 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 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:  <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.ahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230731.330982&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7C9e72d983aad54616733708db92078534%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638264333520972908%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=bI%2FUc3jXa5jgtDPPq%2FgvJaulH2xoxRbtRsmn5d20hYc%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://www.ahajournals.org/do/10.1161/podcast.20230731.330982</a>

Circulation August 1, 2023 Issue

 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 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.ahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230724.155005&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7C39f329051b3441cd75f108db8c5fa488%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638258114972911029%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=Jj0FqVAvB2W8N7bgUHbklwf%2BJ89zRwBFXEf4g6kuA%2BY%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://www.ahajournals.org/do/10.1161/podcast.20230724.155005</a>

Circulation July 25, 2023 Issue

 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 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230709.293635&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7Cb997578f51f8422450ee08db80c1bf2b%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638245341994197369%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=HvC%2B20gZhvcVqy3Ha%2B7HOFIh0ygkZ522zPiMMqwZFnw%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do/10.1161/podcast.20230709.293635</a>

Circulation July 18, 2023 Issue

 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 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230709.411427&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7Cccb5c3b8d24847bcada608db80bc203f%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638245317870841253%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=kBLKDTgMkidb0lcB1ak01rcs%2FSnKyci%2B6F58sCsa454%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do/10.1161/podcast.20230709.411427</a>

Circulation July 11, 2023 Issue

 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, 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo10.1161%2Fpodcast.20230630.576031&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7Cae8b79855bc44f0c808108db799cca0e%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638237487345052143%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=faxWkNbv7eZTIWMTvpnA%2BgC7ZC77zidtApjzOUDbMFc%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do10.1161/podcast.20230630.576031</a>

Circulation July 4, 2023 Issue

 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, 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230626.231366&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7Cfecfd609282f4fc1c43f08db76654bfd%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638233949680918942%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=y2z7yDEMFzhiapXsxeI45jYCijHWlDOjXXlXUEnHwjM%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do/10.1161/podcast.20230626.231366</a>

Circulation on the Run: Discussion Regarding Vascular Medicine Research 

 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 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230619.624297&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7Cf9029d77aa54445465c808db70e0d0a3%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638227883295939542%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=ikuvbyyCwtI0JYwM2%2BARaxV6fvOvQ8bkhptDulnCj%2FY%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do/10.1161/podcast.20230619.624297</a>

Circulation June 20/27, 2023 Issue

 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 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:  <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230612.642952&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7C49ef37d6551a4845dcb208db6b5a8f35%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638221809682186464%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=flMvllYfZ8f4Yi0%2BR%2BOCLvPAAdhRSekMy1x7O7zx%2Brg%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://ahajournals.org/do/10.1161/podcast.20230612.642952</a>

Circulation June 13, 2023 Issue

 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 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:  <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.ahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230601.394643&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7C07cefa55926541c8681208db65f576de%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638215877189701693%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=O3rQQGeeQxmcA7hgOeMfjTZLothUt9yiBEFNUzPO6m8%3D&amp;reserved=0" rel="nofollow" target="_blank"> https://www.ahajournals.org/do/10.1161/podcast.20230601.394643</a>

Circulation June 6, 2023 Issue

 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 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: <a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.ahajournals.org%2Fdo%2F10.1161%2Fpodcast.20230526.118098&amp;data=05%7C01%7CBridgette.Cain%40wolterskluwer.com%7C0e61a26f741f40bf14d508db5e054a19%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C638207149329698479%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&amp;sdata=GZdmWi9HfO7UHSdUJRFzTJtsiBLUa08G2vfM7uw1H3A%3D&amp;reserved=0" rel="nofollow" target="_blank">https://www.ahajournals.org/do/10.1161/podcast.20230526.118098</a>

Circulation May 30, 2023 Issue

Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run. This is followed by a deep dive into a featured article of particular clinical significance: views will be heard from both author and editor teams for a “behind the scenes” look at the publication. Expect a fun, highly conversational and clinically-focused session each week!

awesome; informative; efficient. Capsule summaries of the original research and engaging interview with selected authors and editors.

mcgui007

Great summary of the Circulation issues. Best part is the interview portion which features authors and editors.

Useful CV Podcast

Circulation on the Run

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond this week, who is sadly missing his dear friend, Dr Carolyn Lam, who is away for just a week or two. I hope you've experienced a wonderful holiday season and are able to embrace the new year with joy and hope. In our feature article this week, Dr Marcelo Di Carli and colleagues are going to discuss the role of coronary microvascular dysfunction assessed with cardiac stress during PET, as well as left ventricular remodeling assessed with echocardiography and how both of those relate to clinical outcomes in patients with chronic kidney impairment. But first, let's have a coffee and chat about other articles in this issue. We have four original manuscripts, two or more clinical papers, and two from the world of basic science. So let's go to the clinical papers first. And the first emanates from our own associate editor, Dr Sana Al-Khatib from Duke University. Her paper comes from the ARISTOTLE trial, a randomized study of 18,201 participants that compared apixaban with warfarin in patients with atrial fibrillation at increased risk of stroke. And so this sub study included 17,423 patients in ARISTOTLE without severe renal or liver disease. And the authors evaluated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking either NSAIDs with therapixaban or warfarin. The authors found that those with NSAID use at baseline, so before starting into the study or incident NSAID use, that is they began an NSAID after initiating this study were more likely, both groups were more likely to have a history of bleeding, nearly a quarter of the patients to a fifth of the patients versus only 15% that had never used NSAIDs either before or after entering the study. In addition, the safety and efficacy of apixaban versus warfarin appeared not to significantly be altered by NSAID use. That is whether you were taking apixaban or whether you're taking warfarin, the impact of NSAID use was not different between either of those anticoagulants. The second original clinical article comes from Dr Audrey Blewer, also from Duke University, and evaluates the variation in bystander cardiopulmonary resuscitation delivery and subsequent survival from out of hospital cardiac arrest based on neighborhood level ethnic characteristics. As background for this research, bystander cardiopulmonary resuscitation delivery and survival from out of hospital cardiac arrest varies at the neighborhood level, was generally lower survival seen in neighborhoods predominantly with individuals from black race. Despite Hispanics being the fastest growing minority population in the United States, few studies have assessed whether the proportion of Hispanics in a neighborhood is also associated with delivery of bystander CPR or subsequent survival for an out of hospital cardiac arrest. Accordingly, the authors in this study assessed whether bystander CPR rates and survival buried by neighborhood level ethnicity. And they hypothesized that neighborhoods with a higher proportion of Hispanics would have lower bystander CPR rates and overall lower survival. This study was a retrospective cohort and use data from the Resuscitations Outcome Consortium, or ROC Epistry across the United States. So in this study, the authors identified 18,900 cardiac arrests. And they excluded pediatric arrests, EMS witnessed arrests, or arrest occurring in a healthcare or an institutional facility. And they found overall that bystander CPR was administered in 37% of these out-of-hospital arrests. Among neighborhoods with less than 25% Hispanic residents, bystander CPR was administered in 39% of the events, while it was administered in only 27% of the events in those neighborhoods with greater than 75% Hispanic residents. Also, lower rates of survival occurred in neighborhoods with greater than 75% Hispanic residents. And so the authors conclude that these findings suggest there's an important need to understand the underlying disparities in CPR delivery and an unmet CPR training need among Hispanic communities. Well now let's shift to our two original articles that come from the world of basic science. And the first is from Dr Ying Shen from Baylor College of Medicine and reports on the critical role of cytosolic DNA and its sensing adapters sting in aortic degeneration, dissection and rupture. So as some background for this study, recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing it after sting, a stimulator of interferon genes, plays a critical role in vascular inflammation and destruction. And so in this paper, the authors examine the involvement of this mechanism in aortic degeneration and sporadic aortic aneurysm and dissections. Just like with our other basic science papers, the authors perform both studies in a small animal model, mice, and also in human subjects. So what did they find? The authors found that in human sporadic aortic dissection tissues, they observe the presence of cytosolic DNA in smooth muscle cells and macrophages. And they had significant activation of this sting pathway. In a mouse model, sting deficient mice showed significant reduction in challenged induced aortic enlargement, dissection and rupture in both the thoracic and abdominal aortic regions. Additional single cell transcriptome analyses were performed and provided some mechanistic understanding for the author's findings. So in summary, for this very interesting paper from the world of basic science, the author's findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing it after, or sting signaling, is a key mechanism in aortic degeneration. And therefore future studies, perhaps targeting sting, may be performed to see if they could prevent sporadic aortic aneurysm dissection development. The second basic original article in this issue is entitled In Vivo CRISPR CAS9-mediated gene editing and how that ameliorates atherosclerosis in familial hypercholesterolemia. It comes to us from Dr Bin Zhou from the Chinese Academy of Sciences. So as background for this study, mutations in the low-density lipoprotein receptor are one of the main causes of familial hypercholesterolemia. The clustered regularly interspace short palindromic repeats of CRISPR and caspase-9 system is an effective tool for gene editing to correct gene mutations and thus ameliorate the disease. So these authors tested whether in vivo sematic cell gene editing through the CRISPR CAS based nine system delivered by adeno associated virus could treat familial hypercholesterolemia caused by the LDLr mutant in a mouse model. Well, the authors ... As Carolyn would ask, so what did they find, Greg? Well, the authors observed some really exciting results. They found that the LDLr mutation was corrected in a subset of hepatocytes after the CRISPR CAS based nine treatment with LDLr protein expression partially restored. Compared with control animals, the CRISPR CAS based nine targeted SGRNA group had significant reductions in total cholesterol, total triglyceride, and LDL cholesterol in the serum while the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration. So this study really implicates perhaps not only a mechanism of disease, but a potential treatment. But with the relatively small numbers in this study, more research is needed to confirm and substantiate the findings from this group. So great original articles in this issue. What else is in the issue? And let's move to those. We have a global rounds feature. Remember, global rounds are investigating how cardiovascular disease is assessed and managed in countries from all over the world. Well, in this global rounds feature Professor Ali Oto from Memorial and Cairo Hospital provides a quick reference to the control and management of cardiovascular disease in Turkey. And the next article, an on my mind piece, Dr Milton Packer explorers whether the conditions of atrial fibrillation and heart failure with preserved ejection fraction are two separate diseases that occur frequently together in patients or alternatively, whether these two adverse clinical syndromes may be parallel manifestations of the same underlying myocardial disease with atrial fibrillation affecting the left atrium and heart failure preserved ejection fraction afflicting the left ventricle. In our what's in the mailbag series, Professor Nicholas Mills from the University of Edinburgh shares in a research letter the relationship between exercise intensity and duration on cardiac troponin release in 10 physically active healthy volunteers averaging 34 years in age. A great read for our readership that is actively exercising. And it looks like in this letter, intensity of exercise matters when evaluating post-exercise serum troponin values. I really encourage everyone to take a look at that letter. And then finally, there's a letter to the editors from Dr Abdallah Fayssoil from the Raymond Poincare Hospital in Garches, France regarding a prior publication related to nutrition and functional tricuspid regurgitation. Well, listeners, that sums up our summary. And I hope you had a great coffee or if you're running on your treadmill, a great run. And let's now move on to our feature discussion with Dr Di Carli. Welcome everyone to our feature discussion and we have Dr Marcelo Di Carli from Brigham and Women's Hospital who's going to be discussing with us a manuscript relating to the measurements of coronary micro circulatory function and how they may impact patients with chronic kidney disease. Also discussing today, we have our own associate editor, Dr Victoria Delgado from Leiden in the Netherlands. Well, welcome Marcelo and Victoria. We're so glad to have the opportunity to speak with you. And Marcelo, could you tell us a little bit about what was the hypothesis and some of the background of why you wanted to perform this study? Dr Marcelo Di Carli: Chronic kidney disease represents a relatively large segment of the population. In the US alone, it's estimated that around 50 million people have the diagnosis of chronic kidney disease. And it's a disease that we all know is associated with a high risk of cardiovascular events. Even in the absence of obstructive coronary disease, it's been shown that the incidents of cardiomyopathy and the absence of obstructive disease, of coronary disease, is pretty high and that associates with a high risk of heart failure and death. The mechanisms related to cardiomyopathy in patients with chronic kidney disease have been debated for a long time. This has been associated with LVH incidents of non-transmittal or non-ST-elevation MIs, also with microvascular disease as a measure of ischemic heart disease, but there's no clear association with how do these features of chronic kidney disease link to each other. And so our objective was to look at the associations between LV remodeling, coronary microvascular disease and adverse events. And we hypothesized that coronary microvascular dysfunction as a more integrative marker of myocardial ischemia and injury would associate with changes in cardiac structure and function and with increased risk of adverse cardiovascular events. Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo, about your study population and your study design. Dr Marcelo Di Carli: Well, this is a cross sectional analysis of a cohort that is well-characterized in our registries. And so it consisted of a consecutive group of patients who underwent both PET scanning for measuring coronary vascular function and echocardiography within 90 days of each other. Could it not have evidence of overt obstructive coronary disease as defined by a history of prior revascularization, prior AMI or an abnormal PET scan indicating presence of obstructive disease. We also excluded patients with severe valvular disease, cancer, severe LV disfunction to try to avoid confounding elements in the associations where we're trying to study. We used echocardiography to assess quantitatively the changes in LV geometry, diastolic function and subclinical systolic dysfunction. Most of our patients have relatively preserved LV function, LV ejection fraction. And so we looked at peak longitudinal strain, global radial strain and circumferential strain as indicators of systolic dysfunction. And of course we also looked at changes in LV mass. Patients were followed a little over four years for the occurrence of death, hospitalization for heart failure or myocardial infarction. And all of these myocardial infarctions were non-ST-elevation MIs, or people might call it type two MIs. Dr Greg Hundley: Tell us a little bit about the results. But before you get to that, how old were these patients and what was their breakdown in terms of race and gender? Dr Marcelo Di Carli: Yeah, so we had a population of 352 patients. The mean age was mid-sixties. not surprisingly, 60% of the patients were female. And this is because we obviously excluded obstructive coronary disease that would be more prevalent in male. They have about a 40% incidence of diabetes, a high percentage of them had hypertension. These are all the features that would typically be associated with chronic kidney disease. The rate of obesity was actually lower in patients with CKD. And we call CKD here as a GFR less than 60. That's the population we're targeting here. And so that's essentially the cohort. Dr Greg Hundley: And what did you find? Dr Marcelo Di Carli: Well, there were essentially three or four main findings. Number one and not very surprisingly, patients with CKD had worse myocardial mechanics that is worse diastolic function and worse systolic strain. In multi-variable models, fully adjusted for a number of clinical covariates as well as ejection fraction, we found that these abnormalities in myocardial mechanics were relatively strongly associated with abnormal coronary microvascular function as defined by PET. So this sort of suggests that the variability that we see in diastolic and systolic function are explained largely by microvascular disease, but not necessarily directly linked to GFR as a mediator. The second finding was that patients with CKD, again, not surprisingly, it showed a higher incidence of MACE, including especially death and heart failure, more than triple the rate of death and doubled the rate of heart failure compared to those without CKD. And in multi-variable analysis, again, MACE was associated with coronary flow reserve as a measure of microvascular dysfunction but not glomerular filtration rate. And there was no interaction between coronary flow reserve and GFR. Interestingly, when we looked at the adverse events subgroup by measures of LV remodeling and we picked three measures. One is changes in LV geometry, diastolic dysfunction, and impaired global longitudinal strain, we found that the incidence of both mace as well as heart failure and myocardial infarction were significantly higher when both abnormal LV mechanics or remodeling were present and the patients also had microvascular disease. So in the absence of either one, the rate of mace was relatively low, indicating that there is a clear interaction between abnormalities in cardiac structure and function and microvascular disease. And then lastly, we looked at mediation analysis to try to investigate a plausible pathway between impaired renal function and events and we hypothesized that coronary microvascular dysfunction might actually mediate at least part of that relationship. And indeed we found that about a third of the relationship was explained by the presence of microvascular disease. Very nice, Dr Greg Hundley: Very nice. Very important work. So now we'll turn to our own associate editor, Victoria Delgado. Victoria, help us put this into perspective for what we know about patients with chronic kidney disease. How does the results of this study really move the field forward? Dr Victoria Delgado: I think that this article brings new evidence on phenotyping of these patients and the factors that influence the cardiac abnormalities that we may see. There are not many studies including patients with chronic kidney disease. These patients are usually underrepresented in randomized control trials. And we know that these patients are associated with an increased mortality and morbidity and mainly heart failure hospitalizations. And I think that this study is showing another piece in the person that can help us understand why these patients are associated with much higher cardiovascular morbidity and mortality. I think that relating the coronary microvascular dysfunction is an important piece and important knowledge because then we may think how to improve the microvascular dysfunction on these patients and see if by improving these microvascular dysfunction, these abnormalities that have been described in terms of a structure and function can be reversed and see how these impacts on the outcome of these patients. Dr Greg Hundley: So Marcelo, just briefly, what do you think is the next study that needs to be performed in this area of science? Dr Marcelo Di Carli: I think that obviously our study has some limitations and the causation. Cause and effect cannot be inferred from our study. So I think the next steps will be to try to demonstrate whether indeed modifying microvascular dysfunction leads to improved outcomes. And I think this will be best done by intervention studies that can be targeted towards improving microvascular dysfunction. We can think of novel therapies as well that have been initially associated with improved renal outcomes. I'm talking about for example, SGLT2 inhibitors that can be potentially of benefit not only on renal outcomes but potentially on cardiovascular outcomes as has been shown in populations largely without CKD. Dr Greg Hundley: Victoria, anything to add in terms of how noninvasive imaging could play a role in some of those next future studies? Dr Victoria Delgado: I think that the point that Marcelo raise on the use of SGLT2 inhibitors is very timely and very appealing because we know that for patients with diabetes who have renal dysfunction and you have EGFR below 35, they may not be eligible for these therapies. But as you can see in this study, the mean EGFR of the patients with renal dysfunction was 41. So there is a wide range of patients that could be eligible for these therapies. How imaging can help to see or to detect the patients that may benefit from these therapies and see how these therapies may improve the structure and the function of the heart. Dr Greg Hundley: Well, listeners, we've had a great discussion today with Dr Marcelo Di Carli from Brigham and Women's Hospital and Dr Victoria Delgado from Leiden. And really trying to understand some noninvasive markers of both micro circulatory dysfunction as well as abnormal echocardiographic assessments of both diastolic function as well as systolic dysfunction and how they forecast adverse events in patients with chronic kidney disease. I want to wish you all a great week and on behalf of Carolyn and myself, I hope to see you next week. Take care now. This program is copyright the American Heart Association 2020.

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond this week, who is sadly missing his dear friend, Dr Carolyn Lam, who is away for just a week or two. I hope you've experienced a wonderful holiday season and are able to embrace the new year with joy and hope. In our feature article this week, Dr Marcelo Di Carli and colleagues are going to discuss the role of coronary microvascular dysfunction assessed with cardiac stress during PET, as well as left ventricular remodeling assessed with echocardiography and how both of those relate to clinical outcomes in patients with chronic kidney impairment. But first, let's have a coffee and chat about other articles in this issue. We have four original manuscripts, two or more clinical papers, and two from the world of basic science. So let's go to the clinical papers first. And the first emanates from our own associate editor, Dr Sana Al-Khatib from Duke University. Her paper comes from the ARISTOTLE trial, a randomized study of 18,201 participants that compared apixaban with warfarin in patients with atrial fibrillation at increased risk of stroke. And so this sub study included 17,423 patients in ARISTOTLE without severe renal or liver disease. And the authors evaluated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking either NSAIDs with therapixaban or warfarin. The authors found that those with NSAID use at baseline, so before starting into the study or incident NSAID use, that is they began an NSAID after initiating this study were more likely, both groups were more likely to have a history of bleeding, nearly a quarter of the patients to a fifth of the patients versus only 15% that had never used NSAIDs either before or after entering the study. In addition, the safety and efficacy of apixaban versus warfarin appeared not to significantly be altered by NSAID use. That is whether you were taking apixaban or whether you're taking warfarin, the impact of NSAID use was not different between either of those anticoagulants. The second original clinical article comes from Dr Audrey Blewer, also from Duke University, and evaluates the variation in bystander cardiopulmonary resuscitation delivery and subsequent survival from out of hospital cardiac arrest based on neighborhood level ethnic characteristics. As background for this research, bystander cardiopulmonary resuscitation delivery and survival from out of hospital cardiac arrest varies at the neighborhood level, was generally lower survival seen in neighborhoods predominantly with individuals from black race. Despite Hispanics being the fastest growing minority population in the United States, few studies have assessed whether the proportion of Hispanics in a neighborhood is also associated with delivery of bystander CPR or subsequent survival for an out of hospital cardiac arrest. Accordingly, the authors in this study assessed whether bystander CPR rates and survival buried by neighborhood level ethnicity. And they hypothesized that neighborhoods with a higher proportion of Hispanics would have lower bystander CPR rates and overall lower survival. This study was a retrospective cohort and use data from the Resuscitations Outcome Consortium, or ROC Epistry across the United States. So in this study, the authors identified 18,900 cardiac arrests. And they excluded pediatric arrests, EMS witnessed arrests, or arrest occurring in a healthcare or an institutional facility. And they found overall that bystander CPR was administered in 37% of these out-of-hospital arrests. Among neighborhoods with less than 25% Hispanic residents, bystander CPR was administered in 39% of the events, while it was administered in only 27% of the events in those neighborhoods with greater than 75% Hispanic residents. Also, lower rates of survival occurred in neighborhoods with greater than 75% Hispanic residents. And so the authors conclude that these findings suggest there's an important need to understand the underlying disparities in CPR delivery and an unmet CPR training need among Hispanic communities. Well now let's shift to our two original articles that come from the world of basic science. And the first is from Dr Ying Shen from Baylor College of Medicine and reports on the critical role of cytosolic DNA and its sensing adapters sting in aortic degeneration, dissection and rupture. So as some background for this study, recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing it after sting, a stimulator of interferon genes, plays a critical role in vascular inflammation and destruction. And so in this paper, the authors examine the involvement of this mechanism in aortic degeneration and sporadic aortic aneurysm and dissections. Just like with our other basic science papers, the authors perform both studies in a small animal model, mice, and also in human subjects. So what did they find? The authors found that in human sporadic aortic dissection tissues, they observe the presence of cytosolic DNA in smooth muscle cells and macrophages. And they had significant activation of this sting pathway. In a mouse model, sting deficient mice showed significant reduction in challenged induced aortic enlargement, dissection and rupture in both the thoracic and abdominal aortic regions. Additional single cell transcriptome analyses were performed and provided some mechanistic understanding for the author's findings. So in summary, for this very interesting paper from the world of basic science, the author's findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing it after, or sting signaling, is a key mechanism in aortic degeneration. And therefore future studies, perhaps targeting sting, may be performed to see if they could prevent sporadic aortic aneurysm dissection development. The second basic original article in this issue is entitled In Vivo CRISPR CAS9-mediated gene editing and how that ameliorates atherosclerosis in familial hypercholesterolemia. It comes to us from Dr Bin Zhou from the Chinese Academy of Sciences. So as background for this study, mutations in the low-density lipoprotein receptor are one of the main causes of familial hypercholesterolemia. The clustered regularly interspace short palindromic repeats of CRISPR and caspase-9 system is an effective tool for gene editing to correct gene mutations and thus ameliorate the disease. So these authors tested whether in vivo sematic cell gene editing through the CRISPR CAS based nine system delivered by adeno associated virus could treat familial hypercholesterolemia caused by the LDLr mutant in a mouse model. Well, the authors ... As Carolyn would ask, so what did they find, Greg? Well, the authors observed some really exciting results. They found that the LDLr mutation was corrected in a subset of hepatocytes after the CRISPR CAS based nine treatment with LDLr protein expression partially restored. Compared with control animals, the CRISPR CAS based nine targeted SGRNA group had significant reductions in total cholesterol, total triglyceride, and LDL cholesterol in the serum while the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration. So this study really implicates perhaps not only a mechanism of disease, but a potential treatment. But with the relatively small numbers in this study, more research is needed to confirm and substantiate the findings from this group. So great original articles in this issue. What else is in the issue? And let's move to those. We have a global rounds feature. Remember, global rounds are investigating how cardiovascular disease is assessed and managed in countries from all over the world. Well, in this global rounds feature Professor Ali Oto from Memorial and Cairo Hospital provides a quick reference to the control and management of cardiovascular disease in Turkey. And the next article, an on my mind piece, Dr Milton Packer explorers whether the conditions of atrial fibrillation and heart failure with preserved ejection fraction are two separate diseases that occur frequently together in patients or alternatively, whether these two adverse clinical syndromes may be parallel manifestations of the same underlying myocardial disease with atrial fibrillation affecting the left atrium and heart failure preserved ejection fraction afflicting the left ventricle. In our what's in the mailbag series, Professor Nicholas Mills from the University of Edinburgh shares in a research letter the relationship between exercise intensity and duration on cardiac troponin release in 10 physically active healthy volunteers averaging 34 years in age. A great read for our readership that is actively exercising. And it looks like in this letter, intensity of exercise matters when evaluating post-exercise serum troponin values. I really encourage everyone to take a look at that letter. And then finally, there's a letter to the editors from Dr Abdallah Fayssoil from the Raymond Poincare Hospital in Garches, France regarding a prior publication related to nutrition and functional tricuspid regurgitation. Well, listeners, that sums up our summary. And I hope you had a great coffee or if you're running on your treadmill, a great run. And let's now move on to our feature discussion with Dr Di Carli. Welcome everyone to our feature discussion and we have Dr Marcelo Di Carli from Brigham and Women's Hospital who's going to be discussing with us a manuscript relating to the measurements of coronary micro circulatory function and how they may impact patients with chronic kidney disease. Also discussing today, we have our own associate editor, Dr Victoria Delgado from Leiden in the Netherlands. Well, welcome Marcelo and Victoria. We're so glad to have the opportunity to speak with you. And Marcelo, could you tell us a little bit about what was the hypothesis and some of the background of why you wanted to perform this study? Dr Marcelo Di Carli: Chronic kidney disease represents a relatively large segment of the population. In the US alone, it's estimated that around 50 million people have the diagnosis of chronic kidney disease. And it's a disease that we all know is associated with a high risk of cardiovascular events. Even in the absence of obstructive coronary disease, it's been shown that the incidents of cardiomyopathy and the absence of obstructive disease, of coronary disease, is pretty high and that associates with a high risk of heart failure and death. The mechanisms related to cardiomyopathy in patients with chronic kidney disease have been debated for a long time. This has been associated with LVH incidents of non-transmittal or non-ST-elevation MIs, also with microvascular disease as a measure of ischemic heart disease, but there's no clear association with how do these features of chronic kidney disease link to each other. And so our objective was to look at the associations between LV remodeling, coronary microvascular disease and adverse events. And we hypothesized that coronary microvascular dysfunction as a more integrative marker of myocardial ischemia and injury would associate with changes in cardiac structure and function and with increased risk of adverse cardiovascular events. Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo, about your study population and your study design. Dr Marcelo Di Carli: Well, this is a cross sectional analysis of a cohort that is well-characterized in our registries. And so it consisted of a consecutive group of patients who underwent both PET scanning for measuring coronary vascular function and echocardiography within 90 days of each other. Could it not have evidence of overt obstructive coronary disease as defined by a history of prior revascularization, prior AMI or an abnormal PET scan indicating presence of obstructive disease. We also excluded patients with severe valvular disease, cancer, severe LV disfunction to try to avoid confounding elements in the associations where we're trying to study. We used echocardiography to assess quantitatively the changes in LV geometry, diastolic function and subclinical systolic dysfunction. Most of our patients have relatively preserved LV function, LV ejection fraction. And so we looked at peak longitudinal strain, global radial strain and circumferential strain as indicators of systolic dysfunction. And of course we also looked at changes in LV mass. Patients were followed a little over four years for the occurrence of death, hospitalization for heart failure or myocardial infarction. And all of these myocardial infarctions were non-ST-elevation MIs, or people might call it type two MIs. Dr Greg Hundley: Tell us a little bit about the results. But before you get to that, how old were these patients and what was their breakdown in terms of race and gender? Dr Marcelo Di Carli: Yeah, so we had a population of 352 patients. The mean age was mid-sixties. not surprisingly, 60% of the patients were female. And this is because we obviously excluded obstructive coronary disease that would be more prevalent in male. They have about a 40% incidence of diabetes, a high percentage of them had hypertension. These are all the features that would typically be associated with chronic kidney disease. The rate of obesity was actually lower in patients with CKD. And we call CKD here as a GFR less than 60. That's the population we're targeting here. And so that's essentially the cohort. Dr Greg Hundley: And what did you find? Dr Marcelo Di Carli: Well, there were essentially three or four main findings. Number one and not very surprisingly, patients with CKD had worse myocardial mechanics that is worse diastolic function and worse systolic strain. In multi-variable models, fully adjusted for a number of clinical covariates as well as ejection fraction, we found that these abnormalities in myocardial mechanics were relatively strongly associated with abnormal coronary microvascular function as defined by PET. So this sort of suggests that the variability that we see in diastolic and systolic function are explained largely by microvascular disease, but not necessarily directly linked to GFR as a mediator. The second finding was that patients with CKD, again, not surprisingly, it showed a higher incidence of MACE, including especially death and heart failure, more than triple the rate of death and doubled the rate of heart failure compared to those without CKD. And in multi-variable analysis, again, MACE was associated with coronary flow reserve as a measure of microvascular dysfunction but not glomerular filtration rate. And there was no interaction between coronary flow reserve and GFR. Interestingly, when we looked at the adverse events subgroup by measures of LV remodeling and we picked three measures. One is changes in LV geometry, diastolic dysfunction, and impaired global longitudinal strain, we found that the incidence of both mace as well as heart failure and myocardial infarction were significantly higher when both abnormal LV mechanics or remodeling were present and the patients also had microvascular disease. So in the absence of either one, the rate of mace was relatively low, indicating that there is a clear interaction between abnormalities in cardiac structure and function and microvascular disease. And then lastly, we looked at mediation analysis to try to investigate a plausible pathway between impaired renal function and events and we hypothesized that coronary microvascular dysfunction might actually mediate at least part of that relationship. And indeed we found that about a third of the relationship was explained by the presence of microvascular disease. Very nice, Dr Greg Hundley: Very nice. Very important work. So now we'll turn to our own associate editor, Victoria Delgado. Victoria, help us put this into perspective for what we know about patients with chronic kidney disease. How does the results of this study really move the field forward? Dr Victoria Delgado: I think that this article brings new evidence on phenotyping of these patients and the factors that influence the cardiac abnormalities that we may see. There are not many studies including patients with chronic kidney disease. These patients are usually underrepresented in randomized control trials. And we know that these patients are associated with an increased mortality and morbidity and mainly heart failure hospitalizations. And I think that this study is showing another piece in the person that can help us understand why these patients are associated with much higher cardiovascular morbidity and mortality. I think that relating the coronary microvascular dysfunction is an important piece and important knowledge because then we may think how to improve the microvascular dysfunction on these patients and see if by improving these microvascular dysfunction, these abnormalities that have been described in terms of a structure and function can be reversed and see how these impacts on the outcome of these patients. Dr Greg Hundley: So Marcelo, just briefly, what do you think is the next study that needs to be performed in this area of science? Dr Marcelo Di Carli: I think that obviously our study has some limitations and the causation. Cause and effect cannot be inferred from our study. So I think the next steps will be to try to demonstrate whether indeed modifying microvascular dysfunction leads to improved outcomes. And I think this will be best done by intervention studies that can be targeted towards improving microvascular dysfunction. We can think of novel therapies as well that have been initially associated with improved renal outcomes. I'm talking about for example, SGLT2 inhibitors that can be potentially of benefit not only on renal outcomes but potentially on cardiovascular outcomes as has been shown in populations largely without CKD. Dr Greg Hundley: Victoria, anything to add in terms of how noninvasive imaging could play a role in some of those next future studies? Dr Victoria Delgado: I think that the point that Marcelo raise on the use of SGLT2 inhibitors is very timely and very appealing because we know that for patients with diabetes who have renal dysfunction and you have EGFR below 35, they may not be eligible for these therapies. But as you can see in this study, the mean EGFR of the patients with renal dysfunction was 41. So there is a wide range of patients that could be eligible for these therapies. How imaging can help to see or to detect the patients that may benefit from these therapies and see how these therapies may improve the structure and the function of the heart. Dr Greg Hundley: Well, listeners, we've had a great discussion today with Dr Marcelo Di Carli from Brigham and Women's Hospital and Dr Victoria Delgado from Leiden. And really trying to understand some noninvasive markers of both micro circulatory dysfunction as well as abnormal echocardiographic assessments of both diastolic function as well as systolic dysfunction and how they forecast adverse events in patients with chronic kidney disease. I want to wish you all a great week and on behalf of Carolyn and myself, I hope to see you next week. Take care now. This program is copyright the American Heart Association 2020.

Circulation January 7, 2020 Issue

Circulation February 18, 2020 Issue

Circulation November 19, 2019 Issue

Dr Carolyn Lam:  Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results. Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers. Dr Carolyn Lam:  So... What did they find? Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients. Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized. Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP. Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes. Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study? Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more. Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells. Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find? Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart. Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy. Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them? Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer. Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap. Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece. Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter. Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock. Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy. Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study? Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer. Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population? Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk. Dr Greg Hundley: And who did you include in this study? Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention. Dr Greg Hundley: And how many subjects were in your study? Was this a large study? Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations. Dr Greg Hundley: So what did you find? What were your results? Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis. To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis. Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis. Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women? Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding. Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies? Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer. And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear. Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation? Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial. Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years? Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier? Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy. And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week. Dr Carolyn Lam:  This program is copyright American Heart Association 2019.

Dr Carolyn Lam:  Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results. Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers. Dr Carolyn Lam:  So... What did they find? Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients. Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized. Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP. Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes. Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study? Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more. Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells. Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find? Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart. Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy. Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them? Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer. Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap. Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece. Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter. Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock. Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy. Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study? Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer. Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population? Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk. Dr Greg Hundley: And who did you include in this study? Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention. Dr Greg Hundley: And how many subjects were in your study? Was this a large study? Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations. Dr Greg Hundley: So what did you find? What were your results? Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis. To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis. Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis. Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women? Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding. Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies? Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer. And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear. Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation? Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial. Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years? Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier? Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy. And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week. Dr Carolyn Lam:  This program is copyright American Heart Association 2019.

Circulation October 29, 2019 Issue

Circulation December 10, 2019 Issue

Circulation April 30, 2019 Issue

Circulation April 2, 2019 Issue

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: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start. Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients? Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival. Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study? Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt.   Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation. Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find? Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality. Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus. Dr Greg Hundley: Coated, remember, coated stents. Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction. Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights? Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational? Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI. Dr Carolyn Lam: Whoa, so what did they find? Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal. Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy. Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania. I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute. Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG? Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone? Dr Carolyn Lam: Let's go. Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population. I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find? Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population. At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population. Dr Carolyn Lam: What did you find? Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy. Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important?   Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects. While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting. Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study. Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study. In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results. That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion. Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population?   Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country. Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country. Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there. Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience? Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah. Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner. Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation? Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients. Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide. Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide. Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD. Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide. Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well. Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation. The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that. The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease. Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today.   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: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start. Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients? Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival. Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study? Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt. Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation. Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find? Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality. Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus. Dr Greg Hundley: Coated, remember, coated stents. Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction. Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights? Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational? Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI. Dr Carolyn Lam: Whoa, so what did they find? Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal. Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy. Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania. I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute. Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG? Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone? Dr Carolyn Lam: Let's go. Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population. I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find? Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population. At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population. Dr Carolyn Lam: What did you find? Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy. Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important? Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects. While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting. Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study. Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study. In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results. That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion. Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population? Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country. Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country. Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there. Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience? Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah. Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner. Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation? Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients. Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide. Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide. Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD. Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide. Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well. Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation. The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that. The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease. Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today. Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation March 17, 2020 Issue

Circulation April 16, 2019 Issue

Circulation August 20, 2019 Issue

Circulation April 9, 2019 Issue

Circulation December, 03, 2019 Issue

Circulation October 22, 2019 Issue

Circulation March 12, 2019 Isuue

Circulation May 14, 2019 Issue

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 Greg Hundley, associate editor as well at Circulation, and director of the Poly Heart Center in Richmond, Virginia, at VCU Health. Well, I'm going to talk about anti-hyperglycemic agents and look at a very important meta-analysis. Dr Carolyn Lam:                Those are the rage: GLP-1 receptor agonists and SGLT-2 inhibitors. But first, let's talk about psychosocial stress and cardiovascular health. So what is the joint impact of multiple stressors on racial or ethnic disparities in cardiovascular health?                                                  Well, this question was tackled by Dr Albert, from University of California San Francisco Center for the Study of Adversity and Cardiovascular Disease and her colleagues. They basically studied more than 25,000 women participating in the women's health study follow-up cohort, and examined the relationship between cumulative psychosocial stress and ideal cardiovascular health as defined by the American Heart Association Strategic 2020 Goals.                                                  As a reminder, this health metric includes smoking, BMI, physical activity, diet, blood pressure, total cholesterol and glucose, and higher levels indicate more ideal cardiovascular health and less cardiovascular risk.                                                  So, they found that both cumulative psychosocial stress and ideal cardiovascular health varied by race or ethnicity. Mean cumulative psychosocial stress scores were higher in Hispanic, Black, and Asian women compared to white women, even after adjusting for age, socioeconomic status and psychological status such as depression and anxiety. The mean ideal cardiovascular health scores remained worse in blacks and better in Asians compared to whites, despite taking into account socioeconomic factors and cumulative psychosocial stress. Dr Greg Hundley:             So Carolyn, how should clinicians incorporate this information in what we do every day? Dr Carolyn Lam:                Although the cumulative psychological stress and socioeconomic status did not fully explain the racial or ethnic differences in ideal cardiovascular health that we saw, clinicians should be informed by these data that psychosocial stressors are social determinants of health that have different prevalence according to race and ethnicity. I think that's what we need to learn. And of course these data support the need for additional work that addresses the joint impact of multiple social determinants of health on cardiovascular disease and in diverse populations. Dr Greg Hundley:             Very good, Carolyn. That was really an interesting article. Well, I'm going to switch gears and talk about the role of red blood cells in promoting vascular calcification. My article is from Dimitrios Tziakas from the Department of Cardiology in Thrace, Alexandropoulos, in Greece.                                                  Now, the presence of extravasated erythrocytes in human atherosclerotic lesions was described several years ago, but little is known about a possible active role of red blood cells during these cardiovascular disease processes. Clinical studies suggest that intraplaque hemorrhage may be associated with the progression of coronary, carotid, and atherosclerotic lesions and degenerative calcific aortic valve stenosis. So, in the present study, the authors examined the contribution of erythrocytes to vascular and valvular lesion progression, focusing on the effects of red blood cells on the osteoblastic transdifferentiation of smooth muscle cells in calcification. Dr Carolyn Lam:                Interesting. So, what did they find? Dr Greg Hundley:             So, lysed erythrocytes, and in particular their membrane faction, enhanced human and murine arterial smooth muscle cell mineralization and vascular aortic ring calcification. Red blood cell membranes injected in the vascular regions of atherosclerotic-prone mice also promoted calcification and red blood cells were found to co-localize with osteoblast like cells in human atherosclerotic plaques, stenotic aortic valves, and abdominal aortic aneurysms. And so, the study demonstrated that intra plaque hemorrhage promotes atherosclerotic and valvular lesion calcification and membranes of extravasated lysed red blood cells appeared to play an important role in the process. The investigators also showed a mechanism, that nitric oxide derived from erythrocyte endothelial nitric oxides synthase is involved, at least in part, in mediating the effects of red blood cells on vascular calcification. Dr Carolyn Lam:                Thanks, Greg. Now back to another, well, clinical paper with the next one asking, do mid-life biomarkers of heart and kidney damage associate with the level of and decline in physical capability with aging? Dr Kuh and colleagues from MRC Unit of Lifelong Health and Aging at University College London used data on 1,736 men and women from the oldest British birth cohort study. And, looked at their walking speed, chair rise speed, balance time, and grip strength. Assessed at ages 60 to 64 and 69 years. They tested the associations between Cystatin C, NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64 years with their performance at 69 years. And what they found was the lower levels of NT-proBNP in interleukin-6 in middle aged adults were independently associated with better physical capability up to nine years later. And all these associations were stronger than those observed for conventional risk factors: including lipids, blood pressure, and glycemia, and were not explained by the onset of cardio vascular and kidney disease or diabetes. Dr Greg Hundley:             Carolyn, is this saying we should now measure these biomarkers in mid-life? Dr Carolyn Lam:                Ah, before considering the use of NT-proBNP and IL-6 or interleukin-6 for risk stratification, we really do need further research to untangle whether these associations exist because the biomarkers are an integrated measure of accumulated exposures to stressors. Or, whether they are really capturing early an organ damage. Or, whether they are marking additional risk pathways. So, this and more is discussed in a great accompanying editorial entitled "Putting the Measurement of Physical Capacity in Older Adults in its Place". And that's by Dr Kritchevsky from Wake Forest School of Medicine. Dr Greg Hundley:             That's a favorite of my heart, Caroline. The old institution Wake Forest. But, I'm going to switch now and tell you a little bit about plasma ceramides and this is an article from Wei Zhao from the Department of Epidemiology in Population Health at Albert Einstein College of Medicine in Bronx, New York. The study evaluates the role of ceramides and what are those? Well, they're a class of bio-active lipids composed of sphingosines and fatty acids. And are involved in the development of cardiovascular disease. Elevated circulating levels of ceramides have been shown to be associated with increased risk of cardiovascular events, cardiovascular death, and even so, after adjusting for other cardiovascular disease risk factors. Now, interestingly, ceramide metabolism has long been noted to be closely related to HIV infection. But, the relationship has not been fully understood. HIV infected cells may cause enhancement of sphingomyelin volume breakdown and accumulation of intercellular ceramides, whereas intercellular accumulation is associated with enhanced replication of HIV.                                                  So, what did this study do? They evaluated circulating levels of four ceramides species which have been investigated in previous studies of non-HIV populations. And were measured in 737 women and men, 520 HIV infected and 217 HIV uninfected from the Women's Intra-Agency HIV Study and the Multi-Center Aids Cohort Study. And they compared the relationships with the progression of carotid artery disease assessed by B-mode ultrasound over a seven year period. Dr Carolyn Lam:                Interesting approach. So, what did they find? Dr Greg Hundley:             Elevated ceramide levels were associated with anti-retroviral therapy use. Particularly, protease inhibitor use HIV infected individuals. All four ceramides were highly correlated with each other and significantly correlated with total cholesterol and LDL cholesterol. And of note, remember they were measuring four, but C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides were more closely correlated with specific modified activation and inflammation markers and, surface markers of CD4 t-cell activation. Elevated plasma levels of C16:0 and C24:1 ceramides were also associated with progression of carotid artery atherosclerosis. So, in summary, the results of this study provide new information on biological mechanisms that may involve the specific mono-site activation and inflammation beyond cardiovascular disease traditional risk factors like cholesterol levels. For the association between ceramides and CVD, particularly among individuals living with HIV infection. Dr Carolyn Lam:                Fascinating. Thanks, Greg. Now that sets us up for beautifully for our featured discussion. Dr Greg Hundley:             Welcome everyone, to our podcast. My name is Greg Hundley and we've got a very exciting paper for the second part of our program today. With us we have Dr Thomas Zelniker from Brigham and Women's Hospital. And then, also, a guest editor, Dr John McMurray from Glasgow, Scotland. We're going to be discussing a meta-analysis in type 2 diabetic patients. Thomas, can you tell us a little bit about the study population, your design, and what where the outcomes that you saw in this study. Dr Thomas Zelniker:        As you know, the last half decade, members of two drug classes, GLP1 receptor agonists and SGLT2 inhibitors, so our goal was to provide clear context by comparing or contrasting the benefit of these two drug classes, and in particular to investigate the potential heterogeneity in the treatment site between patients with and without atherosclerotic cardiovascular disease. For that reason, we performed meta-analysis of all randomized partially controlled cardiovascular outcome trials of GLP-1 receptor antagonists and SGLT-2 inhibitors. We included data from more than 77,000 patients, nearly 43,000 patients coming from the five GLP-1 receptor antagonist trials and approximately 34,000 patients coming from the three SGLT-2 inhibitor trials. We tried to compare patients with those with known established atherosclerotic cardiovascular disease with those that have multiple risk factors for but no evident ASCVD. And as you can see, our interests included MACE, or major atherosclerotic cardiovascular events, and its individual components, MI, stroke and cardiovascular death. And then we looked at hospitalization for heart failure and progression of kidney disease. The progression of kidney disease was defined as one of the broad composites consisting of new onset of macroalbuminuria, worsening of eGFR, end-stage kidney disease, or death due to renal cause. And then we also had a more narrow kidney outcome which excluded macroalbuminuria. Dr Greg Hundley:             Thomas, did you observe differences in the types of events between the two agents, as they would have impacted hospitalization for heart failure or the progression of renal disease? Dr Thomas Zelniker:        Right. So foremost both trial analyses reduced the risk of MACE, major atherosclerotic events, but the reduction of MACE was actually confined to those patients with atherosclerotic cardiovascular disease. We saw a 40% reduction in patients with known ASCVD, where neither of these groups reduced the risk of MACE in patients with only multiple risk factors but without ASCVD. Now, in terms of the individual components of MACE, both trial analyses reduced the risk of myocardial infarction cardiovascular death but only GLP-1 receptor agonist reduced the risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced the risk of hospitalization with heart failure by more than 30%, where there was only a non-significant 7% relative risk reduction with GLP-1 receptor antagonist.                                                  GLP-1 receptor antagonists also reduced the broad kidney composite outcome. However, this effect was mainly driven by reduction macroalbuminuria. When excluding macroalbuminuria we found a non-significant relative risk reduction by 8% and this stands in contrast to a very robust relative risk reduction with SGLT-2 inhibitors of more than 45%. Dr Greg Hundley:             Thomas, you mentioned there was a difference in benefit for those with existing cardiovascular disease versus no-known cardiovascular disease upfront. What do you think the reason for that might be, and then did you have the same number of patients in the non-cardiovascular disease group? Did you have enough events in that group? And finally, do you think we might need to follow that patient population a little bit longer in time, to see those events as they didn't have pre-existing cardiovascular disease? Dr Thomas Zelniker:        These are fantastic points. I personally think it's biologically plausible that both drugs and receptors have the same benefit in both patient population to treatment effect may just require more time to become evident in patients with lower risk. You also mentioned a very good point, we had substantially more events in the patient cohort with ASCVD. Dr Greg Hundley:             Very good. So John, we want to turn to you now. Can you help us put those results of this study in perspective? Can you put this into context for us with other published reports using these particular ages? Dr John McMurray:         Certainly Greg, and I'd like to congratulate Thomas on what very important and very timely meta-analysis because, of course, what Thomas and his colleagues have done Greg, is to put all these studies together, to give us what meta-analysis does, which is much more power to look, for example, at components of composite outcomes, and we will in that way compare and contrast the differences and similarities between these two treatments. And as Thomas has mentioned, so interesting differences stand out but there are also some similarities that perhaps were not clear from the individual trials and I suppose the one that would perhaps stand out to me and might not have been realized by many of our readers, is myocardial infarction, that seems to be reduced to pretty much a similar extent by both GLP1 receptor antagonists and SGLT-2 inhibitors.                                                  I think there had perhaps been a view out there from the individual trials, that maybe GLP-1 receptor antagonists have more effect on atherosclerotic events and SGLT-2 inhibitors more effect on heart failure and renal events and to some extent that's true, both agents seem to reduce myocardial infarction to approximately the same extent. Which in itself is interesting, perhaps raises some mechanistic questions. I mean, the differences that stood out is stroke is reduced by GLP-1 receptor antagonists but not by SGLT-2 inhibitors and conversely heart failure which is the opposite, which is by SGLT-2 inhibitors, but not by GLP-1 receptor antagonists in this meta-analysis.                                                  So, I suppose, in summary what this tells us is that these drugs have complementary, perhaps additive cardiovascular benefits. Together, they potentially reduce the whole spectrum of the adverse cardiovascular events that occur in our patients with Type 2 diabetes, especially those who've got established cardiovascular disease. Dr Greg Hundley:             And so, just a last question here, for both Thomas and John, if you're considering in your practice, you have a diabetic patient that's not on these, one of these agents, and they have existing cardiovascular disease, how do you go about considering the addition or the switch to this type of medicine, and what practices do you use to effect that change? Dr Thomas Zelniker:        I guess, looking at patients, so we know that both drug classes have great benefits from MACE, right, but to people on antagonists having also reductions in stroke. So probably the associated risk is in the focus, I would probably rather go with the GLP-1 receptor antagonist. While looking at it from the heart failure perspective, or from the renal perspective, we see obviously bigger advantages attributed to inhibitors. Dr Greg Hundley:             And John, how about you? Dr John McMurray:         I would agree with Thomas' perspective, although I might add just a little caveat which is, of course, that the prevention of heart failure which is what, I think, the clear benefit of SGLT-2 inhibitors is, prevention of heart failure is different to the treatment of heart failure. So, patients at risk of heart failure sadly, an SGLT-2 inhibitor would make sense, but when it comes to patients with established heart failure event, of course we will get that answer because one of the great things about this recent incredible development of new therapies for diabetes, is that now there are now more studies underway including remarkable five trials in patients with different heart failure phenotypes, patients hospitalized, patients in the community, so we will learn a lot more about the use of these drugs, in particular cardiovascular populations. Dr Greg Hundley:             Excellent. I want to thank both Thomas Zelniker from Brigham and Women's Hospital and John McMurray, guest editor from Glasgow, Scotland for helping us work through this just fantastic meta-analysis study pointing us in a new direction for utilizing medications to treat diabetes and those that we see every day, with cardiovascular disease.                                                  On behalf of Carolyn and myself, have a great week and we look forward to seeing you, next week. Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.

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 Greg Hundley, associate editor as well at Circulation, and director of the Poly Heart Center in Richmond, Virginia, at VCU Health. Well, I'm going to talk about anti-hyperglycemic agents and look at a very important meta-analysis. Dr Carolyn Lam:                Those are the rage: GLP-1 receptor agonists and SGLT-2 inhibitors. But first, let's talk about psychosocial stress and cardiovascular health. So what is the joint impact of multiple stressors on racial or ethnic disparities in cardiovascular health?                                                 Well, this question was tackled by Dr Albert, from University of California San Francisco Center for the Study of Adversity and Cardiovascular Disease and her colleagues. They basically studied more than 25,000 women participating in the women's health study follow-up cohort, and examined the relationship between cumulative psychosocial stress and ideal cardiovascular health as defined by the American Heart Association Strategic 2020 Goals.                                                 As a reminder, this health metric includes smoking, BMI, physical activity, diet, blood pressure, total cholesterol and glucose, and higher levels indicate more ideal cardiovascular health and less cardiovascular risk.                                                 So, they found that both cumulative psychosocial stress and ideal cardiovascular health varied by race or ethnicity. Mean cumulative psychosocial stress scores were higher in Hispanic, Black, and Asian women compared to white women, even after adjusting for age, socioeconomic status and psychological status such as depression and anxiety. The mean ideal cardiovascular health scores remained worse in blacks and better in Asians compared to whites, despite taking into account socioeconomic factors and cumulative psychosocial stress. Dr Greg Hundley:             So Carolyn, how should clinicians incorporate this information in what we do every day? Dr Carolyn Lam:                Although the cumulative psychological stress and socioeconomic status did not fully explain the racial or ethnic differences in ideal cardiovascular health that we saw, clinicians should be informed by these data that psychosocial stressors are social determinants of health that have different prevalence according to race and ethnicity. I think that's what we need to learn. And of course these data support the need for additional work that addresses the joint impact of multiple social determinants of health on cardiovascular disease and in diverse populations. Dr Greg Hundley:             Very good, Carolyn. That was really an interesting article. Well, I'm going to switch gears and talk about the role of red blood cells in promoting vascular calcification. My article is from Dimitrios Tziakas from the Department of Cardiology in Thrace, Alexandropoulos, in Greece.                                                 Now, the presence of extravasated erythrocytes in human atherosclerotic lesions was described several years ago, but little is known about a possible active role of red blood cells during these cardiovascular disease processes. Clinical studies suggest that intraplaque hemorrhage may be associated with the progression of coronary, carotid, and atherosclerotic lesions and degenerative calcific aortic valve stenosis. So, in the present study, the authors examined the contribution of erythrocytes to vascular and valvular lesion progression, focusing on the effects of red blood cells on the osteoblastic transdifferentiation of smooth muscle cells in calcification. Dr Carolyn Lam:                Interesting. So, what did they find? Dr Greg Hundley:             So, lysed erythrocytes, and in particular their membrane faction, enhanced human and murine arterial smooth muscle cell mineralization and vascular aortic ring calcification. Red blood cell membranes injected in the vascular regions of atherosclerotic-prone mice also promoted calcification and red blood cells were found to co-localize with osteoblast like cells in human atherosclerotic plaques, stenotic aortic valves, and abdominal aortic aneurysms. And so, the study demonstrated that intra plaque hemorrhage promotes atherosclerotic and valvular lesion calcification and membranes of extravasated lysed red blood cells appeared to play an important role in the process. The investigators also showed a mechanism, that nitric oxide derived from erythrocyte endothelial nitric oxides synthase is involved, at least in part, in mediating the effects of red blood cells on vascular calcification. Dr Carolyn Lam:                Thanks, Greg. Now back to another, well, clinical paper with the next one asking, do mid-life biomarkers of heart and kidney damage associate with the level of and decline in physical capability with aging? Dr Kuh and colleagues from MRC Unit of Lifelong Health and Aging at University College London used data on 1,736 men and women from the oldest British birth cohort study. And, looked at their walking speed, chair rise speed, balance time, and grip strength. Assessed at ages 60 to 64 and 69 years. They tested the associations between Cystatin C, NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64 years with their performance at 69 years. And what they found was the lower levels of NT-proBNP in interleukin-6 in middle aged adults were independently associated with better physical capability up to nine years later. And all these associations were stronger than those observed for conventional risk factors: including lipids, blood pressure, and glycemia, and were not explained by the onset of cardio vascular and kidney disease or diabetes. Dr Greg Hundley:             Carolyn, is this saying we should now measure these biomarkers in mid-life? Dr Carolyn Lam:                Ah, before considering the use of NT-proBNP and IL-6 or interleukin-6 for risk stratification, we really do need further research to untangle whether these associations exist because the biomarkers are an integrated measure of accumulated exposures to stressors. Or, whether they are really capturing early an organ damage. Or, whether they are marking additional risk pathways. So, this and more is discussed in a great accompanying editorial entitled "Putting the Measurement of Physical Capacity in Older Adults in its Place". And that's by Dr Kritchevsky from Wake Forest School of Medicine. Dr Greg Hundley:             That's a favorite of my heart, Caroline. The old institution Wake Forest. But, I'm going to switch now and tell you a little bit about plasma ceramides and this is an article from Wei Zhao from the Department of Epidemiology in Population Health at Albert Einstein College of Medicine in Bronx, New York. The study evaluates the role of ceramides and what are those? Well, they're a class of bio-active lipids composed of sphingosines and fatty acids. And are involved in the development of cardiovascular disease. Elevated circulating levels of ceramides have been shown to be associated with increased risk of cardiovascular events, cardiovascular death, and even so, after adjusting for other cardiovascular disease risk factors. Now, interestingly, ceramide metabolism has long been noted to be closely related to HIV infection. But, the relationship has not been fully understood. HIV infected cells may cause enhancement of sphingomyelin volume breakdown and accumulation of intercellular ceramides, whereas intercellular accumulation is associated with enhanced replication of HIV.                                                 So, what did this study do? They evaluated circulating levels of four ceramides species which have been investigated in previous studies of non-HIV populations. And were measured in 737 women and men, 520 HIV infected and 217 HIV uninfected from the Women's Intra-Agency HIV Study and the Multi-Center Aids Cohort Study. And they compared the relationships with the progression of carotid artery disease assessed by B-mode ultrasound over a seven year period. Dr Carolyn Lam:                Interesting approach. So, what did they find? Dr Greg Hundley:             Elevated ceramide levels were associated with anti-retroviral therapy use. Particularly, protease inhibitor use HIV infected individuals. All four ceramides were highly correlated with each other and significantly correlated with total cholesterol and LDL cholesterol. And of note, remember they were measuring four, but C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides were more closely correlated with specific modified activation and inflammation markers and, surface markers of CD4 t-cell activation. Elevated plasma levels of C16:0 and C24:1 ceramides were also associated with progression of carotid artery atherosclerosis. So, in summary, the results of this study provide new information on biological mechanisms that may involve the specific mono-site activation and inflammation beyond cardiovascular disease traditional risk factors like cholesterol levels. For the association between ceramides and CVD, particularly among individuals living with HIV infection. Dr Carolyn Lam:                Fascinating. Thanks, Greg. Now that sets us up for beautifully for our featured discussion. Dr Greg Hundley:             Welcome everyone, to our podcast. My name is Greg Hundley and we've got a very exciting paper for the second part of our program today. With us we have Dr Thomas Zelniker from Brigham and Women's Hospital. And then, also, a guest editor, Dr John McMurray from Glasgow, Scotland. We're going to be discussing a meta-analysis in type 2 diabetic patients. Thomas, can you tell us a little bit about the study population, your design, and what where the outcomes that you saw in this study. Dr Thomas Zelniker:        As you know, the last half decade, members of two drug classes, GLP1 receptor agonists and SGLT2 inhibitors, so our goal was to provide clear context by comparing or contrasting the benefit of these two drug classes, and in particular to investigate the potential heterogeneity in the treatment site between patients with and without atherosclerotic cardiovascular disease. For that reason, we performed meta-analysis of all randomized partially controlled cardiovascular outcome trials of GLP-1 receptor antagonists and SGLT-2 inhibitors. We included data from more than 77,000 patients, nearly 43,000 patients coming from the five GLP-1 receptor antagonist trials and approximately 34,000 patients coming from the three SGLT-2 inhibitor trials. We tried to compare patients with those with known established atherosclerotic cardiovascular disease with those that have multiple risk factors for but no evident ASCVD. And as you can see, our interests included MACE, or major atherosclerotic cardiovascular events, and its individual components, MI, stroke and cardiovascular death. And then we looked at hospitalization for heart failure and progression of kidney disease. The progression of kidney disease was defined as one of the broad composites consisting of new onset of macroalbuminuria, worsening of eGFR, end-stage kidney disease, or death due to renal cause. And then we also had a more narrow kidney outcome which excluded macroalbuminuria. Dr Greg Hundley:             Thomas, did you observe differences in the types of events between the two agents, as they would have impacted hospitalization for heart failure or the progression of renal disease? Dr Thomas Zelniker:        Right. So foremost both trial analyses reduced the risk of MACE, major atherosclerotic events, but the reduction of MACE was actually confined to those patients with atherosclerotic cardiovascular disease. We saw a 40% reduction in patients with known ASCVD, where neither of these groups reduced the risk of MACE in patients with only multiple risk factors but without ASCVD. Now, in terms of the individual components of MACE, both trial analyses reduced the risk of myocardial infarction cardiovascular death but only GLP-1 receptor agonist reduced the risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced the risk of hospitalization with heart failure by more than 30%, where there was only a non-significant 7% relative risk reduction with GLP-1 receptor antagonist.                                                 GLP-1 receptor antagonists also reduced the broad kidney composite outcome. However, this effect was mainly driven by reduction macroalbuminuria. When excluding macroalbuminuria we found a non-significant relative risk reduction by 8% and this stands in contrast to a very robust relative risk reduction with SGLT-2 inhibitors of more than 45%. Dr Greg Hundley:             Thomas, you mentioned there was a difference in benefit for those with existing cardiovascular disease versus no-known cardiovascular disease upfront. What do you think the reason for that might be, and then did you have the same number of patients in the non-cardiovascular disease group? Did you have enough events in that group? And finally, do you think we might need to follow that patient population a little bit longer in time, to see those events as they didn't have pre-existing cardiovascular disease? Dr Thomas Zelniker:        These are fantastic points. I personally think it's biologically plausible that both drugs and receptors have the same benefit in both patient population to treatment effect may just require more time to become evident in patients with lower risk. You also mentioned a very good point, we had substantially more events in the patient cohort with ASCVD. Dr Greg Hundley:             Very good. So John, we want to turn to you now. Can you help us put those results of this study in perspective? Can you put this into context for us with other published reports using these particular ages? Dr John McMurray:         Certainly Greg, and I'd like to congratulate Thomas on what very important and very timely meta-analysis because, of course, what Thomas and his colleagues have done Greg, is to put all these studies together, to give us what meta-analysis does, which is much more power to look, for example, at components of composite outcomes, and we will in that way compare and contrast the differences and similarities between these two treatments. And as Thomas has mentioned, so interesting differences stand out but there are also some similarities that perhaps were not clear from the individual trials and I suppose the one that would perhaps stand out to me and might not have been realized by many of our readers, is myocardial infarction, that seems to be reduced to pretty much a similar extent by both GLP1 receptor antagonists and SGLT-2 inhibitors.                                                 I think there had perhaps been a view out there from the individual trials, that maybe GLP-1 receptor antagonists have more effect on atherosclerotic events and SGLT-2 inhibitors more effect on heart failure and renal events and to some extent that's true, both agents seem to reduce myocardial infarction to approximately the same extent. Which in itself is interesting, perhaps raises some mechanistic questions. I mean, the differences that stood out is stroke is reduced by GLP-1 receptor antagonists but not by SGLT-2 inhibitors and conversely heart failure which is the opposite, which is by SGLT-2 inhibitors, but not by GLP-1 receptor antagonists in this meta-analysis.                                                 So, I suppose, in summary what this tells us is that these drugs have complementary, perhaps additive cardiovascular benefits. Together, they potentially reduce the whole spectrum of the adverse cardiovascular events that occur in our patients with Type 2 diabetes, especially those who've got established cardiovascular disease. Dr Greg Hundley:             And so, just a last question here, for both Thomas and John, if you're considering in your practice, you have a diabetic patient that's not on these, one of these agents, and they have existing cardiovascular disease, how do you go about considering the addition or the switch to this type of medicine, and what practices do you use to effect that change? Dr Thomas Zelniker:        I guess, looking at patients, so we know that both drug classes have great benefits from MACE, right, but to people on antagonists having also reductions in stroke. So probably the associated risk is in the focus, I would probably rather go with the GLP-1 receptor antagonist. While looking at it from the heart failure perspective, or from the renal perspective, we see obviously bigger advantages attributed to inhibitors. Dr Greg Hundley:             And John, how about you? Dr John McMurray:         I would agree with Thomas' perspective, although I might add just a little caveat which is, of course, that the prevention of heart failure which is what, I think, the clear benefit of SGLT-2 inhibitors is, prevention of heart failure is different to the treatment of heart failure. So, patients at risk of heart failure sadly, an SGLT-2 inhibitor would make sense, but when it comes to patients with established heart failure event, of course we will get that answer because one of the great things about this recent incredible development of new therapies for diabetes, is that now there are now more studies underway including remarkable five trials in patients with different heart failure phenotypes, patients hospitalized, patients in the community, so we will learn a lot more about the use of these drugs, in particular cardiovascular populations. Dr Greg Hundley:             Excellent. I want to thank both Thomas Zelniker from Brigham and Women's Hospital and John McMurray, guest editor from Glasgow, Scotland for helping us work through this just fantastic meta-analysis study pointing us in a new direction for utilizing medications to treat diabetes and those that we see every day, with cardiovascular disease.                                                 On behalf of Carolyn and myself, have a great week and we look forward to seeing you, next week. Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.

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