomized to warfarin. And there was a difference in the randomization because of the stratification by site that was performed with the randomization.

And so within the 82 patients that were randomized to apixaban, the patients, there was one ischemic stroke and one hemorrhagic stroke. There were no hemorrhagic strokes in the warfarin population and two ischemic strokes. Another key finding was the high rates of mortality in this patient population. So 26% of the apixaban patients experienced a mortality event, 18% in the warfarin arm. So again, the mortality rates in these patient populations were extremely high. I would also emphasize some of the data from the PK analysis. So we looked at the PK analysis in two different ways. For the patients that were treated with the 5 mg dose of apixaban, the PK data showed that there was consistent overlap in the steady state concentration at one month compared to patients in the Aristotle trial that had really mild to moderate, moderate to severe and severe chronic kidney disease.

And so there was a consistent overlap in those steady state concentrations between the end-stage kidney disease population on hemodialysis and the chronic kidney disease population who benefited from a apixaban in the Aristotle trial. Similarly, in the 2.5 mg apixaban dose, the patient who had a second dose reduction criteria in addition to chronic kidney disease, those patients had consistent steady state concentrations of apixaban relative to patients with mild to severe chronic kidney disease.

Dr Greg Hundley:           

Very nice. Well thank you so much, Sean. And listeners, now we're going to turn to our associate editor, Dr. Shinya Goto. Shinya, can you, sort of, highlight for us some of the interesting findings that you see from these study results that Sean just presented?

Dr. Shinya Goto:             

Thank you, Greg. Thank you, Sean for your wonderful summary of your study. We had a great discussion with an editor for this paper. As Sean pointed out, this is a kind of underpowered trial or just terminated early, hypothesis was not tested in the trial. But this population of patient clearly needs a real-world clinical trial, patient with atrial fibrillation, end-stage kidney disease, on hemodialysis; things a clinician could do. In some country, nephology society defined warfarin contraindicated in this population. As Sean pointed out, whether the development of this trial include this high-risk population patient. So we had a discussion whether the underpowered trial provided something or nothing may be better than something just provided here. Our consensus finally reached was, this limited trial still provide something like, you have to make a decision to use the anticoagulation. I mean, that the apixaban might be still used due to the PK data. That is the kind of interesting point of this trial.

Dr Greg Hundley:           

Very nice Shinya. Well, Sean, turning back to you and Shinya with that nice lead in really, Sean, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Sean Pokorney:        

Yeah, absolutely. I think this is a challenging patient population to study. And again, our trial, the renal AF trial stopped early. Unfortunately, the AXADIA-AFNET 8 study also stopped early, which was also looking at apixaban versus warfarin outside the US and Europe. And so again, it is a challenging patient population to study. But again, I also think it's a really important population to study because one of the main unanswered questions in this population is whether or not they should receive anticoagulation. And so I think that ultimately more work and additional studies trying to determine whether or not these patients truly benefit from anticoagulation or stroke prevention, I think is really one of the critical directions that we need to take the field in.

Dr Greg Hundley:           

And Shinya, do you have anything to add?

Dr. Shinya Goto:             

Well, I fully agree with Sean. I mean, this is a very challenging area and still raising the question whether anticoagulation is necessary or not by your study. Maybe next generation oral anticoagulant such as Factor XI inhibitor that is more elevated to contact pathway may be beneficial. So we really need a good clinical study in this very important and known answered area.

Dr Greg Hundley:           

Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney from Duke University in Durham, North Carolina and our own associate editor, Dr. Shinya Goto from Tokai University in Japan for bringing us the results of this randomized open-label trial of apixaban versus warfarin in patients with chronic kidney disease on hemodialysis, revealing high rates of bleeding in both groups, but due to low enrollment, was unable to identify its non-inferiority endpoint. It's important to note, however, as both our author and editorialists have identified further research is really needed in this area to really examine the efficacy of anticoagulation for stroke prevention in this high-risk patient population.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please author Gemma Figtree and Associate Editor Nicholas Mills as they discuss the Frontiers article "Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development."

Dr. Greg Hundley:

Welcome listeners to this November 29th, 2022 issue of Circulation On the Run. I am one of your hosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder this week's feature discussion very interesting. It is a state of the art review and it involves noninvasive plaque imaging and really how we might assess plaques to evaluate whether coronary artery disease is accelerating. Very important information by a large group of clinician scientists that will develop programs that, maybe, can be used in therapeutic drug development.

Dr. Peder Myhre:

That's so interesting, Greg.

Dr. Greg Hundley:

Right. A great group of individuals all put together, but before we get to that interesting feature discussion how about we grab a cup of coffee and start with some of the other articles in the issue? How about this week I go first?

Dr. Peder Myhre:

Go ahead Greg.

Dr. Greg Hundley:

Peder, these authors led by Marianna Fontana from University College London Medical School sought to characterize changes in the clinical phenotype of 1,967 patients with a diagnosis of transthyretin cardiac amyloidosis over the last 20 years enrolled and participating in the National Amyloidosis Center from 2002 to 2021.

Dr. Peder Myhre:

Oh yes, Greg, please. This cardiac amyloidosis we have to learn more about it. Please, tell me what did they find.

Dr. Greg Hundley:

Right, Peder.

First, there's been a substantial increase in the number of patients diagnosed with transthyretin amyloid in recent years. This is associated with greater proportions of patients referred following cardiovascular magnetic resonance imaging and bone scintigraphy scans. Second, transthyretin amyloid patients are often now being diagnosed much earlier in their disease process, as evidenced by a shorter duration of symptoms prior to diagnosis, milder stages of disease, and more favorable structural and functional echocardiographic changes at the time of diagnosis. Then, finally, mortality in these transthyretin amyloids patients has improved substantially in recent times aside from any potential benefits from disease modifying treatment or participation in clinical trials.

Dr. Peder Myhre:

Wow. Greg, over the course of 20 years we have seen some differences in the diagnosis or cardiac ATTR amyloidosis, so what would you say are the take home messages from this paper, Greg?

Dr. Greg Hundley:

Right, Peder.

Transthyretin amyloid is now often diagnosed earlier in the disease process with improved prognosis. I think, more data needed to guide decisions on in whom and when to initiate treatment and then which treatments should be used at each stage of the disease. Peder, along with this article there's an excellent editorial by Doctors Patel and Maurer entitled “The Future for Patients with Transthyretin Cardiac Amyloid is, It's Looking Brighter.”

Dr. Peder Myhre:

Okay. Greg, I'm going to continue in the field of clinical research and this paper actually describes a new ablation technique for ventricular tachycardia. Isn't that exciting?

Dr. Greg Hundley:

Absolutely.

Dr. Peder Myhre:

The paper comes to us from corresponding author Miguel Valderrabano from Houston Methodist Hospital in Texas and is entitled “Substrate Ablation by Multi-vein, Multi-balloon Coronary Venous Ethanol for Refractory Ventricular Tachycardia and Structural Heart Disease.” Ablation of ventricular tachycardia, VT, in the setting of structural heart disease often requires extensive substrate elimination, which is not always achievable by endocardial radiofrequency ablation and epicardial ablation is not always feasible. The left ventricle venous circulation allows vascular access to reach intramural substrates of VT in the context of myocardial infarction or non-ischemic scar, where radiofrequency ablation has limited success. Greg, in this study the authors enroll patients with ablation refractory VT and used phonography and epicardial mapping to perform a double balloon venous ethanol ablation. That is, by blocking flow with one balloon and injecting ethnol via this second balloon.

Dr. Greg Hundley:

Peder, what a beautiful description and very interesting strategy to address this situation.

What did they find?

Dr. Peder Myhre:

Greg, after the venous ethanol ablation vein maps and epicardial maps showed elimination of abnormal electrograms of the VT substrate an intracardiac echocardiography demonstrated increased intramural echodensity at the target lesions of the 3D maps and at one year of follow up VT recurrence occurred in seven patients, which translates into a success rate of 84%. The authors conclude that multi-balloon multi-vein intramural ablation by venous ethanol ablation can provide effective substrate ablation in patients with ablation refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful description. Excellent.

Well, this next paper Peder comes to us from the world of preclinical science and these authors led by Professor Christine Sideman from the Harvard Medical School evaluated alpha-kinase 3. Now, alpha-kinase three is a muscle specific protein in which loss of function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults. At presence the muscular functions of alpha-kinase 3 remain poorly understood, so to address this dilemma these investigators explored the punitive kinase activity of alpha-kinase 3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell derived cardiomyocytes. Mice and human patient tissues.

Dr. Peder Myhre:

Okay, Greg.

This sounds like impressive basic science work, so what did the authors find.

Dr. Greg Hundley:

Right, Peder.

Damaging variance in alpha-kinase 3 encoding an abundant muscle specific protein caused both neonatal and adult onset cardiomyopathies and led to both ventricular dilation and hypertrophy. Now, although alpha-kinase three contain an alpha kinase domain the team showed that it lacks catalytic activity and is really a pseudo kinase. Then finally, Peder, alpha-kinase 3 localizes to both the nuclear envelope of cardiomyocytes and the M-band of the sarcomere where it regulates the expression and localization of myomesins, myomesin 1 and myomesin 2, and additional M-band proteins important for sarcomere protein turnover.

Dr. Peder Myhre:

That is a beautiful summary, Greg. Since you did so well at summarizing this difficult topic, I'm not going to ask you what a clinical implications, but rather to take home messages here.

Dr. Greg Hundley:

Very nice. Glad you asked Peder.

First, alpha-kinase 3 cardiomyopathy may cause impaired contractility and ventricular dilation due to miss localization and dysregulation of myomesin proteins which are critical for force buffering in cardiomyocytes. Next, alpha-kinase 3 cardiomyopathy may cause hypertrophy due to dysregulation of key M-band proteins, which are important for sarcomere protein turnover. Then finally, therapeutic strategies to restore cardiomyocyte force buffering functions and sarcomere protein turnover may ameliorate disease phenotypes in patients with alpha-kinase three cardiomyopathy.

Dr. Peder Myhre:

Thank you Greg.

The next paper is also from the field of preclinical science and it is about the Hippo-YAP signaling pathway which maintains sinal atrial node homeostasis. It comes to us from the corresponding author Jun Wang from the University of Texas Health Science Center at Houston. Greg, this paper is not about hippos, but it is about the Hippo signaling pathway, which is known to control organ size and growth in animals and humans. These authors sought to investigate this pathway in relation to the sinal atrial node, i.e. The sinus node. As you know Greg, the sinal atrial node functions as the pacemaker of the heart initiating rhythmic heartbeats. Despite its importance the sinal atrial node is one of the most poorly understood cardiac entities, because of its small size and complex composition and function. To uncover the function of Hippo signaling in sinal atrial node the authors use knockout mice and a series of physiological and molecular experiments including telemetry, electrocardiogram recording, echochoreography, calcium imaging, immunostaining, ANA scope, quantitative real time PCR, and western blotting.

Dr. Greg Hundley:

Wow, Peder, that sounds like quite an extensive series of experiments. What did they find?

Dr. Peder Myhre:

Deletion of essential Hippo kinases caused increased fibroblast proliferation and fibrosis in the sinal atrial node. They also found evidence suggesting that Hippo signaling regulates calcium hemostasis in pacemaker cells and that may be partially mediated by the regulation of genes and coding key calcium handling proteins such as RYR2. Finally, the demonstrated that deletion of Hippo effectors in the sin atrial node can rescue the defect previously described.

Greg, the take home messages is that Hippo signaling was found to be an important regulator of the sinal atrial node homeostasis and that this provide insights applicable to the treatment of patients with sinus node dysfunction.

Dr. Greg Hundley:

Ah, beautifully done Peder. Beautifully done.

We've got some other articles in this issue. Let me tell you about a Research Letter. It's from Professor Nazer entitled “Targeted Screening for Transthyretin Amyloid Cardiomyopathy in Patients with Atrial Fibrillation.” Then Tracy Hampton has a whole series of cardiology news highlighting first that primary cilia are critical for exercise induced muscle hypertrophy. This is from the proceedings of the National Academy of Sciences. Next, there's a discussion of whole body reperfusion techniques to restore function in pig organs after death, that comes to us from nature. Then lastly, there's a final article scientists identify diverse pathogenic gene variants that lead to heart failure from the journal science.

Dr. Peder Myhre:

Thank you, Greg.

Finally, there is one Perspective piece by Dr. Rajiv Agarwal from Indiana University School of Medicine entitled “Hydrochlorothiazide versus Chlorthalidone: What is the difference?”

Now, let's move on to the feature discussion that I know you are very excited about, Greg, to learn more about the non-invasive plaque imaging in our frontiers of medicine.

Dr. Greg Hundley:

You bet.

Well listeners, welcome to this feature discussion today on November 29th and we have with us Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. Welcome to you both. Listeners, this is a really interesting feature discussion. It's one of our Frontiers articles that combines where we are in the past, but also where we want to move in the future and a very nice comprehensive review with many articles.

Gemma, can you describe for us the genesis really of this article and what you've been working on?

Dr. Gemma Figtree:

Thanks so much, Greg. Look, I think it's very exciting times at the moment and it's a really important time for all of our community to actually get together in this space. We are driven by trying to make a more efficient process for drug discovery and translation to occur and to basically move into humans in the space of coronary artery disease. We've actually known, obviously, for a long time that the underlying process driving heart attack, but we've not been able to image and treat the actual underlying disease. What this article focuses on is how we actually merge top current technology with policy and approval of drugs. We are very excited about the team of over 20 different institutes around the world trying to work on the best measures of corona artery disease as the disease itself.

Dr. Greg Hundley:

Very nice. Now, help us understand different techniques and why is this a frontier?

Dr. Gemma Figtree:

Look, I think it's a mixture of the fact that, obviously, we're getting great advances in noninvasive imaging techniques that allow us to actually measure plaque burden, but also plaque characteristics. In the case of drug translation this is an absolutely fundamental piece. You can transform a clinical trial where you can look at the underlying pathology and be able to enrich trials or be able to look at the effect of trials of a new drug in humans.

It's really important to acknowledge the fact that humans are really the only animal on the planet that get corona artery disease itself. To be able to translate some of the exciting new drugs that target the plaque itself and work synergistically with some of our agents on cholesterol, and blood pressure, et cetera, we really need to have these measures of coronary artery disease itself. It's a combination of the technology, but also how we apply it to a clinical trial and then how do we work with our regulatory authorities and policy advisors around getting this into humans. We really aiming to try to accelerate the development of drugs that can try to tackle our greatest burden of cardiovascular disease around the world.

Dr. Greg Hundley:

I'm hearing cardiovascular disease, I also heard in their imaging and lots of different modalities, and then I heard regulatory bodies. Are you thinking maybe we need standards?

Dr. Gemma Figtree:

That's exactly right. I think, importantly, whilst there's a lot of exciting technology and a lot of us are pursuing potentially different avenues of this we also need to be able to coordinate and develop a simple and harmonized approach that's able to be applied across the world in an equitable fashion. Whilst we, obviously, have developing exciting new toys we have to make sure that a measure that we want to work with regulatory authorities is able to be applied in all of our countries around the world to make sure that the drug development is applied in an equitable fashion.

Dr. Greg Hundley:

Very nice. Well listeners, next we're going to turn to our associate editor, Dr. Nick Mills. Nick, you evaluate many manuscripts. What attracted you to this particular paper? Also, help us put it in the context of why you think it's a new frontier that is emerging or needs to emerge in cardiovascular disease.

Dr. Nick Mills:

Yeah, thanks Greg.

Three things, the expertise of this group, the focus and novelty of the topic, and the fact that it's a really timely issue Gemma just outlined. Gemma a phenomenal job bringing together people from all over the world to tackle this area that includes imaging expertise, drug development expertise, industry that gives it a very balanced and diverse range of views and marks it out from other reviews that focus on particular imaging modality. Novelty's really important, but timeliness as well. We've seen in the last five years major breakthroughs in the treatment of diabetes and heart failure. But, drug development of coronary heart disease is stalling. I cannot remember the last time I went to a really exciting late breaking trial on a new development for coronary heart disease that has changed the outcomes for patients. We do need to rethink.

Gemma's absolutely right, that requires us to work with regulators to stimulate industry involvement in drug discovery, and delivery, and testing. This is occurring at a time where we've got more fabulous imaging modalities then we've ever had before. Critically, they're noninvasive. They're easy for patients, they're easy for serial testing, and that really opens up many opportunities. It's the fact that it's timely, novel, great expertise, and also really exciting area for cardio of medicine.

Dr. Greg Hundley:

Very nice. Well listeners, we're going to go back to Gemma. Gemma, what do you think are some of the next research studies that we need to perform to support what we're trying to indicate today in this Frontiers article?

Dr. Gemma Figtree:

Yeah. Thanks very much, Greg.

I think, ultimately, the features that need to be taken into consideration for a surrogate endpoint to be approved by our regulatory authorities need to be considered. There are many drug companies, but also individual investigators with ideas of drugs to take forward. What we need to do is make sure for all those studies that we're actually working together and ideally having a harmonized endpoint for use there. I think, working early with regulatory authorities is going to be key.

I think, if you actually, within the tables that are presented in the paper we demonstrate very clearly that these measures of plaque, particularly, the CT coronary angiography measures of low attenuation plaque are pretty ready for consideration by regulatory authorities. I think, agents that we already know work to reduce mortality, such as statins, we know that they actually have direct effects on plaque both from a pathophysiological perspective, but also from these imaging studies. We know that that change in the plaque characteristics and volume predict the outcomes.

In a sense, we've got a fabulous array of data already. In fact, new agents that have come through have also demonstrated effects on these measures. I think, by bringing all of this together in this article we're already in a position to work with regulatory authorities to see what is needed next. I think, listening to that's going to be very important. I do think that the next steps are really going to be working with effectively, I guess, our colleagues to make sure that we don't continue to rapidly advance the measures whilst losing the opportunity to work with regulatory authorities.

In answer your question about the research side of things, I think, as we gather more and more information about this we have to make sure that phase two studies are then linked and we can retrospectively see how they predict the outcomes in phase three studies, but I firmly believe that we're in a position that over the next couple of years we should be able to do harmonized approaches at phase two studies and then as a whole community be able to look at how that predicts outcome and work with our regulatory authorities to get more confidence in these endpoints as key. This is all driven by my clinical observations and interest in people who look up and say, "Why me" when they're having a heart attack? In our community where we're getting very good primary prevention we see up to 25% of our heart attack patients having plaque events and catastrophic heart attacks without those traditional risk factors that would've worn them.

Part of this is also opening up avenues for driving new diagnostic tools that can pick up the disease itself. Picking up... Treating coronary disease as the disease and using that for diagnostic and therapeutic purposes, I think, is a great opportunity to tackle this great burden that we're currently not winning with.

Dr. Greg Hundley:

With the group that you had assembled were there any primary suggestions on how to unite some of these efforts on a global scale? I really liked, very early in our conversation today, you mentioned that and I wondered what this collective you assembled may have suggested.

Dr. Gemma Figtree:

Yeah. Look, I think at the moment it is a collection of experts. I haven't quite figured out the name for such a thing, but we are also working with some of the leading organizations now to try to also make sure we get their auspicing of the concepts and how to best do that. I think, by not coming out of one particular organization and evolving from the members itself, and in particular, having industry and regulatory authorities involve and drug discovery experts right from the beginning has been fantastic. Also, making sure that we have that pragmatic approach and that consideration of equitable access. Particularly, making sure that any phase two trial can be done or enrichment for phase three trial can be applied right around the globe and make sure we get diversity of patients enrolled in these studies.

Dr. Greg Hundley:

Very nice. Coming back to you, Nick, any additional thoughts to build on Gemma's comments here?

Dr. Nick Mills:

Well, to say as someone who's worked in the field of cardiac biomarkers for many years and felt that we could tackle this with the regulators and drug delivery, but I've seen inflammatory biomarkers, lipoproteins come and go without changing. I think, it's just a really exciting opportunity that we now have the ability to phenotype an image, coronary artery disease noninvasively, but a highly specific surrogate endpoint that we've never had before. It's why I'm starting to do research into DT.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills for bringing us this really provocative Frontiers article highlighting a new strategy. Bringing together regulators, leading researchers, and industry to advance new methodologies and trying to tackle globally how we might address atherosclerosis.

Well, on behalf of Peder, Carolyn, and myself we want to wish you a great week and we will catch you next week on The Run.

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please author Jung-Minh Ahn and Associate Editor Emmanouil Brilakis as they discuss the article "Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial."

Dr. Greg Hundley:

Welcome, listeners to this November 22 issue of Circulation on the Run. And I am Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway, and also a social media editor interpolation.

Dr. Greg Hundley:

Well Peder, our feature this week, we are reviewing a comparison between drug eluting stents and bypass surgery for multi vessel coronary artery disease. Really an extended follow up from the Vest trial.

Dr. Peder Myhre:

I can't wait, Greg.

Dr. Greg Hundley:

Right. But before we get onto that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?

Dr. Peder Myhre:

Sure, I'd love to. And the first paper today is a clinical one and it is entitled, “Efficacy of a Drug Eluting Stent Versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the Eminent Randomized Trial.” And it comes to us from the corresponding author Yann Gouëffic from Groupe Hospitalier Paris St. Joseph in France. So Greg, a clear patency benefit of a drug eluting stent over bare metal stents for treating peripheral artery disease of the femoropopliteal segment has not been definitely demonstrated. But today's paper publishes the primary results of the eminent randomized trials, which was designed to evaluate the patency of the Eluvia drug eluting stent. And this stent is a polymer based paclitaxel eluting stent and it was compared with bare metal stents for the treatment of femoropopliteal artery lesions. In fact, with 775 patients, Eminent is the largest randomized trial of drug eluting stent treatment for symptomatic femoropopliteal arterial disease to report patency to dates.

Dr. Greg Hundley:

Very nice, Peder. So describe for us, what were the results of this very large randomized clinical trial?

Dr. Peder Myhre:

Sure, Greg. So the primary effectivity outcome was primary patency at 12 months, defined as independent core laboratory assessed duplex ultrasound peak systolic velocity ratio less than or equal to 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesions. And primary effectiveness analysis from the Eminent randomized study demonstrated superior one year primary patency for the Eluvia drug eluting stent versus bare metal stent. And that is 83.2% versus 74.3% with a P value less than 0.01. And this treatment was associated with a greater incident of Rutherford classification improvement without the need for re-intervention, and functional parameters demonstrated improvements in both groups, and there were no statistical difference observed in one year mortality between patients treated with the Eluvia drug eluting stents and bare metal stents. So in summary, this high level evidence supports the one year benefit of polymer based paclitaxel elusion over bare metal stents to treat superficial femoral artery and/or proximal popliteal artery lesions. What'd you think of that, Greg?

Dr. Greg Hundley:

Very nice. So sounds like for peripheral arterial interventions, a benefit from the polymer based paclitaxel eluting stents.

Dr. Peder Myhre:

Exactly. And there's also an editorial putting these results in context from Doctors Mosarla and Secemsky entitled, “From Imperialism to Eminence: The Noble Rise of the Second Generation Peripheral Drug Eluting Stents.”

Dr. Greg Hundley:

Excellent, Peder. Well, my article comes to us, Peder, from the world of preclinical science. And Peder, these investigators led by Professor Volker Spindler from University of Basel evaluated arrhythmogenic cardiomyopathy. And as you know, arrhythmogenic cardiomyopathy is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life threatening arrhythmias. So a substantial proportion of arrhythmogenic cardiomyopathy is caused by mutations in genes of the desmosomal cell to cell adhesion complex, but the underlying mechanisms are not well understood. So to address this, the team mutated the binding site of desmoglein two, a crucial desmosomal adhesion molecule in cardiomyocytes. This desmoglein two W2A mutation abrogates the tryptophan swab, a central interaction mechanism of desmogenin two based on structural data. Now, the impaired adhesive function of this DSG2W2A was confirmed by cell to cell dissociation assays and for spectroscopy measurements by atomic force microscopy.

Dr. Peder Myhre:

Wow. We continue to learn more about this disease, arrhythmogenic cardiomyopathy. And this sounds so interesting. Greg, please tell me what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that the DSG2W2A mutation impaired binding on the molecular level and compromised intercellular adhesive function. Now, mice bearing this mutation, developed a severe cardiac phenotype recalling the characteristics of arrhythmogenic cardiomyopathy including cardiac fibrosis, impaired systolic function, and arrhythmia. Now, a comparison of the transcriptome of the mutant mice with arrhythmogenic cardiomyopathy patient data suggested deregulated integrin alpha V beta six and subsequent TGF beta signaling as a driver of cardiac fibrosis. Now accordingly, blocking integrin alpha V beta six led to reduced expression of pro-fibrotic markers and reduced fibrosis formation in the mutant animals in vivo.

Dr. Peder Myhre:

Oh, this is so important mechanistically. And Greg, can you please tell us something about the clinical importance of these findings?

Dr. Greg Hundley:

Right Peder, just like Carolyn always driving at that clinical significance. So these authors show now that disruption of desmosomal adhesion is sufficient to induce a phenotype which fulfills the clinical criteria to establish the diagnosis of arrhythmogenic cardiomyopathy confirming the dysfunctional adhesion hypothesis. Now mechanistically, deregulation of integrin alpha V beta six and TGF beta signaling was identified as a central step in the process toward developing fibrosis. And then finally, a pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. So perhaps, new information leading to future therapeutic strategies to halt myocardial fibrosis in patients with arrhythmogenic cardiomyopathy.

Dr. Peder Myhre:

Oh wow. What an amazing issue this is, Greg, and we actually have even more in the mail bag. We have a Perspective piece by Dr. Prystowsky entitled “Rate versus Rhythm Control for Atrial Fibrillation, Has the Debate Been Settled?” And we have some Cardiology News by Bridget Kuehn entitled, “Fitness Rather than BMI Appears to be Better Predictor of Survival for Women with Heart Disease.” I'm sure Carolyn would love to read that one. And in this paper, Bridget Kuehn discusses a new study published in European Journal of Preventive Cardiology.

Dr. Greg Hundley:

Very nice, Peder. Well, I've got a couple other articles in the issue. First, Dr. Tonelli has a Primer entitled, “Increasing Societal Benefit from Cardiovascular Drugs.” And then Professor Januzzi has a Research Letter entitled, “Association Between Sacubitril/Valsartan Initiation in Mitral Regurgitation Severity and Heart Failure with Reduced Ejection Fraction: The PROVE HF Study.” Well, now let's get on to that feature discussion in this issue to discuss PCI versus CABG for multi vessel coronary artery disease.

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome listeners to this November 22nd feature discussion and we have with us today Dr. Jung-Min Ahn from Seoul, South Korea and our own associate editor, Dr. Manos Brilakis from Minneapolis, Minnesota. Welcome gentlemen. Jung-Min, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Jung-Min Ahn:

Thank you, Greg. So the everolimus-eluting stent Freedom trial, showed a higher mortality after PCI than after bypass surgery in multi vessel disease. However, these findings maybe delimited predictability in the contemporary practice because such trials use the first generation drug stent which may have higher rate of stent thrombosis. The Press trial is the first randomized trial using the second-generation drug eluting stent. The initial approach was published in New England Journal of Medicine five years ago. So they showed that the 4.6 years of follow the PCI with everolimus-eluting stents showed a significantly higher rate of prime endpoint deaths, MI, the target revascularization, but overall mortality, there was no significant difference. So the hypothesis that, in a long term follow, more than 10 years follow, so we want to see the mortality difference between the PCI with the second generation everolimus-eluting stent versus bypass surgery. So we designed this extended follow trial best studies.

Dr. Greg Hundley:

Very nice, Jung-Min. And can you describe for us the study design, and who was your study population, and how many subjects did you enroll?

Dr. Jung-Min Ahn:

Actually, this study is the extended follow original Press trial, enrolled 880 patients from mostly Korea, China, Malaysia, and Thailand. So the study population was Asian population with a symptomatic or symptomatic coronary artery disease with angiopathy confirming the multi vessel coronary artery disease population. One additional criteria is the patient with coronary artery disease should report PCI and bypass surgery decided by the attending physicians and surgeons.

Dr. Greg Hundley:

Thank you, Jung-Min. And so, can you describe for us your study results?

Dr. Jung-Min Ahn:

Yes. During the extended follow-up study we found that there is no significant difference between the PCI with everolimus-eluting stent and bypass surgery regarding prime endpoint deaths, MI, vascularization. In addition, more importantly, we reduced the compost endpoint of death, MI, stroke. There was no significant difference in addition regarding the mortality. Also, there is no significant difference during the long term follow.

Dr. Greg Hundley:

Really interesting results, Jung-Min. Did you notice any differences in men versus women or in younger versus older individuals?

Dr. Jung-Min Ahn:

In our sub-group analysis, there is no interaction according to the sub-groups except the diabetic sub-groups. In diabetics and long term outcomes, have interaction with the treatment assignment regarding the primary endpoint, prime endpoints, death, MI, target vascularization. Even though contrary to the Freedom trial, the overall mortality rate, there is no significant difference between the PCI versus the bypass surgery even in diabetic populations.

Dr. Greg Hundley:

Well thank you so much, Jung-Min. And now listeners, we're going to turn to our Associate Editor, our expert in the area of advanced percutaneous coronary artery interventions, Dr. Manos Brilakis from Minneapolis, Minnesota. Manos, you have many papers come across your desk. What attracted you to this particular paper and how do you put its results in the context of other studies that have been performed to compare multi vessel percutaneous coronary artery intervention versus coronary artery bypass grafting?

Dr. Manos Brilakis:

Yeah, thank you, Greg. And again, congratulations to Jung-Min for a great paper. And the reason we were very interested in this paper is because it is an area that is still debated clinically quite extensively. As Jung-Minh mentioned, there is the Syndex trial showing that there was higher mortality amongst the PCI group over long term, but that was done a long time ago with previous generation drug diluting stents, and the data, the contemporary data with recently the currently used DS, is much more limited. So I think the appeal for us, and I think frankly for the practicing interventionalist, is that this paper provides long term outcomes with contemporary drug eluting stents over a fairly large patient population, and it does so fairly well, but there are plus and minuses.

There was no difference in mortality, which continues to be debated. But this paper is fairly equivalent on this respect. And if we see the coupled myo curves, they also look very similar. And there was some differences in death in myocardial infarction to be taken into consideration. But all this information is important for deciding for each patient we treat right now, which is the best way to go in terms of coronary devascularization.

Dr. Greg Hundley:

Very nice. And so, let's circle back next to Jung-Min. What do you see as the next research study really to be performed in this sphere of investigation?

Dr. Jung-Min Ahn:

Thank you, Greg. So I'd like to talk about the future study, but I'd like to say something about the how to do PCI. So what is the difference between the Press trial and previous randomized trial? In the Pres trial, we used the intracoronary imaging in 72% of PCI population. This is a huge higher rate than what was used compared with the previous randomized trial. Only 10% or less than 10% PCI population used intracoronary imaging. So I think to get the comparable research to the bypass surgery, I think we have to optimize the PCR region. What is the best way shortcut to get optimizing PCR region? It could be intracoronary imaging guided PCI, could be one important way to get optimized PCR region. I think this is very important to take a message from the first trial.

Dr. Greg Hundley:

Well, Jung-Min, it sounds like from your description that the application of intracoronary imaging was very important in this study. Do you want to expand on that for our listeners? You know, what were maybe some subgroup analysis results of using intracoronary ultrasound? And then, how would you recommend to our listening audience that that particular technique be applied?

Dr. Jung-Min Ahn:

Thank you, Greg. So I mentioned that the Press trial used the intravascular ultrasound in 72% of PCI. So we analyzed the the PCI with I, without I. PCI with I showed a very comparable primary endpoint and overall mortality rate to the bypass surgery group. But PCI without I showed a significantly higher rate of primary endpoint and overall mortalities. So intravascular ultrasound guided PCI may improve the PCI outcomes and we can compare our clinical outcomes to the bypass surgery.

Dr. Greg Hundley:

Very nice. And Manos, do you have anything to add?

Dr. Manos Brilakis:

Yeah, I think the era of doing multiple huge mega trials may be tough to find these days. I think we may not have big trials comparing those two modalities, but I do agree with Junh Minh. I think the conclusion from this study as well as the previous studies is that you can choose which way to go. But if you're going to go with PCI for example, you do want to make sure that you do the best possible outcome so that you use intravascular imaging, you use physiology. We know from phase three, that use of intravascular imaging was very limited. So if you're going to go with PCI for a specific patient, the decision of course depends on the study's results and the previous studies and the patients' specific preferences. But if you're going to do PCI, you want to take your time to get the best possible result, make sure you can get as complete revascularization as possible because that will translate into better clinical outcomes as well.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank our main author today, Dr. Jung-Min Anh, and our own associate editor, Dr. Manos Brilakis, for bringing us this important study highlighting that in patients with multi vessel coronary artery disease, there were no significant differences between PCI and coronary artery bypass grafting in the incidence of major adverse cardiac events, the safety composite endpoint, and all cause mortality during an extended follow up period. Well, on behalf of Peder, Carolyn, and myself, we want to wish you a great week and we will catch you next week On the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Qiang Zhang and Matthew Burrage as well as Senior Associate Editor Victoria Delgado as they discuss the article "Artificial Intelligence for Contrast-free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from University of Akershus University Hospital in Norway.

Dr. Carolyn Lam:

Peder, today's feature discussion is on AI for contrast-free MRI. Isn't that so cool, using AI to perhaps understand what we could see only with contrast, but now in a contrast-free manner. Now I know that sound a bit confusing, but I hope very, very enticing, because everyone's going to have to wait for a little while before we get to that interesting feature discussion. And for now, let's talk about some of the papers we have in today's issue, shall we?

Dr. Peder Myhre:

Yes, Carolyn, I can't wait for the feature discussion, but we're going to start with some of the other papers in this week's issue, and we're going to start in the world of preclinical science with a paper looking at human cardiac reprogramming, because Carolyn, direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as one of the promising strategies to remuscularize the injured myocardium. Yet it is still insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails and underlying molecular mechanisms are not really well understood.

Transcriptional factors often act in concert and form tightly controlled networks featuring with common targets among different transcriptional factors. Therefore, missing one component during heart development could lead to heart function defects and congenital heart disease. And in this study by corresponding author Yang Zhou from the University of Alabama at Birmingham, the authors perform transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes to assess additional factors that govern transcriptional activation of gene programs associated with sarcomere contractility.

Dr. Carolyn Lam:

Wow. Really nicely explained. Thanks, Peder. So what did they find?

Dr. Peder Myhre:

So Carolyn, through these computational analysis of transcriptomic data, the authors identified TBX20 as the most under expressed transcription factor in human induced cardiomyocytes compared to endogenous cardiomyocytes. They also demonstrated that TBX20 enhances human cardiac reprogramming and improves contractility and mitochondrial function in the reprogrammed cardiomyocytes.

Dr. Carolyn Lam:

Nice. Could you summarize the clinical implications, please?

Dr. Peder Myhre:

Yes. So the clinical implications are that enhancing the efficiency and quality of direct cardiac reprogramming for human fibroblast is a critical step in the clinical translation of this technology, and better understanding of this synergistic regulation of key cardiac transcription factors during reprogramming will provide new insights into the genetic basis in normal and diseased hearts. Well, Carolyn, please tell me about your next paper.

Dr. Carolyn Lam:

Thanks, and we're moving now to kidney disease. Now end stage renal disease is associated with a high risk of cardiovascular events, but what about mild to moderate kidney dysfunction? Is it causally related to coronary heart disease and stroke? Well, today's authors give us a clue, and it's from corresponding author Dr. Di Angelantonio from University of Cambridge and colleagues who took a very unique combined approach to answer this question.

They first conducted observational analyses using individual level data from four huge population based data sources, namely the emerging risk factors collaboration, Epic CVD, Jillion Veteran Program and UK Biobank. Can you imagine this comprised almost 650,000 participants with no history of cardiovascular disease or diabetes at baseline, yielding almost 43,000 and 15,700 incident coronary heart disease and stroke events respectively during a 6.8 million person years of follow up.

So huge observational study, which they then followed with a Mendelian randomization analyses using a genetic risk score of 218 variants for GFR and involving participants in Epic CVD Million Veterans Program and the UK Biobank.

Dr. Peder Myhre:

Wow, Carolyn, this is a topic that I think many of us have really been wondering and thinking about. The mild to moderate kidney dysfunction, what does it really mean? And what a beautiful study to answer this. So what did they find?

Dr. Carolyn Lam:

First, there was a U-shaped association of creatinine-based GFR with coronary heart disease and stroke with higher risk in participants with GFR values below 60 or more than 105 mills per minute per 1.73 meters squared. Mendelian randomization analyses for coronary heart disease showed an association among participants with GFR below 60, but not for those with GFR above 105.

Results were not materially different after adjustment for traditional cardiovascular risk factors and the Mendelian randomization results for stroke were nonsignificant but broadly similar to those for coronary heart disease. So in summary, in people without manifest cardiovascular disease or diabetes, mild to moderate kidney dysfunction is causally related to the risk of coronary heart disease, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Dr. Peder Myhre:

Thank you, Carolyn, for such a great summary and an important result from that study. I'm going to now take us back to the world of preclinical science and talk about diabetic cardiomyopathy and exercise. And we both know that patients with diabetes are vulnerable to development of myocardial dysfunction, and that exercise, our favorite thing, for maintaining cardiovascular health, especially in patients with diabetes.

And despite a wealth of evidence supporting that cardiometabolic benefits of exercise, the precise exercise responsive signals that confer the beneficial effects of exercise in cardiomyocytes to remain poorly defined. And previous studies have identified fibroblast growth factor 21, FGF21, a peptide hormone with pleiotropic benefits on cardiometabolic hemostasis as an exercise responsive factor.

And in this study from Aimin Xu from the University of Hong Kong, the authors investigated a six-week exercise intervention program in FGF21 knockout mice and wild-type litter mates that all had diabetic cardiomyopathy induced by high fat diet and injection of streptozotocin.

Dr. Carolyn Lam:

Nice. So what did they find?

Dr. Peder Myhre:

Yeah, the authors found that exercise lowers circulating FGF21 levels, therefore remodeling the heart as an FGF21 sensitive target organ. And the protective effects of exercise against diabetic cardiomyopathy are therefore compromised in mice with deficiency of FGF21. They also identified Sirtuin-3 as an obligor downstream effector on FGF21, preserving mitochondrial integrity and cardiac function. Finally, the authors demonstrated that FGF21 induces Sirtuin-3 expression through AMPK-FOXO3 signaling access.

Dr. Carolyn Lam:

So could you put that together for us better? So what are the clinical implications?

Dr. Peder Myhre:

So the clinical implications from this paper is that circulating FGF21 is a potential biomarker for assessment of exercise efficacy in improving cardiac functions. And exercise is a potent FGF21 sensitizer in cardiomyocyte and has the potential to enhance the therapeutic benefits of FGF21 analogs in diabetic cardiomyopathy, and selective activation of FGF21 signal in cardiomyocytes may serve as exercise mimetics and represent a promising targeted intervention for precise management of diabetic cardiomyopathy.

Dr. Carolyn Lam:

Oh my goodness. That is fascinating. Thank you, Peder. Well let's wrap up with what else there is in today's issue. There's an On My Mind paper by Dr. Weir entitled, “The Emperor's New Clothes: Aren't We Just Treating Grades of Heart Failure with Reduced Ejection Fraction.”

Dr. Peder Myhre:

And there is a Research Letter by Dr. James Martin from Baylor College of Medicine entitled “Gene Therapy Knockdown of Hippo Signaling Resolves Arrhythmic Events in Pigs after Myocardial Infarction.”

Dr. Carolyn Lam:

Very nice. Thanks, Peder. So wow, let's go onto a featured discussion on AI for contrast-free MRI and a virtual native enhancement here coming right up.

Dr. Peder Myhre:

Awesome.

Dr. Carolyn Lam:

Now we all know that myocardial scar is currently assessed non-invasively using cardiac MRI with late gadolinium enhancement as what we would call the imaging gold standard. Wouldn't it be amazing to have a contrast-free approach, which could provide the same information with many advantages such as a faster or cheaper scan, and without contrast associated problems? Well guess what? We're about to discuss that today in a feature publication in today's issue, and I am so pleased to have the co first authors with us today. They are Dr. Qiang Zhang and Dr. Matthew Burridge, both from University of Oxford, and to discuss it as well, our senior associate editor, Dr. Victoria Delgado from Barcelona. So welcome, everyone.

Qiang Zhang, could I start with you and ask you, I understand you're a machine learning expert, which means you're probably smarter than all of us here. Could you maybe explain in simple terms what made you and Dr. Burridge do the study?

Dr. Qiang Zhang:

First? Thank you so much, Carolyn and Victoria, for the invitation. As you have mentioned, late gadolinium enhancement, or LGE, has been the imaging gold standard in clinical practice for myocardial catheterization including scar assessment for patients with myocardial infarction. However, LGE requires the injection for gadolinium contrast, and this is cautioned in some patient groups and increases the scan time and cost.

On the other hand, pre-contrast CMR such as Sydney T1-T2 mapping, a gadolinium-free alternative for myocardial catheterization. But their clinical use has been hindered by confounding factors and a lack of clear interpretation. So with our cross deceptor team at Oxford, we developed an artificial intelligence, virtual native enhancement technique VNE.

It can produce a sort of a virtual LGE image but without the need for gadolinium contrast. And we have previously tested it in patients with hypertrophic cardiomyopathy as published in this journal last year. And in this new study together with Matt here, we tested in patients with history of chronic or prior myocardial infarction.

Dr. Carolyn Lam:

Oh wow. Cool. So audience, you heard it. Instead of LGE, we now have VNE, virtual native enhancement. That's super cool. Thank you. Matt, could I bring you in here? So tell us a little bit more about the population you studied and what you both found.

Dr. Matthew Burrage:

Yeah, absolutely. And thank you so much for the invitation as well. So as Chang has said, this was a single sensor study that we performed at the University of Oxford and specifically targeting assessing myocardial scar in patients with a history of chronic or prior MI. So we had two sources for our population data. Well, first we used our real world clinical service data from our institution.

So we screened 11 years worth of patient data for presence of MI. So patients were included. There was a evidence of a previous MI based on an ischemic pattern of LGE, but we specifically excluded patients who had an acute presentation, or if there were features of acute MI on the CMR scan such as presence of myocardial edema or microvascular obstruction. The reason for this is we wanted to keep this as a clean population to avoid the potential confounding effects of myocardial edema or MVO on native T1 values. And so we also excluded other myocardial pathologies such as underlying cardiomyopathies and infiltrative diseases.

A second population dataset came from the OX Army study, which is a single center prospective study of patients presenting with acute MI. And for these patients we used their six month follow up scan to again avoid the confounding effects of edema and pathology. So overall we had a total of 912 patients who have contributed over 4,000 image data sets. The patient characteristics, 81% were male, they had a mean age of 64 years and there were cardiovascular risk factors such as diabetes melitis, hypertension, hypercholesterolemia in 20 to 40% of patients, while just over half had a history of previous revascularization.

We also separately applied the VNE technology to a pig model of myocardial infarction, which was thanks to our collaborator, Rohan Domakuma in the US. And so those were scans performed eight to nine weeks after an induced MI in the LAD territory in a series of pigs. And so this gave us the ability to provide a direct comparison between LGE, VNE, and histopathology in this model.

Dr. Carolyn Lam:

Wow. And results?

Dr. Matthew Burrage:

So what we found and the key results were firstly that VNE provided significantly better image quality than LGE, and this was on blinded analysis by five independent operators from our test data sets. Secondly, the VNE correlated strongly with LGE in terms of quantifying infarct size and the degree of transmurality, so the extent of the MIs in our test data set. We had pretty good overall accuracy of 84% for VNE in detecting scar compared to LGE with no false positive VNE cases.

And finally there was also excellent visuospatial agreement with the histopathology in the pig model of myocardial infarction. So really this, we think, is a technology that provides clinicians with images in a format that firstly they're familiar with, which looks like LGE, provides essentially the same information as LGE, but it can be achieved without the need for any gadolinium contrast agents and can be acquired in a fraction of the time.

So it takes less than one second to generate the VNE image. So as we've said before, we feel there's a lot of potential here for this technology to potentially eliminate the need for gadolinium contrast in a significant proportion of CMR scans, reduced scan times and costs, increased clinical throughput and hopefully improve the accessibility of CMR for patients in the near future.

Dr. Carolyn Lam:

Oh wow. That is tremendous. So first of all, congratulations to both of you. Before I ask Victoria for some thoughts, could I also just check with Qiang Zhang, because all AI algorithms need to be externally validated or surely there's some catch to it, or so-called limitations, or something else you may study. Could you maybe round up by saying is there anything that clinicians should not be applying it to or be aware of some limitations or?

Dr. Qiang Zhang:

Thank you, Carolyn. So a limitation of this study is that the dataset that is used for developing the models, the majority of them are patients around six month after the acute infarction. So where the myocardial infarction is still evolving, which may include residual edema and microvascular obstruction, and that is difficult to assess using the current VNE model.

And also we found it challenging to assess small sub endocardial infarction and actually to address those limitations, we are working on improving the VNE models, training it on even larger data sets and training it on LGE to detect small sub endocardial function. And we will further develop it to detect, for example, acute edema and a microvascular obstruction, and in the meantime develop quality control driven AI models to inform the clinical users of and unreliable results.

Dr. Carolyn Lam:

Wow, thank you. So Victoria, now I'm dying to hear your thoughts. How do you think this fits in the landscape of all AI imaging now?

Dr. Victoria Delgado:

I think that it's an excellent development and I congratulate the others for the article and the proof of concept that we can move away from the late enhancement and the use of gadolinium enhancement. I think that this is a major step forward because as Matt said, they are going to decrease very much the time of scanning and the post processing because is automatically done as far as I understand. So even if you can interpret yourself the amount of so-called virtual enhancement, the system gives you a value for that extension of the virtual in non-gadolinium enhancement. So that reduces very much the variability that can be in each observer if that is done automatically.

But my question to them is also if that can be influenced by the type of scanner that you use, for example on echocardiography, that's much more my field of interest, it depends very much sometimes how the images are processed of which are the vendors that we have used to acquire the images. Is this a limitation for your software? Can you foresee there some variability or is completely independent?

Dr. Qiang Zhang:

Thank you, Victoria. So we are aware of actually the difference of the data produced by different scan of vendors and the advantage of AI-driven methods is that it is data driven. So we plan to incorporate dataset from other vendors so that the trend that VNE models can work with like multiple scanner vendors. This actually will be done alongside the ongoing standardization program of T1 mapping in our group, which is the underpinned technology for VNE. And this is led by Professor Stephan Pitchnik and Vanessa Farrera. And we actually hope the VNE technology as AI driven methods could contribute to a solution to the CMO standardization between the scanner vendor.

Dr. Victoria Delgado:

And another question, if I may follow in this CMR, it has been proposed as a very valuable imaging technique to assess infarct size and to see the efficacy of some therapies to reduce the myocardial infarction size. How do you think that this new methods will impact in future trials and the way we have been interpreting the previous trials, like for example, the one that you use for the validation?

Dr. Matthew Burrage:

Yeah, thanks Victoria. It's a really, really excellent question. I think there's a lot of potential for the new VNE technology to also become a clinical endpoint in some of these trials in terms of reduction in infarct size, because the information that we get is more or less the same as we get from the LGE. So there's lots of potential that we can, again, use this as a biomarker in trials for looking at reduction in infarct size and reperfusion therapies. But it has the benefit that it can be done quicker and without gadolinium contrast.

Dr. Victoria Delgado:

This is amazing guideline and really I would have a lot of questions for them as well. And knowing the literature, for example, in the Scenic center in Madrid that they have been scanning the evolution of myocardial infarction from 0.02 weeks to see how this would translate with your technique. That will be amazing to understand how this can be done.

Dr. Carolyn Lam:

Oh wow, there you go. New research idea right there. Well how about if we end with a very quick question for each of the first authors. So maybe Matt, you could start, I mean is this ready for primetime and clinical use? And if it's not, what needs to be done to get there? In other words, where are you headed as the next step?

Dr. Matthew Burrage:

So again, thank you, Carolyn, that's a really excellent question and I think the next step before this becomes ready for primetime clinical use is validating this technology really across the spectrum of other myocardial pathologies. So the next work that we are developing this on is in patients with acute myocardial infarction, and then extending this to sort of acute inflammatory conditions like myocarditis, other non-ischemic cardiomyopathies, things like amyloidosis as well.

So this will be the next step into rollout and we are looking to track things like VNE burden and how that relates to clinical outcomes, similar to the previous LGE papers have done across different myocardial pathologies, but then ultimately aiming towards clinical rollout within the next few years.

Dr. Qiang Zhang:

Yeah, I think pretty much what Matt has said, we're going to develop the deep learning methods and test it further on pretty much the whole spectrum of commonly encountered diseases, and then more complex pathologies such as acute pathologies like edema, microvascular obstruction, and then we test on large population study like UK Biobank and other prospective clinical trials. And of course the most importantly is to roll out for real world clinical use. And as Matt said, we are aiming to do this within the next two to five years.

Dr. Carolyn Lam:

Wow, this is amazing. Both Victoria and I said thank you, congratulations on this landmark piece of work. Thank you for publishing it in circulation. Audience, thank you for joining us today from Greg, Peder, myself. You've been listening to Circulation on the Run, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And...

Dr. Peder Myhre:

I'm Dr. Peder Myhre from Akershus University Hospital, and University of Oslo in Norway.

Dr. Carolyn Lam:

Peder, I'm so excited about our future discussion. It's about a very important topic of detecting atrial fibrillation in the population using wearable devices. It talks about the Fitbit Heart Study. So exciting, but we're going to keep the audience waiting a bit, because we're going to talk about some other things in the issue. And I would love to start with this now.

We know that fulminant myocarditis presentation is a rare and severe presentation of myocarditis. But, what is its natural history, and clinical features associated with poor outcomes? Peder, what do you think?

Dr. Peder Myhre:

Oh, that's a great question. We really don't know, because prior studies have been relatively small and selected. So Carolyn, let me know.

Dr. Carolyn Lam:

You're absolutely right. But today's paper from Professor Saito, from Nara Medical University in Japan and colleagues, is the largest nationwide cohort study of patients with histologically proven fulminant myocarditis presentation. They study 344 patients, hospitalized with histologically proven myocarditis, who underwent catecholamine and/or mechanical support from 235 cardiovascular training hospitals across Japan, between 2012 and 2017, and here's what they found.

Over a median follow up of 600 days, the accumulative risk of death or heart transplantation at 90 days was 29%. So, really high. These were the risk factors associated with a higher risk of death or heart transplantation, and they were non-sinus rhythm, older age, ventricular tachyarrhythmia, lower left ventricular ejection fraction. Severe histological damage was also associated with a worse 90 day outcome in lymphocytic myocarditis. Cool, huh?

Dr. Peder Myhre:

Oh wow. That was some really solid data. And now Carolyn, I'm going to take us over to the world of preclinical science. And the next paper entitled at “APIC Associated De Novo Purine Synthesis is Critically Involved in Proliferative Arterial Disease” by Yuqing Huo from Augusta University in Georgia.

Dr. Carolyn Lam:

Cool.

Dr. Peder Myhre:

And as you know, Carolyn, vascular smooth muscle cells are extremely important in vascular health. They're located in the medial layers of arteries, and normally exhibit a contractile phenotype that contributes to the regulation of blood vessel tone, blood flow distribution, and blood pressure in normal mature blood vessels. And in response to disease processes, the vascular smooth muscle cells are switched to an activated synthetic and proliferative phenotype, that contribute to the development of a variety of arterial diseases, including atherosclerosis, in-stent restenosis, and bypass graft occlusion. And nucleotides that we are familiar with, such as ATP and GTP, are essential for a large number of biological processes in cells, including proliferation.

And Carolyn, the previous studies have demonstrated that de novo synthesis of purine is a critical pathway for nucleotide synthesis. And in this study, the authors assessed the role of de novo synthesis of purine in vascular smooth muscle cells by using knockout mice.

Dr. Carolyn Lam:

Oh, that was beautifully explained. Thanks, Peder. So what did they find?

Dr. Peder Myhre:

So the authors found that the de novo purine synthesis was increased in proliferative vascular smooth muscle cells. Moreover, they identified an important enzyme in the process called A-P-I-C, APIC. Which was observed in the neointima of the injured vessels, and atherosclerotic lesions in both mice and humans.

Finally, they showed that in a mouse model with knocked out APIC, the atherosclerosis and arterial restenosis was attenuated.

Dr. Carolyn Lam:

Cool. So tell us what the clinical implications are.

Dr. Peder Myhre:

So these findings provide novel insights into the reprogramming of purine metabolism underlying vascular smooth muscle cells proliferation in the development of arterial disease. And that targeting APIC may be a promising therapeutic approach to combat arterial diseases.

So Carolyn, please tell me about your next paper.

Dr. Carolyn Lam:

Ah, thanks, Peder. Well, back to the clinical world, this time, talking about arrhythmogenic right ventricular cardiomyopathy. We know that is characterized by progressive cardiomyocyte loss and fibro fatty replacement. And we know that patients with this a ARVC are at risk for life-threatening ventricular arrhythmias and sudden cardiac death.

The placement of an ICD is a crucial component of ARVC management. But arrhythmic risk stratification and the selection of the optimal candidates for ICD, especially for primary prevention of sudden cardiac death, has, of course, been challenging.

As background, a ventricular arrhythmia risk calculator, in patients without previous sustained ventricular arrhythmias, has been proposed, and includes seven clinical variables derived from non-invasive tests that are routinely performed in these patients. However, the possibility of integrating additional parameters, such as ventricular tachycardia inducibility on programmed ventricular stimulation, with this risk calculator, has been suggested, but not conclusively investigated in a large cohort. And so, here comes corresponding author, Dr. Cadrin-Tourigny, from Montreal Heart Institute and colleagues, who studied 288 patients with a definite ARVC diagnosis, no history of ventricular arrhythmias at diagnosis, and programmed ventricular stimulation performed at baseline. And these patients were identified from six international ARVC registries.

Dr. Peder Myhre:

Oh wow. So we're talking risk stratification for patients with ARVC. Such an interesting topic, Carolyn. So please tell me, what did they find?

Dr. Carolyn Lam:

So, programmed ventricular stimulation significantly improved risk stratification, above and beyond the calculator predicted risk of ventricular arrhythmias, in a primary prevention cohort of patients with ARVC. And this was mainly for patients considered to be at low and intermediate risk by the clinical risk calculator. If negative, its high negative predictive value of 93% in low and intermediate risk patients, may support the decision to forego ICD use in some patients. So, programmed ventricular stimulation results may be applied to the non-invasive ARVC risk calculator, in a two step approach to facilitate personalized decision making for ICD in such patients.

Dr. Peder Myhre:

Thank you, Carolyn. That was a great summary and a great paper. So we're going to move in to see what else is in the mail bag, Carolyn.

Dr. Carolyn Lam:

You bet. There's a letter by Dr. Agirbasli regarding the article, “Coronary Artery and Cardiac Disease in Patients with Type Two Myocardial Infarction, A Prospective Cohort Study,” and this, followed by a response by Dr. Chapman.

There's an ECG Challenge by Dr. [Jingnan] Han, entitled, “Tachycardia Associated with Pacing.”

From our own Molly Robbins, we have highlights from the Circulation Family of Journals. And she covers the experience with stereotactic radio ablation and electrical storm, reported in Circulation: Arrhythmia and Electrophysiology.

The impact of accessibility to primary care on hypertension awareness and control is reported in Circulation: CV Quality and Outcomes.

There's an analysis of lifestyle factors and their impact on the risk of heart failure by background genetic risk, and that's in Circulation: Heart Failure.

There's a deep learning model of PET scans and coronary flow reserve reported in Circulation: CV Imaging.

And finally, OCT based measurement of stent expansion and associations with outcomes are presented in Circulation: CV Interventions.

A lot.

Dr. Peder Myhre:

Yeah, and there's more, Carolyn. In this issue, there is an extensive Frontiers review by the AF-SCREEN International Collaboration, entitled, “Consumer LED Screening for Atrial Fibrillation.”

There is also a Research Letter by corresponding author Qi Fu, from University of Texas Southwestern Medical Center entitled, “Neuro Cardiovascular Dysregulation During Orthostasis in Women with Posttraumatic Stress Disorder.”

And finally, a Research Letter by Pankaj Arora from University of Alabama entitled, “Mechanical Circulatory Support Devices Among Patients with Familial Dilated Cardiomyopathy, Insights from the INTERMACS.”

Dr. Carolyn Lam:

That's awesome, Peder. Thank you. Now let's go onto our feature discussion on atrial fibrillation detection and the Fitbit Heart Study, shall we?

Today's feature discussion is about the Fitbit Heart Study, and none other than the first and corresponding author Dr. Steven Lubitz, from Massachusetts General Hospital in Boston to join us today. Steve, welcome. Congratulations. Am I right to say, this is the largest study of its kind to look at the detection of atrial fibrillation using wearable devices?

Dr. Steven Lubitz:

Thanks for having me, Carolyn. And that's right, this is.

Dr. Carolyn Lam:

Oh my gosh. Okay. Tell us all about it, what you did, what you found.

Dr. Steven Lubitz:

Well, thanks, Carolyn. So as we know, undiagnosed atrial fibrillation is a potential hazard that can cause strokes. And if we can identify people who have undiagnosed atrial fibrillation early, we may be able to prevent strokes. In addition, undiagnosed atrial fibrillation may be associated with additional morbidity, which can be addressed through a number of different ways, if we can detect atrial fibrillation. Obviously, the challenge is to detect atrial fibrillation.

We also know that people are increasingly wearing devices that have sensors on them, specifically using photoplethysmography technology, which can detect the pulse rate. Software algorithms can now be developed, that can assess that pulse rate for regularity or irregularity. But they really need to be assessed and validated, to minimize the potential for false positives, which can have obviously, downstream adverse consequences of their own, if atrial fibrillation is incorrectly identified or diagnosed as a result.

As I was mentioning, we developed this novel software algorithm with frequent overlapping photoplethysmography, post tachogram sampling, which is unique. And then we tested the algorithm's positive predictive value for undiagnosed AFib in a large scale remote clinical trial, using a range of Fitbit wearable fitness trackers and smart watches.

It was a remote trial, so participants were invited. These were people who already had a Fitbit account, they were invited to participate. And in span of just a few months, in the middle of the pandemic, over 455,000 people signed up to participate in the study. And so, big thank you to all of the participants in the study.

Dr. Carolyn Lam:

Wow, that is big. And what did you find?

Dr. Steven Lubitz:

So of the 455, over 455,000 participants that enrolled, over 4,000, had an irregular heart rhythm detection and received a notification. And after inviting those participants to attend a telehealth visit, and at that telehealth visit, the telehealth provider confirmed eligibility criteria, confirmed that they didn't have preexisting atrial fibrillation, for example, and a variety of other inclusion/exclusion criteria.

They were mailed a one week ECG patch, that they applied themselves, and then returned that ECG patch. So in the end, after those exclusions, in participants that returned analyzable patches, 1057 participants were included in this ECG monitoring analytic cohort, of whom, 340 had atrial fibrillation during that ECG patch monitoring period.

The primary endpoint of the study was the positive predictive value of irregular heart rhythm detection that occurred during the ECG patch monitoring period. So a participant had to have an irregular heart rhythm detection to get notified that they were eligible to meet with a telehealth provider and receive an ECG patch monitor. And then, they had to have another irregular heart rhythm detection during ECG patch monitor wear. So the primary outcome was the positive predictive value of the first irregular heart rhythm detection for concurrent atrial fibrillation that occurred during ECG patch monitoring.

Dr. Carolyn Lam:

Okay. Cool. So many questions here, but maybe you should tell us the results first.

Dr. Steven Lubitz:

Sure. So the primary endpoint, the positive predictive value of the IHRD during ECG patch monitoring was 98.2% in the overall cohort. And it was similar between men and women, and those aged 65 or older, or those aged less than 65. And I should mention that, in this study, about 13% of participants enrolled in this study overall, were above the age of 65.

Dr. Carolyn Lam:

And you included more women than in prior similar studies. Right, Steve?

Dr. Steven Lubitz:

Yeah.

Dr. Carolyn Lam:

I was going to congratulate you for that.

Dr. Steven Lubitz:

Yeah, that's right. That's right. We're very excited to see that.

Dr. Carolyn Lam:

Okay, so that's cool. Wow. A positive predictive value of 92%. So couple of things here with-

Dr. Steven Lubitz:

98.

Dr. Carolyn Lam:

Sorry, 98%. That's right. Wow. Okay. Now with this AFib detection, it's always about duration. Right? And what do you call a positive alert? Could you maybe elaborate a bit about that here?

Dr. Steven Lubitz:

Sure. So I think this is an important point. A few points. One, the algorithm is designed. This particular algorithm requires at least 30 minutes of an irregular pulse to be detected, in order for a detection to occur. Which means that, this is unlikely to be detecting trivial amounts of atrial fibrillation. And indeed, that's what we observed. We observed that the median burden of atrial fibrillation was 7% among those who had AFib on the ECG patch monitor. We observed that the median longest episode of atrial fibrillation was seven hours. And just by way of comparison, in other studies in which ECG patch monitors have been distributed to people without this irregular pulse pre-screening, the burden is usually on the order of only a couple of percent, tops. So this, by nature, these types of algorithms, and this algorithm specifically, probably enriches for individuals who have a higher burden of atrial fibrillation. Meaning that, if these detections occur, then it's probably not detecting trivial amounts of atrial fibrillation.

Dr. Carolyn Lam:

Right. And a lot of it seems to send a very clear message that this study, and perhaps even the algorithm, is designed to be specific. Right? So that duration, as well as what you used as the outcome. How much price do you pay in terms of sensitivity? Do you know what I mean? Since we optimized for specificity, am I right to say that?

Dr. Steven Lubitz:

Sure, that's a great point. The algorithm is really optimized for specificity, as you mentioned. And although we didn't specifically calculate the sensitivity of the algorithm, in a secondary analysis, we examined the sensitivity of an IHRD during that ECG patch monitoring period, to detect any AFib that was documented on the ECG patch monitor, and it was about 67%.

So we know that we probably don't detect some atrial fibrillation. Largely, that's a function of this technology at the moment. It's very difficult to assess the pulse rate during periods of activity in motion. So a lot of these algorithms, and this algorithm in particular, doesn't operate during periods of motion. The accelerometers and the devices can tell the algorithm that motion is occurring, and then the algorithm won't operate on that information at that time. So a lot of this has to do with limitations of the technology at the moment.

Dr. Carolyn Lam:

Ah. So the detection probably occurs best at rest or at night.

Dr. Steven Lubitz:

That's exactly right. And we encourage participants to wear their devices at nighttime during the study.

Dr. Carolyn Lam:

Oh, cool. And then of course, I suppose a question you'd anticipate, I mean, we know about the Apple Heart Study, we know about the  watch study, and how does this compare? How is this technology different, and the results?

Dr. Steven Lubitz:

Essentially, one of the most remarkable things about these studies is that, it appears that this pulse rhythm pre-screening really enriches substantially for people who have atrial fibrillation. So for example, in the Fitbit Heart Study, we observed that about 32% of people who had an irregular heart rhythm detection and then returned an ECG patch monitor, had AFib on it. And by comparison, in the Apple Heart Study, that number was about exactly the same, just over 30% or so.

So when we further compare this pre-screening type approach to confirming atrial fibrillation, using an ECG patch monitor, with other approaches in which say, elderly individuals were mailed ECG patch monitors to screen for atrial fibrillation, we usually only see detection in the order of four to 5% of people. So this irregular pulse based pre-screening markedly enriches for atrial fibrillation. And we also know, this is only a one week ECG patch monitor, and if we monitor people longer than one week, we're likely to detect more atrial fibrillation, since this is often paroxysmal atrial fibrillation that we're detecting.

So there are a lot of similarities, and I think the point is that, these types of consumer electronic devices are going to be great tools for identifying undiagnosed atrial fibrillation in the community. I think we have a lot of challenges ahead of us, in terms of figuring out how to integrate that information into our routine healthcare workflow, and counseling consumers and users of these types of technology on exactly what they should be doing when they do get an alert. And then also, counseling providers on how to act on these findings, what they mean and how accurate the technology is.

Dr. Carolyn Lam:

Yeah. And I appreciated a sentence in your manuscript that talks of, what are our society guidelines going to say? If you could look into a crystal ball now, Steve, based on what you found, what would you advise both patients and clinicians, if you don't mind?

Dr. Steven Lubitz:

Well, I think that, in short, if a clinician is alerted by a patient, that they received in a regular heart rhythm detection on their device, in short, I would say, don't blow it off. Take it seriously. Because the odds are, that it does represent an abnormality, and the odds are that that abnormality is atrial fibrillation. And given the potential adverse consequences of undiagnosed atrial fibrillation, there's a real opportunity to intervene, and prevent morbidity in the patient. And then, if you're a consumer who happens to have one of these devices, and you've turned on this feature, and hopefully you have, if you do have an alert, don't blow it off. Contact a provider. Because it may very well mean that you have an irregular heart rhythm that merits attention, and could be addressed to prevent downstream consequences and morbidity for you.

Dr. Carolyn Lam:

Nice. And keep your Fitbit on at night.

Dr. Steven Lubitz:

Yes. And if you do want to maximize the utility of these algorithms that use photoplethysmography, probably wearing them at nighttime will maximize the sensitivity, or utility of the devices and algorithms.

Dr. Carolyn Lam:

Aw, that's just great. What nice take home messages. Thank you so much, Steve, for publishing this really unique and important study in Circulation.

So audience, you heard it right here on Circulation on the Run. From me, Greg, and Peder, please do tune in again next week.

Speaker 4:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Kevin Roedl and Sebastian Wolfrum, as well as Associate Editor Mark Link as they discuss the article "Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the Journal and its editors. We are your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, very interesting, a randomized clinical trial of temperature control after in-hospital cardiac arrest. But before we get to that exciting study, let's grab a cup of coffee, and jump in and discuss some of the other articles in the issue. Carolyn, would you like to go first?

Dr. Carolyn Lam:

Yes. Starting with a great quiz. So Greg, which is better? How about this? It's multiple choice. Is it A; transradial, or B; transfemoral access, in terms of post-procedural mortality?

Dr. Greg Hundley:

I'm going to go with transradial. It has been, hopefully, I'm okay on this. It just seems so many fewer complications.

Dr. Carolyn Lam:

But that's exactly that we need to meta-analyze the studies that have been done. Exactly what this paper did, led by Professor Valgimigli, from USI in Lugano, Switzerland. So what they did is, they performed an individual patient data meta-analysis of 21,600 patients, enrolled in seven multi-center randomized control trials, comparing the transradial with transfemoral access, among patients undergoing coronary angiography with or without PCI. And they found that transradial access was associated with a lower incidence of the primary outcome of all-cause mortality, and the co-primary outcome of major bleeding at 30 days, compared to transfemoral access.

There was also evidence for reductions in major adverse cardiac and cerebral vascular events, net adverse clinical events, vascular complications, excess site bleeding, and blood transfusion. MI, stroke, and stent thrombosis, did not differ. And crossover was higher in the transradial access group.

At predefined subgroup analysis, the authors confirmed that the benefit observed the transradial group was generally consistent across the majority of pre-specified subgroups, except for those with significant baseline anemia. Patients with baseline anemia appear to derive a substantial mortality benefit with transradial access rather than transoral access, compared to those with mild or no anemia.

So, the authors concluded, that the meta-analysis provides evidence that transradial access should be considered the preferable access site for PCI, in patients with acute coronary syndrome, supporting most recent recommendations on the preferential use of this radial approach. So you were right, Greg.

Dr. Greg Hundley:

Very nice, Carolyn. A really important piece of science to disclose to our listeners, in that hurried state, and moving quickly door to balloon times, et cetera. And here we find another positive outcome in study result for transradial approaches.

Well Carolyn, as we know, my next paper, it's really going to come to us from the world of preclinical science. And it pertains to hypertension, which is a common cardiovascular disease, and is related to both genetic and environmental factors. But the mechanisms linking the interplay between the domains of genetics and the environment have not been well studied.

Now, DNA methylation, a classical epigenetic modification, not only regulates gene expression, but is also quite susceptible to environmental factors. Thereby, linking environmental factors to genetic modifications. So therefore, Carolyn, these authors, including Professor Jingzhou Chen, from Fuwai Hospital, National Center for Cardiovascular Diseases, and the Chinese Academy of Medical Sciences, and the Peking Union Medical College, and their colleagues, felt that screening differential genomic DNA methylation, in subjects with hypertension, would be important for investigating this genetic environment interplay in hypertension.

So this study, Carolyn, like many from the world of preclinical science and circulation, incorporated both human and animal model subjects. Methodologically differential genomic DNA methylation in hypertensive, pre-hypertensive, and healthy control individuals, was screened using the Illumina 450K BeadChip, and then verified by pyrosequencing. Plasma oviduct glycoprotein 1, or OVGP1 levels, were determined using an enzyme-linked immunosorbent assay. And OVGP1 transgenic and knockout mice were generated to analyze the function of OVGP1.

Dr. Carolyn Lam:

Wow. Nice approach, Greg. And what did the authors find?

Dr. Greg Hundley:

Right, Carolyn. These authors found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension.

Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression caused an increase in blood pressure. Also, dysfunctional vasoconstriction, and vasodilation, remodeling of the arterial walls, and increased vascular superoxide stress and inflammation. And these phenomenon were exacerbated by angiotensin II infusion.

In contrast, OVGP1 deficiency, attenuated angiotensin II induced vascular oxidase, stress, inflammation, and collagen deposition.

Now pull down, and co-immunoprecipitation assays showed that myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas, inhibition of MYH9 attenuated OVGP1 induced hypertension and vascular remodeling.

Dr. Carolyn Lam:

So Greg, let me try to summarize, is that okay? So hypomethylation, at that specific site in the promoter region of the OVGP1 gene, is associated with hypertension, and induces its upregulation. The interaction of this OVGP1 with myosin heavy chain 2A contributes to vascular remodeling and dysfunction. And so, OVGP1 is a pro hypertensive factor, that promotes vascular remodeling by binding to this myosin heavy chain. So, really cool stuff. Thanks for teaching us.

Dr. Greg Hundley:

Very good.

Dr. Carolyn Lam:

Well thanks so much, Greg. And we go back to the clinical world now, and ask the question, what is the efficacy and safety of prophylactic full dose anticoagulation and antiplatelet therapy, in critically ill COVID-19 patients? So I'm going to tell you the results of the COVID-PACT trial. And this was a multi-center, two-by-two factorial, open label, randomized controlled trial, with blinded endpoint adjudication in 390 ICU level patients. So, severely ill patients with COVID-19, from 34 US centers. Patients were randomized to a strategy of full dose anticoagulation, or standard dose prophylactic anticoagulation. And in the absence of an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Full dose anticoagulation substantially reduced the proportion of patients experiencing a venous or arterial thrombotic event, and there was no benefit from treatment with clopidogrel. Severe bleeding events were rare, but numerically increased in patients on full dose versus standard dose prophylactic anticoagulation, without any fatal bleeding events, GUSTO moderate or severe bleeding was so significantly increased with full dose anticoagulation, but with no difference in all-cause mortality.

So in summary, in a population of critically ill patients with COVID-19, a strategy of prophylaxis with full dose, versus standard dose prophylactic anticoagulation, but not the addition of clopidogrel, reduced thrombotic complications, with an increased risk of bleeding, driven primarily by transfusions in hemodynamically stable patients, with no apparent excess in mortality.

Dr. Greg Hundley:

Very nice, Carolyn. What a important piece of information, as many of us around the world are taking care of critically ill patients with COVID-19.

Well, how about we see what is in the mail bag this week? So first, Carolyn, there's a Frontiers piece by Dr. Packer, entitled, “Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of the Nutrient Deprivation Signaling Autophagy Hypothesis.”

Next, there's a Research Letter, from Professor Airaksinen entitled, “Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-stage Renal Disease.”

Carolyn, there's another Research Letter, from Professor Solomon, entitled, “Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.”

Also, Carolyn, [a] wonderful Cardiovascular News summary from Tracy Hampton, reviewing three articles. First, “Mechanisms Behind Cannabis Effects on Heart Health.” The second, “Exercise Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1 Initiates the Cardiomyocyte Hypertrophic Response to Pressure Overload.”

Dr. Carolyn Lam:

Cool. There's also an exchange of letters between Doctors Jha and Borlaug on latent pulmonary vascular disease in therapeutic atrial shunt.

And finally, an On My Mind, by Dr. David Kass entitled, “What's EF Got To Do, Got To Do With It.” I love it. You must read it. It's so, so cool. All right. But now, let's go on to our feature discussion, shall we?

Dr. Greg Hundley:

You bet, Carolyn.

Welcome listeners, to our feature discussion today, and really delving into the world of in-hospital cardiac arrest, and how we manage those patients. And we have with us today, Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from University of Texas Southwestern in Dallas, Texas. Welcome gentlemen. Kevin, we're going to start with you. Can you describe for us, some of the background information that went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Kevin Roedl:

Thank you, Greg. We thank you for the kind invitation to this podcast. We're very likened to do this podcast with you. And so, talking about the background of hypothermia in-hospital cardiac arrest, we have to go back like two decades almost, because there were two studies in New England Journal of Medicine published 2002, who introduced mild therapeutic hyperthermia to the treatment in post cardiac arrest. Primary, these two studies show the benefit of the therapy in this kind of patients. And then, 2003, it was introduced in also the international guidelines. However, these studies only addressed out-of-hospital cardiac arrest patients, and also, only shockable rhythms. And so, the question arised over the years, what about other patients like non shockable rhythms, or also in-hospital cardiac arrest?

And so, that's basically was the primary aim of our study to address this special population. Because when you see the states, the numbers, there are 290,000 in-hospital cardiac arrests a year. So it's actually, a very large population. And there's no randomized control trial to show any benefit, or maybe harm, in this group. There were some observational studies, 2016 in China published. From China, in this group, they looked at the Get With The Guidelines registry, and actually, they saw that there was probably a negative influence of hypothermia in the study. However, it was only observational. So actually, there were no randomized control trials. And that primary hypothesis was, that we wanted to know actually, does thus mild therapeutic hyperthermia work in this group of patients in the in-hospital cardiac arrest setting? And what is the outcome? Is it like in the out-of-hospital cardiac arrest setting, or not?

Dr. Greg Hundley:

Wonderful, Kevin. And so, can you describe for us then, your study population and your study design?

Dr. Kevin Roedl:

Yes, of course. We did a randomized control trial. There were over 1000 people screened, and overall, we included 242. So you see how hard it is to get people in there. And actually, in terms of hypothermic temperature control, we are 120 about, and long term at 118, and the final others of the endpoints. And when we look at the baseline characters of these patients, they were well balanced actually, about 72 years. When we look at the initial cardiac arrest rhythm, that's interesting because about 70% non-shockable rhythms, and 25% shockable rhythms. And probably also interesting, the location of the cardiac arrest. Medical boards about 50%, and ICU or ED was 22%. So that's probably summed up the baseline characteristics of our study.

Dr. Greg Hundley:

Perfect. And so Kevin, can you describe for us what was the hypothermic target for the group that was going to have their temperature recused?

Dr. Kevin Roedl:

Yes, hypodermic target was 32 degrees to 44. And so two degrees Celsius, basically the same target like in earlier trials.

Dr. Greg Hundley:

Very nice. Well listeners, now we're going to turn to our second co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share with us the study results?

Dr. Sebastian Wolfrum:

Yes, Greg. Thank you very much for the opportunity to participate in this podcast. Only wanted to include unconscious patients, and therefore, we took a time and took 45 minutes after their cardiac arrest, to let the patients get away if they did so. We also excluded patients that had severe functional deficit before the cardiac arrest; since we could not really define the neurological outcome if we would've included those. And we didn't see any differences. Neither in mortality, not in the functional outcome, either when they're treated with 33 degrees Celsius, or whether normothermia was used.

The death rate after six month was in a range which is comparable to other in-hospital cardiac arrest studies, and higher than those performed in the out-of-hospital cardiac arrest studies. It was about slightly over 70% in both groups. And the number of patients with the good functional recovery after six months was 23% of the patients in the hypothermia group, and 24% of the patients in the normothermia group.

And if we look at only the survivors, we see that the ones which are worse functional outcome, were most of them dead after six months. We then also focused on the temperature curves in our patients, and to see whether we have achieved our goal. And we saw that we have reached the target temperature within four and a half hours after cardiac arrest in our hypothermia group. Which is not as fast that we had expected, but still in the range, which is comparable to other studies on this field. And we also saw that our control group was about 37 degrees, within the first 12 and 48 hours. So we truly avoided fever, which has not been done in every previous study on cardiac arrests.

Dr. Greg Hundley:

Very nice. And any differences between the hypothermia and normothermia groups, related to the age of the patient? Or, whether or not they had a shockable rhythm at the time of presentation?

Dr. Sebastian Wolfrum:

We saw as a result of our study, that age is a predictive factor for mortality. But age did not differ between our treatment groups, and therefore, did not interfere with our results. And we didn't see differences in the shockable or non-shockable rate in our patients in the different treatment groups.

Dr. Greg Hundley:

Thank you. Well listeners, now we're going to turn to our associate editor, Dr. Mark Link, one of our expert electrophysiologists at Circulation. And Mark, you have many papers come across your desk, and what attracted you to this particular paper?

Dr. Mark Link:

There were a number of things. One, it's hard to do RCTs in resuscitation, and I thought they did a very nice job with this RCT. Two, the subject of hypothermia, or therapeutic temperature management, is a very hot one in resuscitation. It's one of the few treatments in the past that have been shown to make a difference in outcome. And so, all of those trials were done in out-of-hospital arrest. So to have a trial done in in-hospital arrest was very intriguing also.

And I think we're all disappointed that it wasn't a positive trial, but we have to take the negative trials also. And I think, part of the reason it may have been a negative trial is because the normal thermic group avoided hyperthermia. And I think that's something that's coming out of a lot of these trials is avoid fever. It may not be so important to get hypothermic targets, actually, looks like it's probably not, but it looks like it's very important to avoid fever.

Dr. Greg Hundley:

Very nice. Well listeners, we're going to turn back to our expert panel here really, and start with you Kevin. Kevin, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Kevin Roedl:

Thank you for this interesting question. Yeah, a bunch of studies could be performed, especially maybe in the out-of-hospital cardiac arrest study, because we don't know. This fever harmful, we have to find certain subgroups in which this treatment works. So maybe in this subgroups there is data on this and it could be a benefit. So these are, I think, the two main topics that should be done in the future.

Dr. Greg Hundley:

Thank you. Sebastian, what are your thoughts?

Dr. Sebastian Wolfrum:

As Mark said, the hypothermic treatment was, for decades, maybe the only treatment which we could give to cardiac arrest patients, which has been proven to reduce mortality. And all other studies following didn't see any be benefit of hypothermia, not even in a subgroup. Also, the TTM trials did not. So I'm questioning myself, where is the original HACA study group that benefits? Where did this hide in the other studies?

So I would think, to do another study in out-of-hospital cardiac arrest patients, whether in ventricular fibrillation that had shown in the HACA trial to reduce mortality. This should be done in a similar way to the original study, to see whether there is this subgroup. People who support the idea of hypothermia also focus very much on the fast onset of their hypothermic treatment. And they say we saw a difference in mortality in the HACA trial, and we could very fast. And I think the other studies have to show that they cool as fast as the HACA study. So the main focus should be on the time calls of hypothermia after cardiac arrest, cooling very fast to a target temperature of 33 degrees, maybe holding on for 24, maybe 48 hours.

Dr. Greg Hundley:

Very nice, Sebastian. So focusing on the speed and the timing of that cooling. And Mark, anything to add?

Dr. Mark Link:

Yeah, so if I sit here with my writing group hat on for the HA and say, "What are we going to do for the resuscitation guidelines in 2025?" I think you look at the totality of the data for targeted temperature management. And I think, the main thing you say, walking away from this, is avoid fever. Don't let your patients get hot. I'm not sure you can say much more than that right now, until we get more data.

Dr. Greg Hundley:

Very nice. Well listeners, a really interesting provocative discussion today. And we want to thank Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from Dallas, Texas, bringing us the results of this study highlighting that hypothermic temperature control is compared with normothermia did not improve survival, nor functional outcome, at 180 days in patients presenting with coma after in-hospital cardiac arrest.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On The Run.

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join Circulation's Associate Editor Marc Ruel and Executive Editor James de Lemos as they summarize all of the articles found in Circulation's annual Cardiovascular Surgery-Themed Issue for 2022.

Dr. James de Lemos:

Hi, welcome to Circulation on the Run. Greg and Carolyn are off today. My name is James de Lemos. I'm the executive editor for Circulation and I'm delighted to be joined today by Marc Ruel, who's the editor of our themed issue on cardiac surgery and leads the development and curation of all of the cardiac surgery content in Circulation. Marc, congratulations to you, to Mike Fischbein, to the whole Circ team on another spectacular effort to pull together this issue. Glad to have you here today.

Dr. Marc Ruel:

Well, thank you very much, James. It's really a team effort. I want to salute and thank the vision of Circulation to really give an important component to surgical science. As you often hear me say, your surgery provides the most durable and robust solution for advanced heart disease, right? So it's a very important part of the mission of Circulation as the premier cardiovascular journal. I want to thank you and also Joe Hill, our Editor-in-Chief and obviously the entire team of Circulation as well as all staff. Augie [Rivera], who is helping us on this call as well as Nick [Murphy] and many others who have made this issue possible.

Dr. James de Lemos:

Well, great. Well, let's get to this. And you recognize as well Mike Fischbein, who's the Cardiac Investor surgeon at Stanford who helps to edit the themed issue and really helps us to think about basic science into surgical specialties. Let me start, Marc, with cardiac bypass surgery. We have actually three papers in this issue that cover various aspects of CABG. The first one is one that you and I really resonated with, I know, because we talked about this. It's a paper by Ono from the SYNTAX Extended Survival study titled "Impact of Patient Reported and Pre-Procedural Physical and Mental Health on 10 year Mortality after PCI or CABG." And this is a really fascinating paper, looked at obviously patients with left main or multi vessels coronary disease, but used objective measures of physical and mental function from the SF-36 score and calculated summary physical and mental component scores.

And then used those scores to evaluate whether there were treatment interactions based on physical and mental performance metrics with regard to the benefit of CABG over PCI. And really fascinating, first that there was an interaction and that the magnitude of benefit of CABG over PCI for multi vessel disease was substantially greater among individuals that had higher physical performance as well as mental health performance. What did you think of this paper and data? I know you wrote a tremendous editorial to this. So this is something that you thought about as we were bringing the paper in, but also had to think about in terms of putting this paper in the context of this daily decision for patients with multi vessel disease.

Dr. Marc Ruel:

Thanks James. And I agree with you. I think this is a bit of a new paradigm, right, to really think of the individual patient decision. It's a form of precision medicine if you will, with regards in this case to physical functioning and mental functioning prior to something as invasive as undergoing CABG. So I want to thank you, the Circulation leadership for inviting Anne Williams who's a cardiologist and yours truly to write a tutorial on this piece because I do think you, that is really, it is something that's quite intriguing and it makes sense. I think it is intuitive. I think clinicians who send patients to CABG and see them come back and hopefully in a good state, the very vast majority of the time, do realize nevertheless that CABG is a very invasive procedure. So the patient has to be actively involved in her or his recovery.

And interestingly as you pointed out, there's quite a effect modification if you will, between the benefits of CABG over PCI in the SYNTAX trial, which many will remember as having randomized either left main or three vessel disease, coronary artery disease patients to PCI versus CABG. So there was an effect modification in those patients who had better functioning, not only physical, but interestingly, even more so mental component score of the SF-36 prior to operation. These patients would derive a greater benefit from having been randomized to CABG over PCI. So I think this is obviously logical, it makes sense and the converse will be true, but it's nice to see it formalized, to my knowledge, for the first time in the context of a rigorous randomized control trial such as SYNTAX with a long-term follow up.

Now obviously this, like any study, there are a few caveats. Not every single patient had their SF-36 at baseline, but roughly about 90 plus percent of patients did. And I think that is quite an important clinical lesson in terms of allocating PCI versus CBG... I've often said over the years as a division head and someone who performs this operation often to my more junior colleagues, "Don't perform bypass surgery if someone's not going to live five years." That might be a bit of a simplistic approach but the data and the conclusions from this paper would support that. It's probably not too farfetched to think as such.

Dr. James de Lemos:

I think that's a great point and your clinical experience is so valuable for us here. One question I have is, do you think that it would be advantageous to objectively measure these parameters or is this something that the heart team or the surgeon at the bedside can assess intuitively? Because I think that's the question, right? Is this something... It certainly fits with what we would expect intuitively, that the more complete and durable procedure works better in people that are more robust physically, mentally. But should we be measuring this preoperatively to help make that decision or should this be a intuitive decision by expert clinicians?

Dr. Marc Ruel:

It's a great question and I think it's one that's not yet answered. I mean, the data from the paper would suggest that it has to be a formalized physical component score and mental component score and then ready allocate according to turnstiles. But that being said, we all know that we can address those issues by an end of bed type of eyeball test, right? So I think you're absolutely right. It may be that a clinical expert may provide the same type of information. Unfortunately we don't have that from the paper but I think there will be several subsequent papers that will look at this.

I think we are in the era of precision medicine and one would even think, why has this not been done before considering how invasive bypass surgery is? You guys, you cardiologists and primary care physicians all know that it takes patients six to 12 months to be recover from sternal bypass surgery. Surgeons all be, I'll say that with a blink in my eye, don't always necessarily always see that, right? And think that's more like a one to three months but the data would suggest including that from randomized controlled trials such as Feedem, that it takes six to 12 months. So it's been one of my career long quest if you will, to make bypass surgery less invasive. And I think this type of paper really provides the impetus to do so.

Dr. James de Lemos:

Well, thanks. Let's shift gears from a study that makes perfect sense and fits our preconceived notions to maybe one that doesn't. And this is a research letter from a group led by Steve Goldman at University of Arizona looking at long term mortality from the VA study comparing radial arteries with saphenous vein conduits in CABG. And this looked at long term mortality from this study, which included over 700 individuals that had extended follow up beyond 10 years. At one year, the cath data had not shown differences in patency in this study, I think important to interpret, but they find absolutely no difference in mortality within similar median survival of 14 to 15 years after CABG in this study. This was controversial among the editors when we discussed it, but what are your thoughts about these data and how this informs the radial artery question in CABG?

Dr. Marc Ruel:

Absolutely. You are so right in seeing that this was controversial because there are in fact two ways to look at this paper, right? You can drain the information that's in there or you can be a naysayer. And there's credence to both approaches, in my opinion. One could say, "Well, there was no difference at one year in terms of graph patency, so why would there be one at 14-15 years?" Well, the answer to that would be the durability of the compared conduits would be potentially different, right? One to five years is what we call the "golden age of saphenous vein grafts." And beyond that time period, one could perhaps expect that the radial artery would do better and start translating into clinical benefits. But that was not seen in this long-term analysis of the VA RCT that compared the use of a saphenous vein versus a radial artery.

The other way to perhaps find why the data is discrepant versus the methodology that had been performed before showing an advantage for the radial artery, would be that this is more perhaps of a real world type of experience. It comes from VA centers. Perhaps the expertise or the level of penetrance if you will, of use of the radial artery was not the same as other centers that maybe more "academic" and more vested into using the radial. So it's possible that those could have played a difference in nullifying if you will, the results of radial artery. But I nevertheless think that it's very important data. It makes us think and it is the largest single series data available that compares the radial to saphenous vein in a randomized control setting. So one cannot ignore it, and I think it's a very important piece of information that strengthens the surgery themed dish.

Dr. James de Lemos:

Thank you, Marc. And then the last CABG related article that I'd like to talk about is the prospective piece by Mario Gaudino and Bruce Lytle discussing the right internal thoracic artery for bypass. Asking the question, did we get it wrong? And this is really a very interesting piece. I encourage our readers to look at. That attempts really to reconcile the strong promise of the RITA with the disappointing results from art and the higher than expected failure rates in other trials. And what the authors do here really resonates with, Marc some of your points about individualizing treatment.

They point out that some of the worse than expected RITA results may reflect the artery to which the RITA has been anecimosed, simply that results when an anecimosed to non-LED targets aren't as good and potentially the experience of the operators. Their final conclusion really isn't that, the reader's not a superior conduit but that perhaps more individualization, both at the patient level but also based on physician experience, maybe what's needed to achieve the optimal selection of conduits and bypass results. What did you think of this? How did their conclusions and interpretation resonate with you?

Dr. Marc Ruel:

I agree with your summary James and I think you are spot on. What's interesting in addition from this frame of reference is that it unites the opinions of two key opinion leaders, i.e Mario Gaudino, who's essentially behind much of the data favoring the radial artery over the use of the saphenous vein. And Bruce Lytle, who historically was behind really proposing the use of the right internal thoracic artery and this bilateral ITA grafting if you will, and they are really coming together and putting their thoughts in a really sensible manner with regards to the points that you raised already. I would add in my own opinion, it's twofold. One, there's nothing biologically wrong with the right internal thoracic artery. So if the LITA works, the RITA should work as well from a biologic point of view. In fact, surgeons know that it's often bigger than the left internal thoracic artery and even more suitable or suited as account with.

What might be wrong is the applicability of it and that question really goes in a couple of important manners. Let's remember surgery is a craft, right? And it's a bit different. It's something I like to repeat, and it's not always captured. It's not really a pure science, like for instance, giving atorvastatin 40 milligrams would be this much more variability. And if you allow me a ten second example, if you were to take one of the bronze tools from Rodin, a grape sculptures, and take it away from him, the sculptures would not be as good. But if you were to give that tool to all semi-professional sculptures around the globe, the United States or France for instance, you may not see any benefit from that tool. So again, the crafty example of surgery is something that we have to compose with all the time.

So the RITA is a great conduit, but it's often not onto the LED per se. And we know that LED in an average patient, which doesn't exist, it's probably about 50% of the left heart profusion. So really the LITA has an advantage from that point of view. And when we compare studies that have used the RITA on a non LED target, there are in some cases bound to fail or at least be neutral. So I think the jury's still out but really the perspective that's denoted here, as you said, is a fascinating one coming from two key opinion leaders, each in their camp of radial versus right internal thoracic artery use.

Dr. James de Lemos:

Well, fabulous discussion, Marc. I really appreciate your insights. I think as cardiologists, the decision making about conduits can often be opaque, and this is really insightful. Let's switch gears and talk about valve surgery. We have two papers on valve surgery. First, an original research article by Johan Wedin from Uppsala on bicuspid aortic stenosis demonstrating adverse ventricular remodeling and impaired cardiac function prior to surgery with a heightened risk of postoperative heart failure. This is a really interesting study that looked at 271 patients that were undergoing surgical aortic valve replacement.

About half with bicuspid valves and half with tricuspid aortic valves, and they did comprehensive preoperative echo-cardiography and then followed the patients for four to five years after followup. And despite the expected finding that the bicuspid patients for younger, they had a substantially worse LV echo parameters pre-op with greater LV wall fitness, greater LV mass, worse preoperative LV function. And that translated even after successful AVR into increased risks for postoperative heart failure hospitalizations when compared to individuals with tricuspid aortic valves. And so the authors conclude that at least in contemporary practice, perhaps individuals are undergoing surgery for bicuspid aortic valve stenosis relatively later in the natural history, and they might merit closer civilians and possibly earlier intervention. What did you think of these data and do they make you think about your timing of recommendation for surgery with bicuspid aortic stenosis?

Dr. Marc Ruel:

Absolutely, and thank you James. I think this is very much in line with the current precision medicine led trends of operating earlier on patients with aortic stenosis. I think this is another subgroup that really deserves our attention. I think there are two things at play here with regards to patients who would have a comparable degree of hemodynamic aortic stenosis, either coming from a bicuspid aortic valve phenotype versus a normal tricuspid aortic valve phenotype. And I think the two important differences are, first, often the bicuspid valves are more prone to have a mixed disease and being more calcified as well. We often see surgery, what I call these black valves, like the valve is so calcified and necrotic that it actually turns black or navy blue in color. And this is not an uncommon finding in younger patients typically than tricuspid aortic valve patients.

The second thing is that we have to remember that bicuspid aortic valve disease is a lifelong illness. So these patients often go undetected for a very long time. They may be 55 years old compared to someone who's 68 and have the same degree of hemodynamic aortic stenosis and even AI. But the disease has really, in the bicuspid aortic valve patient, has probably been there for decades, sometimes even the whole life. So I think the effects on the left ventricle are destined to be worse, and also in terms of recovery after resection and after aortic valve replacement. So I think these are humbling tidbits that come from this paper that really even allow us in this era of early TAVR and now two randomized trials that have looked... One from Europe and one from Korea that have looked at asymptomatic aortic valve replacement interventions with favorable results towards early intervention. That really tell us that we should pay even closer attention to those patients with bicuspid aortic valve phenotypes.

Dr. James de Lemos:

Thanks, Marc.

And the second valve related paper is a prospective piece by [Rebecca] Becky Hahn, Vincent Chan and David Adams, evaluating current indications for a transcatheter edged edge repair of the mitral valve for primary mitral regurgitation. I thought this was a really well done piece and one that I appreciated focus specifically on primary micro-regurgitation. The piece includes a terrific algorithm for clinicians that really helps to guide decision making through a multidisciplinary approach.

They talk about the importance of specialized valve imagers, given the complexity of evaluating even the etiology of micro-regurgitation. The importance of excellence in determining the quantitation of severe MR, valve morphology and dimensions. And then really take it a step further to drive decision makings based on risk assessment of the patient. Obviously for primary MR for adequate surgical risk patients surgery is recommended, but then it walks through the decision making for which of the patients that are not surgical candidates might be optimal candidates for transcatheter techniques. How do you think this field's moving and how did this perspective change your thinking?

Dr. Marc Ruel:

This is such an excellent piece as you denoted. I think it really comes from three experts in the field representing different school of thoughts, if you will. One, more hybrid, more catheter based and more surgery based. And I think the jury's still out on transcatheter edge to edge repair, especially for primary marginal regurgitation. It's paradoxical as we're hoping that edge to edge repair would be primarily used in secondary MR and have great results. We now know and somewhat humbling, that it works not as great as we were hoping for secondary MR and it seems to be working pretty well where we already had a fantastic surgical therapy for it, which is essentially primary MR and Fibroelastic Deficiency type of lesions. Now, as you know, these patients do extremely well with surgery. There are several series of 800, 900, a thousand patients operated either conventionally or minimal invasively with maybe one death. Still one too much I would argue, but extremely low risks.

These are the healthiest patients that a cardiac surgeon often can operate because I would argue this probably an inverse correlation with coronary artery and peripheral vascular disease in those patients. It's hard to know. There's some elements of the answer that we don't have yet. What about the very long term follow up? What about 10 years? What happens when an edge to edge repair fails and it was for primary MR in a younger patient?

And I think the authors really captured those very important caveats quite elegantly and provide a very balanced view. So like you, I'm very happy with this piece. Lastly, I'll conclude by saying there's even controversy as to sub-clinical parameters with edge to edge versus surgical mitral valve pair for primary MR. What does two plus mitral regurgitation that is post-procedure, What does that mean? Is this something that's going to impact the patient at 10 years, at 20 years and perhaps churn, what was it initially, a great therapeutic solution into one that's not so desirable? So again, as I said, the jury's still out on this and I think these really captures the main element of the answer as we know them in 2022.

Dr. James de Lemos:

Excellent points. I think really, I love your conclusion that hopefully there will be a better transcatheter solution than this for patients that aren't surgical candidates, obviously, because it doesn't, unlike TAVR, this doesn't come close to matching the surgical option. The last couple of papers in the issue focus on putting cardiac surgery in the greater context of the patient experience and the healthcare system experience and are in the health services research phase. The first one is from multi-centered team led by Amgad Mentias at Cleveland Clinic and Ambarish Pandey at UT Southwestern. And it focuses on a new performance metric that they're calling, 90 day risk standardized home time for cardiac surgery hospitals in the US.

And this group has done several studies with this new metric that basically is attempting to evaluate performance at the patient level with a very patient-centric metric of how much time they spend at home. They've published previously using data from heart failure patients and post MI patients and now are extending this to cardiac surgery and using risk adjustment of time outside the hospital in the 90 days after surgery to evaluate the variability among cardiac surgical programs. And they find that the metric correlates with mortality and readmission, that higher volume surgical centers are associated with more time spent out of the hospital.

And then when they compare it more directly with approaches that are used to currently rank performance, they see that this results in some reclassification of performance categories versus the other metrics. It's early in the life of this new metric but I'm interested to see intuitively is a cardiac surgeon, how does another tool to evaluate your performance, your team's performance and your hospital's performance resonate? And does this have any intrinsic advantages to you over the other risk standardized tools that are currently being used? Certainly in the US I don't know what's happening in Canada.

Dr. Marc Ruel:

Great points, James and I agree, this is an impressive data set. It's almost on 1 million patients from more than 1000 centers in the US. And as you said, it is a new patient based metric. It's a bit of a patient before the outcome if you will, those PROs that are so more commonly now the object of research with regards to outcomes. I would somewhat simplistically say that there are three possible outcomes to any heart surgery, patient survives and feels better. That's number one, that's what we want to achieve for everybody. Unfortunately, there are two other outcomes that can happen. Patient survives but patient is not improved by the surgery or has a complication as a result of it and quality of life does not improve. And third, obviously the one that is the obvious, highly detrimental is that patient does not make it from the surgery.

But I think really what this paper highlights is the importance of really focusing on the first one by the number of days spent at home during the first 90 days post intervention, post-surgery itself. So I think it is really a marker of how well the patient's doing. It closes the loop, if you will, with the first paper that we looked at, in an observational large data set type of way. But it again calls to, how was the patient functioning pre-op? And that data, as we know, is not available from this series. So it could be three things essentially. It could be performance and definitely it pleases the mind to think that the performance of the institution i.e, the quality of the care provided has a huge impact. But it could also be two other things.

It could be the level of functioning of the patient. The ability to get back and spend many of those first 90 days at home versus not, of the patient himself or herself, depending on the various populations that are served by those institutions. And third, it could also be a little bit of a recurrent theme of mine and I apologize for that, but it could be the degree of invasiveness that's provided if you out of surgeries offered to these patients. So I think these are interesting paradigms. They are very important. Again, they're completely in line with precision medicine and I think that this performance measure, as you alluded to, is an important point because a patient who survives but doesn't go back home really is not deriving a benefit from any operation.

Dr. James de Lemos:

Yeah, great points. And I think this discussion really leads us into our discussion, the last paper, which is another paper that attempts to put surgery in the greater context of the population and environment in which patients come. And this is led by Aditya Sengupta and her team from Boston Children's Hospital evaluating contemporary socioeconomic and childhood opportunity disparities in congenital heart surgery. This is a really next level analysis of associations between socioeconomic status and outcomes after congenital heart disease surgery in children focusing in one high volume quaternary center in Boston. And what they did is developed a novel predictor that was a US census tract based nationally normed composite metric of contemporary childhood, what they called neighborhood opportunity. And this comprised 29 indicators across three domains.

The three domains were education, health, and environment and socioeconomic domains. And they classified the patients into very low, low, moderate, high and very high neighborhood opportunity. And then they looked at evaluations across multiple outcomes. They did not see any association of neighborhood opportunity with early deaths, which I think is encouraging, but they did see that children with lower neighborhood opportunity had longer length of stay, higher healthcare costs and then significantly higher late deaths following surgery when the multiple components of long term care of these children probably have time to operationalize. I found this sobering and a complex message that excellent cardiac surgery can deliver superb outcomes across all levels of opportunity but if these issues aren't addressed, there are financial implications, but more importantly, the long term benefits of the cardiac surgical procedures aren't fully realized. Interested to hear your thoughts on this and how this might apply more broadly even to adult surgery.

Dr. Marc Ruel:

I agree, James and I too, really love this paper. As you say, it is sobering. It's a paper for physicians, but I would argue it's probably bedtime reading for Mr. Biden, any other country leaders as well. Whether it's Mr. Macron or Mr. Trudeau. Definitely something that is shows that what happens after the hospital stay, even in something as complex as congenital heart surgery, performed at Boston children, obviously a great institution. But what is shown here is that the institution with its top quality outcomes as we know them to be, is a fantastic societal and outcome equalizer, if you will. But once that passage through the tertiary or coronary institution has occurred, then reality sets in. And the childhood opportunity index that the authors had previously published in JAMA proves to be, again, a very important predictor of how these kids do later on. So this refers really to the societal contract that we're all part of as physicians. And we obviously, a big part of our mission is to improve the outcomes in hospital, but also beyond it. And I think this paper illustrates this very nicely as you so eloquently summarized.

Dr. James de Lemos:

Well, thanks. And I'll just, before I hand it over to you to conclude and wrap up, just compliment you and Mike and the entire team, as well as the authors who have submitted not just these but so many other superb papers covering the full spectrum of surgical sciences Circulation. I'm proud for us to have the opportunity to share these terrific papers with our readers and with researchers. And congratulations again to you for pulling this together.

Dr. Marc Ruel:

Well, you're very kind and thank you, James. To you and Joe, Darren and our and entire editorial leadership for the important place given to surgery within Circulation. It's something that I believe is important and resonates with surgeons but also non-surgeons who are part of the greater cardiovascular community. So it's tremendously important and we're very thankful for that opportunity.

Dr. James de Lemos:

Well, I'd like to thank all our listeners for joining us today and remind you to tune in next week when Greg and Carolyn will be back for their regularly scheduled podcast.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first?

Dr. Greg Hundley:

You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations.

Dr. Carolyn Lam:

Wow. Sounds like a really large effort, Greg. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed.

Dr. Carolyn Lam:

Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial.

Dr. Greg Hundley:

The DELIVER trial. Carolyn, tell us about the DELIVER trial?

Dr. Carolyn Lam:

Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach.

And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail.

Dr. Greg Hundley:

Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function.

Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension.

Dr. Carolyn Lam:

Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find?

Dr. Greg Hundley:

Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension.

Dr. Carolyn Lam:

Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.”

Dr. Carolyn Lam:

There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg?

Dr. Greg Hundley:

You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Sunil Rao:

Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk.

Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications.

Dr. Greg Hundley:

Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects?

Dr. Sunil Rao:

Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge.

Dr. Greg Hundley:

Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population?

Dr. Sunil Rao:

We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation.

Dr. Greg Hundley:

Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results?

Dr. Sunil Rao:

Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms.

Dr. Greg Hundley:

And did you find the same results for the men and the women? And what about older individuals and younger individuals?

Dr. Sunil Rao:

Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study.

Dr. Greg Hundley:

Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies?

Dr. Gregory Lip:

Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants.

And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding.

Dr. Greg Hundley:

Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research?

Dr. Sunil Rao:

I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding.

Dr. Greg Hundley:

And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further?

Dr. Gregory Lip:

Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants.

Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance.

Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Michelle O'Donoghue and Associate Editor Parag Joshi as they discuss the article "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, very interesting feature this week. Evolocumab, another application for that in patients with established atherosclerotic cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other very interesting articles in this issue?

Dr. Carolyn Lam:

Oh, I'd love that. And I'd like to go first, because Craig, have you heard of hybrid debranching repair? I know, I know. I had that same look, and can I tell you about it? Because I found it so interesting.

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

Now, the management of complex aortic aneurysmal disease involving the visceral vessels is challenging due to its very high morbidity and mortality. After four decades of experience in open repair, only a few centers worldwide report laudable results. And numerous factors limit total endovascular repair, including the access to devices, experience in deploying them, and several anatomical restrictions. So, hybrid debranching procedures were introduced for those patients who are unfit for the open or endovascular excluded patients. And while these have been developed, small series have only been done and revealed a wide range of short term results. So, today's paper is very important, and it's from Dr. Oderich from UT Memorial Herman Texas Medical Center and colleagues.

It's a large multi-institutional study, which contains the five year outcomes in 200 patients offering greater clarity in the usefulness and limitations of these hybrid debranching repair procedures. What they found was that hybrid aortic debranching had a low early mortality when done in lower risk patients, but mortality remained very elevated in high risk patients. And so, this suggests that deep branching could be a good alternative in patients adequate for traditional open repair, although pulmonary complications are quite common. The bypass grafts to the visceral vessels had very good patency with a five year primary patency of 90%. Permanent spinal cord injury occurred in 6%, suggesting that deep branching in experienced centers may offer outcomes comparable to centers of excellence for open thoracoabdominal aortic aneurysm repair.

Dr. Greg Hundley:

Wow, Carolyn, very nice and so beautifully explained.

Dr. Carolyn Lam:

You know what, Greg? I'm on a roll and I'd like to tell you about one more, this time a preclinical study. First, a little bit about the background. You see, transplantation with pleuripotent stem cell derived cardiomyocytes, as we know, represents a very promising therapeutic strategy for cardiac regeneration. We even have first clinical studies in humans, but yet little is known about the mechanism of action underlying graft induced benefits. So in this paper from Dr. Weinberger from University Medical Center Hamburg in Germany and colleagues, they explored whether transplanted cardiomyocytes actually actively contribute to heart function by injecting these cardiomyocytes with an optogenetic off on switch in a Guinea pig cardiac injury model.

Dr. Greg Hundley:

Wow, Carolyn, this is so interesting. So what did they find?

Dr. Carolyn Lam:

So, light induced inhibition of endo-grafted cardiomyocyte contractility resulted in a rapid decrease in left ventricular function in about 50% of the animals that was fully reversible with the offset of photo stimulation. So in conclusion, this optogenetic approach demonstrated that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force generating myocardium can serve as a regenerative therapeutic strategy.

Dr. Greg Hundley:

Oh wow, Carolyn. That was just fascinating. Such incredible preclinical science in our journal. Well, Carolyn, this next paper comes to us from the world of myocarditis. And Carolyn, it involves a population based cohort of 336 consecutively recruited patients with acute myocarditis enrolled in both London and Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal Brompton Hospital, investigated the frequency and clinical consequences of dilated cardiomyopathy and arrhythmogenic cardiomyopathy genetic variants in this population based cohorts of patients with acute myocarditis. Now, Carolyn, all participants underwent targeted DNA sequencing for well characterized cardiomyopathy associated genes and their comparison to healthy controls, of which they had 1,053 that were sequenced on the same platform. Case ascertainment of their outcomes in England was assessed against their national hospital admission data, and the primary outcome was all cause mortality.

Dr. Carolyn Lam:

So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So these authors identified for dilated cardiomyopathy or arrhythmogenic cardiomyopathy associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of desmoplakin truncating variants in those with normal LVF, and then titin truncating variants in those with a reduced LVF. So Carolyn, importantly, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing would be considered in patients with acute myocarditis to help reassure the majority of individuals that don't have one of these genes, while improving the management of those that do have one of the underlying genetic variants. Very interesting findings from the world of myocarditis.

Dr. Carolyn Lam:

Great. And a great clinical take home message. Thank you, Greg. Well, this next paper sought to investigate the influence of age on the diagnostic performance of cardiac troponins in patients presenting with suspected myocardial infarction. Dr. Atul Anand from the BHF Center for Cardiovascular Science and University of Edinburgh and colleagues did this by performing a secondary analysis of the high stakes stepped wedge cluster randomized control trial that evaluated the implementation of a high sensitivity cardiac troponin ISA in consecutive patients presenting with suspected acute coronary syndrome.

Dr. Greg Hundley:

Oh wow. Carolyn. Super interesting, and very applicable clinically. So what did they find here?

Dr. Carolyn Lam:

In older patients presenting with suspected MI, the majority of cardiac troponin elevations are explained by acute or chronic myocardial injury or type two MI. The specificity and positive predictive value of high sensitivity cardiac troponin to identify myocardial infarction decreases with age and is observed, whether applying sex specific or age adjusted 99th percentile diagnostic thresholds or a rolling threshold for the triage of patients at high probability of myocardial infarction. Serial troponin testing incorporating an absolute change in troponin concentration increased the discrimination for myocardial infarction in older adults.

Dr. Greg Hundley:

Oh wow, Carolyn. Such clinically applicable findings in this particular study, particularly when managing our aging population. Well, Carolyn, how about we discuss some of the other articles in this issue. And there's a very nice In-depth piece by our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac Memory.” And then, there's an exchange of letters by Drs. Giannitsis and Mueller regarding the article, “Unexpected Sensitivity Issue of Three High Sensitivity Cardiac Troponin I-Assays in Patients with Severe Cardiac Disease and Chronic Skeletal Muscle Diseases.”

Dr. Carolyn Lam:

Nice. There's also a Research Letter by Dr. Szendroedi on “Impaired Mitochondrial Respiration in Humans with Prediabetes: A Footprint of Prediabetic Cardiomyopathy.” And there's a CV case series by Dr. Kalra on very high cholesterol mimicking homozygous familial hypercholesterolemia. Interesting case. Well, I suppose that wraps it up. Let's go on to the feature discussion, shall we, Greg?

Dr. Greg Hundley:

You bet.

Evolocumab. Welcome listers to this feature discussion on October 11th, and we're very fortunate today. We have with us Dr. Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag Joshi from UT Southwestern, the Associate Editor for this paper. Well, Michelle, can you describe for us some of the background information that went into the preparation of your study, and then what was the hypothesis that you wanted to address?

Dr. Michelle O'Donoghue:

Sure. Happy to do so, and thank you for having me. So by way of background, the Fourier study, which was previously published in the New England Journal, compared Evolocumab to placebo in 27,000 plus patients with established atherosclerotic cardiovascular disease, and Evolocumab significantly reduced the risk of major adverse cardiovascular events. But, the follow up duration was relatively short. Median follow up was 2.2 years. So this was now an open label extension study to Fourier known as the Fourier OLE study that allowed an additional median follow up time of five years, during which time all patients were now treated with open label Evolocumab. T.

He primary hypothesis that we were testing in this extension study was primarily to look at long term safety. We had limited data to really assure us of the safety of PCSK9 inhibitors over the course of several years. And so, safety was the primary hypothesis that we were testing, but also of course of key interest, during the parent Fourier study, we know that the benefit for cardiovascular risk reduction appeared to grow over time. So this was also an opportunity to see that pattern and to see whether or not there was in fact legacy effect for patients who were treated earlier with Evolocumab versus placebo.

Dr. Greg Hundley:

Very nice, Michelle. And so, sounds like we have a substudy of the Fourier trial. Can you describe for us a little bit more, for this substudy, your study population and your study design?

Dr. Michelle O'Donoghue:

Sure. So the patients enrolled in the open label extension were a subset of those who participated in the parent study. So as I previously mentioned, more than 27,000 participated in Fourier. It was a global study. For the open label extension, it was more than 6,500 patients who participated, and those were patients who were at sites in Europe and United States. And so, those patients were then followed on average for a meeting of five years. So that means that all together, patients who had been randomized to Evolocumab in the parent study had potentially more than eight years of drug exposure for us to examine safety.

Dr. Greg Hundley:

Very nice. And so, what did you find?

Dr. Michelle O'Donoghue:

Well, first, looking at the first hypothesis of safety, we saw no evidence that there was any increased risk of any adverse events of interest when it comes to PCSK9 inhibitors as a drug class, or achieving very low levels of LDL cholesterol. So there was no uptick in terms of neurocognitive events, the risk of diabetes. We do know that there was an increased risk of injection site reactions with the PCSK9 inhibitors, but not one that appeared to persist over time. So first was the safety, but importantly, I think that the more interesting results perhaps were those for MACE, for cardiovascular risk reduction. So we saw, even though all patients were being treated with open label Evolocumab during the extension phase, the benefit that was seen during the parent study persisted.

So there was a 15% reduction in the primary outcome, a broad composite of cardiovascular events. There was also a 20% reduction in the triple composite of cardiovascular death, MI, or stroke. And then perhaps of the most interest to your listeners is that there was a 23% reduction in cardiovascular mortality, and that was not something that was seen in the parent study. It really took time for that mortality benefit to emerge.

Dr. Greg Hundley:

Very nice. Michelle. Just a couple quick clarification points. Did you see these effects in both men and women? And then was there any impact of age on those results?

Dr. Michelle O'Donoghue:

Great questions. Some of those subgroup analyses are still ongoing, but no, we did not see any evidence of effect modification at first pass. But again, we'll be continuing to dig into all potential subgroups.

Dr. Greg Hundley:

Very nice. Parag, I know you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Parag Joshi:

Yeah, thanks. And congratulations again, Michelle. It's a really phenomenal study, and the findings, as you highlighted, are just really impactful for the field. I think for our journal at circulation, this is a really high impact finding in terms of extending out, giving us a rigorous way to look at long term follow up for people on PCSK9 inhibitors and really reassure that there is safety there. And as you highlighted, a sustained reduction in LDL cholesterol, other compounds in the space, Bococizumab in particular, that there were induced antibodies against the monoclonal antibody, and that sustained response was not there. So I thought that was also really reassuring, that over the course of eight years, we see sustained LDL reduction. And with that, really reaffirming the idea that the longer you can reduce LDL, there's an associated reduction in events.

And as you highlighted, the initial Fourier, there was some question about why there wasn't a CV death mortality signal while there was in the Odyssey outcome study and slightly different patient populations of course, but just really needed more time to start to tease that out. So all of this, I think this is the first that we're seeing this kind of long-term data on this impactful class of medications that really made this a fantastic manuscript for us at Circulation.

Dr. Greg Hundley:

Wow. Boy, Parag, I don't know that you could have stated that any better. So Michelle, looking forward, what is your group thinking? And then maybe just as your comment on the field in general, what do you think is the next study or series of studies that needs to be performed in this sphere of research?

Dr. Michelle O'Donoghue:

Well, I think he started to touch upon the areas of interest to us, is that I think that there are still many opportunities to answer more questions even within this existing data set. In particular, there was a dedicated neurocognitive substudy that was built into the parent study. And we also have that now through the extension period. So, that was a sort of more rigorous assessment of neurocognitive outcomes. And so, that's another analysis that we're going to be pursuing in the near future and I think is of potential key interest. And then beyond that, I think that the PCSK9 inhibitor class in general is just so interesting. There are additional compounds that are under study, such as small interfering RNA, so different mechanisms of getting to the PCSK9 protein. And I think it'll be reassuring to see whether or not they are consistent results, regardless of how you lower PCSK9, whether it translates into similar types of clinical benefit. So I think it's an exciting field. And then stay tuned. I think there'll be more to come.

Dr. Greg Hundley:

Parag, do you have anything to add? What do you see really as the next series of studies that might be performed here in this area of research?

Dr. Parag Joshi:

Yeah, I think Michelle hit the nail on the head that seeing confirmatory evidence here would be great. And then really, what's so exciting about this space is there's so much interest in ways to address this protein, including gene editing, vaccination against it. And now you're getting the necessary evidence that, hey, you can really suppress these levels in patients for years without concerning safety signals, at least from what we've seen so far. So that's more excitement as to long term ways to address cardiovascular risk.

Dr. Greg Hundley:

Wow. Well, listeners, we've been very fortunate today to have with us Dr. Michelle O'Donaghue from Brigham and Women's Hospital, and Dr. Parag Joshi from UT Southwestern as the Associate Editor of Circulation to really bring us these exciting results, highlighting that long term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events over eight years that did not exceed those observed in the original placebo arm during the parent Fourier study, and led to further reductions in cardiovascular events compared with delayed treatment initiation.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study."

Dr. Carolyn Lam:

Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA?

Dr. Greg Hundley:

Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure.

Dr. Carolyn Lam:

Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology.

However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes.

Dr. Greg Hundley:

Oh wow, Carolyn, this sounds really informative. So what did they find?

Dr. Carolyn Lam:

Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts.

Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis.

Dr. Greg Hundley:

Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction.

So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily.

Dr. Carolyn Lam:

All right. So the Paradise MI echo substudy, what did they find?

Dr. Greg Hundley:

Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure.

Dr. Carolyn Lam:

Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial.

Dr. Greg Hundley:

Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us?

Dr. Carolyn Lam:

Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction.

Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new.

Dr. Carolyn Lam:

Wow, that's interesting. So what did this paper find?

Dr. Greg Hundley:

Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.

So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting.

Dr. Carolyn Lam:

Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing.

Dr. Greg Hundley:

Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke?

Dr. Carolyn Lam:

Yep. In patients with EF, here we go.

Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation.

Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place?

Dr. Signild Åsberg:

Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question.

Dr. Jonas Oldgren:

My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies.

So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?"

And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment?

Dr. Carolyn Lam:

Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used?

Dr. Jonas Oldgren:

Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence.

And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study.

Dr. Carolyn Lam:

Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results?

Dr. Signild Åsberg:

Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients.

Dr. Carolyn Lam:

That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome?

Dr. Jonas Oldgren:

Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well.

So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started.

So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention.

Dr. Carolyn Lam:

Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit?

Dr. Signild Åsberg:

We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase.

Dr. Carolyn Lam:

I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds?

Dr. Signild Åsberg:

We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale.

Dr. Carolyn Lam:

Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results.

Dr. Signild Åsberg:

Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that.

We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation.

Dr. Jonas Oldgren:

And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials.

So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences.

And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients.

Dr. Carolyn Lam:

Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view?

Dr. Signild Åsberg:

Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention.

Dr. Jonas Oldgren:

I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study.

Dr. Carolyn Lam:

And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week.

Dr. Greg Hundley:

This program is Copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway.

Dr. Carolyn Lam:

Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we?

Dr. Greg Hundley:

Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom.

New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination.

Dr. Peder Myhre:

Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population.

Dr. Peder Myhre:

Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners.

Dr. Greg Hundley:

Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings.

Dr. Peder Myhre:

Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs.

Dr. Greg Hundley:

So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but-

Dr. Carolyn Lam:

Way to go, Peder. Way to go.

Dr. Greg Hundley:

Yeah. Well, the good news is, I can just say yes. I did know that.

Dr. Peder Myhre:

That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline.

Dr. Greg Hundley:

Oh, wow, Peder. So what did they find?

Dr. Peder Myhre:

So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59.

And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline.

Dr. Greg Hundley:

Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension.

Dr. Peder Myhre:

Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg?

Dr. Greg Hundley:

Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung.

They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag?

Dr. Peder Myhre:

So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag?

Dr. Greg Hundley:

Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.”

Dr. Peder Myhre:

And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn.

Dr. Carolyn Lam:

Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis.

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found?

Dr. Hanna-Kaisa Nordenswan:

Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis.

The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up.

Dr. Carolyn Lam:

Great. What did you find?

Dr. Hanna-Kaisa Nordenswan:

So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis.

Dr. Carolyn Lam:

Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings.

Dr. Jukka Lehtonen:

Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis.

So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients.

So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases.

Dr. Carolyn Lam:

Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk.

Dr. Mark Link:

Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid.

Dr. Carolyn Lam:

Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah?

Dr. Jukka Lehtonen:

I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well.

Dr. Carolyn Lam:

Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD?

Dr. Hanna-Kaisa Nordenswan:

Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up.

Dr. Carolyn Lam:

That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark?

Dr. Mark Link:

Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data.

Dr. Carolyn Lam:

Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first?

Dr. Jukka Lehtonen:

Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference.

I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group.

Dr. Carolyn Lam:

Thank you, Hannah?

Dr. Hanna-Kaisa Nordenswan:

Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography.

Dr. Mark Link:

Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue.

Dr. Carolyn Lam:

Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder.

Dr. Peder Myhre:

Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today.

Dr. Carolyn Lam:

Awesome. Well, here we go. Looks like we have a feature paper, Greg?

Dr. Greg Hundley:

Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first?

My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records.

Dr. Peder Myhre:

Wow, Greg. That sounds amazing. Tell us, what did they find?

Dr. Greg Hundley:

You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week.

And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations.

Dr. Peder Myhre:

Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI.

Dr. Greg Hundley:

Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find?

Dr. Peder Myhre:

So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today?

Dr. Greg Hundley:

Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic.

The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity.

Dr. Peder Myhre:

Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications?

Dr. Greg Hundley:

Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy.

Dr. Carolyn Lam:

So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper?

Dr. Peder Myhre:

So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants.

Dr. Greg Hundley:

Very nice, Peder. So, more about cardiac gene expression. So, what did they find?

Dr. Peder Myhre:

Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease."

Dr. Greg Hundley:

Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment."

Dr. Peder Myhre:

Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction."

Dr. Greg Hundley:

Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease.

Dr. Carolyn Lam:

You bet! Let's go, Greg and Peder.

Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time?

Dr. Jonathan Stern:

So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics.

Dr. Carolyn Lam:

I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that?

Dr. Jonathan Stern:

Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination.

So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions.

Dr. Carolyn Lam:

Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please?

Dr. Jonathan Stern:

So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events.

Dr. Carolyn Lam:

Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications?

Dr. Shinya Goto:

First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions.

Dr. Jonathan Stern:

Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it?

Dr. Shinya Goto:

Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19.

Dr. Jonathan Stern:

Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time.

Dr. Carolyn Lam:

That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it?

Dr. Jonathan Stern:

So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID.

In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now.

So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020.

Dr. Shinya Goto:

Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important.

Dr. Jonathan Stern:

I completely agree.

Dr. Carolyn Lam:

And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week.

Speaker 6:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism."

Dr. Carolyn Lam:

Welcome to Circulation On Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health Richmond, Virginia.

Dr. Carolyn Lam:

In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg?

Dr. Greg Hundley:

You bet, Carolyn. Well, how about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4.

Dr. Carolyn Lam:

Nice. Okay. Important question, what did they find?

Dr. Greg Hundley:

Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women.

Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome.

Dr. Carolyn Lam:

Oh, you are right. A lot of interesting data here. What's a take home message?

Dr. Greg Hundley:

Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step.

Dr. Carolyn Lam:

Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis.

Dr. Greg Hundley:

Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find?

Dr. Carolyn Lam:

Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC.

Dr. Greg Hundley:

Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight?

Dr. Carolyn Lam:

Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth?

Dr. Greg Hundley:

Yeah. Remember seven dwarfs, Sleepy.

Dr. Carolyn Lam:

Sleep.

Dr. Greg Hundley:

Very good. Great job, Carolyn.

Dr. Carolyn Lam:

Thank you.

Dr. Greg Hundley:

Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018.

Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression.

Dr. Carolyn Lam:

Okay, Greg. What did they find?

Dr. Greg Hundley:

Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years.

Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group.

Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large.

Dr. Carolyn Lam:

Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility.

Dr. Greg Hundley:

Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Yes, let's go Greg.

Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found.

Dr. Senthil Selvaraj:

Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites.

To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment.

The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity.

Dr. Carolyn Lam:

Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati?

Dr. Svati Shah:

Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself.

To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn.

Dr. Carolyn Lam:

Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically?

Dr. Manuel Mayr:

Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress.

Dr. Carolyn Lam:

Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that?

Dr. Senthil Selvaraj:

I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space.

The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet.

Dr. Svati Shah:

Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do.

Dr. Carolyn Lam:

And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps?

Dr. Manuel Mayr:

Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis.

Dr. Senthil Selvaraj:

That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process.

Dr. Carolyn Lam:

Anything to add, Svati?

Dr. Svati Shah:

No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also.

Dr. Carolyn Lam:

Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view?

Dr. Manuel Mayr:

Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure.

Dr. Carolyn Lam:

Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Keith Channon as he discusses the article "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, today's feature paper, something that's really been discussed a lot in the press and in lay public as well, the risk of myocarditis following sequential doses of the COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Everyone's going to want to tune into that one. But before we get there, shall we go through some of the key papers in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. How about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

So Carolyn, this first manuscript involves the world of machine learning and ECG interpretation. And as you know, novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy detection; however, it's low prevalence, 0.5%, and resemblance to common diseases really present challenges. So Carolyn, these authors, led by Dr. Rahul Deo from Brigham and Women's Hospital, sought to develop machine learning models to detect hypertrophic cardiomyopathy and differentiate it from other cardiac conditions using EKGs and echocardiograms with a robust generalizability across multiple cohorts.

So Carolyn, what did they do? They used single-institution hypertrophic cardiomyopathy EKG models that were then trained and validated on data from three academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of hypertrophic cardiomyopathy from aortic stenosis, long-standing hypertension, and cardiac amyloidosis. And then finally, automated detection was compared to manual interpretation by three cardiologists on a data set with a realistic hypertrophic cardiomyopathy prevalence.

Dr. Carolyn Lam:

Wow, incredible. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So the authors identified 74,476 EKGs for 56,129 patients and 8,392 echocardiograms for 6,825 patients across the four academic medical centers. Now, while ECG models trained on data from each institution displayed excellent discrimination of hypertrophic cardiomyopathy on internal test data, the generalizability was limited, most notably for a model trained in Japan and then subsequently tested in the United States. Now, however, when trained in a federated manner, discrimination of hypertrophic cardiomyopathy was excellent across all institutions, including for phenotypic subgroups. The models further discriminated hypertrophic cardiomyopathy from hypertension, aortic stenosis, and cardiac amyloid. Analysis of ECG and echocardiography paired data from 11,823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists.

So Carolyn, in conclusion, federated learning improved the generalizability of models that use EKGs and echocardiograms to detect and differentiate hypertrophic cardiomyopathy from other causes of left ventricular hypertrophy compared to training within a single institution. It will be really interesting to see the future applicability of these methods.

Dr. Carolyn Lam:

Oh, I'm such a fan of this work. Awesome. Thank you, Greg. My paper, it's a preclinical paper that uncovers a novel mechanism through which GATA4 mutations can lead to heart disease.

Dr. Greg Hundley:

All right, Carolyn, no quiz this time, I'm just coming right out. I'm reversing the question on the teacher. Tell me, what is GATA4?

Dr. Carolyn Lam:

I'm glad you asked, Greg. GATA4 is a zinc finger-containing DNA binding transcription factor essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Now, in today's paper, authors led by Dr. Srivastava from Gladstone Institutes in San Francisco, California, showed that GATA4 regulated cell-type-specific splicing through direct interaction with RNA and the spliceosome in human-induced pluripotent stem cell-derived cardiac progenitors.

An unbiased search for GATA4 interacting proteins in these human iPS cells revealed interaction with many members of the spliceosome complex. GATA4 also bound to pre-messenger RNAs in a sequence-specific manner that resulted in generation of alternatively spliced isoforms in human iPS cells. Many of these GATA4-dependent isoforms had distinct functional properties illustrating the importance of the splicing regulation to cardiac function.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the world of preclinical science. So what's the take home message here?

Dr. Carolyn Lam:

So these results essentially uncover a previously unrecognized function for GATA4 in regulating alternative splicing through direct RNA interaction. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, thus suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Dr. Greg Hundley:

Very nice, Carolyn, wow. Well, my next paper comes to us from back in the world of clinical science and it's from Professor Bertrand Cariou from L'institut du Thorax in Inserm UMR1087. So Carolyn, only a few genes causally related to plasma LDL-C levels have been identified so far, and only one, ANGPTL3, has been causally related to combined hypocholesterolemia. In this study, the authors aim to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in four generations of a French family and used next generation sequencing and identified a novel dominant rare variant in the LIPC gene encoding for hepatic lipase, which co-segregates with the phenotype. They characterize the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance based lipoprotein profiling and lipids.

Dr. Carolyn Lam:

Wow, what an interesting approach to study patients and families with hypocholesterolemia for once instead of hyper. Interesting. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the investigative team found that this unique LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase without affecting triglyceride lipase activity. And second, the hypocholesterolemic phenotype related to LIPC-E97G variant is due to an increased clearance of cholesterol within triglyceride-rich lipoprotein remnants predominantly by extrahepatic tissues.

Dr. Carolyn Lam:

Wow, so what are the implications?

Dr. Greg Hundley:

Right, Carolyn. So the novel gain of function variant in LIPC potentially represents the second cause of familial combined hypocholesterolemia after loss of function variants in ANGPTL3. And second, this study highlights an unexpected and critical role of the phospholipase activity of hepatic lipase encoded by LIPC in LDL-C metabolism and identifies it as a potential novel drug target. And then finally, Carolyn, additional data, I think, are warranted to clarify the impact of LIPC-E97G-related combined hypocholesterolemia on atherosclerosis and atherosclerotic cardiovascular disease due to the occurrence of documented coronary stenosis and evolutive carotid atherosclerosis in index cases.

Dr. Carolyn Lam:

Oh, very, very interesting. Thanks, Greg. Well, let's wrap up with the discussion of what else is in today's issue. There's an In Depth paper by Dr. Hadley on protecting cardiovascular health from wildfire smoke. There's also a Research Letter by Dr. Mevorach on myocarditis after BNT162b2 COVID-19 third booster vaccine in Israel.

Dr. Greg Hundley:

Right, Carolyn. And then I've got an exchange of letters from Professors Condello and Doenst regarding the article Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis from the REMOVE study: Results From a Multicenter Randomized Controlled Trial. Well, how about we get on to that feature discussion and learn a little bit more about COVID-19 vaccine and SARS-CoV-2 infection.

Dr. Carolyn Lam:

Let's go, Greg, thanks.

Dr. Greg Hundley:

Listeners, welcome to this September 6th feature discussion. And with us today, very interesting topic pertaining to vaccination for SARS-CoV-2 virus prevention. And we have with us Dr. Keith Channon from Oxford, England, to discuss this very interesting paper.

Well, Keith, welcome. I wanted to start by asking you, can you describe for us a little the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Keith Channon:

Thanks, Greg, for the opportunity to join you in this interesting conversation today. A group of cardiologists in the UK based at the University of Oxford, and principally at the University of Edinburgh, have been interested in the question as to whether COVID infection and/or COVID vaccination might lead to a higher incidence of myocarditis. And this is a topic that has been the subject of previous publications in the field.

And the provocation for us undertaking this study is that those previous studies have tended to be relatively small, and they've also not been able to necessarily test the details, time association, between myocarditis occurring in relation to sequential doses of vaccination. And that's important because, of course, we're now all receiving sequential doses of booster vaccines, and also those vaccines are often delivered, different vaccine types to different people in different countries. So we wanted to test whether there does appear to be a significant association between the occurrence of myocarditis and both COVID infection and the sequential different COVID vaccinations.

Dr. Greg Hundley:

Very nice. So Keith, can you describe for us, what study population did you enroll for this initiative? And then also, what was your study design?

Dr. Keith Channon:

Thank you. So, one of the really exciting things about this type of study and probably what makes it unique is that in countries with healthcare system, like that in the UK, which is the National Health Service, and universities, such as the University of Oxford and the University of Edinburgh, where there are very strong academic links between researchers and the National Health Service, we've been able to leverage an enormous data set, which is almost 43 million people in the UK who underwent vaccination against COVID-19. And rather than having to follow up 43 million people as part of a research study, we were able to take advantage of National Health Service centralized coded hospital records, number one. Number two, we took advantage of the UK's national database on COVID vaccination. And number three, we were able to look at hospital outcomes and also COVID testing.

So we were able to put together those three data sets for us to understand who developed COVID infection, who received COVID vaccination, and if so, which vaccine and when, and who then was admitted to hospital with a coded diagnosis of myocarditis. And in 43 million people, even though myocarditis is a very uncommon outcome, there were sufficient cases in that very large population to draw statistically meaningful conclusions.

I think that the UK is probably one of the few countries where this type of research can be done. And academic organizations, like our universities, the National Health Service, and also cardiovascular research funders, such as the British Heart Foundation, have put in a lot of resource and effort into giving us those capabilities to answer questions like this, and it's turned out to be a very powerful capability.

Dr. Greg Hundley:

Very nice. And so Keith, can you describe for us your study results?

Dr. Keith Channon:

So the study looked at a large 43 million people approximately over a period of time during the early to mid-phase of the COVID pandemic and looked at the likelihood that people would be diagnosed with myocarditis following either vaccination or COVID test positive. And we compared that likelihood with the likelihood of myocarditis occurring outside of those periods; because, of course, myocarditis occurs reasonably commonly in the general population. So this is another powerful aspect of the study design. It has a curated approach to look at the incidence of myocarditis in the 28 days after either vaccination or COVID infection, and it corrects, or it controls for that relative to the incidence of myocarditis outside of those sampling periods.

And what we found simply is that there is indeed, as previous studies have shown, a small but significant association between receiving a COVID-19 vaccine and being diagnosed with myocarditis in the following 28 days. However, in the population as a whole, the risk of myocarditis after vaccination is substantially lower than the risk of developing myocarditis after COVID infection, and I think that's an important finding. When we looked at subgroups, which is interesting, we found that the highest risk of developing myocarditis was in men less than age 40, so younger men, and that was one finding. And also, there did seem to be some differences in the risk of myocarditis occurring after different sequential vaccine doses.

Dr. Greg Hundley:

Keith, just a quick clarification point, what vaccines did you examine?

Dr. Keith Channon:

So in the UK, the three vaccines that have been largely used of the AstraZeneca Oxford viral vaccine, ChAdOx1, which was of course introduced very early in the UK, along with the Pfizer mRNA vaccine, and then laterally, Moderna vaccine, which of course in the UK was brought in rather later. And I think that's interesting because, as we can go on and discuss, there do appear to be some possible differences between those vaccines in terms of the likelihood of being diagnosed with myocarditis afterwards. But of course, even our experiment in 43 million people is not a perfect design because it's an observational study, and the periods in the pandemic when people were receiving principally the first two vaccines, which were by far the most numerous, was a different period in the natural history of the pandemic than when we started administering Moderna.

So it is important to recognize that it was not a prospectively controlled randomized trial of different vaccines; it was an observational study of pretty much a whole country and how it responded to the implementation of those different vaccines, which were all given to different people at different times of the pandemic. And of course, different times of the pandemic means that many different people will have already had a COVID infection and then gone on to have a booster or third vaccination. So, if you like, the immunological landscape in which these different vaccines were given in this very large population will have been different.

Dr. Greg Hundley:

Right. So I understand there are differences in timing, great point, but did you see any differences in the occurrence of myocarditis relative to either of the mRNA vaccines versus the adenovirus vaccine?

Dr. Keith Channon:

Yeah, we did. What we found is that, interestingly, there did appear to be a higher likelihood of being diagnosed with myocarditis in the 28 days after the mRNA-1273 vaccine, Moderna vaccine, and that was particularly, as I've already said, in men younger than the age of 40 years. I should say again, of course, that vaccine was given to the smallest number of people in the UK and it also tended to be rolled out later, so it was the second or third dose of the vaccine where that signal was most seen. But again, the second and third dose was by definition typically the booster vaccine later on in the pandemic. But that's what we found.

We did find these interesting differences. The incidence of myocarditis was increased after all of the vaccine doses compared with the period when people had not received a vaccine, but this was a very modest increase for most of the vaccines; but for the mRNA vaccines, particularly Moderna, it seemed to be more strikingly increased in the 28 days after the second or third dose of the vaccine. So I guess the message from that result is that there do seem to be these intriguing differences, both in the response to different COVID vaccines, either viral or mRNA or indeed even different types of mRNA vaccine, and possibly after the different dose of vaccines. In other words, after second or third sequential doses.

Dr. Greg Hundley:

And Keith, you mentioned a few minutes ago that you also had an opportunity to examine situations where maybe a patient had a vaccine and then subsequently contracted COVID, or vice versa, maybe they had had COVID and then later on had a vaccine, did you find any differences in the incidence of myocarditis in those situations as opposed to, perhaps, patients that really never had a documented episode of a COVID infection and then always had received the two vaccines and the booster dose?

Dr. Keith Channon:

Yeah, that's a harder question and is less powerfully addressed by our study, even though we were able to temporally control for that. Previous COVID infection did not preclude the risk of myocarditis after subsequent vaccine doses, but it wasn't a big enough signal to be able to give much detail over the relative risk between... Because if you think of the permutations of COVID infection plus or minus three vaccines, there's a lot of different sequential steps there, but having had COVID first doesn't prevent this small but significant signal; having a vaccine before you then get COVID infection does reduce your risk of myocarditis along with pretty much all other COVID complications.

So I think that's a really important public health message here and indeed the overarching finding of our study, which you could argue is the least exciting one but perhaps the most important, which is that you have a higher likelihood of suffering with myocarditis after COVID infection compared with after a COVID vaccination. And if you have COVID vaccination, in general, your risk of myocarditis is lower, obviously your risk of COVID infection is lower, and your risk of getting myocarditis after that COVID infection, should you still get one is also lower. So I think these are very intriguing, interesting findings that might make us think about mechanism and vaccine policy, but ultimately there are very strong endorsement of getting vaccinated to prevent the consequences of COVID-19.

Dr. Greg Hundley:

Excellent point. And then, Keith, just quickly, next study that maybe your group is considering in this space with this large database?

Dr. Keith Channon:

Yes. Well, I think there are two aspects to the study. Our group, which, as I've said, focuses mainly on large epidemiological data sets, having established this infrastructure in the UK led by universities like Oxford and Edinburgh and funded by the British Heart Foundation and others, means that we now have this infrastructure. So the surveillance and the data collection and the analysis is ongoing and we'll be able to add more cases and more power and more data, and there will be other studies that we can look at.

Second, I think there are some really quite interesting mechanistic studies that could be done based on these provocative findings to try to understand which different types of vaccines and, indeed, the immune responses which those vaccines generate. How are they linked to myocarditis and, indeed, to other cardiac and even other organ complications from COVID-19? And there are ongoing studies in the UK and elsewhere in the world that are very much focused on looking at the organ-specific consequences of COVID infection in patients who've been vaccinated or not. For example, using detailed cardiac MRI to look at the heart and look for subclinical myocarditis and to correlate any evidence of subclinical myocarditis with the immune signature, both the antibody and the cellular immune response, in the blood from those patients.

So I think what we're going to see here are enormous epidemiological studies with n=43 million, and we're also going to see more mechanistic experimental medicine immunology studies to try and tease out mechanism, and I think to understand two things. One is how to protect ourselves best against COVID-19, and what are the best vaccines and how best to use them. And second, if we can learn something about the mechanisms of myocarditis along the way, that's a really useful bonus that's come out of this pandemic.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Keith Channon for bringing us this very interesting article from Great Britain highlighting that, overall, the risk of myocarditis is greater following SARS-CoV-2 infection as opposed to a COVID-19 vaccination, and even really remains modest following sequential doses, including the booster dose of some of the mRNA vaccines.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is a copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through the journal and its editors. We're your co-hosts! I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease?

Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue?

Dr. Carolyn Lam:

Yeah, let's do that, Greg. Do you have a paper to share first?

Dr. Greg Hundley:

Oh, thanks Carolyn. Sure.

So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years.

Dr. Carolyn Lam:

Oh, right. So what were the results, Greg?

Dr. Greg Hundley:

Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting?

Dr. Carolyn Lam:

Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes.

Dr. Greg Hundley:

So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show?

Dr. Carolyn Lam:

Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues.

Dr. Greg Hundley:

Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes.

Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive.

Dr. Carolyn Lam:

Wow. I am always learning from these cool papers. Thanks Greg. So what were the results?

Dr. Greg Hundley:

So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene.

Dr. Carolyn Lam:

Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages?

Dr. Greg Hundley:

Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease.

Dr. Greg Hundley:

And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography.

Dr. Carolyn Lam:

Great, let's go.

Dr. Greg Hundley:

Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Rod Staples:

Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial.

Dr. Greg Hundley:

Very nice. And so the exact hypothesis that you were going to test was what?

Dr. Rod Staples:

At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone.

Dr. Greg Hundley:

Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include?

Dr. Rod Staples:

Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line.

Dr. Greg Hundley:

And just a quick breakdown, how many men, how many women?

Dr. Rod Staples:

Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment.

Dr. Greg Hundley:

Very nice. And so about 1100 patients. And then what were your study results?

Dr. Rod Staples:

Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification.

Dr. Greg Hundley:

Very nice. And then, what about clinical events? Did you examine those as well?

Dr. Rod Staples:

We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups.

Dr. Greg Hundley:

Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results.

Dr. Nick Mills:

Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease.

And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question.

Dr. Greg Hundley:

Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed?

Dr. Rod Staples:

Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use.

Dr. Greg Hundley:

And Nick, turning to you, what do you think is the next research study that could be informative in this space?

Dr. Nick Mills:

I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Kory Lavine and Associate Editor Thomas Eschenhagen as they discuss the article "Donor Macrophages Modulate Rejection After Heart Transplantation."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:          

I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature, we are going to the world of preclinical science and we are going to learn about a very important new finding pertaining to heart transplant rejection, and macrophages may modulate this, but before we get to that feature, how about we grab a cup of coffee and go through some of the other articles in the issue?

Dr. Carolyn Lam:            

I got mine. Would you like to go first, Greg?

Dr. Greg Hundley:          

You bet, Carolyn. Well, my first study comes to us from Dr. Michael Pencino from Duke University. Carolyn, this study was performed to understand the predictive utility of a previously derived polygenic risk score for long-term risk of coronary heart disease and its additive value beyond traditional risk factors and how that might be able to inform prevention strategies. To accomplish this, data from adults aged 20 to 59 free of cardiovascular health disease from the Framingham Offspring Study and the Atherosclerosis Risk in Communities, or ARIC Study, were analyzed. Now, since the polygenic risk score was derived from people of predominantly European ancestry, individuals who self-reported white race were those that were included.

Dr. Carolyn Lam:            

Oh, interesting, so what did they find, Greg?

Dr. Greg Hundley:          

Right, Carolyn. Somewhat surprisingly, they found that, among 9,757 participants, both the traditional risk factor score and the polygenic risk score where significantly associated with incident cardiovascular heart disease in young, early midlife, and late midlife. Now, the delta C index, when the polygenic risk score was added to the traditional risk factor, score was 0.03, 0.02, and 0.002 in the young, the early midlife, and the late-midlife participants, respectively.

Carolyn, despite a statistically significant association between the polygenic risk score and the 30-year risk of cardiovascular heart disease, the C index improved only marginally with the addition of the polygenic risk score to the traditional risk factor model among young adults and did not improve among midlife adults and, thus, Carolyn, the polygenic risk score, an immutable factor, has limited clinical utility for long-term cardiovascular heart disease prediction when added to a traditional risk factor model.

Dr. Carolyn Lam:            

I really like that, Greg, because I think it also tells us that the traditional risk factors, which we can do something about, are still very important. Isn't that great? Well, the next paper is about POTS. Remember what that is? Should I give you a quiz? All right. It's okay. POTS, or Postural Orthostatic Tachycardia Syndrome, is a disorder of orthostatic intolerance that primarily affects females of childbearing age. While the underlying pathophysiology of POTS is not fully understood, it has been suggested that autoimmunity may play a role. Now, the aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between 116 POTS patients and 81 healthy controls, and they were from Calgary, Canada, and Malmo, Sweden.

Dr. Greg Hundley:          

Carolyn, really interesting, so what did they find here?

Dr. Carolyn Lam:            

The investigators, led by Dr. Raj from University of Calgary in Canada, found that commercially available autoantibody concentrations to G protein-coupled receptors were not increased or altered in POTS patients relative to healthy controls as assessed using ELISA. Now, while this study suggests that these G protein-coupled receptor autoantibody concentrations alone cannot explain the pathophysiology of POTS, autoantibody activity and signals not picked up by ELISA should still be explored as these results may provide more insights into the pathophysiology of POTS.

Dr. Greg Hundley:          

Very nice, Carolyn. Well, my next study comes to us from the world of pulmonary arterial hypertension. Carolyn, clinical worsening is commonly used as an endpoint in pulmonary arterial hypertension trials. These authors, led by Dr. Steeve Provencher from the Institut Universitaire de Cardiologie Pneumologie de Quebec, aimed to assess the trial-level surrogacy of clinical worsening for mortality in pulmonary artery hypertension trials and whether the various clinical worsening components were similar in terms of frequency of occurrence, treatment-related relative risk reduction and importance to patients.

Dr. Carolyn Lam:            

Okay, so what did they find?

Dr. Greg Hundley:          

Right, Carolyn, so they searched MEDLINE, Embase and the Cochrane Library for trials evaluating the effects of pulmonary arterial hypertension on clinical worsening and, among 35 independent cohorts, so 9,450 patients, the effects of pulmonary arterial hypertension-specific therapies on clinical worsening modestly correlated with mortality. Additionally, study-level clinical worsening was not found to be a surrogate for mortality in pulmonary arterial-hypertension trials. Moreover, components of clinical worsening largely vary in frequency, response to therapy and importance to patients and, thus, are not necessarily interchangeable.

Dr. Carolyn Lam:            

Thank you, Greg. Can I tell you about some other papers in today's issue? There's a Research Letter from Dr. Cosentino on cardiorenal outcomes with ertugliflozin by baseline metformin use, and this is a post hoc analysis of the VERTIS CV trial.

Dr. Greg Hundley:          

Oh, very good, Carolyn. Well, I've got an exchange of letters from Professors Boriani and Steinberg regarding the article “Driving Restrictions and Early Arrhythmias in Patients Receiving a Secondary Prevention Implantable Cardioverter-Defibrillator, the DREAM-ICD-II Study.” There's also an ECG Challenge from Professor Gao entitled “Syncope in a 3-Year-Old Child During the Perioperative Period. What is the diagnosis? What Signs Point Toward Impending Life-threatening Event?”

Then, finally, there's a nice, On My Mind piece from Professor Greenland entitled “Insurance Payers Should Cover Selective Coronary Artery Calcium Testing in Intermediate Risk Primary Prevention Patients.” Well, Carolyn, how about we get on to that feature discussion and dive into the world of rejection after heart transplantation?

Dr. Carolyn Lam:            

Yay. Here we go.

Dr. Greg Hundley:          

Welcome, listeners, to this feature discussion on August 23rd. We have a very interesting article today to discuss with our author and associate editor pertaining to preclinical science and cardiac transplant rejection. Our author today is Dr. Kory Lavine from Washington University in St. Louis and our associate editor today is Dr. Thomas Eschenhagen from Hamburg, Germany. Welcome gentlemen.

Kory, we'll start with you. Can you describe for us some of the background information pertaining to the construct of your study and what was the hypothesis that you wanted to address?

Dr. Kory Lavine:              

Well, thank you for having me. Our study focused on heart transplant rejection, which remains a major clinical challenge that limits both the survival of heart transplant recipients as well as availability of donor hearts. Current clinical practice really focuses on suppressing the immune system in a global way, and that is somewhat effective, but carries important risks that include infection and life-threatening malignancies.

Many studies have appropriately focused on immune cells that infiltrate the transplanted heart that come from the recipient to search for new ways to suppress the immune system safely. What we've understood and learned over the past several years is that the donor heart has its own immune system and its own immune cells, and the majority of those immune cells that come with the donor heart are macrophages that can be broadly divided into two distinct lineages with different functions, tissue-resident macrophages, which lack the cell surface receptors CCR2, and monocyte-derived macrophages with expressed cell surface receptors CCR2. We tested the hypothesis in this study that these macrophages that come with the donor heart remain active for a period of time after transplantation and play important roles in either suppressing or accelerating heart transplant rejection.

Dr. Greg Hundley:          

What was the hypothesis that you wanted to address with your study?

Dr. Kory Lavine:              

Yeah, so our prior work and others' work within this field had suggested that tissue-resident macrophages, CCR2-negative macrophages, are inflammatory, and CCR2-positive macrophages have the opposite functions being inflammatory and play roles in potentiating and initiating inflammation in the heart. In this study, we hypothesized that CCR2-negative macrophages would protect from rejection, while CCR2-positive macrophages may promote heart transplant rejection and could serve as a new therapeutic target to prevent rejection in transplant recipients.

Dr. Greg Hundley:          

Excellent. Kory, can you describe for us the study design that you used to test your hypothesis?

Dr. Kory Lavine:              

Yeah. The study design and approach we used involved a mouse model of heart transplantation where we transplant a donor heart into a recipient mouse that's fully mismatched at all the MHC loci, and this serves as a nice model for both cellular and antibody-mediated rejection. To facilitate tracking these donor macrophages, we used various genetic lineage tracing systems and, to study their phenotypes, we used single-cell RNA sequencing and, to understand their function, we used mouse models that allow us to specifically deplete each of the donor macrophage populations as well as genetic models to manipulate their activation and signaling.

Dr. Greg Hundley:          

The outcome measures were going to be what?

Dr. Kory Lavine:              

Yeah. The outcome measures for transplant rejection in this mouse model are allograph survival, so the survival of the transplanted heart. We're able to directly look at how much rejection is present by histopathology, and then we're able to observe various mechanistic features using detailed phenotyping such as single-cell RNA sequencing and T-cell activation assays.

Dr. Greg Hundley:          

Very nice, Kory. Well, all, our listeners, we're very excited to hear what were your study results?

Dr. Kory Lavine:              

We learned that donor macrophages are dynamic and they survive for a period of time after transplantation or eventually lost due to transplant rejection. When we phenotyped the macrophages that came from the donor heart, we learned that they remained transcriptionally distinct from immune cells that enter the heart that were derived from the recipients, and they had important and distinct functions. If we depleted the tissue-resident macrophages that were CCR2-negative, we observed reduced allograph survival and increased rejection. If we depleted CCR2-positive macrophages that came from the donor heart, we observed improved allograph survival and reduced rejection.

Mechanistically, we learned that CCR2-positive macrophages are activated through a MyD88-dependent pathway and, if we inhibited MyD88 cytokines which controls the expression of pro-inflammatory cytokines and chemokines, we could prolong the survival of the donor heart for a very significant period of time, reduce rejection and prevent the development of T-cells that would attack the donor heart. From a mechanistic aspect, what we uncovered is that this signaling pathway in CCR2-positive macrophages regulated the recruitment of an activation of antigen-presenting cells which played important roles in generating T-cells that would target the transplanted heart.

Dr. Greg Hundley:          

It sounds like a really informative and leap forward in the whole sphere of transplant rejection. Well, listeners, now we're going to turn to our associate editor, Dr. Thomas Eschenhagen.

Thomas, you have many papers come across your desk. What attracted you to this particular paper and then, secondly, how do you put the results of this study really in the context of other research examining heart transplant rejection?

Dr. Thomas Eschenhagen:          

Yeah, thanks for having me. I mean, first, we got attracted by this paper because it's somewhat an out-of-the-box approach. It's not the standard approach to improve the systemic immunosuppression as many studies did and with actually a lot of success over the last 30 years, survivor got much better. There had been a lot of progress in the field of transplantation medicine as we all know, but as Kory said already, we still have 30% rejection, and these immunosuppressions come at a price. Having this study which turns around somehow the argumentation and looks at the donor organ was something which really attracted us. It uses advanced methods and it applies somewhat in a practical way a concept which emerged over the last, I don't know, maybe decade this concept that macrophages are really very different kind of cells. They're all called macrophages, but they're quite different and even maybe in certain respects having opposing effect.

I think many people know about this M1/M2 concept. It's CCR2 receptor positive and negative. It's criticized by some people, but here we see that it really seems to be really important and, of course, then the third argument why we really like the story is that it has a specific, clear translation impact. I mean, looking at the heart, the donor heart, and potentially even treating the donor heart before transplanting it is something which comes immediately out of the story, and that's something which we found super attractive.

Dr. Greg Hundley:          

Really interesting, so really understanding the mechanism and focusing on donor hearts. Well, listeners, let's circle back with Kory.

Kory, given that, what do you think is the next study that really needs to be performed in this sphere of research?

Dr. Kory Lavine:              

I think Thomas said it exactly as we're thinking about it, so the next area that we're really excited to attack and we're hopeful that the field will focus on is ways to build methods and technologies to treat the donor heart between the time of procurement and the time of transplant, when it's being transported and potentially even being perfused for a period of time. We're really interested in finding approaches to identify small molecules and other potential biologic therapies that could be used to prevent the activation of donor CCR2-positive macrophages.

It's a really attractive approach because treating the donor heart ex vivo decreases the risk of adversely affecting other organs that may be transplanted if you're treating the donor, for instance, and it may decrease the risk of immunosuppression and infection by not having to treat the recipient and we're catching the heart in this window where the risks are much lower.

The other area that we're really excited to focus on is trying to identify the exact mediators that are generated from donor CCR2-positive macrophages that mediate the recruitment and activation of antigen-presenting cells because that would represent another potential therapeutic target.

Dr. Greg Hundley:          

Very nice. Thomas, what are your thoughts about what might be the next study to be performed really in this sphere of research?

Dr. Thomas Eschenhagen:

It's obviously something rather a question to Kory than to me, but I agree to what he said. I think it is pretty obvious what are the next steps mechanistically on the one hand, but practically on the other hand. I mean, at this point, we are at the mouse level, so the question is to which extent can this concept be translated into larger animals and then finally in humans? I was wondering, given these newer methods to keep donor hearts alive for long, extended periods, I was wondering which extent you are already collaborating with the respective groups who develop this approach because that obviously would increase the window of opportunity here for drugs. I think it's really an exciting and pretty visible next steps which we see here, and I can just hope that you're going this path and that it will be successful.

Dr. Greg Hundley:          

Kory, any thoughts on those collaborations that Thomas just spoke of?

Dr. Kory Lavine:              

We're definitely establishing collaborations to focus on ex vivo profusion of donor hearts because that's, as Thomas mentioned, is a perfect window to manipulate the immune populations that are within the donor heart. Those studies have to be team science, they have to be collaborative and they have to have a focus on large animals and then moving into clinic. We're definitely forming those collaborations and excited to work as a group.

Dr. Greg Hundley:          

Very nice. Well, listeners, what an exciting paper to discuss here as part of this feature discussion from the world of preclinical science. We want to thank Dr. Kory Lavine from Washington University in St. Louis, Missouri, and also our own associate editor, Dr. Thomas Eschenhagen from Hamburg Germany, for really bringing us this research study highlighting that distinct populations of donor and recipient macrophages coexist within the transplanted heart, and donor CCR2-positive macrophages are key mediators of allograph rejection and deletion of MyD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograph survival.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley:          

This program is copyright of the American Heart association, 2022. The opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first?

Dr. Greg Hundley:

You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality.

Dr. Greg Hundley:

Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality.

Dr. Carolyn Lam:

Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results.

Dr. Greg Hundley:

Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm.

Dr. Carolyn Lam:

Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified.

Dr. Carolyn Lam:

Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation.

Dr. Greg Hundley:

Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension.

Dr. Carolyn Lam:

Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial.

Dr. Greg Hundley:

Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction.

Dr. Carolyn Lam:

Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that?

Dr. Daniel Burkhoff:

Yeah, no, we debated how to pronounce it. HFQRef…a question mark?

Dr. Carolyn Lam:

HFQRef. Oh my goodness. What are we going to come up with next?

Dr. Daniel Burkhoff:

And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see.

Dr. Carolyn Lam:

No, I'm not knocking you down.

Dr. Daniel Burkhoff:

But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment.

Dr. Carolyn Lam:

That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF?

Dr. Philipp Lurz:

Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction.

Dr. Philipp Lurz:

And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results.

Dr. Philipp Lurz:

And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did.

Dr. Carolyn Lam:

Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found?

Dr. Philipp Lurz:

We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising.

Dr. Philipp Lurz:

And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%.

Dr. Philipp Lurz:

And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix.

Dr. Philipp Lurz:

So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling.

Dr. Philipp Lurz:

The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly.

Dr. Carolyn Lam:

Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message.

Dr. Daniel Burkhoff:

Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point.

Dr. Daniel Burkhoff:

As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output.

Dr. Daniel Burkhoff:

In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction.

Dr. Daniel Burkhoff:

That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output.

Dr. Daniel Burkhoff:

Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding.

Dr. Daniel Burkhoff:

The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF.

Dr. Daniel Burkhoff:

So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be.

Dr. Daniel Burkhoff:

And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization.

Dr. Daniel Burkhoff:

And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients.

Dr. Carolyn Lam:

Philip, what are your thoughts?

Dr. Philipp Lurz:

No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that.

Dr. Philipp Lurz:

But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further.

Dr. Carolyn Lam:

If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur?

Dr. Philipp Lurz:

I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same.

Dr. Carolyn Lam:

Nice. And Dan, what do you think?

Dr. Daniel Burkhoff:

Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn.

Dr. Daniel Burkhoff:

I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning,

Dr. Daniel Burkhoff:

I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper.

Dr. Carolyn Lam:

Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up.

Dr. Carolyn Lam:

I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week,

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit hajournals.org.

This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we?

Dr. Greg Hundley:

You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research.

Dr. Greg Hundley:

Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle.

Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.”

Dr. Carolyn Lam:

There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we?

Dr. Greg Hundley:

You bet, Carolyn. Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto.

Dr. Carolyn Lam:

We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please.

Dr. John McMurray:

Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.

Dr. John McMurray:

Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite.

Dr. Carolyn Lam:

Thank you so much. That was really clear. David, are you going to tell us why this decline occurs?

Dr. David Cherney:

Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR.

Dr. David Cherney:

In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study.

Dr. Carolyn Lam:

Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David.

Dr. David Cherney:

Pleasure. Thank you.

Dr. John McMurray:

Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern.

Dr. Carolyn Lam:

Thank you, John. In fact, you're saying, stay the course, right-

Dr. John McMurray:

I have.

Dr. Carolyn Lam:

... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience?

Dr. Kausik Umanath:

Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are.

Dr. Kausik Umanath:

The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored.

Dr. Kausik Umanath:

The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes.

Dr. Carolyn Lam:

Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan?

Dr. Brendan Everett:

Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change.

Dr. David Cherney:

Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time.

Dr. David Cherney:

The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term.

Dr. Carolyn Lam:

Ian?

Dr. Ian Neeland:

I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights.

Dr. Ian Neeland:

I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding?

Dr. John McMurray:

Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines.

Dr. John McMurray:

I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working.

Dr. David Cherney:

Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning.

Dr. John McMurray:

But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists.

Dr. Carolyn Lam:

Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik.

Dr. David Cherney:

I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us.

Dr. Carolyn Lam:

John?

Dr. John McMurray:

Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating.

Dr. Carolyn Lam:

Kausik?

Dr. Kausik Umanath:

That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into.

Dr. Kausik Umanath:

I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on?

Dr. Carolyn Lam:

Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:          

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:            

It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials.

The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we?

Dr. Greg Hundley:          

You bet, Carolyn. And how about if I go first?

Dr. Carolyn Lam:            

Please.

Dr. Greg Hundley:          

So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control.

Dr. Carolyn Lam:            

Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg?

Dr. Greg Hundley:          

Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease.

Dr. Carolyn Lam:            

Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age.

Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart.

Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls.

Dr. Greg Hundley:          

Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find?

Dr. Carolyn Lam:            

Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients.

Dr. Greg Hundley:          

Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.”

Dr. Carolyn Lam:            

There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we?

Dr. Greg Hundley:          

You bet.

Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all.

And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Paul Ridker:

Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts.

The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there.

In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting.

Dr. Greg Hundley:          

Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design?

Dr. Paul Ridker:

We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like.

What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in.

And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated.

It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it.

Dr. Greg Hundley:          

Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women.

Dr. Paul Ridker:

No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results.

Dr. Greg Hundley:          

Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article?

Dr. Allan Jaffe:  

Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look.

So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on.

Dr. Greg Hundley:          

Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts?

Dr. Robert Harrington:  

So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials?

And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results.

And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial.

Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here.

It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know.

Dr. Greg Hundley:          

Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform?

Dr. Paul Ridker:

Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture?

Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with.

On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with.

Dr. Greg Hundley:          

Allan, turning to you. What do you think is a next study to perform in this space?

Dr. Allan Jaffe:  

Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial.

Dr. Greg Hundley:          

And Bob, your thoughts.

Dr. Robert Harrington:  

Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial."

But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth.

Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?"

I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this.

On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently.

Dr. Greg Hundley:          

Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events.

And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures.

Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen.

And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address?

Dr. Eric Van Belle:          

Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population.

And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device.

In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease.

So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure.

Dr. Greg Hundley:          

Very nice. And Eric, can you describe for us, your study design, and who was your study population?

Dr. Eric Van Belle:          

Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population.

And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure.

Dr. Greg Hundley:          

So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find?

Dr. Eric Van Belle:          

So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population.

But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population.

Dr. Greg Hundley:          

Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures?

Dr. Emmanouil Brilakis:

Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation.

I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds.

Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is.

Dr. Greg Hundley:          

Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research?

Dr. Eric Van Belle:          

Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this.

So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome.

Dr. Greg Hundley:          

And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space?

Dr. Emmanouil Brilakis:

Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient.

So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week’s episode of Circulation on the Run features author Ami Aronheim and Associate Editor Thomas Eschenhagen as they discuss early cardiac remodeling that promotes tumor growth and metastasis.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor of the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, today we're taking a look at the cardio-oncology world in our feature discussion, but in a very interesting reverse way. Cardio-oncology, what would you think of? I suppose the effects on the heart of cardiotoxic drugs that we use in oncology, right? But this feature paper looks at it the other way around and says does the heart and its remodeling promote tumor growth and cancer? Terribly interesting data coming right up after we discuss a couple of papers, well, all the papers in today's issue.

So I want to start. Greg, do you remember what parasites are and why they're important?

Dr Greg Hundley: Well, Carolyn, this is actually one of the things that I do remember because we study the parasites when we're looking at microcirculatory dysfunction after the administration of potentially cardiotoxic agents for treatment of cancer. But how about you tell us a little bit more.

Dr Carolyn Lam: This is going to be very basic just for all of us. Now, the blood vessels are composed of endothelial cells and mural cells. Endothelial cells line the vascular lumen. Whereas the mural cells, which include faster smooth muscle cells and parasites adhere to the abluminal surface of the endothelium. Parasites regulate vessels stabilization and function, and their loss has been associated in diseases such as diabetic retinopathy, vascular malformation, stroke, and cancer. Just like you said, Greg.

Now here we have a series of elegant experiments by Dr Mariona Graupera from IDIBELL in Barcelona and colleagues who use genetic mouse models to identify the specific molecular signature of mural cells at early and late stages of the energetic process and unveil their biological relevance. Their results show that phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator of parasite, proliferation and maturation in vessel growth. PI3K-beta deletion in parasites triggered early parasite maturation, whereas exacerbated PI3K signaling delayed parasite maturation, and thus vessel maturation during angiogenesis.

Dr Greg Hundley: So clinically what's the take home message here.

Dr Carolyn Lam: The proposed model of mural cell maturation together with the tools developed would be instrumental for the characterization of mural cells in pathologies associated with deregulated vessel growth, such as ischemia stroke, vascular malformation, diabetic retinopathy, and cancer. The therapeutic potential of modulating parasite biology through PI3K signaling provides a new window of clinical intervention for vascular related diseases in which parasite dysfunction contributes to their onset and or progression.

Dr Greg Hundley: Very nice, a very important cell type Carolyn. Well, my paper comes from Professor Xiang Qian Lao from The Chinese University of Hong Kong. In this paper, the authors investigated in 140,072 adults all greater than the age of 18, without hypertension who joined a standard medical screening program with 360,905 medical exams that occurred between the years of 2001 and 2016. They assess the joint associations of habitual physical activity and long-term exposure to find particulate matter with the development of hypertension in Taiwan.

Dr Carolyn Lam: Wow. A huge study. So what did they find Greg?

Dr Greg Hundley: After adjusting for a wide range of co-variants including a mutual adjustment for physical activity or particulate matter, a higher physical activity level was associated with a lower risk of hypertension. Whereas a higher level of particulate matter was associated with a higher risk of hypertension. No significant interaction was observed between physical activity and particulate matter.

So Carolyn in conclusion, a high physical activity and a low particulate matter exposure were associated with a lower risk of hypertension. What we would expect the negative association between physical activity and hypertension remain stable in people exposed to various levels of particulate matter. The positive association between particulate matter and hypertension was not modified by physical activity. Thus, Carolyn the authors believed their results indicate that physical activity is a suitable hypertension prevention strategy for people residing in relatively polluted regions.

Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg, Hey, I've got a question for you. Do you measure a high density, lipoprotein cholesterol or HDL cholesterol? Do you measure the levels or do you measure the particle concentration in your clinical practice?

Dr Greg Hundley: I think just the levels Carolyn.

Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out about the particle concentration. Let's review a little bit about that. So the HDL cholesterol is an established athero-protective marker, particularly for coronary artery disease, but HDL particle concentration may better predict the risk. However, the associations of HDL cholesterol and HDL particle concentration with ischemic stroke and with myocardial infarction among women and blacks has not been well defined. And so Dr Rohatgi from UT Southwestern and colleagues analyzed individual level participant data in a pool cohort of four large population studies without baseline atherosclerotic cardiovascular disease. These were the Dallas Heart Study, the ERIC study and the MISA study, as well as the PREVENT study.

Dr Greg Hundley: What did they find? Were there any unique pieces of data related to either sex or those of black race?

Dr Carolyn Lam: They found that HDL particle concentration is inversely associated with the specific endpoint of ischemic stroke overall and among women. Whereas HDL cholesterol was not associated with ischemic stroke. Neither HDL particle concentration nor HDL cholesterol levels were associated with myocardial infarction in blacks. Thus HDL particle concentration, but not HDL cholesterol may be a useful risk marker for ischemic stroke. HDL particle concentration may be a useful risk marker for both myocardial infarction and ischemic stroke among women. There is likely minimal utility of HDL markers for risk prediction of myocardial infarction in the black population.

Dr Greg Hundley: Thanks Carolyn. That was such a great introduction and overview and then the results was so clear. Carolyn, my next paper comes from Dr Peter Willeit from the Medical University of Innsbrook. In this paper, the author systematically collated carotid intima-medial thickness data from randomized controlled trials. The primary outcome was a combined cardiovascular disease endpoint defined as myocardial infarction, stroke, revascularization procedures, or a fatal cardiovascular event. The authors estimated intervention effects on carotid intima-medial thickness progression and incident CVD for each trial before relating the two using a Bayesian eta- regression approach.

Dr Carolyn Lam: Oh, this is important. So what did they find?

Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per year evaluations. So across all intervention, each 10 micrometer per year reduction of carotid intima-medial thickness progression resulted in a relative risk for cardiovascular disease of 0.91 with an additional relative risk for cardiovascular disease of 0.92 being achieved independent of carotid intima-medial thickness progression. So combining these results, the authors estimate that interventions reducing carotid intima-medial thickness progression by 10, 20, 30 or 40 micrometers per year would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each incrementing with the magnitude of reduction in micrometers per year. Results were similar when grouping trials by type of intervention. Time of conduct, time to ultrasound follow-up, availability of individual participant data, primary versus secondary prevention trials, the type of carotid intima-medial thickness measurement, and the proportion of women in the studies.

Dr Carolyn Lam: So could you summarize that Greg?

Dr Greg Hundley: You bet, Carolyn. So the extent of intervention effects on carotid intimal-medial thickness progression predicted the degree of cardiovascular disease risk reduction. This provides a missing link supporting the usefulness of carotid intimal-medial thickness progression as a surrogate marker for cardiovascular disease risk prediction in clinical trials.

Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it also quantifies that risk reduction. Very nice. Now let's just round up with some other papers in the issue. There is a perspective paper by Dr Bunch on Dementia and atrial fibrillation, a research letter by Dr Ellinor on myocyte specific upregulation of ACE two in cardiovascular disease, the implications for our SARS-coronavirus to mediated myocarditis. There are letters to the editor regarding the article small extra cellular macrovesicles mediated, pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism, exacerbating ischemia reperfusion injury in diabetic mice. These letters were by Dr Li with response by Dr Ma. There's a research letter by Dr Natarajan on genetic variation and cardiometabolic traits and medication targets and the risk of hypertensive disorders of pregnancy.

Dr Greg Hundley: Carolyn, I've got a couple other features to describe. Aaron Baggish and Ben Levine provide an On My Mind piece, related to sports after COVID-19. Jeffrey Smietana has an ECG challenge regarding an ELVAD artifact. Then finally, Bridget Kuhn has cardiology news related to an announcement from the Association of Black Cardiologists calling for an urgent effort to address health inequality and diversity in cardiology. Can't wait to get to that feature discussion and that really unique twist in cardio-oncology.

Dr Carolyn Lam: Here we go. Greg.

Based feature discussion. We are diving into the world of cardio-oncology. Now, usually that refers to the intersection between cancer and cardiovascular disease, where we usually talk about cancer and cancer treatment effects on the cardiovascular system. But emerging data now suggests the concept of reverse cardio-oncology, whereby heart disease potentiates cancer. Today's feature paper really provides very important and significant preclinical data to support this. I'm so pleased to have with us, the corresponding author, Dr Ami Aronheim from Israel Institute of Technology, as well as our associate editor, Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf in Germany. Ami, thank you very much for joining us today. Please. Could you walk us through your very elegance study and the results?

Prof Ami Aronheim: We used a model, which is called the transfers, all the constriction, which promotes pressure overload on the heart. Actually following this procedure, we implanted cancer cells into mice and we followed the growth of these tumors. Actually we found out that the tumors of a tuck operated mice is growing much faster. Also when we used a metastatic model, namely, when we injected cells into the tail vein, we obtained more metastatic lesions in the lungs. Actually we found out that the serum from these mice is able to promote the variation of cancer cells in vitro. Then we also identified a protein, which is potentially promoting these cell proliferation in vitro.

Dr Carolyn Lam: That is really significant. I mean, am I right that this is the first study to show that cardiac remodeling actually promotes tumor growth and metastasis and this is probably via secreted factor.

Prof Ami Aronheim: This is the first paper showing that early events of cardiac remodeling promote cancer cell proliferation. It is known that heart failure by the work of De Boer’s group, that heart failure is promoting cancer load in mice. This paper was also published in Circulation 2018.

Dr Carolyn Lam: Indeed. Thank you for reminding me about that. And I am a huge fan of Rudolph de Boer and his work. Indeed. Could I ask though, in your study, did you identify a particular secreted factor?

Prof Ami Aronheim: We looked at the RNA seq from conduct remodeled heart, and we looked for secreted factors in the heart and we focused on two secreted factors CTGF and periostin, which are known to promote cancer growth. And indeed we found in our mice models that reduced in level is increased in the serum of mice of tuck operated mice. Once we deplete the serum from periostin, we ambulated this increase in cell proliferation.

Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure the listeners are dying to know. Was there any human data that you had that supported the animal findings?

Prof Ami Aronheim: The model in mice, the tack operation, it's hard to find the right model in human because the operation is really rapid. When the mice wake up, they have this pressure overload, the only disease which in human correlates or is mimicked by the tag is Altucher's stenosis, which is the restriction of the outtake evolve, the right aortic valve]. And we looked in these patients and what we found out, we looked at the echo cardiography data of a lot of patients. We actually found out that for young basically patients 40 to 60 years old, if they have moderate to severe aortic stenosis, they have higher risk to develop cancer about 1.6-fold higher than our external these patients. Although I must say with caution that this size group is quite small and it should be repeated with much higher number of patients.

Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to bring you in here. Thank you for managing this very remarkable paper. Could you share some thoughts on what you think this means for the field?

Thomas Eschenhagen: We all immediately as editorial team like this paper. When it came in on the background of the different paper, it really provides significant additional evidence that this interaction between cancer and the heart is two sided. And that's, as you said in the intro, that's really very important. And it's all very interesting that apparently these two different models used by Rudolf de Boer, which wasn't ischemia myocardial injury model. And here it's a hypertrophy model with early remodeling. They both do similar things, but apparently by different mechanisms. Because the number of the factors identified in the de Boer paper do not match with, with these two factors, CTGF and periostin. And for both, I think we have now convincing evidence that they may play a role, but it also shows that this is probably a quite complex interaction between the heart and the cancer. That makes it extremely interesting.

Of course it's important because it's such a common comorbidity, I mean, cancer, cardiovascular diseases, are the most prevalent and the second most prevalent diseases is cancer. So this interaction must be very, very important. And it's very good that these two papers now focus of you on the reverse side and not only on the classic cardiac toxicity side, which me as pharmacologists, of course, we, I was always interested in.

Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart failure clinical trial list and epidemiologists, if I may, I always thought it was just shared risk factors, you know, age being particularly one of them.

Thomas Eschenhagen:   Obviously, as you said, shared risk factors do play a role must, must their role. So it's certainly not only this direct interaction, but this new paper shows that there is in addition to this risk factor model, something specific. And that of course could be, I mean, at least theoretically be addressed.

Dr Carolyn Lam: For both Thomas and Ami, what do you think are the implications now? I mean, should we be screening all patients with aortic stenosis more closely for cancers? What do you think are the clinical implications? Maybe Ami first?

Prof Ami Aronheim: I think cardiovascular disease patients are already watched very carefully beforehand. But certainly I think that they should be also observed for cancer specifically. So yes I believe it should be. Also I this cardiovascular treatment should consider to make them early as possible to avoid any interaction with cancer.

Dr Carolyn Lam: Yeah, that completely opens the field to, for example. Early aortic valve replacement, reducing subsequent cancer risk, like you mentioned in your paper, I mean, that's just mind blowing. Thomas, what do you think?

Thomas Eschenhagen: I agree, 10 years ago, we said that more cancer patients, particularly those under treatment should be sent to the cardiologist to look for the heart. Now we will say the other way around as well. We really need to look more carefully for cancer. So I think this paper and the other one have the consequences we should do more here. There's also obviously a number of very interesting questions because one of the findings I found fascinating in this paper by Ami and this group was that this mouse strain, which finally did not show the classical science of remodeling after transverse aortic striction. So no BNP, no NP, no BDMEC increase in this small strain. There was no increase in cancer growth.

Very interesting, because normally you would think somehow that these mice, which were kind of normal in the cardiac response would be worse, but in this respect they were better. So that's a very interesting aspect. The second aspect I found really fascinating is the human data suggest, I guess it's quite preliminary data, but there's a suggestion here that this interaction is mainly seen in younger patients. And I'm not quite sure what that means, but it's something to look at.

Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami maybe the last word from you. Given all of this remaining questions and so on, what are your next steps?

Prof Ami Aronheim: First, I wanted to comment something more wide view for this interaction that we find with cancer. I think all the organs actually communicate with one another. The fact that we are looking on a heart and cancer, this is due to the fact that it's easy. We have the models working in the lab and it's easy. But I'm sure if we're going to look to other diseases and other organs, there will be other connections of the heart with other organs and other diseases and maladies, which by conducting modeling, they will promote or maybe even reverse other maladies. So I'm sure that there is a communication between all organs, many organs altogether, and they will affect one another.

Our directions currently are to look more precisely for the periostin story because we follow this mainly in vitro and would like to follow it in vivo. Also I think this mice model are nice, but to look also in human, where the periostin in aortic stenosis patients, where then, we can find out earliest in, in the serum before intervention, and to look after whether this secreted factor goes down or reduced. Also we are looking in other transgenic model that we generated along the years, which are known to result in cardiac modeling. We want to see whether these mechanisms are similar or different and whether they can promote also cancer progression. The use of these transgenic mice is very nice because we can induce them and we can shut down them so we can learn more about the kinetic, which influence one another, and exactly whether they can be reversed or not.

Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts on those future actions, a lot of work and such worthwhile areas to explore. Thank you too, Thomas for sharing your thoughts.

Listeners. Thank you for joining us today on circulation on the run.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, guess what we're discussing for the feature discussion? We're talking about sugar sweetened beverage tax. Isn't that interesting? We talk about sugar sweetened beverages and their health impacts, but don't actually look at how tax policies may impact cardiovascular outcomes. So this paper is super interesting, can't wait to get to it, but I really want to get my cup of coffee and discuss a couple of other really cool stuff in today's issue. I'm going to start. Do you think about factor V Leiden much?

Dr Greg Hundley: Carolyn, we are early in August and we have all new house officers rotating, and actually we do discuss factor V Leiden, and we think about Protein C and Protein S deficiencies, et cetera. But how about if you tell us about your paper and educate us a little bit more on the topic?

Dr Carolyn Lam: Okay. So first of all, it's Leiden or Leiden, I'm not sure. So I'm going to go with your pronunciation. Factor V Leiden is a genetic variant leading to alteration of the inactivation site of factor V, which in turn leads to activate a Protein C resistance and a prothrombotic state, just like you said, Greg. Affecting almost 5% of the Caucasian population, carriers of a factor V Leiden mutation have a fourfold higher risk of venous thromboembolism. However, the risk of arterial atherothrombotic events, such as myocardial infarction or stroke, conferred by the presence of this variant is less certain. So Dr Patel from University College London, and Dr Asselbergs from University Medical Center Utrecht and colleagues assess the association of the factor V Leiden polymorphism with subsequent atherothrombotic events, including mortality in individuals with established coronary heart disease using an individual level data meta-analysis of 25 prospective studies from the genetics of subsequent or GENIUS coronary heart disease consortium.

Dr Greg Hundley: Well Carolyn, what did they find?

Dr Carolyn Lam: In nearly 70,000 patients with established coronary heart disease, factor V Leiden was not associated with an increased risk of further atherothrombotic events or death compared to non-carriers. A post hoc analysis, however, suggested that factor V Leiden carriers with established coronary heart disease may gain greater protection from subsequent coronary heart disease, death, or myocardial infarction from dual antiplatelet therapy compared to non-carriers. The routine assessment of factor V Leiden genotype to improve risk stratification in secondary prevention settings is therefore unlikely to be of value and is not recommended. However, further work is required to understand if there may instead be a pharmacogenomic role for factor V Leiden status to help personalize treatment with intensive antiplatelet therapy.

Dr Greg Hundley: Very nice, Carolyn. Well, my next paper is from Dr Michelle O'Donoghue from Brigham and Women's Hospital, and creates an interesting question for you, Carolyn. Would you be comfortable discontinuing aspirin three months after PCI in lieu of continuing a P2Y12 inhibitor?

Dr Carolyn Lam: Ah, big, big question. Not until guidelines change, but tell me, tell me, tell me, Greg, what this paper said.

Dr Greg Hundley: Well, before we get some of these more randomized trial, this study included a meta-analysis of 32,145 patients, 14,095, or 43%, with stable coronary artery disease and 18,000, nearly 56%, with ACS from randomized trials during the time period of 2001 to 2020. And they had to study discontinuing aspirin one to three months after PCI with continued P2Y12 inhibitor monotherapy compared to traditional dual antiplatelet therapy. Five trials were included, and the follow-up duration range from 12 to 15 months after PCI. The primary bleeding and MACE outcomes were the pre-specified definitions in each trial.

Dr Carolyn Lam: An important study. So what did they find, Greg?

Dr Greg Hundley: Well in the experimental arm, background use of a P2Y12 inhibitor with Clopidogrel in 16.5% of cases, and prasugrel or ticagrelor in 84% of patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. So the results, discontinuation of aspirin therapy one to three months post PCI significantly reduced the risk of major bleeding by 40% compared to dual antiplatelet therapy with no observed increase in the risk of MACE, myocardial infarction, or death. The findings were consistent among patients who underwent PCI for an ACS in whom discontinuation of aspirin after one to three months reduced bleeding by 50%, to 1.78% versus 3.58%, and did not appear to increase the risk of MACE where both were 2.5% and 2.98%.

Dr Carolyn Lam: Nice, Greg. Could you summarize the take home message for us?

Dr Greg Hundley: Sure, Carolyn. So in summary, discontinuation of aspirin with continued P2Y12 inhibitor monotherapy reduced the risk of bleeding when stopped one to three months after PCI. An increased risk of MACE was not observed following discontinuation of aspirin, including patients that had previously sustained ACS.

Dr Carolyn Lam: Thanks Greg. Well, my next paper is a preclinical one showing that circular RNAs delivered via extracellular vesicles may be a new treatment for ischemic stroke.

Dr Greg Hundley: Oh my goodness. Carolyn, can you orient us to circular RNAs and these extracellular vesicles?

Dr Carolyn Lam: Sure, Greg. I decided not to quiz you on them. Circular RNAs are a type of endogenous non-coding RNA molecule characterized by back splicing and covalently closed continuous loops, hence circular. Previous studies have demonstrated that multiple circular RNAs have functional roles relating to ischemic brain injury. Although administering circulating RNAs using lentiviruses is efficient for experimental examination, this route is limited for clinical translation due, of course, to disadvantages in onset time and safety issues. So this is where the extracellular vesicles come in as a potential cargo delivering system, if you may, for brain remodeling after stroke. These extracellular vesicles are lipid membrane vesicles of 30 to 150 nanometers in diameter that are released by cells and can cross the blood brain barrier and have been shown capable of carrying proteins, lipids, and nucleotides as their cargo.

So today's co-corresponding authors, Dr Yao from Medical School of Southeast University in Nanjing, and Dr Wang from Chinese Academy of Sciences Kunming, Yunnan in China envisioned the potential of delivering candidate circular RNAs to the brain in vivo by constructing engineered extracellular vesicles bearing circular RNAs. They initially explored this circular RNA delivery strategy idea in the context of their ongoing work regarding the functional roles of circulating RNAs in ischemic brain injury. Their microarray based profiling of acute ischemic stroke patients reveal that a circular RNA generated from the SCM-polycomb group protein homolog 1, or SCMH1 gene, is decreased in plasma of acute ischemic stroke patients and confirmed that a similar decrease occurs in stroke model mice. So they successfully engineered extracellular vesicles with circular SCMH1 over-expression and were thus able to experimentally characterize the ischemia related functional benefits of this circular RNA administration in stroke models in both mice and macaque monkeys. Cool, huh?

Dr Greg Hundley: Yeah. Very nice, Carolyn. That was a great explanation. My study comes from Dr Juyong Kim from Stanford University School of Medicine, and Carolyn, this study combined RNA sequencing, chip sequencing, ATEC sequencing, and in vitro assays in human coronary artery smooth muscle cells with single cell RNA sequencing, histology, and RNA scope in a smooth muscle cell specific lineage tracing aryl hydrocarbon receptor knockout mouse model of atherosclerosis to better understand the role of the aryl hydrocarbon receptor in vascular disease. This aryl hydrocarbon receptor, heretofore AHR, is an environment sensing transcription factor that contributes to vascular development.

Dr Carolyn Lam: Wow, what a comprehensive study. So what do they find?

Dr Greg Hundley: The authors identified a novel population of cells derived from smooth muscle cells, termed condramyocytes, which have gene expression features of cartilage and bone formation within an atherosclerotic lesion. In addition, the environment sensing transcription factor aryl hydrocarbon receptor plays an important role in smooth muscle cell differentiation, ossification, and maintains the smooth muscle cell derived fibrous cap structure.

Dr Carolyn Lam: Interesting. Okay, you know what I'm going to ask. What are the clinical implications?

Dr Greg Hundley: Yeah, I knew you'd ask me that, Carolyn. So human genetics suggests a protective role of the aryl hydrocarbon receptor in the smooth muscle cell during atherosclerosis, and therapies targeted to increase the aryl hydrocarbon receptor activity in smooth muscle cells may confer protection against adverse calcific remodeling of the atherosclerotic plaque. This study also highlights a methodological advance, and further characterization of the pathways that direct the modulation of smooth muscle cells during atherosclerosis at the single cell level may be able to identify potential therapeutic targets to mitigate the risk of atherosclerosis.

Dr Carolyn Lam: Oh, I like that summary, Greg. Thanks. Now, let's move on to other things in today's issue. There's a perspective by Dr Al-Lamee on the ISCHEMIA trial asking was it worth the wait? There's also a perspective by Dr Levine on the ISCHEMIA-CKD trial, providing contemporary randomized clinical data at last in this important population. There's a white paper by Dr Emmaullee on Fontan-Associated Liver Disease, screening, management, and transplant consideration. And finally, there are letters to the editor from Dr Helgestad, Chieffo, and Waksman, with replies from Dr Amin on the article The Evolving Landscape of Impella Use in the United States Among Patients Undergoing PCI With Mechanical Circulatory Support.

Dr Greg Hundley: Very good, Carolyn. Well, I have a few other items in the mail bag. Xiang Cheng has a research letter entitled Cardiac Troponin I is an Independent Predictor for Mortality in Hospitalized Patients with Coronavirus Disease 2019. Also, Corinne Frere has a research letter regarding the Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, and they provide insights from a perspective single center cohort study. And finally, Dr Jeffrey Wagner has an ECG challenge regarding the infamous is it VT or not VT? Well, Carolyn, how about we get on to that feature discussion.

Dr Carolyn Lam: Let's go, Greg. Beverage Texas are a promising policy approach to reduce consumption of sugar sweetened beverages. And as we know, these are linked to adverse health outcomes, such as Type 2 diabetes and obesity. Now these taxes have been adopted by seven localities in the United States, and in more than 40 countries around the world using different tax designs, but until now a critical answered question where we lack empirical data is the health impact of these beverage taxes. That is until today's feature paper, and I'm so pleased to have with us, Dr Yujin Lee from Friedman School of Nutrition Science and Policy, Tufts University, as well as our associate editor, Dr Naveed Sattar from University of Glasgow. Welcome both, and Yujin, could I start with you please? What an interesting and important idea to look at this. Could you start by perhaps first explaining to us what are the different types of tax designs?

Dr Yujin Lee: There are three types of tax design. First, the volume tax is taxing sugar sweetened beverages based on the volume. For example, a penny per owns for volume tax. So the tax rate is same whether a beverage contains 5 or 20 grams of added sugar for 8 ounces. The second design is the absolute sugar content tax, which is taxing beverages based on the sugar content regardless of the volume. So for example, one cent per one teaspoon of sugar, or one cent per one gram of sugar. Lastly, tier tax is hybrid of volume and absolute sugar content tax. For example, creating different tiers products based on the sugar content and taxing based on the volume at different rates. So for example, the American Heart Association suggested three tiers. First, no tax on beverages with less than five grams of added sugar per eight ounces. And second, 1 cent per ounce on beverages with 5 to 20 grams of added sugar per 8 ounces. And lastly, 2 cents per ounce on beverages with more than 20 grams of added sugar per 8 ounces.

Dr Carolyn Lam: Great. So thank you for explaining that. I mean, to be honest, I didn't even realize there were so many different tax designs. Now, could I understand a bit better? So in the US, are they mostly volume-based? And then perhaps you could tell us how did you go about your study of comparing these things, and looking on their impact on outcomes.

Dr Yujin Lee: Sure. So as you mentioned, all seven US locality have been implementing the volume tax, and in this study, this is the modeling study, so we're using the nationally representative data and using a microsimulation model, and we wanted to compare and estimate the health and economic impact of the volume, absolute sugar content. And the tier tax designs in the United States.

Dr Carolyn Lam: Great. And tell us what you found.

Dr Yujin Lee: What we found is we found that implementing a volume-based sugar sweetened beverage tax could prevent 850,000 cardiovascular events and 270,000 diabetes over a lifetime of current US adults aged 35 years or older. And this tax design could save tens of billions of dollars in healthcare costs. In addition, taxing sugar sweetened beverage based on their sugar content, for example, the tier or absolute sugar content based tax design, could generate about double the health and economic benefits compared to the volume tax.

Dr Carolyn Lam: Wow, that is so intriguing. Naveed, I have to bring you in here. So in the UK they use a tier tax. Do you? And what are your thoughts?

Dr Naveed Sattar: Oh, well clearly, Carolyn, I mean, I think taxation of sugar sweetened beverages is something that all of us can agree on is beneficial. I think it's really important that many other countries and states consider this. I'm surprised that only seven states in the US are currently doing this. And in some respects, this papers is very timely. It's based on modeling. I mean maybe you can come back to Yujin about how good the modeling is, but if you think about the issue we have now in terms of health inequalities and COVID related deaths, going forward we need mechanisms to help reduce health inequalities. And this particular paper will flag up that places need to think about sugar sweetened beverage taxes and how best to do them.

And I completely agree, they should be based on sugar content. I don't see why they should be more convoluted than that. And although Yujin explained it, it still seems a bit complex to me, the different mechanisms, but I think your paper is very timely and very important. And for me, the key question for Yujin is people looking at this may say well, how robust is that model? How do we know how accurate you've been in terms of the money saved, because that's going to be really important going forward, and in particular, the number of lives or cardiovascular and diabetes cases prevented?

Dr Yujin Lee: Sure. So let me explain how we estimated how many cases of cardiovascular disease and Type 2 diabetes were prevented. So we use a microsimulation model, which is a computer simulation model, which is developed by the research team, led by Dr Thomas Casiano and Harvard School of Public Health. So this model predicts the probability of an individual experiencing cardiovascular disease or diabetes based on each person's risk factor, such as sex, age, total cholesterol, or smoking or diabetes, and also their SSB-consumption also be part of this input. So it estimate the probability of one person, individual, developing the future cardiovascular disease, or Type 2 diabetes, and it estimate how this prevention can save healthcare costs associated with these diseases. So in this study, this model simulates the status quo, so the way things now stand, and also it assimilate the three different tax design. After that, we compute the health outcome and costs associated with this policy options and, by comparing this model, outputs for these three tax design with the status quo.

Dr Naveed Sattar: Has any country got long enough perspective data that have implemented such taxes to validate the model, or is that still to come? I mean it would be nice to get it validated in real life, but I think most people would accept that reducing sugar in beverages is a really good thing, and presumably the part of the mechanisms by reducing weight, and reducing all of the implications of excess calorie intake, particularly refined sugar, on a variety of different diseases. Is that fair?

Dr Yujin Lee: Yeah, and I wanted to make a point that, since this is a modeling study, so our study cannot prove the health and economic impacts of this tax design in the United States, so rather our estimates provide evidence that can be considered and incorporate into the design, and implementation, and evaluation of future SSB taxes.

Dr Carolyn Lam: That's a really good point. And maybe just to round up, Yujin, could I just ask you to were any particular individuals in the population simulated to experience larger gains? We know that it's exactly like Naveed said, it's the minorities, it's perhaps lower income region individuals who might need this more. I mean did your simulation show anything to that effect?

Dr Yujin Lee: We also investigate this tax design and how this influence in sub population. Particularly we found that the SSB taxes have a larger benefit among younger adults, minorities, and adults with the lower income. Given that these population, their SSB consumption is higher than the other group, so this SSB tax implementation gives them a greater health and economic benefit to these subpopulations.

Dr Carolyn Lam: Thank you so much, Yujin, for this really, really, I think, novel and very important data. Naveed, could I give you the last say as the associate editor who is managing this, and you even invited an editorial, which I liked very much, the title, Simple is Better for Local Beverage Tax Policy Diffusion. It's kind of in line with what you've been saying, but maybe some take home messages?

Dr Naveed Sattar: Obviously in Circulation, we get lots of beautiful papers that very molecular depth and various other factors, but actually this paper brings us back to the reality that for many of the diseases that we treat, diet and drink intake is really relevant to our diseases and the likelihood of diseases, and there are simple mechanisms whereby we can help people in the community to actually lead better lifestyles that also are actually economically beneficial. And I think that in this paper, if it was to be implemented and looked at seriously by many states in the US, by many other countries to go along this route would have huge potential benefits on health, And it's really important at this time, given what's happened with the pandemic, and as we move forward over the next 5 to 10 years. So I think it's really timely and I congratulate the authors on it.

Dr Carolyn Lam: Well, listeners, you heard it right here, novel, impactful data. That's what Circulation is about. Thank you for listening to Circulation on the Run. Don't forget to tune in again. Next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains?

Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe?

Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress.

Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find?

Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease.

Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same?

Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different.

Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.

Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common?

Dr Greg Hundley: I definitely need phone a friend.

Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms.

Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI.

Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg?

Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate.

Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find?

Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points.

Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR.

Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found.

Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock.

So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation.

Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too.

Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies?

Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease.

We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function.

Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not?

Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome.

But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease.

Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts.

Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution.

And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them.

Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community?

Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that.

The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well.

Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best.

Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively.

Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee?

Dr Greg Hundley: I am.

Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis.

So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis.

So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity.

A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance.

In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.

Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here?

Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that.

Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College.

So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis.

So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation.

Dr Carolyn Lam: So what did they find, Greg?

Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model.

The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases.

Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice.

Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center.

Dr Greg Hundley: So Carolyn, what did they find in this series?

Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction.

Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis.

Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age.

Dr Carolyn Lam: Interesting. And what were the results?

Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials.

However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively.

So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy.

Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial.

There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis.

Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith.

Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid.

Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19.

And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion.

Dr Carolyn Lam: Yay. Let's go, Greg.

Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome.

Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address?

Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families.

However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder.

But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges.

The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families.

Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population.

Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study.

The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation.

So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands.

The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome.

What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome.

So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes.

So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility.

Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients.

We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients.

So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability.

Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement?

Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected.

Dr Greg Hundley: I see. I-

Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected.

Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on?

Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we should go preferably for a similar design where we will approach the same centers. And hopefully, we can organize the next study, which will have these probands and their relatives.

Dr Greg Hundley: Now, just quickly, for us working in the clinic, how should we approach genetic testing in patients with long QT?

Prof Connie Bezzina: At the moment, I think our findings don't have an immediate impact. I think our findings tell us about the genetic architecture of the disorder. And actually, one thing I haven't gone into yet is the fact that what we also found is that patients who do not have mutations in the no-long QT genes, which were called mutation-negative, which are about 20% of all long QT syndrome probands, actually have a higher burden of these common variants that prolong the QT interval.

So we think, actually, that mutation-negative long QT syndrome probands will not have a Mendelian large effect variant but will have perhaps a higher burden of these QT-prolonging alleles.

Therefore, I think this has direct implications for clinical genetics of these patients, because if you have a proband in whom you don't find a mutation in the known genes, you could think that maybe it is not monogenic, which has implications because you don't have a single genetic defect to test on that family. One would need to keep follow-up of more family members until we understand more about the genetics of those individuals.

Dr Greg Hundley: So Connie, this has been just a wonderful discussion. Any additional studies examining the genetic architecture of individuals that we need to think about for the future?

Prof Connie Bezzina: Sure. So for long QT syndrome in particular, as additional SNPs that modulate the QT interval in the germ population are identified, it will be very important to incorporate these into larger polygenic risk scores, and see whether we could have a better discriminative capacity of such polygenic risk scores in discriminating between severely affected and less severely affected people, or who is more at risk for an arrhythmic event.

Outside of long QT syndrome, I think there's a lot of work to be done with respect to the likely complex inheritance of many of these disorders that we previously considered to be Mendelian. So for instance, ongoing work in our group concerns Brugada syndrome, where we're seeing the same kind of thing, and hypertrophic cardiomyopathy, where we're seeing the same kind of inheritance.

Dr Greg Hundley: Well listeners, on behalf of both Carolyn and myself, we look forward to catching you on the run next week. Take care. This program is copyright the American Heart Association 2020.

This week’s episode of Circulation on the Run features author Robert Yeh and Associate Editor Brendan Everett as they discuss the article "Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the EXTEND Study."

TRANSCRIPT

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week, we're going to examine outcomes in patients that have undergone transcatheter aortic valve replacement or TAVR. I can't wait to get to the results from the EXTEND study. But before we do that, how about we grab a cup of coffee and start in with some of the papers and maybe I'll go first this time.

My paper involves a validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. And the corresponding author is Dr Seema Mital from the Hospital for Sick Children. Well, Carolyn in this study, the objective was to develop and validate a sudden cardiac death risk prediction model in pediatric hypertrophic cardiomyopathy to guide sudden cardiac death prevention strategies.

To address this, the authors performed an international multi-center observational cohort analysis. Phenotype positive patients with isolated hypertrophic cardiomyopathy, who were under the age of 18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of sudden cardiac death events at five years of follow-up. That included sudden cardiac death, resuscitated sudden cardiac arrest, and aborted sudden cardiac death, that is, an appropriate shock following primary prevention ICD.

Carolyn Lam: Nice. What did they find?

Greg Hundley:   Well, overall 572 patients met the eligibility criteria with 2,855 patient years of follow-up. The five-year cumulative proportion of sudden cardiac death events was 9%. Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter Z scores, LV posterior wall diameter Z scores, LA diameter Z scores, peak LV outflow tract gradients, and the presence of a pathogenic variant.

Now, unlike adults, LV outflow tract gradient had an inverse association and family history of sudden cardiac death had no association with sudden cardiac death. The combination of clinical and genetic data were developed to predict five-year freedom from sudden cardiac death.

In conclusion, the authors study provides a validated sudden cardiac death risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. These results therefore raise the possibility that an individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for these children prior to an ICD insertion.

Carolyn Lam: Very interesting. Well, Greg, have you ever wondered what are the temporal trends in the burden of comorbidities and risk of mortality among patients with heart failure with preserved ejection fraction or HFpEF and heart failure with reduced ejection fraction or HFrEF? Well, the next paper comes from Dr Caughey and colleagues from University of North Carolina and North Carolina State University who performed an analysis of the community surveillance component of the atherosclerosis risk in communities, or ARIC study, and they found a significant increase in the burden of comorbidities among hospitalized patients with HFpEF as well as HFrEF across both sexes. Higher number of comorbidities was associated with higher risk of one-year mortality with a stronger association noted among patients with HFpEF compared to HFrEF. The one-year mortality risk associated with increasing comorbidity burden also increased over time.

Greg Hundley: Interesting, Carolyn. So more comorbidities in HFpEF versus HFrEF. How do we use this clinically?

Carolyn Lam: This study demonstrated a shift from ischemic etiology heart failure to multi morbidity heart failure over time, particularly among patients with HFpEF. This really highlights the importance of a holistic approach in targeting multimorbidity burden and guiding the management of patients with heart failure.

Greg Hundley: Very interesting. Well, Carolyn, my next paper comes from Professor Matthias Nahrendorf from Mass General Hospital and involves the relationship between bone marrow endothelial cells and myelopoiesis in those with diabetes.

 Carolyn, this study investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. The authors utilized three types of mice with diabetes, including a streptozotocin model, a high fat diet model, and a genetic induction using leptin receptor deficient mice. They assayed leukocytes, hematopoietic stem cell and progenitor cells, and endothelial cells in the bone marrow with flow cytometry and expression profiling.

Carolyn Lam:  What did they find?

Greg Hundley:   Well in diabetes, they observed enhanced proliferation of hematopoietic stem cells leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less CXCL-12, a retention factor promoting hematopoietic stem and progenitor cell quiescence. Transcriptome wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor signaling in mice with diet induced diabetes.

In summary, Carolyn, in diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow haematopoiesis specifically diabetes reduces endothelial production of CXCL-12, a quiescence promoting niche factor that reduces stem cell proliferation. The authors also describe a previously unknown counterregulatory pathway in which protective endothelial EGFR signaling curbs hematopoietic stem cell and progenitor cell proliferation as well as myeloid cell production.

Carolyn Lam:     Wow, thanks for explaining all of that, Greg. For this next paper, we're going to switch tracks a little. This comes from Dr Drakos and colleagues from University of Utah in Salt Lake City. They noted that significant improvements in myocardial structure and function have been reported in some advanced heart failure patients. This is they're going to call responders and the responders improve the myocardial structure and function following left ventricular assist device induced mechanical unloading.

This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Dr Drakos and colleagues hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, which may mediate myocardial recovery in these responders.

To test this hypothesis, they prospectively obtained paired left ventricular atypical myocardial tissue from non-failing donor hearts, as well as responders and non-responders at left ventricular assist device implant and at transplantation. They conducted protein expression and metabolic profiling and evaluated mitochondrial structure using electron microscopy.

Greg Hundley:   Interesting. What did they find, Carolyn?

Carolyn Lam:     The recovering heart appears to direct glycolytic metabolites into pentose phosphate pathway and one carbon metabolism, which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. This new information could redirect future translational investigations to efforts to identify novel therapeutic targets for myocardial recovery in patients with chronic heart failure.

Well, Greg, can I tell you a little bit more about what else is in this issue? There's a letter by Dr Wang regarding the article, A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction, and there's also a response by Dr Yan. In Cardiovascular Case Series, there's a paper by Dr Michelena on the nosology spectrum of the bicuspid aortic valve condition, the complex presentation of valvular aortopathy. That's so interesting.

There's a research letter by Dr Gaudino on the response of cardiac surgery units to COVID-19, an internationally based quantitative survey. As well as another research letter by Dr Salem on cardiovascular toxicities associated with Hydroxychloroquine and azithromycin and analysis of the World Health Organization pharmacovigilance database.

There is a perspective piece by Dr Jacobs entitled The Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA's Mission: Lifeline.

In cardiology news, Tracy Hampton reviews three papers, one, Video-Based AI for Beat-to-Beat Assessment of Cardiac Function in Nature, 2020. Two, Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by single Nucleus RNA Sequencing, that is in developmental cell 2020. And three, ATP and Voltage-Dependent Electro-Metabolic Signaling Regulates Blood Flow in the Heart, the proceedings of the National Academy of Science, 2020.

Greg Hundley:   Very nice. Well, I've got an in-depth review from Dr Bin Zhou regarding the heart regeneration by endogenous stem cells and cardiomyocyte proliferation, controversy, fallacy, and progress. And then there are three on my mind pieces. The first is from Dr Rashmee Shah regarding machine learning and artificial intelligence. Do we need more data, or do we need the right data? The next one is from Sharon Reimold and it discusses the importance of gathering historical information on risk factors when seeing patients with, or suspected, of COVID-19. And then finally, Dr Prateeti discusses ethical challenges in cardiology during the COVID-19 pandemic.

Well, Carolyn, what a great review. How about we proceed to that feature discussion?

Carolyn Lam: Let's go.

Greg Hundley: Well listeners, we are now turning to our feature discussion and this week we have Dr Robert Yeh, also Bobby Yeh, from Beth Israel Hospital and our own associate editor, Dr Brendan Everett from Brigham and Women's Hospital. Welcome gentlemen. Bobby let's start with you. Can you tell us a little bit about some of the background related to your study, and then what hypothesis were you trying to address?

Robert Yeh: The study that we performed is the sub study of what we're calling the EXTEND study, which is an NIH funded group of investigations meant to really examine what the value is of real world data and how it can augment clinical trial evaluations of medical devices and therapies.

We know that randomized clinical trials remain the gold standard for therapeutic evaluation, but they are expensive, difficult to do, and sometimes impractical. Real world data is cheaper, it's potentially more efficient to do observational research studies, and in fact the 21st Century Cures Act explicitly asks, among other things, that the FDA explore the use of real-world data for regulatory evaluations.

People have problems with real world data, of course, they have their own inherent challenges which are subject really to confounding. What we thought about is, well, there's probably this middle ground that we and others have proposed, which is can't real world data somehow supplement or augment randomized clinical evaluations, and in particular, in our question, can real world data be the provider of outcomes in place of adjudicated clinical trial outcomes?

What we did is we took two large pivotal randomized clinical trials of transcatheter aortic valve replacement, namely the CoreValve, high risk, and intermediate risk trials. Otherwise, the intermediate risk trials known as the SURTAVI trial. And we found those patients in those trials and then linked them with real world data from administrative claims databases in Medicare.

Our hypothesis was that had the trial been evaluated in terms of outcomes by the Medicare claims instead of the clinical trial adjudicated outcomes. Our main question was, would we have had the same findings within those trials? Would the primary hypothesis of those trials still have been met with this alternative clinical trial end point ascertainment strategy?

Greg Hundley: In your study design, how did you accomplish the comparisons? You've told us a lot about the study population. Was this everyone from those two studies or was this a subgroup of them? Maybe just expand on that a little bit.

Robert Yeh: Good question. This is a US based comparison, so we have claims for US patients, and most patients in these trials were in the United States, but the CoreValve trial and the SURTAVI trials, we took all of this patients and then tried to find those patients who we could also find in Medicare claims.

It turns out that in order to qualify for Medicare, you have to be over 65 years of age, under most circumstances. And so it's limited to really those patients over age 65, who we could then search for in Medicare and then within Medicare, there's two types of insurance, fee for service and Medicare Advantage managed care. And what we can only find are those patients who are in Medicare fee for service, which represents somewhere between two thirds and three quarters of patients age greater than 65 or older. So it is a subgroup of patients in these two large pivotal randomized trials.

We've compared those who could not be linked versus those who could, find large part, from some of the age differences, which are just inherent in looking at Medicare, there are really not that many differences between those two groups.

Greg Hundley: Bobby, what did you find?

Robert Yeh: We found those patients. So now we have this situation where we have patients in trials, and we can look at them from two lenses. The same group of patients, one lens is through the clinical trial lens and the second is through the lens of real-world data, those exact same patients.

We found that whether or not we ascertained their outcomes via claims or with clinical trial adjudication, essentially the primary hypotheses were identical, that in both scenarios, the transcatheter aortic valve was non-inferior to the traditional surgical aortic valve replacement, that the effect sizes and the hazard ratios, the confidence intervals, they were roughly the same. In fact, for the primary endpoint of the high-risk pivotal study, which was all cause mortality, it was identical. It turns out that Medicare claims and what we called the denominator file very accurately identifies exactly when a patient dies. It does so equally well compared to rigorous clinical trial adjudication.

For SURTAVI the primary endpoint was combined death or stroke in that case, stroke is reasonably accurate. There were a lot of deaths that also drove that combined end point. And the net result was that really very similar, both effect sizes and primary, P values for those comparisons.

Greg Hundley: Now how about secondary analysis?

Robert Yeh: I think the secondary analysis that's where you had some variability. There are some types of outcomes in this device specific trial that are procedure oriented. Pacemakers are a concern. Aortic valve reintervention is a concern. Those end points in billing claims turns out are quite accurate. You can understand why. I think providers and institutions, when they do a service that requires insertion of a new device, they want to get paid for those devices and they do that billing accurately.

 But there are other claims which I think are a little bit more subjective, diagnoses that are more subjective, those like bleeding or cardiogenic shock, those things actually started to look different. And in fact, in some cases started to give you different inferences if you used the clinical trial data versus the real-world data. And so if I were to summarize it, I would say that mortality looked absolutely pristine identical between the two groups that some diagnoses, particularly procedural ones, looked quite good, sufficient, I think, for an accurate estimation of the treatment effect size as well as the magnitude of the risk, but then some end points, I think the softer more subjective endpoints are slightly different.

Greg Hundley:   Thank you so much, Bobby. Now we're going to turn to our associate editor, Dr Brendan Everett, who has helped work this article through the entire editorial process and is also an expert epidemiologist. Brendan, we have randomized trial data versus real world data. How do you interpret these results in the context of how we're conducting studies both now and then how we will conduct them in the future?

Brendan Everett: If you think of observational research and clinical research on a spectrum with truly just observational studies on one end, where you were trying to look at an exposure and an outcome and adjusting for potential confounders, to tightly controlled randomized trials on the other, Bobby's group has managed to create a hybrid, which I think gives us some opportunity to not have to be either on one and or the other of the spectrum.

What I mean by that is that there are a couple key features of trials that are retained in the approach that Bobby used, and his group used. He mentioned those, but I want to emphasize them. I think the key thing is that there's a randomization step. From the perspective of an epidemiologist, that's key because it balances between the people who get your therapy, in this case a TAVR and don't get the new therapy…confounders that you can measure and confounders that you can't measure, the unmeasured confounders. So it allows some balance between the two treatment groups so that you can be sure, at least at baseline, that they're similar groups and what you're measuring after that point is the effect of the intervention.

The key piece that Bobby replaced is the classical trial ascertained end points where investigators are asked if their patient had one of these outcomes such as a stroke or a death, and then they're adjudicated independently.

As he pointed out, I think there are many of those outcomes, at least in this particular application, are really well collected by billing data. And in fact, some might argue that in some cases they're actually better collected. There's a higher sensitivity, if a somewhat lower specificity for the events of interest.

I think the key question, and you touched on this, Greg, is what about the outcomes that maybe are not collected quite as well by billing data? In particular, remember that any clinical trial is looking at both the efficacy of a novel treatment as well as its safety. You ultimately, at the end of the trial, want to be able to compare efficacy with safety, to make a decision, in this case from the FDA, a regulatory decision about whether to approve the device or the drug.

The question becomes, what safety events are you worried about and how reliably are you going to be able to collect them with claims data? In this case, I think Bobby mentioned that the bleeding data maybe was not quite as good as some of the other safety concerns that are common in TAVR.

I think when you look to apply this approach, which I think is ingenious, to a different research question, you have to ask whether or not the end points, the efficacy end points, and the safety end points that you're collecting will be done in a valid and consistent and sensitive way with claims data as compared with the traditional trial ascertainment process. In this case, I think they were, but that's not always the case. We can all think of examples where you might run into some trouble depending upon what your end points are.

Greg Hundley:   Well, gentlemen, this has been really an informative study to present and talk about in this feature discussion. I want to ask you both just briefly, in a minute or so, what do you see as the next step forward in research in this particular area? Maybe Bobby you first and then we'll follow with Brendan.

Robert Yeh:  I think that there are a couple of different areas that really need to be pushed forward. One, and Brendan alluded to this, is because these studies are really domain specific this validation does not tell us that all claims can be used to answer all questions, that in this particular question it worked, but in others it might not, so more validation work in different fields, different randomized trials, need to be done.

We're doing some of those, but they need to be done throughout so we can really get a better sense of what are the types of questions that are best answered by this type of linkage approach.

The second that is more operational, we were limited to Medicare claims data, so for questions for patients who are younger than 65, this approach just doesn't work. Whereas a place like Sweden can do a large national registry like they did in the TASTE randomized clinical trial and do this for their entire country.

We do need to develop better systems that have comprehensive real-world data collection. Maybe those involve more consolidated electronic health system, health record data that are available in big integrated health systems, for example, but a better system needs to be developed that can answer questions among more than just Medicare fee for service patients.

Greg Hundley:   Very good. And Brendan?

Brendan Everett: Well, I think it's a really promising approach to trying to lower the cost of clinical trials and to do valid research on the effect of some treatments as compared to others. From my standpoint, we have to be careful that we don't try and shortcut the process too much. In particular, I think the randomization step, at least for novel treatments, is of fundamental importance. And of course, to do that, you have to collect a population that is then willing to be randomized to option A or B.

There's a lot of upfront work that is not eliminated by looking solely at the outcomes, using this technique to look at the outcomes. There's a lot of upfront work to collect the patients and then randomize them.

I think also it's important, as we saw recently, that the quality and validity of the database be ascertained and be well-established both with the investigators and the providers of the database. We can see that sometimes, if you're not careful, you can come up with outcomes that are not correct because of the example. Of course, I'm alluding to is the two papers in Lancet and the New England Journal that had to be retracted that were large database studies as well.

The quality of the underlying data remains paramount. That, of course, is where a lot of the elbow grease comes in. It's not just in the ascertainment of the events, but a lot of the stuff that leads up to counting the events at the end of the study.

Greg Hundley:   Well, listeners, this has been just a superb discussion. On behalf of Carolyn and myself, we wish you another great week and look forward to catching you on the run next week. Take care.

 This program is copyright, the American Heart Association 2020.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure.

Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B?

Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines.

Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study?

Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties.

Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events?

Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results.

Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS.

 Dr Carolyn Lam: Wow. What did they find Greg?

Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel.

Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction.

Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored.

 Dr Carolyn Lam: Summarize that for us.

Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors,

Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score.

Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19?

Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper.

Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly.

 Dr Carolyn Lam: Wow. So what did they find, Greg?

Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.

 Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg?

Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments.

Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox.

Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden.

Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter?

Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings?

Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say.

Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases?

Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application.

Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found?

Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals.

Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors.

Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very, very challenging, Carolyn.

Dr Peipei Ping: The beauty of the study is it utilized already in clinical trial, existing human antibody inhibitor, interleukin alpha-one antibody. You said antibody. So the reagent is already bile approved. Then examine very carefully in a post-ischemic fashion to see how relevant that agent in a time window reasonable to rescue ischemic injury. You can already tell from Lucas introduction; the results are profound, and it has stimulated many discussions in the field. It's very relevant to clinical center piece, even though it's still at that translational stage. So we saw this as a beautiful representation of how clinicians and scientists capable of not only bring something from the bench to the clinic or the clinic or to the bench. This is something comes to a full circle. It went from clinic where the reagent was used and created for something to the bench, understanding mechanistic insight, have a beautiful animal of human disease stroke model to test them and then take it to the clinic again.

Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I actually didn't see that Luc[a], till you put it that way. I do have a couple of questions for Luca though. I understand you made it very clear in your paper that the human monoclonal antibody is in clinical use, but in this experiment, you had to use the rodent equivalent because the human antibody doesn't block the rodent IL-1α, which is very reasonable. But then it brings the question, how closely does this rodent model recapitulate thrombotic ischemic, or a stroke in humans? I mean, what do you think?

Dr Luca Liberale: Well, what we see when we use our usual approach, this is a model that we're using in our center for molecular cardiology here in Zurich, and this been used in that specific group of Professor Ameche for many years. And this is usually quite well accepted as a model. So that, that the timeframe is 45 minutes of ischemia and 48 hours of reperfusion. I'll got to quite mirror the acute phase of an acute ischemic stroke, which is actually where we think that the inflammatory pathways can play the major roles. Also. I mean, everybody of us know that the recent anti-inflammatory trials confirmed this, that reducing the inflammation and the inflammatory pathways is good but can also be harmful.

Dr Luca Liberale: So in the case, we can use an approach, which is limited in the time, maybe really close to that acute phase, really during the acute rates goes to the acute event. Well, maybe this can be quite useful and quite a translationally relevant that prolongs inactivation of such pathways as result. They can ask some for, so the balance in between the benefits and the harms cannot be that clear, can, I mean, needs to be quite well addressed.

Dr Carolyn Lam: And that actually brings me to the next question. You know, the word translational has been mentioned quite a number of times here. So can you give us a sneak-peak on what the translational plans that your team may have? What's the next steps?

Dr Luca Liberale: The next steps now is back to the company. So our basic findings are here. They will be published soon, and now it's all about the clinical scientist, and how they want to implement these basic findings into the clinic.

Dr Carolyn Lam: So target engagement and mechanistic information as well. Peipei, could I just give you the last word, if you don't mind, maybe a bit of a cheeky question. What would you have loved to see in this paper or in a subsequent paper that offers a step closer to translation?

Dr Peipei Ping: I think this study has shown most necessary components as a basic science research paper. I think the next level closer to the translation as Luca has already alluded to, has to do with both efficacy studies, as well as safety studies, and those actually would need to be done in the clinic because the mouse model. I think it's a fantastic model to offer these lines of information. Ischemic-wise I think it's very strong and translational value is very high and that was the predominant reason we voted to accept the paper. As you know, the accept and raise of circulation is very, very low as our bar is very high.

Dr Carolyn Lam:  Very nice. So target engagement and mechanistic information as well. Congratulations, Luca. Thank you so much Peipei for your great comments. Now, listeners, you heard it first time here on Circulation on the Run. Thank you for joining us today.

 Dr Greg Hundley: This program is copyright at the American Heart Association, 2020.

Dr Carolyn Lam: Well, the Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature involves the Compass trial, and we'll be talking about a comparison of low-dose rivaroxaban plus aspirin compared to aspirin alone in patients with chronic vascular disease. But before we get to that, how about if we break away and discuss a few other papers. And I'll go first this time, because this week we're going to introduce another new feature in addition to Carolyn's Quiz.

Dr Carolyn Lam: Wait a minute. This was not on the script. What's going on, Greg?

Dr Greg Hundley: It's on the script!

Carolyn, let me get to my first paper. It's from Professor Junling Liu from Shanghai Jiao Tong University School of Medicine, and it involves branched-chain amino acid catabolism and how that may promote thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.

But first, we've got a new feature to add to Carolyn's Quiz. It's called Way or No Way.

Dr Carolyn Lam: Just so everybody knows. This was a one-way decision to add this new component of Carolyn's Quiz, but okay, I'm all for it. Go, Greg!

Dr Greg Hundley: Okay. All right. It's a fast, quick question where our listeners seek your guidance regarding an important scientific discovery from one of our published manuscripts. Are you ready?

Dr Carolyn Lam: No.

Dr Greg Hundley: Okay. Here's your question. Do branched-chain amino acids promote arterial thrombosis. Way or no way?

Dr Carolyn Lam: Maybe?

Dr Greg Hundley: Okay, Carolyn.

Dr Carolyn Lam: I have a feeling you're going to tell us yes, although I wouldn't have guessed that straight away.

Dr Greg Hundley: Okay. Remember that branched-chain amino acids are essential nutrients, including leucine, isoleucine, and valine, and they serve as a resource for energy production and the regulator of important nutrient and metabolic signals.

In this study, the activity of human platelets from healthy subjects before and after ingestion of branched-chain amino acids were measured. PP2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation.

Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no way?

Dr Greg Hundley: Ingestion of branched-chain amino acids significantly enhanced the activity of platelets in response to agonists and increased the risk of arterial thrombosis. The branched-chain amino acid catabolic pathway-driven propionylation of tropomodulin-3 at K255 was found to be an important mechanism underlying the branched-chain amino acid-facilitated platelet activation, and elevated levels of branched-chain amino acids and enhanced expression of positive regulators of branched-chain amino acid catabolism in platelets were found probably responsible for the high platelet activity in type 2 diabetes mellitus.

Dr Carolyn Lam: Very interesting. So yes, it is possible. And what is the clinical implications?

Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or their catabolites, enhance the risk of arterial thrombosis in small animals, and perhaps future human subject studies, that restrict branched-chain amino acid intake or target branched-chain amino acid catabolism may serve as a novel strategy for anti-thrombosis therapy.

Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question for me. Have you heard of Home Time?

Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time out for our kids, but we've been having a lot of Home Time in this COVID-19 with our families.

Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you know it is a patient-centered outcome measure that accounts for rehospitalization mortality and post-discharge care? In the paper I want to talk about, Dr Pandey from UT Southwestern and colleagues aim to characterize risk-adjusted 30-day Home Time in patients with acute myocardial infarction as a hospital-level performance metric, and to evaluate associations with risk-standardized readmission rates. The study included almost 985,000 patients with AMI hospitalization across almost 2,400 hospitals between 2009 and 2015 derived from a hundred percent of Medicare claims data. And they found that 30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varied across hospitals, was associated with post-discharge readmission and mortality outcomes, and meaningfully reclassified hospital performance compared with the 30-day readmission and mortality metric.

Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you again with another quiz. But first, this paper is from Kamal Khabbaz from Beth Israel Deaconess Medical Center and the Harvard Medical School, and it's going to assess whether left atrial appendage closure or exclusion during bypass surgery has impact on short-term outcomes.

So, Carolyn, here's your quiz. Do you think that patients receiving CABG with atrial fibrillation should undergo ligation of their left atrial appendage?

Dr Carolyn Lam: Well, I think there's definitely equipoise there. On the one hand, you're already in a surgery. Why not just ligate it? It's not like we need a left atrial appendage. And then on the other hand, I suppose it extends the surgery, it involves some risk, and we don't know if it actually prevents further events. Did I answer that right?

Dr Greg Hundley: Yes. Quite the politically correct answer, I think. Now, the objective of this study was to evaluate the impact of left atrial appendage exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. The study analyzed 250,287 CABG patients, of whom 7% received left atrial appendage closure. Only patients with a history of atrial fibrillation were included in the analysis, and the primary outcome was 30-day readmissions following discharge. Secondary outcomes included hospital mortality and stroke. And to assess the postoperative outcomes, the team utilized multivariable logistic regression models, and they adjusted for clinical and demographic co-variables.

Dr Carolyn Lam: Great. So what did they find, Greg?

Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial appendage exclusion was associated with a greater risk of postoperative respiratory failure, acute kidney injury, but it did not significantly change the rate of blood transfusions or the occurrence of cardiac tamponade. Second, left atrial appendage exclusion was associated with a nonsignificant reduction in stroke, no difference in in-hospital mortality, and a greater risk of 30-day readmissions. Number three, after adjusting for these co-variables, left atrial appendage ligation remained a significant predictor of this 30-day readmissions. And so, Carolyn, in this study, it looks like left atrial appendage exclusion during isolated CABG in patients with AFib is associated with a higher rate of 30-day readmissions.

Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else is in this issue. First is a pair of letters, one from Kai Wu regarding the article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared to Men With HFpEF: Insights From PARAGON-HF" and the response from Dr John McMurry. There are also two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and Inflammation: Mind the Gap" by Dr Lazzerini, and another entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms" by Dr Naveed Sattar.

There are two perspective pieces, "Establishment and Management of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by Dr Blake Thomson. There's an in-depth paper entitled "The Science Underlying COVID-19: Implications for the Cardiovascular System" by Dr Peter Liu. This is important. This one's an editor's pick, so don't forget to read this.

There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with ST Elevation: Looking Behind the Masquerade." In Cardiology News by Tracy Hampton, she reviews the literature and highlights three papers, one, "A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors" in Cell 2020; two, "Noninvasive Localization of Cardiac Arrhythmias Using Electromechanical Wave Imaging" in Science and Translational Medicine 2020; and three, "Somatic Gene Editing Ameliorates Skeletal and Cardiac Muscle Failure in Pig and Human Models of Duchenne Muscular Dystrophy", and that in Nature Medicine 2020.

For the President's Page, we have a piece by Keith Churchill, who's the Executive Vice President and CEO of Yale New Haven Hospital entitled "The Compelling Need to Address Uncertainty, Anxiety, and Financial Peril for Patients".

There's Highlights from Circulation Family of Journals by Sara O'Brien, including "Factors Associated With Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results From the ORBIT-AF" from Circulation Arrhythmia and Electrophysiology. There's "Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from Circulation Cardiovascular Imaging. There's also "The Impact of a 10 Rules Protocol on COVID-19 Hospital-Related Transmission: Insights from Padua University Hospital in Italy" from Circulation Cardiovascular Interventions. There's "The Association of an AMI Readmission-Reduction Program with Mortality and Readmission" from Circulation Cardiovascular Qualities and Outcomes. And finally, "Treatment Differences in Chronic Heart Failure Patients with Reduced Ejection Fraction According to Blood Pressure" in Check HF, and that's in Circulation Heart Failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few Research Letters that I reviewed. First is from Professor Puck Peltenburg, and the Research Letter involves children and adolescents from Brugada syndrome families in which only the SCN5A mutation carriers develop a type one ECG pattern induced by fever. And the second research letter is from Dr David Saadoun, and this evaluates the long-term outcome and prognosis factors associated with isolated aortitis. And then finally, Carolyn, there's a very nice piece related to the current status of cardiovascular medicine in Israel from Professor Ran Kornowski at the Rabin Medical Center.

Well, Carolyn, what a packed issue we have, and how about now we get on to that feature discussion?

Dr Carolyn Lam: Let's go, Greg.

Dr Greg Hundley: Well, listeners, we have a wonderful feature discussion for you in this next segment. We have Professor Keith Fox from Edinburgh and our own associate editor, Professor Stefan James from Uppsala. And we're going to discuss anticoagulation and antiplatelet therapy and rivaroxaban and aspirin and results from the COMPASS trial.

Keith, could you tell us what was the background information and what was the hypothesis that you wanted to test with your study?

Professor Keith Fox: The hypothesis was whether the combination of a very small dose, a quarter of the dose tested here, of a NOAC alongside an antiplatelet would be superior to aspirin alone, or we also tested a half dose of the NOAC by itself. And the overall trial showed that the quarter dose of rivaroxaban plus aspirin was substantially superior to aspirin alone in preventing cardiovascular death, MI, and stroke, with its biggest impact on strokes and cardiovascular death. So that's the trial as a whole.

But our specific goal here was to look at the question of net clinical benefit because clinicians are challenged by any therapy that has a balance of both potential hazard, like bleeding risk, and benefit. So what we analyzed here were the pre-specified characteristics of net clinical benefit in terms of life-threatening and major bleeding into a critical organ, plus cardiovascular death, MI, and stroke. And I asked the question, what was the net clinical benefit?

Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit about what population you were looking to understand net clinical benefit, and then what was the study design?

Professor Keith Fox: This is the whole of the COMPASS trial without the arm that tested rivaroxaban alone, because that did not show significant benefit. So this is the remaining 18,000 patients, double-blind randomized trial. And the trial, as a whole, was stopped early on the recommendation of the DSMB because it met the criteria for benefit by four standard deviations. Now, what's unusual about this is the population of our patients and vascular risk. So these are people who in the past would just be treated with aspirin. So they're not post-MI. They are people with chronic vascular disease, either peripheral or coronary. And in the past, on top of standard secondary prevention care, they would only have got aspirin.

Dr Greg Hundley: And what were the results?

Professor Keith Fox: There was a 20% reduction in terms of the net clinical benefit favoring the combination of rivaroxaban and aspirin, and that net clinical benefit being the combined impact of cardiovascular death, MI, stroke, fatal bleeding, or bleeding into a critical organ.

Dr Greg Hundley: And did you find the same results in, for example, older versus some of the younger patients? Or were there any other high-risk subgroups, those with impaired renal function or those with heart failure where you saw particular differences?

Professor Keith Fox: Yes, Greg. This is a really important issue. If one looked at the whole trial, the number needed to treat to prevent one of these adverse events, N equals 52. But then if we looked at some of the higher-risk cohorts, which we defined prospectively ... For example, these were the risk factors like polyvascular disease, impaired renal function, ambulant heart failure, or diabetes. And if you had all four risk factors, the number needed to treat was nine. If you had three risk factors, it was 12. Two risk factors, 31. So I think there's clearly a message for clinicians to be able to identify people with a combination of these risk factors, one or more, in order to get the most benefit and the least hazard.

Dr Greg Hundley: Very interesting. Any speculation on mechanism?

Professor Keith Fox: Yes. One of the things that we've done in the past is we've hammered one antithrombotic pathway. Like, for example, we've used more and more potent anti-platelets or combination of anti-platelets. But perhaps one of the things that we've forgotten is the fact that the platelet activation pathway is triggered by thrombin activation and vice versa. So the concept that was new behind the whole COMPASS study was that augmentation of the antithrombotic effects by combining a very small dose of a novel anticoagulant would be beneficial. And the critical question is, would it be sufficiently beneficial without producing a lot of bleeding? So that's why we did this particular analysis.

Dr Greg Hundley: So lower doses of some of these drugs. Well, Stefan, can you help us put these study results into context with what we know today about using aspirin alone, rivaroxaban, et cetera?

Professor Stefan James: The reason I think this study's so important and interesting is that, first, it's a very common population that we see now in the practice, patients with a stable phase of atherosclerotic disease, both coronary and peripheral vascular. And we need to take care of these patients better. Until now, we have not had very great alternatives for these patients. Now, we've learned what Keith said, that if you combine a low dose of both anti-platelet and antithrombin, you can inhibit and reduce the risk of ischemic events. And the other important finding here is that, I think conceptually very interesting, that if you are able to reduce their number of ischemic complications or thrombotic complications, but not doing that to such an extent that bleeding increases too much, not to an extent that bleeding causes fatal events, then you can find a nice balance between safety and efficacy that can lead to substantial reductions and improvements in terms of the clinical benefit.

And that's what we see here in this trial. You can see that there is a reduction of thrombotic events, ischemic events, and there is also some bleeding, but not to such an extent that it affects overall survival and the overall event rate in these patients. And particularly in patients at high risk that you pointed out, these patients have a very high event rate. Although the relative benefit is similar, the absolute benefit is quite impressive.

Dr Greg Hundley: Just very exciting to me. Very low doses of some of these common drugs. What's the next study in this field, Keith?

Professor Keith Fox: We've got a big gap because we know that modern dual antiplatelet therapy works really well after an acute coronary syndrome and it's highly effective. In the longer term, we know, for example, from some of the studies with ticagrelor that there are cohorts that do well for a period of time after ACS, but really we don't know the bridge between this period and the long term and what role this therapy may have after essential dual antiplatelet therapy.

Dr Greg Hundley: Stefan, do you have any thoughts?

Professor Stefan James: I agree with Keith. This transition period, when is patient transitioned from being an acute coronary syndrome patient to a chronic coronary syndrome patient? When does that happen? And then probably it differs between individuals and type of events, and so we need to understand more of when is this patient acutely affected and when do we need potent dual antiplatelet therapy? And when can we transition to a more stable phase in which we can inhibit thrombotic events, ischemic events, but not increased bleeding to such a degree that it affects overall survival? And so I think we need to learn a lot more about that transition period and these subgroups of patients of different risks and risks of ischemic events and bleeding events.

Dr Greg Hundley: Keith, how would you go about conducting a study in that regard?

Professor Keith Fox: I think really one of the very interesting questions is whether the combination of the standard of care of, for example, aspirin and ticagrelor may be better, worse, or the same than this therapy instituted at the end of the period of essential dual antiplatelet therapy. And we need to know that.

Dr Greg Hundley: In closing and summing up, Keith, are there any concepts that we want to take home here?

Professor Keith Fox: I think that there are two key concepts. One is the synergy between the anticoagulation system and the antiplatelet system, with the potential to use very low doses, to minimize bleeding risk, yet have the benefits. That is the first concept. The second concept is that these chronic vascular disease patients Stefan has described are at continuing risk of vascular events, especially stroke, myocardial infarction, and cardiovascular death. And these can be modified.

Dr Greg Hundley: And Stefan, any thoughts from you in closing?

Professor Stefan James: I think this paper and the work that Keith has described is fantastic and fascinating to think about because these populations are incredibly large, and they are not doing well. They have a high risk of events, and we tend to forget that, and so we need to both identify them and start treating them now, as we have some evidence, but we'll also need to learn more of how to identify them, how to select them appropriately, and how to identify the transition from acute events to chronic events or current chronic phase of the disease.

Dr Greg Hundley: Well, listeners, I want to thank both Professor Keith Fox and our own associate editor, Professor Stefan James, for this very interesting presentation of lower doses of anticoagulant and antiplatelet therapy in patients with chronic vascular disease and really being able to reduce events and diminish bleeding.

On behalf of Carolyn and myself, we want to wish you a great week and look forward to catching you next week. Take care.

This program is copyright of the American Heart Association 2020.

This week’s episode is special: we have the former and current Editors-in-Chief of Circulation on Circulation on the Run. Join Dr Amit Khera, Digital Strategies Editor of Circulation, as he speaks with Dr James T. Willerson, Editor-in-Chief from 1993 to 2004; Dr Joseph Loscalzo, Editor-in-Chief from 2004 to 2016; and Dr Joseph A. Hill, the current Editor-in-Chief. They will discuss the history of Circulation and how it continues to evolve.

TRANSCRIPT

Dr Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation from UT Southwestern Medical Center in Dallas. Today we have a very special Circulation on the Run. We have three Editors-in-Chief from Circulation. First, we have Dr James Willerson, who was the Editor-in-Chief from 1993 to 2004. He's a President Emeritus at the Texas Heart Institute. We also have Dr Joseph Loscalzo, who was Editor-in-Chief from 2004 to 2016, the Chairman of Department of Medicine from Brigham and Women's Hospital. And finally, Dr Joseph Hill, the current Editor-in-Chief, the Chief of Cardiology at UT Southwestern Medical Center. Welcome, gentlemen.

Dr Joseph Hill: Thank you.

Dr James Willerson: Thank you.

Dr Joseph Loscalzo: Thank you.

Dr Amit Khera: Dr Willerson, I must say, looking over the tenure prior to Dr Loscalzo, you had one of the longest tenures ever as Editor-in-Chief of Circulation, and certainly a lot happened in the practice of cardiology during that period. It was a really formative period in cardiology. As you think back, what were some of the most important topics that you covered during that time as Editor-in-Chief, thinking about the evolution of cardiovascular care and science at that time?

Dr James Willerson: You have to remember, there have been many editors at Circulation. We all build on the shoulders of others, certainly I did. I really wanted Circulation to be the premier cardiovascular journal in the world. I wanted it to be much like the New England Journal of Medicine, but the New England Journal of Medicine Circulation of Cardiology. I wanted to publish it every week. We got permission to do that. That wasn't easy, but we were fortunate. I've been accused of wanting to publish it every day. There's actually some truth to that. I didn't make that. I didn't try very hard. I wanted to be able to present the information, important information, to everybody who cared about cardiovascular medicine: physicians, scientists, students, nurses, those who cared for people, and I wanted to do it frequently. I wanted to publish it quickly. So, we had some success with that. There are many other things that are well-known to the other editors, all of whom have built before me and after me, and I'm very proud of them.

Dr Amit Khera: Well, thanks for that. And certainly, as you pointed out, this has been an evolution where you took the gauntlet, if you will, from the people before you, and then built on that and had many advances. I guess after you, Dr Loscalzo, you I think did have the longest tenure if I saw of any of the editors and similarly, a lot of evolutions in cardiovascular care and a lot in science, particularly during your time. Tell us a little bit about any particular papers or topics that you focused on, or that really were revolutionary in the cardiovascular space during your tenure.

Dr Joseph Loscalzo: I'll pick up where Jim left off and just make the case that as you're suggesting, I mean, there's sort of been a natural transition of the kind of science that Circulation has been publishing over the tenure of the three editors here today. Before Dr Willerson, it was largely physiology and excellent clinical science. Jim really expanded the scope of what Circulation published to begin to put in press in its pages, fairly basic and translational science as well. I picked up from what he'd laid the groundwork for to expand the scope of that science. And as you know, expand it to the point that we had to develop daughter journals that would pick up the mantle in each of these increasingly subspecialized areas.

So, it's hard to think about those papers that I found have the greatest impact because every field had several of them in my several years as editor. As you know, the subspecialty journals that we established, which remain active to the current time, are also broad in their scope from outcomes based research to genomics and proteomics insistence, cardiovascular medicine, to everything in between, imaging, intervention, heart failure, and electrophysiology to arrhythmias. Each of these was led, and continues to be led, by outstanding leaders in their subspecialty fields.

I think the beauty of Circulation in contrast to even fine journals like the New England Journal of Medicine, is that Circulation has been able to put on its pages those studies that really do span quite a spectrum. We don't shy away from very basic studies. That actually began with Jim, I must say, because that wasn't the case previously. And of course, we move right through to epidemiology and outcomes based research. And the impacts have been broad in each of those fields, as witnessed by the excitement and uptake of the journal, measured however you wish, by impact factor, or citations, or the frequency with which it's referred to in the lay press. So, I think that tradition certainly continues under the current editor with papers of extraordinary impact.

Dr Amit Khera: Thanks for that. I think your point about the evolution of science over time from Dr Willerson and certainly during your tenure and beyond to the breadth of Circulation currently. You also touched on the subspecialty journals. That happened in your watch and that was quite a marked change in cardiovascular medicine to have that explosion of new journals, if you will. What do you think the impact of those subspecialty journals has been for the cardiovascular field?

Dr Joseph Loscalzo: We struggled with the idea about whether or not we should pursue that kind of fragmentation. What really pushed us was the fact that the acceptance rate remains quite low, in those days, probably eight or so percent range at its nadir. So, we were rejecting a lot of really excellent papers which wound up in competitor journal pages, that we would like to have accepted and been given the scrutiny of the careful reviews and editorials that accompany papers accepted by Circulation. We felt the best way to do that under the circumstances was to create these daughter journals. They succeeded, in many respects, beyond our wildest imagination. The numbers of papers that were published in the family increased, I think in the first two or three years, by at least 2-to 3000.

So, that really speaks to the fact that we kept the best papers in the family. We gave them the right kind of audience. Some of these would have been too technical or too highly specialized to have been published in Circulation proper, but certainly of the highest quality and of significant relevance to the subspecialist. So, we think that it was a successful experiment. Now it's sort of become tradition. I think that the question that will always come up, of course, is can we fragment things more? I would say one of the best reasons to make the case that this was a successful experiment is that if imitation's the sincerest form of flattery, the New England Journal is now going to start three subspecialty journals. In fact, in my role now as an editor of the New England Journal, editor-at-large, they asked my input in how to design those daughter journals and what to expect from them.

Dr Amit Khera: Well, I think that's a great point. It certainly has been a resounding success and as you pointed out, imitation is the best form of flattery. I'm going to pivot now to Joe Hill. Dr Hill, you have certainly been the beneficiary of all the great work that these two editors have done in the past. You've inherited a very successful journal and also have crafted your own vision for where you want Circulation to go in your mark. Tell us a little bit about some of the new initiatives you've tried to implement, leveraging on these past successes.

Dr Joseph Hill: Thank you, Amit, it's an honor and a privilege to be in this conversation, frankly. I mean, Dr Willerson made this a weekly journal. That was back in the day when FedExes were flying around. Everything was paper. That kind of volume with that technology is impressive. And Dr Loscalzo, who has been a friend and mentor for many, many years, spearheaded the subspecialty journals, as we just heard, and took the journal to yet new heights. Each of you has been a pioneer and we've been fortunate to put together a team that I think has moved in exciting directions. We've leveraged technology now, such that we have our video conference meetings. We meet in a video conference with editors from 17 different countries. We have a third of our editors in Dallas, where I live, a third in the US outside of Dallas, and another third in 16 other countries.

It turns out we alternate the time of that meeting each week because there's no single hour of the day that works around the globe, so we move it around to capture Asia or to capture California in alternating weeks. That has been a thrill and, honestly, I believe a robust success. We have leaders on the ground in all these different countries. We have a highly diverse team across the different subspecialty domains of cardiology, across different geographic regions, across race and sex and gender lines. It is an amazing team. And Amit, who leads our robust digital efforts, including this podcast and our efforts on social media, again, the opportunity now in the 21st century to take these initiatives forward has been a real privilege.

Dr Amit Khera: It's ironic that Circulation was doing Zoom before everybody else was in the modern era. I'm going to pivot back to Dr Willerson. As Dr Hill just mentioned during your tenure how the volume of papers was handled, FedEx and sort of the nature of the journal publishing process. And now in the modern era, we have so much different information. We have a huge volume of journals. We have online, we have Twitter, we have podcasts. We have people that are consuming information in so many different ways. Tell us from your perspective, what's the role of the scientific journal currently and how has it changed at all in the last few decades?

Dr James Willerson: It's always going to continue to evolve. It's about as good as it can be right now with Dr Loscalzo and Dr Hill's leadership, and I'm really proud of them. There'll be more. We can't even imagine what it will be in two or three years. Of course, it'll be better and better, faster, almost momentary. Thank you, Dr Hill.

Dr Amit Khera: Thank you for that. I think we all look forward to seeing how this evolves more rapid information, rapid turnaround. I'm certain that will change. Dr Hill, you had a comment on that?

Dr Joseph Hill: We live in an era now where peer review is under attack in many ways and pre-print journals, blogs and so forth. And one of the things that I've really seen, and we've all seen, is how the peer review process, and we're all authors, right, we live on the other end of that stick, but it really is important. It makes a big difference. And people who are anxious to accelerate that process, I totally get it. We work very hard to do that. At the same time we, following the traditions here, have an intentionally redundant review process where every paper is evaluated by multiple editors and multiple peer reviewers. On a number of occasions, we've avoided a pothole, or we've improved a paper many, many times. And that is something that has really been impressed on me that I think people who aren't on this side of the editorial fence might not appreciate as much.

Dr Amit Khera: I think that's an important point about sort of the rigor about the way that articles come out in Circulation. And Dr Loscalzo, maybe as an extension of the last question, what do you see as some of the challenges going forward or opportunities for Circulation? You think about where it's been, but what are some of the things that you look forward to for Circulation in the future and what are some of the things you're concerned about?

Dr Joseph Loscalzo: Well, I too am concerned about this issue of peer review being under attack, and I'm particularly concerned about it for papers that have direct clinical impact. A good example of that concern, of course, are papers published, or at least publicly released, on non-peer reviewed websites like the archive sites because of their importance in the COVID epidemic, potentially. We all know of cases of drugs, at least in test tubes, with cultured cells and viruses appear to be effective that have adverse clinical consequences.

So that, and more than in any other sphere of science, ensuring that proper peer review from as many perspectives as possible is always a part of the process is absolutely critical for clinical medicine. And to me, the threat that this need for acceleration and rapid peer review poses and the sort of socialization of the transmission of scientific information that we're all interested in doing really has to have the brakes put on it a bit for the clinical science that the journal represents for this very important reason. Not to say we want to slow things down, we want to make sure that the best possible reviews are performed before we release it to the public.

I know that, as Joe was pointing out, one of the most exciting parts of the role of when I led the journal was the weekly meeting. We had a face-to-face meeting because all of our associate editors, save one, was actually physically proximate and they could travel to our conference room. But it's a wonderful exercise to have people of very different perspectives, from basic scientists, to clinical electrophysiologists, to outcomes researchers, make comments on papers that were completely outside their sphere.

The argument, of course, is if one can write and transmit a thought with the clear intent in a way that's rigorous and logical, that any reasonably bright person with reasonable scientific background should be able to understand it. And often these folks with very different scientific backgrounds have perspectives that very clearly improved the paper when they were acted upon. That's a process that doesn't exist in many other journals, I have to say. And I would encourage Joe, which I know, well, he's doing this because he enjoys it and he recognizes its importance, and Joe's successors continue to do that as well because that will ensure the value of the journal through all of the challenges that it is going to have to face in the next decade or two.

Dr Amit Khera: I think that was a great point. We're certainly seeing candy bowl examples of the importance of this rigorous process of the editors looking through it carefully and, as you both mentioned, peer review. Joe Hill, I'm going to let you maybe have the last word. I know how hard the three of you have historically worked on your craft for the journal, how much effort you've put in, but I also know it's quite a rewarding job. What would you see as the best part of being Editor-in-Chief of Circulation?

Dr Joseph Hill: Oh my, I'm learning something every day. I've been on about a steep a learning curve as when I was an intern at Dr Loscalzo's hospital long ago. Under Dr Willerson's term, I imagine many, many studies came in on acute coronary syndromes and thrombolytic therapy, primary PCI, antiarrhythmic drugs. We haven't seen an antiarrhythmic drug paper except for a recent review we did, but for quite a long time. It's artificial intelligence, it's big data, it's the UK Biobank, it's Omix, it's incredibly sophisticated genetics and genomics and basic science with genetic manipulations, IPS cells.

It's a very different world now than it was 10 years ago, 20 years ago and it certainly will be again, 10 and 20 years down the road. We are now approaching, I will say, 600 COVID related papers, and they're still coming in at a record pace. The world has changed. As I said before, this is the 70th anniversary of this storied journal. And it is truly my honor to be able to stand on the shoulders of Doctors Loscalzo and Willerson.

Dr Amit Khera: Thank you. I think that's a great way to end this podcast and congratulations on the 70th anniversary. It truly has been a privilege to chat with the three of you today. I want to thank you not only for what you've done for Circulation, but for the field of cardiovascular medicine. This is Amit Khera, digital strategies editor for Circulation. Next week we're back to our usual podcast with Carolyn Lam and Greg Hundley. Take care.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.