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    Life Sciences

    Circulation on the Run

    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!

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    Copyright: © 2016 American Heart Association, Inc.

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    Circulation August 4, 2020 Issue Aug 03, 2020
    Show notes

    Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains? Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe? Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress. Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find? Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease. Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same? Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different. Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart. Dr Carolyn Lam: Wow. What did they find? Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases. Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common? Dr Greg Hundley: I definitely need phone a friend. Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms. Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI. Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg? Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate. Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find? Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points. Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19. Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR. Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we? Dr Greg Hundley: You bet. Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found. Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock. So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation. Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too. Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies? Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease. We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function. Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not? Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome. But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease. Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts. Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution. And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It's just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them. Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community? Dr Damien Bonnet…

    Full show notes at the publisher

    Circulation July 28, 2020 Issue Jul 27, 2020
    Show notes

    Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee? Dr Greg Hundley: I am. Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis. So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis. So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance. In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state. Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here? Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that. Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College. So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis. So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model. The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases. Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice. Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center. Dr Greg Hundley: So Carolyn, what did they find in this series? Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction. Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis. Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age. Dr Carolyn Lam: Interesting. And what were the results? Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials. However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively. So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy. Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial. There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis. Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith. Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid. Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19. And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion. Dr Carolyn Lam: Yay. Let's go, Greg. Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome. Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address? Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families. However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder. But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges. The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families. Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population. Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study. The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation. So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands. The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome. What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome. So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes. So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility. Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients. We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients. So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability. Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement? Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected. Dr Greg Hundley: I see. I- Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected. Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on? Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we sho…

    Full show notes at the publisher

    Circulation July 21, 2020 Issue Jul 20, 2020
    Show notes

    This week's episode of Circulation on the Run features author Robert Yeh and Associate Editor Brendan Everett as they discuss the article "Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the EXTEND Study." TRANSCRIPT Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week, we're going to examine outcomes in patients that have undergone transcatheter aortic valve replacement or TAVR. I can't wait to get to the results from the EXTEND study. But before we do that, how about we grab a cup of coffee and start in with some of the papers and maybe I'll go first this time. My paper involves a validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. And the corresponding author is Dr Seema Mital from the Hospital for Sick Children. Well, Carolyn in this study, the objective was to develop and validate a sudden cardiac death risk prediction model in pediatric hypertrophic cardiomyopathy to guide sudden cardiac death prevention strategies. To address this, the authors performed an international multi-center observational cohort analysis. Phenotype positive patients with isolated hypertrophic cardiomyopathy, who were under the age of 18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of sudden cardiac death events at five years of follow-up. That included sudden cardiac death, resuscitated sudden cardiac arrest, and aborted sudden cardiac death, that is, an appropriate shock following primary prevention ICD. Carolyn Lam: Nice. What did they find? Greg Hundley: Well, overall 572 patients met the eligibility criteria with 2,855 patient years of follow-up. The five-year cumulative proportion of sudden cardiac death events was 9%. Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter Z scores, LV posterior wall diameter Z scores, LA diameter Z scores, peak LV outflow tract gradients, and the presence of a pathogenic variant. Now, unlike adults, LV outflow tract gradient had an inverse association and family history of sudden cardiac death had no association with sudden cardiac death. The combination of clinical and genetic data were developed to predict five-year freedom from sudden cardiac death. In conclusion, the authors study provides a validated sudden cardiac death risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. These results therefore raise the possibility that an individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for these children prior to an ICD insertion. Carolyn Lam: Very interesting. Well, Greg, have you ever wondered what are the temporal trends in the burden of comorbidities and risk of mortality among patients with heart failure with preserved ejection fraction or HFpEF and heart failure with reduced ejection fraction or HFrEF? Well, the next paper comes from Dr Caughey and colleagues from University of North Carolina and North Carolina State University who performed an analysis of the community surveillance component of the atherosclerosis risk in communities, or ARIC study, and they found a significant increase in the burden of comorbidities among hospitalized patients with HFpEF as well as HFrEF across both sexes. Higher number of comorbidities was associated with higher risk of one-year mortality with a stronger association noted among patients with HFpEF compared to HFrEF. The one-year mortality risk associated with increasing comorbidity burden also increased over time. Greg Hundley: Interesting, Carolyn. So more comorbidities in HFpEF versus HFrEF. How do we use this clinically? Carolyn Lam: This study demonstrated a shift from ischemic etiology heart failure to multi morbidity heart failure over time, particularly among patients with HFpEF. This really highlights the importance of a holistic approach in targeting multimorbidity burden and guiding the management of patients with heart failure. Greg Hundley: Very interesting. Well, Carolyn, my next paper comes from Professor Matthias Nahrendorf from Mass General Hospital and involves the relationship between bone marrow endothelial cells and myelopoiesis in those with diabetes. Carolyn, this study investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. The authors utilized three types of mice with diabetes, including a streptozotocin model, a high fat diet model, and a genetic induction using leptin receptor deficient mice. They assayed leukocytes, hematopoietic stem cell and progenitor cells, and endothelial cells in the bone marrow with flow cytometry and expression profiling. Carolyn Lam: What did they find? Greg Hundley: Well in diabetes, they observed enhanced proliferation of hematopoietic stem cells leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less CXCL-12, a retention factor promoting hematopoietic stem and progenitor cell quiescence. Transcriptome wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor signaling in mice with diet induced diabetes. In summary, Carolyn, in diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow haematopoiesis specifically diabetes reduces endothelial production of CXCL-12, a quiescence promoting niche factor that reduces stem cell proliferation. The authors also describe a previously unknown counterregulatory pathway in which protective endothelial EGFR signaling curbs hematopoietic stem cell and progenitor cell proliferation as well as myeloid cell production. Carolyn Lam: Wow, thanks for explaining all of that, Greg. For this next paper, we're going to switch tracks a little. This comes from Dr Drakos and colleagues from University of Utah in Salt Lake City. They noted that significant improvements in myocardial structure and function have been reported in some advanced heart failure patients. This is they're going to call responders and the responders improve the myocardial structure and function following left ventricular assist device induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Dr Drakos and colleagues hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, which may mediate myocardial recovery in these responders. To test this hypothesis, they prospectively obtained paired left ventricular atypical myocardial tissue from non-failing donor hearts, as well as responders and non-responders at left ventricular assist device implant and at transplantation. They conducted protein expression and metabolic profiling and evaluated mitochondrial structure using electron microscopy. Greg Hundley: Interesting. What did they find, Carolyn? Carolyn Lam: The recovering heart appears to direct glycolytic metabolites into pentose phosphate pathway and one carbon metabolism, which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. This new information could redirect future translational investigations to efforts to identify novel therapeutic targets for myocardial recovery in patients with chronic heart failure. Well, Greg, can I tell you a little bit more about what else is in this issue? There's a letter by Dr Wang regarding the article, A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction, and there's also a response by Dr Yan. In Cardiovascular Case Series, there's a paper by Dr Michelena on the nosology spectrum of the bicuspid aortic valve condition, the complex presentation of valvular aortopathy. That's so interesting. There's a research letter by Dr Gaudino on the response of cardiac surgery units to COVID-19, an internationally based quantitative survey. As well as another research letter by Dr Salem on cardiovascular toxicities associated with Hydroxychloroquine and azithromycin and analysis of the World Health Organization pharmacovigilance database. There is a perspective piece by Dr Jacobs entitled The Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA's Mission: Lifeline. In cardiology news, Tracy Hampton reviews three papers, one, Video-Based AI for Beat-to-Beat Assessment of Cardiac Function in Nature, 2020. Two, Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by single Nucleus RNA Sequencing, that is in developmental cell 2020. And three, ATP and Voltage-Dependent Electro-Metabolic Signaling Regulates Blood Flow in the Heart, the proceedings of the National Academy of Science, 2020. Greg Hundley: Very nice. Well, I've got an in-depth review from Dr Bin Zhou regarding the heart regeneration by endogenous stem cells and cardiomyocyte proliferation, controversy, fallacy, and progress. And then there are three on my mind pieces. The first is from Dr Rashmee Shah regarding machine learning and artificial intelligence. Do we need more data, or do we need the right data? The next one is from Sharon Reimold and it discusses the importance of gathering historical information on risk factors when seeing patients with, or suspected, of COVID-19. And then finally, Dr Prateeti discusses ethical challenges in cardiology during the COVID-19 pandemic. Well, Carolyn, what a great review. How about we proceed to that feature discussion? Carolyn Lam: Let's go. Greg Hundley: Well listeners, we are now turning to our feature discussion and this week we have Dr Robert Yeh, also Bobby Yeh, from Beth Israel Hospital and our own associate editor, Dr Brendan Everett from Brigham and Women's Hospital. Welcome gentlemen. Bobby let's start with you. Can you tell us a little bit about some of the background related to your study, and then what hypothesis were you trying to address? Robert Yeh: The study that we performed is the sub study of what we're calling the EXTEND study, which is an NIH funded group of investigations meant to really examine what the value is of real world data and how it can augment clinical trial evaluations of medical devices and therapies. We know that randomized clinical trials remain the gold standard for therapeutic evaluation, but they are expensive, difficult to do, and sometimes impractical. Real world data is cheaper, it's potentially more efficient to do observational research studies, and in fact the 21st Century Cures Act explicitly asks, among other things, that the FDA explore the use of real-world data for regulatory evaluations. People have problems with real world data, of course, they have their own inherent challenges which are subject really to confounding. What we thought about is, well, there's probably this middle ground that we and others have proposed, which is can't real world data somehow supplement or augment randomized clinical evaluations, and in particular, in our question, can real world data be the provider of outcomes in place of adjudicated clinical trial outcomes? What we did is we took two large pivotal randomized clinical trials of transcatheter aortic valve replacement, namely the CoreValve, high risk, and intermediate risk trials. Otherwise, the intermediate risk trials known as the SURTAVI trial. And we found those patients in those trials and then linked them with real world data from administrative claims databases in Medicare. Our hypothesis was that had the trial been evaluated in terms of outcomes by the Medicare claims instead of the clinical trial adjudicated outcomes. Our main question was, would we have had the same findings within those trials? Would the primary hypothesis of those trials still have been met with this alternative clinical trial end point ascertainment strategy? Greg Hundley: In your study design, how did you accomplish the comparisons? You've told us a lot about the study population. Was this everyone from those two studies or was this a subgroup of them? Maybe just expand on that a little bit. Robert Yeh: Good question. This is a US based comparison, so we have claims for US patients, and most patients in these trials were in the United States, but the CoreValve trial and the SURTAVI trials, we took all of this patients and then tried to find those patients who we could also find in Medicare claims. It turns out that in order to qualify for Medicare, you have to be over 65 years of age, under most circumstances. And so it's limited to really those patients over age 65, who we could then search for in Medicare and then within Medicare, there's two types of insurance, fee for service and Medicare Advantage managed care. And what we can only find are those patients who are in Medicare fee for service, which represents somewhere between two thirds and three quarters of patients age greater than 65 or older. So it is a subgroup of patients in these two large pivotal randomized trials. We've compared those who could not be linked versus those who could, find large part, from some of the age differences, which are just inherent in looking at Medicare, there are really not that many differences between those two groups. Greg Hundley: Bobby, what did you find? Robert Yeh: We found those patients. So now we have this situation where we have patients in trials, and we can look at them from two lenses. The same group of patients, one lens is through the clinical trial lens and the second is through the lens of real-world data, those exact same patients. We found that whether or not we ascertained their outcomes via claims or with clinical trial adjudication, essentially the primary hypotheses were identical, that in both scenarios, the transcatheter aortic valve was non-inferior to the traditional surgical aortic valve replacement, that the effect sizes and the hazard ratios, the confidence intervals, they were roughly the same. In fact, for the primary endpoint of the high-risk pivotal study, which was all cause mortality, it was identical. It turns out that Medicare claims and what we called the denominator file very accurately identifies exactly when a patient dies. It does so equally well compared to rigorous clinical trial adjudication. For SURTAVI the primary endpoint was combined death or stroke in that case, stroke is reasonably accurate. There were a lot of deaths that also drove that combined end point. And the net result was that really very similar, both effect sizes and primary, P values for those comparisons. Greg Hundley: Now how about secondary analysis? Robert Yeh: I think the secondary analysis that's where you had some variability. There are some types of outcomes in this device specific trial that are procedure oriented. Pacemakers are a concern. Aortic valve reintervention is a concern. Those end points in billing claims turns out are quite accurate. You can understand why. I think providers and institutions, when they do a service that requires insertion of a new device, they want to get paid for those devices and they d…

    Full show notes at the publisher

    Circulation July 14, 2020 Issue Jul 13, 2020
    Show notes

    Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure. Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B? Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines. Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study? Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties. Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events? Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results. Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS. Dr Carolyn Lam: Wow. What did they find Greg? Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel. Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction. Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored. Dr Carolyn Lam: Summarize that for us. Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors, Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score. Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19? Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper. Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly. Dr Carolyn Lam: Wow. So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg? Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments. Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox. Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden. Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter? Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings? Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say. Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases? Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application. Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found? Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals. Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors. Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very,…

    Full show notes at the publisher

    Circulation July 7, 2020 Issue Jul 06, 2020
    Show notes

    Dr Carolyn Lam: Well, the Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature involves the Compass trial, and we'll be talking about a comparison of low-dose rivaroxaban plus aspirin compared to aspirin alone in patients with chronic vascular disease. But before we get to that, how about if we break away and discuss a few other papers. And I'll go first this time, because this week we're going to introduce another new feature in addition to Carolyn's Quiz. Dr Carolyn Lam: Wait a minute. This was not on the script. What's going on, Greg? Dr Greg Hundley: It's on the script! Carolyn, let me get to my first paper. It's from Professor Junling Liu from Shanghai Jiao Tong University School of Medicine, and it involves branched-chain amino acid catabolism and how that may promote thrombosis risk by enhancing tropomodulin-3 propionylation in platelets. But first, we've got a new feature to add to Carolyn's Quiz. It's called Way or No Way. Dr Carolyn Lam: Just so everybody knows. This was a one-way decision to add this new component of Carolyn's Quiz, but okay, I'm all for it. Go, Greg! Dr Greg Hundley: Okay. All right. It's a fast, quick question where our listeners seek your guidance regarding an important scientific discovery from one of our published manuscripts. Are you ready? Dr Carolyn Lam: No. Dr Greg Hundley: Okay. Here's your question. Do branched-chain amino acids promote arterial thrombosis. Way or no way? Dr Carolyn Lam: Maybe? Dr Greg Hundley: Okay, Carolyn. Dr Carolyn Lam: I have a feeling you're going to tell us yes, although I wouldn't have guessed that straight away. Dr Greg Hundley: Okay. Remember that branched-chain amino acids are essential nutrients, including leucine, isoleucine, and valine, and they serve as a resource for energy production and the regulator of important nutrient and metabolic signals. In this study, the activity of human platelets from healthy subjects before and after ingestion of branched-chain amino acids were measured. PP2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no way? Dr Greg Hundley: Ingestion of branched-chain amino acids significantly enhanced the activity of platelets in response to agonists and increased the risk of arterial thrombosis. The branched-chain amino acid catabolic pathway-driven propionylation of tropomodulin-3 at K255 was found to be an important mechanism underlying the branched-chain amino acid-facilitated platelet activation, and elevated levels of branched-chain amino acids and enhanced expression of positive regulators of branched-chain amino acid catabolism in platelets were found probably responsible for the high platelet activity in type 2 diabetes mellitus. Dr Carolyn Lam: Very interesting. So yes, it is possible. And what is the clinical implications? Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or their catabolites, enhance the risk of arterial thrombosis in small animals, and perhaps future human subject studies, that restrict branched-chain amino acid intake or target branched-chain amino acid catabolism may serve as a novel strategy for anti-thrombosis therapy. Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question for me. Have you heard of Home Time? Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time out for our kids, but we've been having a lot of Home Time in this COVID-19 with our families. Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you know it is a patient-centered outcome measure that accounts for rehospitalization mortality and post-discharge care? In the paper I want to talk about, Dr Pandey from UT Southwestern and colleagues aim to characterize risk-adjusted 30-day Home Time in patients with acute myocardial infarction as a hospital-level performance metric, and to evaluate associations with risk-standardized readmission rates. The study included almost 985,000 patients with AMI hospitalization across almost 2,400 hospitals between 2009 and 2015 derived from a hundred percent of Medicare claims data. And they found that 30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varied across hospitals, was associated with post-discharge readmission and mortality outcomes, and meaningfully reclassified hospital performance compared with the 30-day readmission and mortality metric. Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you again with another quiz. But first, this paper is from Kamal Khabbaz from Beth Israel Deaconess Medical Center and the Harvard Medical School, and it's going to assess whether left atrial appendage closure or exclusion during bypass surgery has impact on short-term outcomes. So, Carolyn, here's your quiz. Do you think that patients receiving CABG with atrial fibrillation should undergo ligation of their left atrial appendage? Dr Carolyn Lam: Well, I think there's definitely equipoise there. On the one hand, you're already in a surgery. Why not just ligate it? It's not like we need a left atrial appendage. And then on the other hand, I suppose it extends the surgery, it involves some risk, and we don't know if it actually prevents further events. Did I answer that right? Dr Greg Hundley: Yes. Quite the politically correct answer, I think. Now, the objective of this study was to evaluate the impact of left atrial appendage exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. The study analyzed 250,287 CABG patients, of whom 7% received left atrial appendage closure. Only patients with a history of atrial fibrillation were included in the analysis, and the primary outcome was 30-day readmissions following discharge. Secondary outcomes included hospital mortality and stroke. And to assess the postoperative outcomes, the team utilized multivariable logistic regression models, and they adjusted for clinical and demographic co-variables. Dr Carolyn Lam: Great. So what did they find, Greg? Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial appendage exclusion was associated with a greater risk of postoperative respiratory failure, acute kidney injury, but it did not significantly change the rate of blood transfusions or the occurrence of cardiac tamponade. Second, left atrial appendage exclusion was associated with a nonsignificant reduction in stroke, no difference in in-hospital mortality, and a greater risk of 30-day readmissions. Number three, after adjusting for these co-variables, left atrial appendage ligation remained a significant predictor of this 30-day readmissions. And so, Carolyn, in this study, it looks like left atrial appendage exclusion during isolated CABG in patients with AFib is associated with a higher rate of 30-day readmissions. Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else is in this issue. First is a pair of letters, one from Kai Wu regarding the article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared to Men With HFpEF: Insights From PARAGON-HF" and the response from Dr John McMurry. There are also two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and Inflammation: Mind the Gap" by Dr Lazzerini, and another entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms" by Dr Naveed Sattar. There are two perspective pieces, "Establishment and Management of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by Dr Blake Thomson. There's an in-depth paper entitled "The Science Underlying COVID-19: Implications for the Cardiovascular System" by Dr Peter Liu. This is important. This one's an editor's pick, so don't forget to read this. There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with ST Elevation: Looking Behind the Masquerade." In Cardiology News by Tracy Hampton, she reviews the literature and highlights three papers, one, "A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors" in Cell 2020; two, "Noninvasive Localization of Cardiac Arrhythmias Using Electromechanical Wave Imaging" in Science and Translational Medicine 2020; and three, "Somatic Gene Editing Ameliorates Skeletal and Cardiac Muscle Failure in Pig and Human Models of Duchenne Muscular Dystrophy", and that in Nature Medicine 2020. For the President's Page, we have a piece by Keith Churchill, who's the Executive Vice President and CEO of Yale New Haven Hospital entitled "The Compelling Need to Address Uncertainty, Anxiety, and Financial Peril for Patients". There's Highlights from Circulation Family of Journals by Sara O'Brien, including "Factors Associated With Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results From the ORBIT-AF" from Circulation Arrhythmia and Electrophysiology. There's "Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from Circulation Cardiovascular Imaging. There's also "The Impact of a 10 Rules Protocol on COVID-19 Hospital-Related Transmission: Insights from Padua University Hospital in Italy" from Circulation Cardiovascular Interventions. There's "The Association of an AMI Readmission-Reduction Program with Mortality and Readmission" from Circulation Cardiovascular Qualities and Outcomes. And finally, "Treatment Differences in Chronic Heart Failure Patients with Reduced Ejection Fraction According to Blood Pressure" in Check HF, and that's in Circulation Heart Failure. Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few Research Letters that I reviewed. First is from Professor Puck Peltenburg, and the Research Letter involves children and adolescents from Brugada syndrome families in which only the SCN5A mutation carriers develop a type one ECG pattern induced by fever. And the second research letter is from Dr David Saadoun, and this evaluates the long-term outcome and prognosis factors associated with isolated aortitis. And then finally, Carolyn, there's a very nice piece related to the current status of cardiovascular medicine in Israel from Professor Ran Kornowski at the Rabin Medical Center. Well, Carolyn, what a packed issue we have, and how about now we get on to that feature discussion? Dr Carolyn Lam: Let's go, Greg. Dr Greg Hundley: Well, listeners, we have a wonderful feature discussion for you in this next segment. We have Professor Keith Fox from Edinburgh and our own associate editor, Professor Stefan James from Uppsala. And we're going to discuss anticoagulation and antiplatelet therapy and rivaroxaban and aspirin and results from the COMPASS trial. Keith, could you tell us what was the background information and what was the hypothesis that you wanted to test with your study? Professor Keith Fox: The hypothesis was whether the combination of a very small dose, a quarter of the dose tested here, of a NOAC alongside an antiplatelet would be superior to aspirin alone, or we also tested a half dose of the NOAC by itself. And the overall trial showed that the quarter dose of rivaroxaban plus aspirin was substantially superior to aspirin alone in preventing cardiovascular death, MI, and stroke, with its biggest impact on strokes and cardiovascular death. So that's the trial as a whole. But our specific goal here was to look at the question of net clinical benefit because clinicians are challenged by any therapy that has a balance of both potential hazard, like bleeding risk, and benefit. So what we analyzed here were the pre-specified characteristics of net clinical benefit in terms of life-threatening and major bleeding into a critical organ, plus cardiovascular death, MI, and stroke. And I asked the question, what was the net clinical benefit? Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit about what population you were looking to understand net clinical benefit, and then what was the study design? Professor Keith Fox: This is the whole of the COMPASS trial without the arm that tested rivaroxaban alone, because that did not show significant benefit. So this is the remaining 18,000 patients, double-blind randomized trial. And the trial, as a whole, was stopped early on the recommendation of the DSMB because it met the criteria for benefit by four standard deviations. Now, what's unusual about this is the population of our patients and vascular risk. So these are people who in the past would just be treated with aspirin. So they're not post-MI. They are people with chronic vascular disease, either peripheral or coronary. And in the past, on top of standard secondary prevention care, they would only have got aspirin. Dr Greg Hundley: And what were the results? Professor Keith Fox: There was a 20% reduction in terms of the net clinical benefit favoring the combination of rivaroxaban and aspirin, and that net clinical benefit being the combined impact of cardiovascular death, MI, stroke, fatal bleeding, or bleeding into a critical organ. Dr Greg Hundley: And did you find the same results in, for example, older versus some of the younger patients? Or were there any other high-risk subgroups, those with impaired renal function or those with heart failure where you saw particular differences? Professor Keith Fox: Yes, Greg. This is a really important issue. If one looked at the whole trial, the number needed to treat to prevent one of these adverse events, N equals 52. But then if we looked at some of the higher-risk cohorts, which we defined prospectively ... For example, these were the risk factors like polyvascular disease, impaired renal function, ambulant heart failure, or diabetes. And if you had all four risk factors, the number needed to treat was nine. If you had three risk factors, it was 12. Two risk factors, 31. So I think there's clearly a message for clinicians to be able to identify people with a combination of these risk factors, one or more, in order to get the most benefit and the least hazard. Dr Greg Hundley: Very interesting. Any speculation on mechanism? Professor Keith Fox: Yes. One of the things that we've done in the past is we've hammered one antithrombotic pathway. Like, for example, we've used more and more potent anti-platelets or combination of anti-platelets. But perhaps one of the things that we've forgotten is the fact that the platelet activation pathway is triggered by thrombin activation and vice versa. So the concept that was new behind the whole COMPASS study was that augmentation of the antithrombotic effects by combining a very small dose of a novel anticoagulant would be beneficial. And the critical question is, would it be sufficiently beneficial without producing a lot of bleeding? So that's why we did this particular analysis. Dr Greg Hundley: So lower doses of some of these drugs. Well, Stefan, can you help us put these study results into context with what we know today about using aspirin alone, rivaroxaban, et cetera? Professor Stefan James: The reason I think this study's s…

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    Circulation on the Run: Special Conversation with Former and Current Editors-in-Chief of Circulation Jun 29, 2020
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    This week's episode is special: we have the former and current Editors-in-Chief of Circulation on Circulation on the Run. Join Dr Amit Khera, Digital Strategies Editor of Circulation, as he speaks with Dr James T. Willerson, Editor-in-Chief from 1993 to 2004; Dr Joseph Loscalzo, Editor-in-Chief from 2004 to 2016; and Dr Joseph A. Hill, the current Editor-in-Chief. They will discuss the history of Circulation and how it continues to evolve. TRANSCRIPT Dr Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation from UT Southwestern Medical Center in Dallas. Today we have a very special Circulation on the Run. We have three Editors-in-Chief from Circulation. First, we have Dr James Willerson, who was the Editor-in-Chief from 1993 to 2004. He's a President Emeritus at the Texas Heart Institute. We also have Dr Joseph Loscalzo, who was Editor-in-Chief from 2004 to 2016, the Chairman of Department of Medicine from Brigham and Women's Hospital. And finally, Dr Joseph Hill, the current Editor-in-Chief, the Chief of Cardiology at UT Southwestern Medical Center. Welcome, gentlemen. Dr Joseph Hill: Thank you. Dr James Willerson: Thank you. Dr Joseph Loscalzo: Thank you. Dr Amit Khera: Dr Willerson, I must say, looking over the tenure prior to Dr Loscalzo, you had one of the longest tenures ever as Editor-in-Chief of Circulation, and certainly a lot happened in the practice of cardiology during that period. It was a really formative period in cardiology. As you think back, what were some of the most important topics that you covered during that time as Editor-in-Chief, thinking about the evolution of cardiovascular care and science at that time? Dr James Willerson: You have to remember, there have been many editors at Circulation. We all build on the shoulders of others, certainly I did. I really wanted Circulation to be the premier cardiovascular journal in the world. I wanted it to be much like the New England Journal of Medicine, but the New England Journal of Medicine Circulation of Cardiology. I wanted to publish it every week. We got permission to do that. That wasn't easy, but we were fortunate. I've been accused of wanting to publish it every day. There's actually some truth to that. I didn't make that. I didn't try very hard. I wanted to be able to present the information, important information, to everybody who cared about cardiovascular medicine: physicians, scientists, students, nurses, those who cared for people, and I wanted to do it frequently. I wanted to publish it quickly. So, we had some success with that. There are many other things that are well-known to the other editors, all of whom have built before me and after me, and I'm very proud of them. Dr Amit Khera: Well, thanks for that. And certainly, as you pointed out, this has been an evolution where you took the gauntlet, if you will, from the people before you, and then built on that and had many advances. I guess after you, Dr Loscalzo, you I think did have the longest tenure if I saw of any of the editors and similarly, a lot of evolutions in cardiovascular care and a lot in science, particularly during your time. Tell us a little bit about any particular papers or topics that you focused on, or that really were revolutionary in the cardiovascular space during your tenure. Dr Joseph Loscalzo: I'll pick up where Jim left off and just make the case that as you're suggesting, I mean, there's sort of been a natural transition of the kind of science that Circulation has been publishing over the tenure of the three editors here today. Before Dr Willerson, it was largely physiology and excellent clinical science. Jim really expanded the scope of what Circulation published to begin to put in press in its pages, fairly basic and translational science as well. I picked up from what he'd laid the groundwork for to expand the scope of that science. And as you know, expand it to the point that we had to develop daughter journals that would pick up the mantle in each of these increasingly subspecialized areas. So, it's hard to think about those papers that I found have the greatest impact because every field had several of them in my several years as editor. As you know, the subspecialty journals that we established, which remain active to the current time, are also broad in their scope from outcomes based research to genomics and proteomics insistence, cardiovascular medicine, to everything in between, imaging, intervention, heart failure, and electrophysiology to arrhythmias. Each of these was led, and continues to be led, by outstanding leaders in their subspecialty fields. I think the beauty of Circulation in contrast to even fine journals like the New England Journal of Medicine, is that Circulation has been able to put on its pages those studies that really do span quite a spectrum. We don't shy away from very basic studies. That actually began with Jim, I must say, because that wasn't the case previously. And of course, we move right through to epidemiology and outcomes based research. And the impacts have been broad in each of those fields, as witnessed by the excitement and uptake of the journal, measured however you wish, by impact factor, or citations, or the frequency with which it's referred to in the lay press. So, I think that tradition certainly continues under the current editor with papers of extraordinary impact. Dr Amit Khera: Thanks for that. I think your point about the evolution of science over time from Dr Willerson and certainly during your tenure and beyond to the breadth of Circulation currently. You also touched on the subspecialty journals. That happened in your watch and that was quite a marked change in cardiovascular medicine to have that explosion of new journals, if you will. What do you think the impact of those subspecialty journals has been for the cardiovascular field? Dr Joseph Loscalzo: We struggled with the idea about whether or not we should pursue that kind of fragmentation. What really pushed us was the fact that the acceptance rate remains quite low, in those days, probably eight or so percent range at its nadir. So, we were rejecting a lot of really excellent papers which wound up in competitor journal pages, that we would like to have accepted and been given the scrutiny of the careful reviews and editorials that accompany papers accepted by Circulation. We felt the best way to do that under the circumstances was to create these daughter journals. They succeeded, in many respects, beyond our wildest imagination. The numbers of papers that were published in the family increased, I think in the first two or three years, by at least 2-to 3000. So, that really speaks to the fact that we kept the best papers in the family. We gave them the right kind of audience. Some of these would have been too technical or too highly specialized to have been published in Circulation proper, but certainly of the highest quality and of significant relevance to the subspecialist. So, we think that it was a successful experiment. Now it's sort of become tradition. I think that the question that will always come up, of course, is can we fragment things more? I would say one of the best reasons to make the case that this was a successful experiment is that if imitation's the sincerest form of flattery, the New England Journal is now going to start three subspecialty journals. In fact, in my role now as an editor of the New England Journal, editor-at-large, they asked my input in how to design those daughter journals and what to expect from them. Dr Amit Khera: Well, I think that's a great point. It certainly has been a resounding success and as you pointed out, imitation is the best form of flattery. I'm going to pivot now to Joe Hill. Dr Hill, you have certainly been the beneficiary of all the great work that these two editors have done in the past. You've inherited a very successful journal and also have crafted your own vision for where you want Circulation to go in your mark. Tell us a little bit about some of the new initiatives you've tried to implement, leveraging on these past successes. Dr Joseph Hill: Thank you, Amit, it's an honor and a privilege to be in this conversation, frankly. I mean, Dr Willerson made this a weekly journal. That was back in the day when FedExes were flying around. Everything was paper. That kind of volume with that technology is impressive. And Dr Loscalzo, who has been a friend and mentor for many, many years, spearheaded the subspecialty journals, as we just heard, and took the journal to yet new heights. Each of you has been a pioneer and we've been fortunate to put together a team that I think has moved in exciting directions. We've leveraged technology now, such that we have our video conference meetings. We meet in a video conference with editors from 17 different countries. We have a third of our editors in Dallas, where I live, a third in the US outside of Dallas, and another third in 16 other countries. It turns out we alternate the time of that meeting each week because there's no single hour of the day that works around the globe, so we move it around to capture Asia or to capture California in alternating weeks. That has been a thrill and, honestly, I believe a robust success. We have leaders on the ground in all these different countries. We have a highly diverse team across the different subspecialty domains of cardiology, across different geographic regions, across race and sex and gender lines. It is an amazing team. And Amit, who leads our robust digital efforts, including this podcast and our efforts on social media, again, the opportunity now in the 21st century to take these initiatives forward has been a real privilege. Dr Amit Khera: It's ironic that Circulation was doing Zoom before everybody else was in the modern era. I'm going to pivot back to Dr Willerson. As Dr Hill just mentioned during your tenure how the volume of papers was handled, FedEx and sort of the nature of the journal publishing process. And now in the modern era, we have so much different information. We have a huge volume of journals. We have online, we have Twitter, we have podcasts. We have people that are consuming information in so many different ways. Tell us from your perspective, what's the role of the scientific journal currently and how has it changed at all in the last few decades? Dr James Willerson: It's always going to continue to evolve. It's about as good as it can be right now with Dr Loscalzo and Dr Hill's leadership, and I'm really proud of them. There'll be more. We can't even imagine what it will be in two or three years. Of course, it'll be better and better, faster, almost momentary. Thank you, Dr Hill. Dr Amit Khera: Thank you for that. I think we all look forward to seeing how this evolves more rapid information, rapid turnaround. I'm certain that will change. Dr Hill, you had a comment on that? Dr Joseph Hill: We live in an era now where peer review is under attack in many ways and pre-print journals, blogs and so forth. And one of the things that I've really seen, and we've all seen, is how the peer review process, and we're all authors, right, we live on the other end of that stick, but it really is important. It makes a big difference. And people who are anxious to accelerate that process, I totally get it. We work very hard to do that. At the same time we, following the traditions here, have an intentionally redundant review process where every paper is evaluated by multiple editors and multiple peer reviewers. On a number of occasions, we've avoided a pothole, or we've improved a paper many, many times. And that is something that has really been impressed on me that I think people who aren't on this side of the editorial fence might not appreciate as much. Dr Amit Khera: I think that's an important point about sort of the rigor about the way that articles come out in Circulation. And Dr Loscalzo, maybe as an extension of the last question, what do you see as some of the challenges going forward or opportunities for Circulation? You think about where it's been, but what are some of the things that you look forward to for Circulation in the future and what are some of the things you're concerned about? Dr Joseph Loscalzo: Well, I too am concerned about this issue of peer review being under attack, and I'm particularly concerned about it for papers that have direct clinical impact. A good example of that concern, of course, are papers published, or at least publicly released, on non-peer reviewed websites like the archive sites because of their importance in the COVID epidemic, potentially. We all know of cases of drugs, at least in test tubes, with cultured cells and viruses appear to be effective that have adverse clinical consequences. So that, and more than in any other sphere of science, ensuring that proper peer review from as many perspectives as possible is always a part of the process is absolutely critical for clinical medicine. And to me, the threat that this need for acceleration and rapid peer review poses and the sort of socialization of the transmission of scientific information that we're all interested in doing really has to have the brakes put on it a bit for the clinical science that the journal represents for this very important reason. Not to say we want to slow things down, we want to make sure that the best possible reviews are performed before we release it to the public. I know that, as Joe was pointing out, one of the most exciting parts of the role of when I led the journal was the weekly meeting. We had a face-to-face meeting because all of our associate editors, save one, was actually physically proximate and they could travel to our conference room. But it's a wonderful exercise to have people of very different perspectives, from basic scientists, to clinical electrophysiologists, to outcomes researchers, make comments on papers that were completely outside their sphere. The argument, of course, is if one can write and transmit a thought with the clear intent in a way that's rigorous and logical, that any reasonably bright person with reasonable scientific background should be able to understand it. And often these folks with very different scientific backgrounds have perspectives that very clearly improved the paper when they were acted upon. That's a process that doesn't exist in many other journals, I have to say. And I would encourage Joe, which I know, well, he's doing this because he enjoys it and he recognizes its importance, and Joe's successors continue to do that as well because that will ensure the value of the journal through all of the challenges that it is going to have to face in the next decade or two. Dr Amit Khera: I think that was a great point. We're certainly seeing candy bowl examples of the importance of this rigorous process of the editors looking through it carefully and, as you both mentioned, peer review. Joe Hill, I'm going to let you maybe have the last word. I know how hard the three of you have historically worked on your craft for the journal, how much effort you've put in, but I also know it's quite a rewarding job. What would you see as the best part of being Editor-in-Chief of Circulation? Dr Joseph Hill: Oh my, I'm learning something every day. I've been on about a steep a learning curve as when I was an intern at Dr Loscalzo's hospital long ago. Under Dr Willerson's term, I imagine many, many studies came in on acute coronary syndromes and thrombolytic therapy, primary PCI, antiarrhythmic drugs. We haven't seen an antiarrhythmic drug paper except for a recent…

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    Circulation June 23, 2020 Issue Jun 22, 2020
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    Today's episode discusses the paper "Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial" Dr Carolyn Lam and Dr Greg Hundley also discuss the following: "Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis" by Shah et al. "Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage" by Joutel et al. TRANSCRIPT 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 from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature. But before we do that, how about we get to other articles in our journal today? Would you like to start? Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland. Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets. Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study? Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly. Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality. Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results. A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration. Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling. And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg? Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites. In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells. Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial. Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans? Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Okay, so put it together for us, Greg. Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss. The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results. Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg. Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China. There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting. There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations. A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic. Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research. So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript. Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic. Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic. Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes. And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care. Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents. Dr Carolyn Lam: Great. Let's go, Greg. Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors. Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address? Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget. For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also. We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome. Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent? Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years. And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month. Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population? Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients. Dr Greg Hundley: And what outcomes were you looking for? Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed. Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes? Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority. Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other? Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference. Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting? Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population. So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice. There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis. I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent. So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US. So I think this does add to the overall body of literature for this group of stents. Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette. Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less. It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year. I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy. Dr Greg Hundley: Very good. Dharam, your thoughts? Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma. So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general. So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents. Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting. For all our listeners out there on behalf of Carolyn and myself, we wish you a great week…

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    Circulation June 16, 2020 Issue Jun 15, 2020
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    Today's episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries. Dr Carolyn Lam and Dr Greg Hundley also discuss the following: Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al. Autoantibody Signature in Cardiac Arrest by Li et al. Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al. TRANSCRIPT Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue? Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function? Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase. Dr Carolyn Lam: You are just too smart, Greg Hundley! Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review. Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies. Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis. Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality? Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course. Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory. Dr Carolyn Lam: Interesting. So what did they find? Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients. Dr Carolyn Lam: Huh? So what most predictive? Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality. Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg? Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models. Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2. Dr Greg Hundley: Carolyn, what is that? Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling. The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects. The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression. Dr Greg Hundley: Carolyn, so what did they find regarding to TET2? Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients. Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation. Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics. Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. "The Future of Cardiovascular Prevention: Unprecedented Times," by Laurence Sperling. "Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic," by Erin Michos. "Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?" by Dharam Kumbhani. And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes. Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries? Dr Carolyn Lam: You bet. Let's go, Greg. Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue? Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries. So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group. Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort? Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine. So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole. So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus. Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions. Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us? Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there. And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines. And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. A…

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    Circulation June 09, 2020 Issue Jun 08, 2020
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    Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue? Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified. Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message? Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations. Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity. Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg? Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy. Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date. Dr Greg Hundley: So Carolyn, what did they find here? Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy. Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic. And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction. Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now. Dr Greg Hundley: Look forward to it. Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important. Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day. And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone. Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that? Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other. So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well. Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results? Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication. So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a rea…

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    Circulation June 2, 2020 Issue Jun 01, 2020
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    In today's episode, Dr Carolyn Lam discusses the prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease with Dr Kausik Ray (KOSH) and Dr Amit Khera. Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg. I'm the associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia. Dr Carolyn Lam: Greg, ever wondered what's the prevalence of familial hypercholesterolemia in the general population? It's an important question, but we're going to wait to discuss that with our feature discussion coming right up. First, I want to tell you all about valvular heart disease. In a preclinical model, would you believe, but first let me just remind us all that primary valvular heart disease is a really prevalent cause of morbidity and mortality. And although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart disease has always centered around valve repair or replacement, rather than the prevention or reversal of myocardial dysfunction. In fact, have you thought about this? We know very little about the mechanisms, the actual preclinical underlying mechanisms of left ventricular dysfunction and primary severe mitral regurgitation. Well, in the first paper I want to talk about today, Dr Li from First Affiliated Hospital, Sun Yat-sen, University Guangzhou, and Dr Sadek, from UT Southwestern Medical Center and their colleagues develop the first mouse model of severe mitral regurgitation. And they did this by severing the mitral valve leaflets and chords using iridectomy scissors. Similar to the human condition, induction of mitral regurgitation was followed by gradual left ventricular dilatation and dysfunction resulting in severe systolic dysfunction. Further analysis revealed that severe mitral regurgitation resulted in a marked increase in cardiac mass, increased cardiomyocyte length, but not with, and electron microscopy evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe mitral regurgitation resulted in activation of multiple components of both the mTOR and Kelson urine pathways. Now intriguingly, inhibition of mTOR signaling even preserved sarcomeric structure and prevented left ventricular remodeling and systolic dysfunction. Finally, immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator CRB2, along the longitudinal axis of cardiomyocytes and close to the intercalated discs, with a similar pattern of polysome localization. And all of this suggests a potential new mechanism of longitudinal cardiomyocyte growth. Dr Greg Hundley: Well, Carolyn, there is a lot of basic science and a lot going on both histopathologically, but also mechanically with this model. What's our take home message? Dr Carolyn Lam: Well, Greg, this mitral regurgitation mouse models suggest that cardiomyocyte hypertrophy in response to mitral regurgitation is a maladaptive process that may be pharmacologically targeted by mTOR inhibitors. Dr Greg Hundley: Oh my, very nice Carolyn. Well, I'm going to bring you another kind of basic science paper as well. And it's from Dr Jin Li from the Institute of Biochemistry and Molecular Medicine at the University of Bern. And it really involves auto antibody signatures in cardiac arrests. So Carolyn, a quiz of what percentage of individuals sustaining out of hospital cardiac arrest have no known cause? Dr Carolyn Lam: You said, "Oh oh!" I'm on the spot here, Greg. Okay. What about if I start with what I do know? Coronary artery disease is the most common cause. I think that may be, I don't know, large majority, 80% of it. And then we get inherited cardiomyopathy, channelopathies. So I'm going to guess less than 10%. Dr Greg Hundley: Wow. That is why you're just the stellar extraordinaire. So it's exactly about 5% to 10%. So Carolyn this study sought to address the etiology for this out of hospital arrests in this 5% to 10% of individuals, using a peptide micro-ray designed to screen for IgG targeting epitopes from all known cardiac ion channels with extracellular domains. So plasma samples from 23 patients with unexplained cardiac arrest were compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age, sex, and BMI matched healthy subjects. Dr Carolyn Lam: Wow. What did they find, Greg? Dr Greg Hundley: The auto antibody against the poor domain of the L tight voltage gated calcium channel or Cav 1.2 was consistently identified as a biomarker of idiopathic cardiac arrest and functional studies on human induced pluripotent STEM cell derived cardiomyocytes demonstrated that the anti Cav 1.2 IgG purified from patients with idiopathic cardiac arrest is pro-arrhythmogenic by reducing the action potential duration through calcium channel inhibition. Dr Carolyn Lam: Wow, that seems huge. Clinical implications? Dr Greg Hundley: I thought you'd asked me that. So the present report addresses the concept of autoimmunity and cardiac arrest and hitherto unknown auto antibodies targeting extra cellular sequences of cardiac ion channels were detected. And so moreover, this study identifies an auto antibody signature to specific patients with cardiac arrest, thereby explaining perhaps a potential etiology for this 5% to 10% of individuals that here to for, we were uncertain of that particular ideology. Dr Carolyn Lam: Wow. That clearly needs follow-up, but you know what? What also needs follow-up is a quiz question for you. What do you say to a young adult with stage one hypertension about his or her future health risks? Dr Greg Hundley: Well, how about A, see a physician, B, listen to that physician and follow their recommendations? Dr Carolyn Lam: Oh, you are brilliant. Well, guess what? I'm going to tell you a little bit more about this in the next paper from Dr Kim from Yonsei University College of Medicine and Colleagues who looked at almost six and a half million participants aged 20 to 39 years. So young, and without taking any antihypertensive medication in 2003 to 2007 in a nationwide health screening database. Now participants were categorized according to the 2017 ACCAHA guidelines as having a normal blood pressure. That is an untreated systolic blood pressure, less than 120 and diastolic blood pressure less than 80. Or stage one, isolated diastolic hypertension. So that's when systolic is less than 130 and diastolic between 80 and 89. Or stage one isolated systolic hypertension. So that's when systolic blood pressure is between 130-139 and diastolic is less than 80. Or finally, stage one systolic and diastolic hypertension. So that's when systolic is between 130-139 and diastolic is between 80 and 89. And these were followed up for the primary outcome of composite cardiovascular disease events, including myocardial infarction, stroke, heart failure, and cardiovascular related death. Dr Greg Hundley: Caroline, I am dying to hear what did they find? Dr Carolyn Lam: So over a median follow-up of 13.2 years, more than 44,000 new cardiovascular disease events occurred. Among these young adults who had a median age of only 30 years stage one, isolated systolic hypertension, isolated diastolic hypertension, and systolic and diastolic hypertension were each associated with higher cardiovascular risks compared to normal blood pressure. Cardiovascular risk of stage one systolic and diastolic hypertension was higher than the risks of stage one isolated systolic and isolated diastolic hypertension. Dr Greg Hundley: Very good. That was an outstanding presentation and very pertinent to our younger listeners as well as young patients with hypertension. In the rest of this journal, we are jammed packed with more articles. Let me tell you about a few. First, I've got a research letter by Professor G. Kees Hovingh from Amsterdam UMC discussing Inclisiran and how that durably lowers LDLC and PCSK-9 expression in homozygous familial hypercholesterolemia. Next there's an ECG challenge from Dr Miguel Arías from Complejo Hospitalario Universitario de Toledo involving syncope and alternating QRS morphologies. Next Professor Qing Yang from Tianjin Medical University General Hospital has a perspective piece regarding anti-platelet therapy following percutaneous coronary interventions in patients complicated by COVID-19. One of our own associate editors, Dr Nicholas Mills, has a very nice on my mind piece related to the use of serum troponin and biomarkers, as well as their utility in managing patients with COVID-19. Next, Dr Courtney Campbell from Ohio State University and Wexner Medical Center has a perspective piece regarding will compliment inhibition be the new target in treating COVID-19 related systemic thrombosis. And then finally, Carolyn, there's a nice exchange of research letters regarding Orai 1 channel inhibition, preserving left ventricular systolic function, and normal calcium handling after pressure overload. And the contributing authors that provided these letters are Dr Muddassir Mehmood from University of Tennessee Medical Center and Dr Jessica Sabourin from INSERM UMR S1180. Dr Carolyn Lam: And that's not all, Greg. There's also an in-depth article on the implications of altered ketone metabolism and therapeutic ketosis in heart failure by Dr Salvaraj, Kelly, and Margulies. Now this review is a must read. It summarizes the current evidence supporting a role for ketones in heart failure and covers normal myocardial ketone utilization, alterations, and ketone metabolism in a failing heart and effects of therapeutic ketosis in both animals and humans with heart failure. There's also a research letter by Dr Susanna Larson who used the UK Biobank Cohort to perform a Mendalian Randomization investigation into the causal effects of circulating LPA levels on atherosclerotic, cerebral vascular thrombotic, and valvular disease. There's another research letter by Dr Eliseo Guallar and that's on mitochondrial DNA copy number, which is an indirect biomarker of mitochondrial dysfunction and its association with incident heart failure in the Eric study. Wow, such a full issue, but now let's go on to our feature discussion. Shall we, Greg? Dr Greg Hundley: You bet. Dr Carolyn Lam: Today's feature discussion is all about familial hypercholesterolemia. Now, recent study suggests it is more frequent than previously reported. And in fact, increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Well, today's feature paper really represents one of the most comprehensive assessments of the prevalence of familial hypercholesterolemia. More than 7.3 million individuals from 62 studies. So pleased to have with us the corresponding author of this beautiful paper, Dr Ray Kosh from Imperial College London, as well as our editor of digital strategies, Dr Amit Khera from UT Southwestern. Kosh, if I may call you that, congratulations again on another just really important paper. This systematic review and meta-analysis is really revealing. So could you tell us a little bit more of the details of what you did and just really tell us the take home messages. Dr Kausik Ray: We've been getting signals that familial hypercholesterolemia... So this is where essentially individuals inherited an abnormality that results in lifelong elevations of LDL cholesterol birth, increases risk of cardiovascular disease. The previous prevalence was believed to be about one in 500 and suggestions... It's actually not just a suggestion, there's a lot of data suggesting that it's a lot more prevalent than that. And one of the queries that we often have, if you think about global health is does it affect all regions of the world? And if we don't go out looking for it, you're not going to find it. So this is really why this was done. And we basically synthesize the global data and there was basically over 7 million people approximately from general population primary care settings, if you will. And the global prevalence for FH is one in 311. Confidence interval is between about one and 250 to one in 397. If you look at WHO regions of the world, it's equally prevalent across all regions of the world. And we know there are many regions of the world where they're not going out looking for this. So if you don't look for it, you won't find it. And we think that that should inform public health policies. The other key things about this or that because this is a condition that results in premature cardiovascular disease, there's been emerging data that actually in people with early myocardial infarction, for example, the possibility of FH may be higher. So in proportion of studies where we had participants with established cardiovascular disease, the possibility of this being present is about one in 17. Now they're not all going to be FH, but it means that actually the coronary care unit where the vast majority of these patients arose from, that's a great starting place. If you see somebody with premature MI before the age of 55, high LDL cholesterol above 190, start thinking about it. If you find one, you can think about cascade testing and finding family members because each effected individual potentially the likelihood in a first degree relative is 50%, 1 in 2. So that becomes really important. And I think those are probably where I'd stop now and maybe take a few more questions, but I think that's the take home message. Dr Carolyn Lam: Very, very important and practical take home messages. So thanks for that, Kosh. But could I just go back with one basic question? For those of us who don't think of it every day, what is the definition of familial hypercholesterolemia? There are so many definitions out there. Could you simplify it for us? Dr Kausik Ray: Yeah, so basically all the definitions, the common ones that have been used in making an early diagnosis. So met that criteria, looking at family history, looking at elevated cholesterol levels. There's the Simon-Broome criteria with some clinical signs, as well as family history and genetic mutations. And then there's the Dutch lipid criteria. That's probably the most used in the world, looking at the physical signs, LDL cholesterol levels, and also family history. And they give you essentially a score of the likelihood of this. And if you like, the gold standard really is probably genetic testing. That's not available in all regions of the world. There may be cost and other issues with that, but essentially that is giving you a diagnosis of a known variant of monogenic disorder and there's over 1,800 or so variants identified. So those are the ways that you can essentially do this. Dr Carolyn Lam: Thanks, Kosh. Amit, I have to bring you in here. Thank you so much for managing this beautiful paper and recognizing how important it is. You invited an editorial as well. Could you share some of your thoughts? Dr Amit Khera: Sure. The one thing, Kosh, as we look at this, which is so important to understand the prevalence worldwide and really glad that your group took on this project. But if you look at your figure, what's striking is how many areas are essentially white where there's no data. I mean, huge proportions of countries around the world. Why do you think that is? And how do we close that gap? Dr Kausik Ray: That becomes really important. So what I would say is this was looking at prevalence and those are are…

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