Circulation on the Run

Circulation December 28, 2021 Special

Circulation December 21, 2021 Issue

Circulation December 14, 2021 Issue

Circulation December 7, 2021 Issue

Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS 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. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial? Dr. Greg Hundley: Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there? Dr. Carolyn Lam: The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina. Dr. Greg Hundley: Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research? Dr. Carolyn Lam: Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function. Dr. Greg Hundley: Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that. Dr. Carolyn Lam: No, we don't (laughs). Dr. Greg Hundley: Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome? Dr. Carolyn Lam: Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs). Dr. Greg Hundley: Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification- Dr. Carolyn Lam: (laughing) Dr. Greg Hundley: Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. Dr. Carolyn Lam: Wow, you've really, really piqued my interest. So what did these investigators do and what did they find? Dr. Greg Hundley: Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types. Dr. Greg Hundley: Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Wow, just fascinating, but, okay. What is the clinical take home message? Dr. Greg Hundley: Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results. Dr. Greg Hundley: Oh wow, Carolyn, I can't wait. So tell us about this novel methodology. Dr. Carolyn Lam: Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat? Dr. Greg Hundley: Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods? Dr. Carolyn Lam: A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool? Dr. Greg Hundley: Absolutely, Carolyn. Beautifully explained. Dr. Carolyn Lam: Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom. Dr. Greg Hundley: Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address? Dr. Cecilia Bahit: Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke. Dr. Greg Hundley: Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population. Dr. Cecilia Bahit: So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation. Dr. Greg Hundley: Very good. And what were your results? Dr. Cecilia Bahit: So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation. Dr. Cecilia Bahit: So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small. Dr. Greg Hundley: Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk. Dr. Graeme Hankey: Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy. Dr. Graeme Hankey: And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up. Dr. Graeme Hankey: And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin. Dr. Greg Hundley: Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research? Dr. Cecilia Bahit: Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area. Dr. Greg Hundley: Very nice. And Graeae, what are your thoughts? Dr. Graeme Hankey: Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities. Dr. Graeme Hankey: Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation. Dr. Greg Hundley: Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event. Dr. Greg Hundley: Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Circulation November 30, 2021 Issue

Circulation November 23, 2021 Issue

Circulation November 16, 2021 Issue

Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.” Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first? Dr. Carolyn Lam:             I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not? Dr. Greg Hundley:           Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us? Dr. Carolyn Lam:             Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet. Dr. Greg Hundley:           Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease. Dr. Carolyn Lam:             Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke. Dr. Carolyn Lam:             Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute. Dr. Greg Hundley:           Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find? Dr. Carolyn Lam:             The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.” Dr. Greg Hundley:           And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease. Dr. Carolyn Lam:             Yay. Let's go, Greg. Dr. Greg Hundley:           Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Maria Nunes:             Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy. Dr. Greg Hundley:           Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study. Dr. Maria Nunes:             We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease’s screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers. Dr. Greg Hundley:           Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long? Dr. Maria Nunes:             Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019. Dr. Greg Hundley:           Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results? Dr. Maria Nunes:             We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too. Dr. Greg Hundley:           Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women? Dr. Maria Nunes:             Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages. Dr. Greg Hundley:           And your results confirmed what was previously known in that regard. Dr. Maria Nunez:             Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking. Dr. Greg Hundley:           Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described? Dr. Ntobeko Ntusi:          Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field. Dr. Greg Hundley:           Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation? Dr. Ntobeko Ntusi:          Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels. In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world. Dr. Greg Hundley:           Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research? Dr. Maria Nunes:             We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup. Dr. Greg Hundley:           Very good. And Ntobeko, anything to add? Dr. Ntobeko Ntusi:          Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story. Dr. Greg Hundley:           Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation November 9, 2021 Issue

Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter 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 in Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this? Dr. Carolyn Lam: I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo. Dr. Carolyn Lam: Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome. Dr. Greg Hundley: Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find? Dr. Carolyn Lam: Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients. Dr. Carolyn Lam: Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction. Dr. Greg Hundley: Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury. Dr. Carolyn Lam: Oh, very interesting. What were the results? Dr. Greg Hundley: Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury. Dr. Carolyn Lam: Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.   Dr. Greg Hundley: Very interesting, Carolyn. What did they find here? Dr. Carolyn Lam: IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University. Dr. Greg Hundley: Very nice, Carolyn. Dr. Carolyn Lam: Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis. Dr. Greg Hundley: Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction. Dr. Carolyn Lam: Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results. Dr. Ole Fröbert: Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease. Dr. Ole Fröbert: The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial. Dr. Ole Fröbert: Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI. Dr. Carolyn Lam: Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because- Dr. Ole Fröbert: Yes, this was- Dr. Carolyn Lam: That's amazing. Dr. Ole Fröbert: ... an idea that just popped up, and then yeah, we did it, but it was seven years of work. Dr. Carolyn Lam: Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out? Dr. Dharam Kumbhani: Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time. Dr. Ole Fröbert: Thank you very much. Dr. Dharam Kumbhani: Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines? Dr. Ole Fröbert: Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist. Dr. Dharam Kumbhani: Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients. Dr. Ole Fröbert: I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it. Dr. Carolyn Lam: Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise? Dr. Ole Fröbert: There is influenza seasons in all parts of the world, I'm sorry. Dr. Carolyn Lam: True. Dr. Ole Fröbert: For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study. Dr. Carolyn Lam: Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit? Dr. Ole Fröbert: Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups. Dr. Carolyn Lam: Thank you. Dharam, any final responses to that? Dr. Dharam Kumbhani: No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.   Dr. Carolyn Lam: I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

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

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Circulation on the Run

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