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Circulation April 11, 2023 Issue Apr 10, 2023

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This week, please join author Kavita Sharma and Associate Editor Svati Shah as they discuss the article "Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction." Dr. Greg Hundley: Welcome listeners, to this April 11th issue of Circulation on the Run. And I am one of your cohosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I am Dr. Peder Myhre from Akershus University Hospital, and the University of Oslo in Norway. Dr. Greg Hundley: Well, Peder, wow. This week's feature discussion, very interesting. We spend a lot of time, especially with our colleague, Dr. Carolyn Lam, on heart failure preserved ejection fraction. But this week's feature discussion, it's going to focus on some of the myocardial metabolomics in this condition. But before we get to that, how about we grab a cup of coffee, and jump into some of the other articles in the issue? How about if I go first? Dr. Peder Myhre: Let's go, Greg. Dr. Greg Hundley: Okay. So Peder, some believe that cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. And so, the American Heart Association, as you know, recently released an updated algorithm for evaluating cardiovascular health. Life's Essential 8, and it has a very nice score. So these authors, led by Dr. Lu Qi, from Tulane University, aimed to quantify the associations of the Life Essential 8 scores with life expectancy in a nationally representative sample of US adults. And the team included 23,000 non-pregnant non- institutionalized participants who were age 20 to 79 years, who participated in the National Health and Nutrition Examination survey, or NHANES, from 2005 to 2018. And whose mortality was identified through linkage to the National Death Index, from the period extending through December of 2019. Dr. Peder Myhre: Oh wow. So really, a validation of the Life's Essential 8. Greg, that's so interesting. What did they find? Dr. Greg Hundley: Right Peder, as you say, very interesting. So here are some of the data, and let's itemize them. So, during a median of 7.8 years of follow up, 1,359 total deaths occurred. Now, the estimated life expectancy at age 50 was 27.3 years, 32.9 years, and 36.2 years, in participants with low Life's Essential 8 scores, less than 50. Moderate, so Life's Essential 8 scores of greater than or equal to 50, but less than 80. And then, high scores, greater than 80. Okay? So equivalently, participants with high Life's Essential 8 scores had an average of 8.9 more years of life expectancy at age 50, compared to those with low scores. Next, on average, 42.6% of the gained life expectancy at age 50, from adhering to sort of that cardiovascular health, those recommendations, was attributable to reduced cardiovascular death. Next, significant associations with the Life's Essential 8 score and life expectancy were observed in both men and women. Next, similarly significant associations of cardiovascular health, Life's Essential 8, with life expectancy were observed in non-Hispanic Whites and non-Hispanic Blacks, but not in those originating from the country of Mexico. So Peder, finally, in summarizing all of this, adhering to the cardiovascular health lifestyle, defined by the Life's Essential 8 score, it was related to a considerably increased life expectancy. However, because of the findings from the individuals from the country of Mexico, more research is needed to be done in some of these minority groups, and particularly, those of Hispanic ethnicity, and perhaps other races. Dr. Peder Myhre: Oh, wow. Very interesting. And I would love to learn more about this subgroup analysis in future studies. So Greg, the next paper is about the hospitalization for heart failure measures. Because contemporary measures of hospital performance for heart failure hospitalization, the 30-day risk standardized readmission and mortality rate, are estimated using the same risk adjusted model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial ethnic groups, and may not adequately represent the hospital performance for patients of Black or other races. And in this study, led by co-corresponding authors, Mentias from Cleveland Clinic and Pandey from University of Texas Southwestern Medical Center, the authors used fee for service Medicare beneficiaries from 2014 to 2019 hospitalized with heart failure, in hospital level 30 day risk standardized remission and mortality rates were estimated using traditional race agnostic models and the race specific approach, with measures derived separately for each race ethnicity group. Dr. Greg Hundley: Ah, very interesting, Peder. So what did they find from this study? Dr. Peder Myhre: So the study included more than 1.9 million patients, comprising of 75% White patients, 15% Black patients, and 10% patients of other races, with heart failure from 1,860 hospitals. And compared with the race agnostic model, composite race-specific metrics for all patients demonstrated stronger correlation with 30 days readmissions. And that is correlation coefficient 0.78 versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black patients. In concordance in hospital performance was for all patients and patients of Black race was also higher with race specific as compared to race agnostic metrics. So Greg, the authors conclude that among patients hospitalized with heart failure race specific 30 day risk standardized remission and mortality rates are more equitable in representing hospital performance for patients of Black and other races. Dr. Greg Hundley: Very nice, Peder. What a beautiful summary in a very elegant study. Peder, myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlining molecular mechanisms for this relationship remain unclear. Now, recent studies demonstrate, that the diabetic heart is resistant to several cardioprotective interventions, including adiponectin and pre-conditioning. The universal quote, unquote, resistance to multiple therapeutic interventions suggest, impairment of the requisite molecule, or molecules, involved in broad pro survival signaling cascades. Now caveolin is a scaffolding protein coordinating trans-membrane signaling transduction. However, the role of caveolin-3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. And so these investigators, led by Dr. Xinliang Ma, from Thomas Jefferson University, studied mice fed a normal diet or high fat diet for two to 12 weeks, and subjected them to myocardial ischemia and reperfusion. Dr. Peder Myhre: Oh wow. What an interesting preclinical science paper, Greg. What did they find? Dr. Greg Hundley: Right. So the authors found that nitration of caveolin-3 at tyrosine 73 and resulted signal complex dissociation was responsible for cardiac insulin adiponectin resistance in the pre-diabetic heart. And this contributed to ischemic heart failure progression. Now, early interventions preserving caveolin-3 centered signal zone integrity was found to be an effective novel strategy against diabetic exacerbation of ischemic heart failure. And Peder, I think these very exciting results suggest that this is a new area of research and further experiments are warranted. And there's a very nice editorial by Professor Heidenreich, entitled "Pursuing Equity in Performance Measurement. Well Peder, there's some other articles in this issue, and we'll dip in this week to the mail bag, for a Research Letter from Professor Hibbert, entitled "Utility of a Smartphone Application in Assessing Palmar Circulation Prior to Radial Artery Harvesting for Coronary Artery Bypass Grafting." Dr. Peder Myhre: That is so cool. And we also have a Letter from Dr. Kim, regarding the article entitled, "Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study." Dr. Greg Hundley: Very nice. Well, how about we get along to one of Carolyn's favorite topics, heart failure with preserved ejection fraction, and learn more about myocardial metabolomics? Dr. Peder Myhre: Can't wait. Dr. Carolyn Lam: Today's feature discussion is on my favorite topic, heart failure with preserved ejection fraction, or HFpEF. But today, what we're focusing on is truly novel. We are looking at the myocardial metabolomics of human HFpEF, very, very valuable data and insights. We're so pleased to have with us the corresponding author of today's feature paper, Dr. Kavita Sharma, who's from the Johns Hopkins University School of Medicine, and our associate editor, Dr. Svati Shah, who's, of course, from Duke University School of Medicine. So welcome Kavita and Svati. Kavita, if I could start by, please put us and bring us all to the same level of knowledge, by perhaps explaining in simple terms, what is metabolomics? And what is normal versus perhaps abnormal metabolomics, in a known condition, like systolic heart failure or heart failure with reduced ejection fraction? Dr. Kavita Sharma: Sure. Well thank you, Carolyn, for the opportunity to chat around this topic. And it's great to be with you and Svati this morning. Metabolomics is a broad general study of essentially, all the chemical processes involving metabolites, or small molecule substrates, their intermediates, and even the products of cellular metabolism. This can be studied in really, any organ system, in any organ. What is really unique, I think, to this particular paper in our project is that, it has yet to have been defined or described in human HFpEF from the myocardial tissue. We call this heart failure with preserved ejection fraction, and inherent to that name in this complicated syndrome is that, there is something probably wrong with the heart, yet we have not really had much insight to what that might be from direct myocardial tissue. We are also still learning about what metabolomics looks like in, for example, the heart failure with reduced ejection fraction state. Though, there is more published in this space than in HFpEF. From the limited knowledge that we have, it does appear that heart failure with reduced ejection fraction hearts, and this is certainly seen in the plasma, which is where most of metabolomic studies have generated from, those hearts tend to utilize various forms of energy banks, if you will. Whether that's fatty acid oxidation, whether that is glucose utilization or intermediates and so on. And our primary interest was to understand, how do the preserved EF parts in patients fare in comparison? Dr. Carolyn Lam: Oh, thank you so much, Kavita. That was beautifully explained. And indeed, what's so special about your paper is, it's not just circulating metabolites but myocardial metabolites. And you have the control groups that are so important to study at the same time. So patients with HFpEF, but also those with HFrEF and versus controls. And thank you for establishing too, that if I'm not wrong, fatty acid metabolism accounts for the majority of ATP generation in the normal heart. Whereas, this declines a little in the HFrEF heart. And now, I think we're about to find out what happens in the HFpEF heart. So if you could explain what you did and what you find. Dr. Kavita Sharma: Yes, absolutely. So we examined, again, tissue and plasma metabolomics from 38 subjects with HFpEF. These are patients referred to the Hopkins HFpEF Clinic. And so they have been essentially, clinically evaluated, and have what we define as HFpEF, based on hemodynamic testing. So a right heart catheterization, often with exercise, that meets criteria for diagnosis of the syndrome. As you stated, we compared our HFpEF patient tissue and plasma samples to samples coming from patients with HFrEF, dilated cardiomyopathy, and non-failing controls. And the latter two sources were a tissue bank from the University of Pennsylvania, that is long-standing, where patients with endstage dilated cardiomyopathy are able to have tissue banked at the University of Pennsylvania at the time of explant prior to transplant. So albeit, we are comparing to fairly advanced end stage dilated cardiomyopathy, and control tissue comes from unused donor hearts, essentially. So presumably, normal heart function patients, likely in a brain death state, who for whatever reason, the hearts were not utilized for transplantation. Again, not an entirely perfect controlled state, but again, given the nature of the work, the fact that it's myocardial tissue, the closest that we have found we've been able to come to for a control comparison. We started out performing what we call quantitative targeted metabolomics. We measured organic acids, amino acids, and acylcarnitines in the myocardium. And that was totaling around 72 metabolites. And we did the same in plasma, so close to 69 metabolites. And our metabolomics work was actually completed at the University of Pennsylvania. And so, I wish to credit Dr. Zoltan Arany and Dr. Dan Kelly for their great collaboration in this study. Dr. Carolyn Lam: That's wonderful. Kavita, if you could tell us a little bit more about the patients with HFpEF. We understand it was end stage dilated cardiomyopathy, HFrEF, and donor hearts as the controls, but the patients with HFpEF, in relation to obesity, diabetes, and how that may impact the interpretation of the results. Dr. Kavita Sharma: Sure. So these are HFpEF patients that are in an ambulatory state outpatient setting. They have many of the comorbidities we know are intrinsic today to HFpEF. Out of our HFpEF population, the majority were women. So 71%, that's 27 out of the 38 we serve. And we're very fortunate to serve a African-American enriched population in Baltimore that's intrinsic to our center. And so, over half of our patients were Black. The remaining Caucasian, one non-Caucasian. Over half had been hospitalized, for example, in the prior one year. So these are certainly symptomatic patients. And all had NYHA II or greater symptoms. We do have a rather obese cohort at Hopkins. And so, our median BMI, for example, was 39, our mean is very similar. And the majority have, as we see often in HFpEF, the majority with hypertension, over half with diabetes. In fact, it was actually 70% or so. Rather few with coronary disease, and this is a trend we're seeing in general in HFpEF in the present day kind of common phenotypes, and about a third with atrial fibrillation. So really, representative, I think, of this kind of cardiometabolic as we call it, phenotype of HFpEF, that is the predominant phenotype we're seeing, at least in North America. Dr. Carolyn Lam: Oh, that's perfect. And then, maybe just a few words about the results before I bring Svati in for her thoughts. Thanks. Dr. Kavita Sharma: Sure, absolutely. So we conducted this study in a couple different stages. We first started with performing a principal component analysis and hierarchical clustering analysis, to see whether the myocardial metabolites and the plasma metabolites, respectively, would they distinguish these three patient groups? So HFpEF from HFrEF and controls. And interestingly, in the myocardial tissue, our PCA analysis and our hierarchical clustering analysis show that actually, in fact, as few as 70 metabolites in the myocardium really distinctly differentiate these three subgroups. The top contributors that separated HF from controls, for example, and HFrEF, were mostly related to amino acids, including branched chain amino acids and their catabolites, as well as medium and long chain acylcarnitines, which are byproducts of fatty acid oxidation. When it cam…

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Circulation April 4, 2023 Issue Apr 03, 2023

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This week, please join authors Tatsuhiko Naito and Kosuke Inoue as well as Associate Editor Wendy Post as they discuss the article "Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Study." Dr. Greg Hundley: Welcome listeners, to this April 4th discussion of Circulation on the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre from Akershus University Hospital and the University of Oslo in Norway. So Greg, today we have the feature paper, discussing the genetic risk of primary aldosteronism and its contribution to hypertension. So this is such an interesting topic and av very important cost on hypertension. And in this paper, they use cross-ancestry meta-analysis from GWAS studies to assess this very interesting discussion. But first, Greg, I have a paper that comes to us from the DELIVER trial, and it is about dapagliflozin to patients with HFpEF, and assessing the association with the duration of the heart failure. So Greg, it is important to understand how the effects of new treatments vary by the duration of heart failure. Because on one hand, physicians may think that a patient who has longer standing heart failure represents a stable survivor where new treatment is unnecessary. On the other hand, the view has been expressed that patients with long-standing heart failure may have more advanced disease, and there may come a point where they no longer respond to or tolerate the addition of new therapies, particularly because of hypotension, kidney dysfunctional and electrolyte abnormality. So the investigators from the DELIVER trial, led by corresponding all author John McMurray from University of Glasgow, therefore, aimed to assess the efficacy and safety of the SGLT2 inhibitor dapagliflozin, according to the duration of heart failure with EF above 40%. So that is mildly reduced or preserved. Dr. Greg Hundley: Wow, Peder, very timely, very timely article. So what did they find? Dr. Peder Myhre: So Greg, the authors categorized patients by duration of heart failure, one category less than six months, and then six to 12 months, and then one to two years, two to five years, and finally, more than five years. And longer duration heart failure patients were older, and more comorbid with worse symptoms, and the rate of the primary outcome increased with heart failure duration. And so, the benefit of dapagliflozin was consistent across heart failure duration categories with hazard ratios 0.67, 0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of 0.41. So the absolute benefit was therefore since there was no P4 interaction, greatest among those with highest risk, and that it was the longest duration heart failure. So there was a number needed to create for heart failure above five years of 24, versus 32 for those with the shortest duration of heart failure. And the authors therefore conclude, that even in patients with long-standing heart failure and generally mild symptoms cannot be considered stable, and it is not too late for such patients to benefit from an SGLT2 inhibitor. Dr. Greg Hundley: Ah, very practical information, Peder, beautiful description. Well Peder, this next paper comes to us evaluating low density lipoprotein cholesterol. And as you know, low density lipoprotein cholesterol is an important causal risk factor for atherosclerotic cardiovascular disease. However, a sizable proportion of middle-aged individuals have not developed coronary atherosclerosis as assessed by the presence of coronary artery calcification. Now whether the presence of coronary artery calcification modifies the association of LDL cholesterol with atherosclerotic cardiovascular disease risk, well, that's unknown. So these authors, led by the corresponding author of Martin Mortensen from Aarhus University Hospital, evaluated the association of LDL cholesterol with future atherosclerotic cardiovascular disease events, in patients with and without coronary artery calcium, from 23,132 consecutive symptomatic patients evaluated for coronary artery disease, using coronary commuted tomography angiography, or CTA, that were included in the Western Denmark Heart Registry, which is a semi-national multi-center based registry with longitudinal registration of both patient and procedural data. Dr. Peder Myhre: Oh, that is so important, Greg. So we're looking at LDL cholesterol and the association with ASCVD in patients with and without coronary artery calcification. So what did they find? Dr. Greg Hundley: Right, Peder. So during a median follow up of 4.3 years, 552 patients experienced a first cardiovascular disease event. In the overall population, LDL cholesterol per 38.7 milligrams per deciliter increase, was associated with cardiovascular disease events during the follow-up period. Now, when stratified by the presence or absence of a baseline coronary artery calcium score, LDL cholesterol was only associated with a cardiovascular disease event in the 47% of patients with a coronary CAC score greater than zero. While no association was observed in the 53% of individuals with a coronary artery calcium score equal to zero. Now similarly, very high LDL cholesterol, so greater than 193 milligrams per deciliter, versus an LDL cholesterol of less than 116 milligrams per deciliter, was associated with a cardiovascular disease event in patients with a CAC score greater than zero, but not in those without coronary artery calcium. Next, Peder, in patients with coronary artery calcium equal to zero, diabetes, current smoking, and low HDL cholesterol levels, were associated with future cardiovascular disease events. This principle finding was replicated in the multiethnic study of atherosclerosis. And so, Peder, LDL cholesterol appears almost exclusively associated with a cardiovascular disease event over the ensuing five years of follow-up in middle-aged patients with versus without evidence of coronary atherosclerosis, as identified by coronary artery calcium scores. This information is quite valuable for individualized risk assessment among middle-aged patients. Dr. Peder Myhre: Oh, that is so important, Greg. So really, LDL seems to be more predictive of atherosclerotic cardiovascular disease than those with calcium in their coronaries, while there was no association in those with no calcium in their coronaries. Very interesting. Dr. Greg Hundley: Absolutely. And there's a very nice editorial by Professor Sniderman entitled, "Cholesterol Coronary Calcification and Cardiovascular Prevention: Lessons We Can Learn from the Western Denmark Heart Registry." Dr. Peder Myhre: Thank you, Greg, that was a beautiful summary. And we are going to stay in clinical science, but we're going to move to aortic disease and look at gut microbiota. Now, Greg, large scale human and mechanistic mouse studies indicate a strong relationship between the microbiome dependent metabolyte, Trimethylamine-N-oxide, abbreviated TMAO, and several cardiometabolic diseases. And in this study, which comes to us from corresponding author Philip Owens from University of Cincinnati, the investigators aim to assess TMAO's role in the pathogenesis of AAA and targeting its parent microbes as a potential pharmacologic intervention. Dr. Greg Hundley: Ah, very interesting, Peder. So what methodology did they use? Dr. Peder Myhre: So Greg, this is one of those fantastic studies combining clinical and preclinical science. And the investigator measured TMAO in two independent patient cohorts, with a total of 2,129. And in addition, they used the murine AAA model, and fed the mice a high choline diet, which is a diet that markedly augment plasma levels of TMAO. And these mice were then treated with broad spectrum antibiotics, targeted inhibition of a gut microbial enzyme with fluorometer chloroquine, called FMC, or utilizing mice genetically deficient of Fmo3. Dr. Greg Hundley: Very nice. So what did they find, Peder? Dr. Peder Myhre: So the authors found that elevated TMAO was associated with increased AAA incidence and growth in both patient cohort studies. And dietary colon supplementations augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad spectrum antibiotics. In treatment with FMC ablated TMAO production attenuated colon augmented aneurysm in the initiation, and halted progression of an established aneurysm model. And additionally, the Fmo3 knockout mice had reduced plasma TMAO, aortic diameters, and were protected from AAA rupture compared to wild type mice. So Greg, in conclusion, this study defined a role for gut microbiota generated TMAO in AAA formation, and additionally, increased microbiome derived TMAO may serve as a novel therapeutic approach for AAA treatment where non currently exists. Dr. Greg Hundley: Beautifully described, Peder. And another one of their articles in Circulation that, as you indicated, very nicely complying the world of preclinical and clinical science. Well, we've got some other articles in the issue, and how about we jump into some of those? So first, there's a very nice Letter to the Editor from Professor Wong entitled, "Frailty and Age Correlation in Clinical Trials." And there is another reply to a prior Letter to the Editor from Professor McMurray entitled, "Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure, a Pre-specified Analysis of the DELIVER Trial." And then next, Peder, Michelle A. Albert has a very nice synopsis of the American Heart Association Presidential Address, entitled, "Economic Adversity and Healthcare." Dr. Peder Myhre: Nice. And finally, there's a Research Letter from Dr. Baggish entitled, "Association Between Concussion Burden During Professional American-style Football and Post-career Hypertension." Dr. Greg Hundley: Very good, Peder. Well, what a packed issue we have this week, and how about we jump next to that feature discussion with our colleague Carolyn? Ah. Dr. Peder Myhre: Let's go. Dr. Carolyn Lam: Primary aldosteronism, or, we're going to say PA for this discussion, is one of the most common causes of secondary hypertension, and it is also a particularly morbid form of secondary hypertension. So identifying this subgroup of hypertensive patients with primary aldosteronism, again PA, would allow us to perhaps, direct more aggressive management to their cardiometabolic risk. Now, is a genetic approach the way to do it? Well, we're about to find out in today's very special paper. We're very honored to have the first author, Dr. Tatsuhiko Naito, from Osaka University Graduate School of Medicine, and his second and co-author Dr. Kosuke Inoue, from the Graduate School of Medicine in Kyoto University, as well as our associate editor, Dr. Wendy Post, from Johns Hopkins University School of Medicine, here to discuss this very important paper. Perhaps I could start with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a little bit about what made you do this study, what you did, and what you found? Dr. Tatsuhiko Naito: I would like to thank you for inviting us to present the information from our paper. In terms of genetic, germline genetic factors behind the development of PA has not been isolated. And in addition, the PA is the cause of hypertension, but the genetic relationship between hypertension and PA has not been discussed previously. That is why we conducted a genome-wide association study, GWAS, of PA here. Our GWAS consisted of three defined cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our Japanese cohort, we collected samples in Hiroshima University, and we used controls from Biobank Japan, which is the largest Japanese biobank. And we also used two publicly available biobanks, UK Biobank and FinnGen. So they can be used upon registration. By utilizing these resources, we conducted a cross-ancestry, meta-analysis of GWAS. Dr. Carolyn Lam: Thank you. And the results, please? Dr. Tatsuhiko Naito: In the meta-analysis, we identified five genetic loci that were significantly associated with the risk of PA satisfied in the genome world significant threshold. The strongest association was observed at WNT2B, which is located in chromosome 1. And in addition, we identified one near the genome-wide association locus CYP11B1 and B2, which is located on chromosome 8. So CYP11B2 is the key enzyme that acts in producing aldosterone in the adrenal gland, thus, we consider that resource. This locus would be also our PA risk associated locus with a high probability. Of interest, these loci were reported to be associated with hypertension, but we thought this results is resemble, because PA occupies around five to 10% of causes of hypertension. Does the PA associated loci could be reported as hypertension associated loci in previous GWAS with large sample size? So to support our assumption, we compared the risk effect of these genetic loci between PA and hypertension. So if there are risk effects who are coming from PA, these loci should present higher effect on PA than on hypertension. And expectedly, these loci presented significantly higher effect on PA here. And lastly, inspired by these results, we hypothesized that some of other loci, that had been reported to be associated with hypertension, might come from the primary effects on PA. To investigate this, we picked up blood pressure rated genetic loci from previous GWAS of blood pressure, and compared their risk effects between PA and hypertension. The result was that, 66.7% presented a higher risk effect for PA than for hypertension. And two strictly demonstrates the result. We also performed the adjustment of blood pressure values, and even in this adjustment, 61.9% showed a higher effect on PA than on hypertension. So considering the prevalence of PA among hypertensive individuals, this result is little bit surprising, we think. So PA may explain an unexpectedly large amount of genetic background of hypertension, we think. Dr. Carolyn Lam: Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence for genetic predisposition to PA susceptibility, and then, revealing that two thirds of previously established BP associated variants were in fact a higher risk effect for PA than for hypertension. Wow. So Wendy, could you help us put these findings into perspective, please? Dr. Wendy Post: Thank you, Carolyn. Congratulations to the authors. This was a really interesting paper that we enjoyed discussing in our meetings. We were especially interested in the clinical potential, clinical implications of your study. We all see patients with hypertension, whether we're cardiologists, or endocrinologists, or primary care physicians. And so, trying to understand more about what is potentially the underlying causes for hypertension, from a biological standpoint, that might help us to identify and treat our patients appropriately, is really so important. And so, I was wondering, Kosuke, if you could tell us, from your perspective as an endocrinologist and a researcher, how you interpret these studies in a way that our readers might be able to use these results to think about the next patient we're seeing in our clinic with hypertension? Dr. Kosuke Inoue: Yeah. Thank you very much for asking this important point, Wendy. We're, first of all, I'm very pleased that our research is published in Circulation, and thank you very much for your consideration. And I think there are two major implications of our findings, treatment and a diagnosis. First of all, for treatment, well, our findings advance our current state of knowledge about PA pathogenesis. Like Wendy said, what…

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Circulation March 28, 2023 Issue Mar 27, 2023

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This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study." Dr. Gregory Hundley: Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion. Dr. Gregory Hundley: Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966. Dr. Peder Myhre: Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find? Dr. Gregory Hundley: Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery. Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race. So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients. Dr. Peder Myhre: Well, that is really interesting, Greg. Are you ready for the next paper? Dr. Gregory Hundley: Absolutely. Dr. Peder Myhre: So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events. Dr. Gregory Hundley: Interesting, Peder. So what did they find? Dr. Peder Myhre: So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits. Dr. Gregory Hundley: Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses. Dr. Peder Myhre: Oh, this is really interesting, Greg. So what did they find? Dr. Gregory Hundley: Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction. So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. Dr. Peder Myhre: Oh wow. That was really impressive. Dr. Gregory Hundley: Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled "A Mouse Model of Atrial Fibrillation in Sepsis." And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled "Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure." And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled "Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes." And that particular paper is published in Nature. Dr. Peder Myhre: That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article "Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy." And finally we have On My Mind by Bertram Pitt entitled "Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension." Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes. Dr. Gregory Hundley: Very good. Let's go. Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Vincent Aengevaeren: So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis. And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density. Dr. Gregory Hundley: Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here? Dr. Vincent Aengevaeren: The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics. So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise. Dr. Gregory Hundley: Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here. Dr. Vincent Aengevaeren: So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes. Dr. Gregory Hundley: Very nice. So Vince, describe for us your study results. Dr. Vincent Aengevaeren: During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings. Dr. Gregory Hundley: And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples. Dr. Vincent Aengevaeren: So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher in…

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Circulation March 21, 2023 Issue Mar 20, 2023

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This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age." Dr. Greg Hundley: Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Dr. Peder Myhre: And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway. Dr. Greg Hundley: Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first? Dr. Peder Myhre: I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts. Dr. Greg Hundley: Wow, Peder, so a very large gene-wide association study. So what did they find? Dr. Peder Myhre: So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease. Dr. Greg Hundley: Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development. Dr. Peder Myhre: Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find? Dr. Greg Hundley: Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects. Dr. Peder Myhre: Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first? Dr. Greg Hundley: Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study." Dr. Peder Myhre: And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions. And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century." And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that? Dr. Greg Hundley: Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion? Dr. Peder Myhre: Let's go. Dr. Mercedes Carnethon: Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found. Professor Mikael Dellborg: Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor. Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD. Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline. So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed. Dr. Mercedes Carnethon: Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you? Professor Mikael Dellborg: What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age. Dr. Mercedes Carnethon: Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation? Dr. Gerald Greil: Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future? Professor Mikael Dellborg: Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years. The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet. It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers. We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper. Dr. Gerald Greil: Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients? Professor Mikael Dellborg: I think they relate to…

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Circulation March 14, 2023 Issue Mar 13, 2023

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This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first. I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs. Dr. Greg Hundley: Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study. Dr. Carolyn Lam: Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination. Dr. Carolyn Lam: Wow. Wow. Important question. Everyone's interested in the results. So what did they find? Dr. Greg Hundley: Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis. Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science. Dr. Carolyn Lam: Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, "Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction." That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we? Dr. Greg Hundley: Absolutely. Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address? Dr. Milind Desai: Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers. So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today. Dr. Greg Hundley: Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll? Dr. Milind Desai: Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients. Dr. Greg Hundley: Very nice. So Milind, what were your study results? Dr. Milind Desai: Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers. But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT. Dr. Greg Hundley: And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex? Dr. Milind Desai: No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders. Dr. Greg Hundley: And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there? Dr. Milind Desai: There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity. Dr. Greg Hundley: And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles? Dr. Milind Desai: The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy? Dr. Mark Link: Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper. Dr. Greg Hundley: Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research? Dr. Milind Desai: Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out. Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging. Dr. Greg Hundley: Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about? Dr. Milind Desai: So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very carefu…

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Circulation March 7, 2023 Issue Mar 06, 2023

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This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume. Dr. Greg Hundley: Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform? Dr. Carolyn Lam: So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment. Dr. Greg Hundley: Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative. Dr. Carolyn Lam: Oh wow. So a new gene variant. So what was the relationship? Dr. Greg Hundley: Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials. And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling. Dr. Carolyn Lam: Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go. So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes. Dr. Greg Hundley: Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find? Dr. Carolyn Lam: They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar. In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration. So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more. Dr. Greg Hundley: Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals." Dr. Carolyn Lam: There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare. Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us. Dr. Xuerong Wen: Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone. Dr. Mercedes Carnethon: Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth. Dr. Sandeep Das: Thanks Mercedes. It's great to be with you. Dr. Mercedes Carnethon: Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found? Dr. Xuerong Wen: So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population. So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results. Dr. Mercedes Carnethon: Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team? Dr. Xuerong Wen: That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population. Dr. Mercedes Carnethon: Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation? Dr. Sandeep Das: Yeah, absolutely. Thanks for the question. So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question. Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello. Dr. Mercedes Carnethon: Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well. Dr. Sandeep Das: Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients? Dr. Xuerong Wen: I would say yes. Okay. Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced. And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist. And also there are some misclassifications and out of all this limitations and we still found the two drugs performed d…

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Circulation February 28, 2023 Issue Feb 27, 2023

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This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start? Dr. Carolyn Lam: I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction. Dr. Greg Hundley: Wow. Pray tell. Dr. Carolyn Lam: I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury. Dr. Greg Hundley: Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models. Dr. Carolyn Lam: Oh, wow. So a vaccine against atherosclerosis? Cool. Dr. Greg Hundley: Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler. Dr. Carolyn Lam: Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months. Dr. Greg Hundley: Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find? Dr. Carolyn Lam: Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar. Dr. Greg Hundley: Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe. Dr. Carolyn Lam: Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on "Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?" There's a Research Letter by Dr. Soehnlein on "Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice." There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine. The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy? Dr. Carolyn Lam: So important. Let's go. Dr. Greg Hundley: Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Jennifer Conway: Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults. Dr. Greg Hundley: And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population? Dr. Jennifer Conway: This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at. Dr. Greg Hundley: And in the study population, I know it's a pediatric population, what was the age range? Dr. Jennifer Conway: The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients. Dr. Greg Hundley: And of these pediatric populations, what percentage were, I guess, boys versus girls? Dr. Jennifer Conway: Yeah, so just over 75% were males within this study population. Dr. Greg Hundley: Okay. And then now Jennifer, can you describe for us your study results? Dr. Jennifer Conway: Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events. So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event. Dr. Greg Hundley: Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter? Dr. Jennifer Conway: Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance. Dr. Greg Hundley: Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward? Dr. Jennifer Conway: I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers. We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important. Another study that I'm doing that's not p…

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Circulation February 21, 2023 Issue Feb 20, 2023

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This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on "Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?" And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed…

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Circulation February 14, 2023 Issue Feb 13, 2023

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Please join Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal. Dr. Sana Al-Khatib: Hello and welcome to the Special Circulation on the Run podcast focused on the seventh Go Red for Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I had the pleasure of co-leading this issue with a colleague and friend, Dr. Dr. Mercedes Carnethon: Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going. Dr. Sana Al-Khatib: Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it. The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think? Dr. Mercedes Carnethon: Absolutely. This is such an important issue, particularly for survivors of breast cancer. Dr. Sana Al-Khatib: Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain. And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training. Dr. Mercedes Carnethon: That is so exciting to hear, especially with the potential to intervene for better outcomes. Dr. Sana Al-Khatib: Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci. Dr. Mercedes Carnethon: That is such great news. What did the authors have to say about these findings? Dr. Sana Al-Khatib: Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising. Dr. Mercedes Carnethon: I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer. Dr. Sana Al-Khatib: Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles. Dr. Mercedes Carnethon: Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause. However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution. And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it. Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool? Dr. Sana Al-Khatib: Wow. How interesting. Absolutely. Dr. Mercedes Carnethon: Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes. Dr. Sana Al-Khatib: Wow. Well, I can't wait to hear the results. Dr. Mercedes Carnethon: So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births. Dr. Sana Al-Khatib: That's a very large study. Dr. Mercedes Carnethon: Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35. So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health. Dr. Sana Al-Khatib: Yeah, no, absolutely. Very important implications here, Merci. I agree. Dr. Mercedes Carnethon: Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here. Dr. Sana Al-Khatib: Yes, please. Dr. Mercedes Carnethon: In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women. Dr. Sana Al-Khatib: A very important topic. Yeah, I agree, Merci. Dr. Mercedes Carnethon: Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications. And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events. Dr. Sana Al-Khatib: That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful. Dr. Mercedes Carnethon: It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode. Dr. Sana Al-Khatib: Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you. So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion. And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks. And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation. And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males. And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients. Dr. Mercedes Carnethon: Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an ex…

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Circulation February 7, 2023 Issue Feb 06, 2023

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Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting? Dr. Carolyn Lam: Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee. Dr. Peder Myhre: Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content. Dr. Carolyn Lam: It's true. That's a very interesting question. And will you tell us more? Dr. Peder Myhre: Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Dr. Carolyn Lam: Okay, that's deep investigation. And what did they find? Dr. Peder Myhre: So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging. Dr. Carolyn Lam: Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins. And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans. Dr. Peder Myhre: Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings? Dr. Carolyn Lam: Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management. Dr. Peder Myhre: Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries. Dr. Carolyn Lam: Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications? Dr. Peder Myhre: So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis. Dr. Carolyn Lam: Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart? Dr. Peder Myhre: Oh, that's interesting. We also have some cardiology news by our own ‪Bridget Kuehn entitled "No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications." And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled "Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction" by Dr. Joseph Wu from Stanford University School of Medicine. Dr. Carolyn Lam: While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go. Dr. Greg Hundley: Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address? Dr. Petr Ostadal: According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes. Dr. Greg Hundley: Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis? Dr. Petr Ostadal: We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis. The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock. Dr. Greg Hundley: Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial? Dr. Petr Ostadal: The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm. Dr. Greg Hundley: Sounds great Petr. And then tell us and describe your study results. Dr. Petr Ostadal: The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm. Dr. Greg Hundley: Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously? Dr. Dharam Kumbhani: Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized. So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm. Dr. Petr Ostadal: Thank you for this question. The situation is maybe a littl…

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