Carolyn Lam, MBBS, PhD
Circulation April 27, 2021 Issue
Dr Carolyn Lam: Welcome to Circulation on the Run! Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we got double features today. Now, the first one's all about fruit and vegetables. Now, before you switch off, this is a very important one, okay? So, listen on. And the second is on the EMBRACE heart failure trial. Now, this was a late breaker, very important, more data on empagliflozin, that SGLT2 inhibitor. So really, really fun discussions coming right up. But first, can I dig into one of the papers that I'm really dying to tell you about? Dr. Greg Hundley: Absolutely. Dr Carolyn Lam: Okay. This is all about the diagnostic performance of high-sensitivity cardiac troponin T strategies, that super hot topic. We know that European data support the use of low high sensitivity troponin measurements or a 0/1 hour algorithm for myocardial infarction or to exclude MACE among emergency department patients with possible acute coronary syndrome. However, there's really very modest U.S. data to validate these strategies. This study today from Dr. Allen and colleagues from University of Florida, really evaluated the diagnostic performance of an initial high sensitivity cardiac troponin T measure below the limit of quantification. And that is six nanograms per liter, a 0/1 hour algorithm, and their combination with heart scores for excluding MACE in a multi-site U.S. cohort. And this is the largest prospective multi-site U.S. study of high sensitivity troponin T strategies to date. Dr. Greg Hundley: Wow, Carolyn you've really piqued my interest. So what did they find? Dr Carolyn Lam: Okay. And initial high sensitivity, cardiac troponin T below that level of quantification of six nanograms per liter was associated with a negative predictive value of 98.3% for 30-day MACE. Okay. That was that value itself. Now the 0/1 hour algorithm rolled out 57.8% of patients with a negative predictive value of 97.2% for 30-day MACE. The addition of a low-risk heart score to that initial high sensitivity troponin T level below that six nanogram per liter and the 0/1 hour algorithm improved the negative predictive value for 30-day MACE to 99% and 98.4% respectively. Dr. Greg Hundley: Wow. Carolyn, it looks like a really comprehensive analysis of the high sensitivity troponin. So tell us what are the clinical implications of this study? Dr Carolyn Lam: So these data seem to imply that when used without a risk score and initial high sensitivity troponin T below six nanograms per liter, or a 0/1 one hour algorithm, may not have sufficient sensitivity or negative predictive value to exclude 30-day MACE in the U.S emergency department patients. But the addition of that low-risk heart score to those measures improves the negative predictive value, but rolls out fewer patients. And so in totality, these results suggest that in the U.S. Emergency departments, adding a risk score to either of these strategies really increases their safety. Dr. Greg Hundley: Boy, great new information in our journal. Well, Carolyn, I'm going to switch to the world of basic science and start to evaluate in this next paper, the regulation of cellular signatures in children with dilated cardiomyopathy, and the work comes to us from Dr. Stephanie Dimmeler from Goethe University in Frankfurt. So Carolyn, Stephanie's team performed single nuclei RNA sequencing with heart tissues from six children with dilated cardiomyopathy. One was age 0.5, 1.75 and another at 5, 6, 12, and then 13 years of age. And they did this to gain insight into age and disease-related pathophysiology, pathology, and molecular fingerprints. And the goal was to gain further insight into dilated cardiomyopathy, which is a leading cause of death in children with heart failure. Dr Carolyn Lam: Cool. So what did they find Greg? Dr. Greg Hundley: Right, Carolyn. So, the number of nuclei in fibroblast clusters increased with age in dilated cardiomyopathy patients, a finding that was consistent with an age-related increase in cardiac fibrosis quantified by cardiovascular magnetic resonance imaging. Dr. Greg Hundley: Now Carolyn, fibroblast of the dilated cardiomyopathy patients over six years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans and a switch in thrombospondin isoforms and signatures for fibroblast activation. Additionally, Carolyn, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant dilated cardiomyopathy patients, but was absent in those children that were greater than six years old. And this cluster in these infants showed high expression of cell cycle activators, such cyclin D family members increased glycolytic metabolism and any oxidative genes and alterations in beta adrenergic signaling genes. Dr Carolyn Lam: Wow. That sounds like a magnificent and elegant study. Could you boil it down to the take home messages? Dr. Greg Hundley: You bet. Carolyn. Great question. So two points first, infants with a predominantly regenerative cardiomyocyte profile, may preferentially receive treatment strategies to support cardiac regeneration while patients with a pattern associable with cardiac fibrosis may benefit from an early anti-fibrotic therapy to avoid diastolic dysfunction. And second, despite the impracticality of performing these large cohort studies in children with dilated cardiomyopathies, tailored pharmacological treatment is possibly realistic. For example, based on the expression of beta adrenergic signaling genes. Dr Carolyn Lam: Oh wow. That is super cool. That's Circulation for you, publishing these amazing basic science papers with very big clinical implications. Well, I've got another basic science paper for you and this time I've learned a new word actually. It's called O-GlcNAcylation. I should get you to say it after me. I had to get our editor-in-chief Joe Hill to teach me to say that, O-GlcNAcylation. So, cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Now, in this paper, co-corresponding authors, Dr. Anderson and Umapathi from Johns Hopkins University provide a new genetic mouse model to control myocardial O-GlcNAcylation independent of pathological stress. Their data actually provided evidence that excessive O-GlcNAcylation caused cardiomyopathy, at least in part due to defective energetics. Enhanced O-GlcNAcase activity was well-tolerated. And conversely, attenuation of O-GlcNAcylation was beneficial against pressure overload induced pathological remodeling in heart failure. Dr. Greg Hundley: Interesting, Carolyn. So what are the clinical implications of these findings? Dr Carolyn Lam: Well, the data really provide new proof of concept that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy, and they also suggest that attenuation of this excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy. Dr Carolyn Lam: Shall we go on and sort of wrap up on what else is in this issue? Because I'd like to talk about highlights from the Circulation family of journals that Sarah O’Brien really beautifully summarizes, talking about everything from Circulation: Arrhythmia & Electrophysiology, to [Circulation:] Cardiovascular Quality & Outcomes. It's just a beautiful piece where we get all the highlights. Must read. There's also a Perspective piece by Dr. Gillis on Rhythm Control in Atrial Fibrillation: Is Earlier the Better?, and that discusses the EAST-AFNET 4 and early AF trials. Dr. Greg Hundley: Very good, Carolyn. Well, from the mailbox, professors Pan and Liu exchange letters regarding a prior response to a letter regarding the article Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program. Also, Dr. Arbus-Redondo has an EKG challenge entitled, Dual Chamber Pacemaker after Sinus Node Dysfunction and an Enlarged Right Atrium. Is it what it seems? Dr. Greg Hundley: And then finally, Dr. Corrado has a very nice Research Letter, entitled, Serial versus Single Cardiovascular Screening of Adolescent Athletes. Dr. Greg Hundley: Well, Carolyn, I'm dying to hear about fruits and vegetables. How about we get onto those featured discussions? Dr Carolyn Lam: Cheeky, cheeky, Greg. Here we go. Dr Carolyn Lam: Oh, I'm so excited about today's featured discussion because it's about my favorite thing, fruits and vegetables. Okay, wait a minute, everybody. Before you start rolling your eyes, this is a really important one. Have you ever asked yourself, what is the optimal intake levels of fruit and vegetables for maintaining long-term health? Well, guess what? We're about to find out and I'm so pleased to have the first author of today's feature paper, Dr. Wang Dong, and he's from Harvard medical school and Brigham Women's Hospital. We also have our Associate Editor, Dr. Mercedes Carnethon from Northwestern University and our Associate Editor who is also the editorialist to this paper, Dr. Naveed Sattar from University of Glasgow. So welcome, everyone. Dr. Wang, please tell us what you did in this study and what were your main results? Dr. Wang Dong: Thank you, Carolyn. So, basically, in this study, we analyzed the data from two long running cohort study. That is the Nurses' Health Study and Health Professional Follow-Up Study. So these two study includes more than 100,000 participants who had been followed for up to 30 years. And we also include a meta-analysis that includes in total 26 studies and about two million participant from 29 countries, and had countries around the world. So, basically, the major finding from this study is, of course, the intake of fruits, vegetable is inversely associated with the risk of death from all cause and the different kinds of cause-specific mortality. And we have a very interesting finding that is intake of about five servings per day, that can be translated into two serving of fruits and three servings of vegetables per day, was associated with the lowest risk of total mortality. So that's an optimal intake level for fruits and vegetable. Dr. Wang Dong: And another important finding from this study is, not all foods that some people consider to be fruits and vegetables can offer the same health benefits. For example, in this study, we found that starch vegetables such as peas and corn, and some fruits juice and potatoes are actually not associated with any benefit in terms of longevity. On the other hand, if you look at green living vegetables such as spinach, kale, and fruits that's orange color fruits and vegetables, that's rich in beta-carotene and vitamin C such as citrus fruits and berries, carrots they're associated with a substantial reduction in the risk of total mortality. That's a major finding from this paper. Dr Carolyn Lam: Oh, I just love it. I mean, just like such wholesome, beautiful findings from a wonderful study. Now, if I could ask you, cause I think the first thing everyone's going to say is, okay, these are associations. I mean, what'd you do about the residual risks? Could you maybe describe how you try to address some of these things like, is taking in fruits and vegetables just a surrogate for people who, I don't know, exercise more, for example? Dr. Wang Dong: Yeah. So in original data analysis, we actually have extensive data collection of all kinds of foods, lifestyle, risk factors, medication use, any health-related variables. So we carefully adjust for a large number of confounding factors. So actually another thing I want to point out, most all of these health-related lifestyle factors actually are inverse confounding factors in this kind of analysis. So when you adjust for other confounding factors, it's tend to attenuated your inverse association. So the review from confounding actually wouldn't be a major explanation for this association. Dr Carolyn Lam: Oh, that's great. And by the way, I think I misspoke. I'm not sure if I said residual confounding or residual risk just now, but you absolutely read me right, that I meant residual confounding. So thanks. Now that we've got that out of the way, if I could ask Mercedes, please. I mean, ah, another fruits and vegetables paper, I mean, what made this one different that we said we have to have it at Circulation. Dr Mercedes Carnethon: Well, thanks so much, Carolyn. And thank you Dong, for your team's outstanding work. I know what excited me about it was the demonstration of something that we have adopted into our lexicon, that one needs five fruits and vegetables. So I was excited to see you quantify it. In particular, the question I have for you is, did you see that these patterns of association of fresh fruit and vegetable intake were consistent across the age range and in both sexes? Dr. Wang Dong: Yes, of course. In total, this acts as a stratification variable. So basically, in our original data analysis, we did the analysis in the Nurses' Health Study, which all the participants are women, and in the Health Professional Follow-Up study, in which all the participants are men, would be analyzed separately and we found very consistent results in both cohorts. Then will be the meta-analysis to meta-analyze the results from these two cohorts. It comes out age, actually if you look at the paper, I think in one of the supplemental table, with the age stratified analysis, to look at the a better association if it still holds in different age group. And we did found that the results is pretty consistent in different age groups. And also, I would point out this meta-analysis provides further support to show that this results is generalizable in different people with different social economic status, demographics status also from different background. Dr Mercedes Carnethon: Thank you so much, Dong. it brings me to what Naveed wrote about in his editorial, that food is medicine and I just really loved that and loved the implications of that. So, I don't know, Naveed, if you've got some comments to make? Questions? Dr Naveed Sattar: Yeah, thanks Mercedes. No, I really love this as well because clearly the cardiovascular community, we do lots of trials. Lots of us are nihilists and just look at trials, but actually it's hard to do trials in the food and the dietary area, but these data are very consistent. I think there are multiple potential mechanisms that may explain this. We all have to eat every day, so it's a big part of our lives. Increase fiber intake, increase potassium, micronutrients, food displacement, the more fruit and veggies you eat, the less you'll eat of other things that perhaps are not as protective. And actually, part of the motivation to write an editorial was to put all that into context in terms of mechanisms. And particularly fiber, I think we underestimate the importance of fiber, but then it was also to discuss, well, if this is true, how do we help people make the changes? Dr Naveed Sattar: And at the level of policy, at the level of high risk groups, and my own particular favorite is really communicating dietary change in the clinic. And one of the things I often try, and we put this in a kind of headline figure in the editorial, was actually getting people to try to undergo the palate test or the retraining their palates. I have lots of patients, who, would you believe, in the west of Scotland, never really eat fruit and veg, and I really pushed them to say, "Look, would you please try? And it might take a few weeks for you to retrain your palate". And lots of people come back saying, "Ah, you're correct. And my God, now I like banana and I now like salad." Dr Naveed Sattar: So actually, there's lots of tips that we can do to help people increase from their average of two to three intake, which is the vast majority of population, to four to five, but it's a gradual process and it requires good communication with our patients and to compel them that these changes might take time, but that if they make these changes, they can get to a point where they really enjoy eating fruit and veg and all the multiple health benefits that come, which this paper has now showed, Mercedes. Dr Naveed Sattar: I think for me, that was the real nub of this. Dr Carolyn Lam: Naveed, I just love the way you express it. And indeed, everyone take up that editorial and look at that beautiful figure. I love the colorful fruits and vegetables on top because it also reminds us, and this paper shows, we are not talking about potato chips, and was it those, corn and peas. But, you know, we're talking about nutrition and fiber and the good stuff. Oh, this is just amazing. I wish we could go on forever, but we have a double feature this issue. And I just want to end by saying, thank you, thank you all of you, for being on the show today. It was such an important topic and I really loved the discussion as I'm sure the audience did. Thank you. Dr Mercedes Carnethon: Thank You. Dr Naveed Sattar: Thanks very much. Dr. Wang Dong: Thank you so much. Dr Carolyn Lam: I am so pleased to have with us today, a friend, a deeply admired colleague and the corresponding author of today's feature discussion, Dr. Mikhail Kosiborod from Saint Luke's Mid America Heart Institute. Dr Carolyn Lam: Welcome, Mikhail. And thank you for publishing this beautiful paper on EMBRACE heart failure with us. I know that this was presented as a late-breaking trial at the Heart Failure Society of America meeting, and it's a very much anticipated paper, but maybe I could start with it's all about SGLT2 inhibitors these days. So please tell us how does EMBRACE add to this accumulating knowledge that we have on SGLT2 inhibitors and heart failure? Dr. Mikhail Kosiborod: Well, first of all, Carolyn, thanks so much for publishing our trial in Circulation. And you're right, SGLT2 inhibitors have been taking the world of cardiometabolic medicine and heart failure by storm over the past few years. EMBRACE is a very unique trial because it really, took this world of rapidly developing technology in heart failure and heart failure monitoring, and coupled it with one of the hottest topics in heart failure today in terms of drug management, which is the advent of SGLT2 inhibitors and the emergence SGLT2 inhibitors as a efficacious therapy, not just for prevention of heart failure, but also treatment of heart failure. Because as you know, pulmonary artery pressure and hemodynamic status are one of the strongest predictors of patient outcomes, both in terms of symptoms, hospitalizations, and deaths in heart failure. And we know actually that monitoring and intervening on elevated pulmonary pressure in this patient population may lead to hospitalizations and possibly even death. Dr. Mikhail Kosiborod: But up until recently, it's been very difficult to monitor pulmonary pressures and to use them as an outcome in heart failure trials, because you will have to use invasive monitoring, essentially a right heart catheterization to get that data. Well, now we can actually have this implanted sensors like CardioMEMS, which are the sensors that we use in EMBRACE-HF trial. So, the question we wanted to ask is, we know SGLT2 inhibitors in DAPA-HF and EMPEROR-Reduced trials, clearly reduce the risk of cardiovascular death and hospitalization for heart failure, worsening heart failure, but the mechanisms have been hotly debated. Is there a possibility these agents can actually have an impact on hemodynamic status and pulmonary pressures? And that's the key central question that we tried to address and EMBRACE-HF trial by using this novel technology at the time, now it's been around for a few years, to noninvasively measure pulmonary pressures and use it as a primary outcome in our trial. Dr Carolyn Lam: Mikhail, first of all, hats off, it was a very, very clever idea to look at these patient populations who already have CardioMEMS right, and then perform this randomized trial. I mean, when I saw this, I was like, "Aw, man, how come I didn't think of that? That's just like so clever, but it's just so Mikhail to be ahead of the curve." But I'd like to remind the audience, this was a prospective randomized trial, the pre-specified outcomes, right? So maybe you could describe that in a greater detail and then the results. Yeah. Dr. Mikhail Kosiborod: Absolutely. Well, Carolyn, first of all, once again, thank you very much. You're being very kind. We do think it was a very novel clever idea and that you're absolutely correct, as this was very rigorously designed, randomized, double blind placebo controlled investigating trial within this study and 10 sites in United States. And the patients had to have heart failure, either with reduced or preserved ejection fraction, about half-and-half actually, as it turned out to be once it's all said and done with the trial. Because they had to have implanted CardioMEMS for clinical indication previously, they were quite advanced in terms of their heart failure. So more than half of the patients were in NYHA class III or IV, they had elevated brain natriuretic peptide levels, they had hybrid symptoms as you would expect. And essentially the patients were screened, and if they were eligible, randomized to use a empagliflozin-placebo in a double-blind fashion. Dr. Mikhail Kosiborod: And they were monitored actually for a couple of weeks prior to randomization to get a baseline pulmonary artery diastolic pressure. They were then treated for 12 weeks with empagliflozin, 10 milligrams a day, or a matching placebo. And we were measuring pulmonary pressure twice a day, every day for the 12 week treatment period, and then at the end of the treatment period, the treatment was stopped, but we actually continued to measure pulmonary pressure for one additional week again, twice a day, every day. So we actually saw what happened for one week after the treatment was stopped. And, as I mentioned before, the patient population was quite advanced from a heart failure standpoint. These were patients that were adequately managed with guideline-directed medical therapy for heart failure. Of course, about half of those patients have, have HFpEF. Did I mention before was the standard of care is not a thoroughly defined? Dr. Mikhail Kosiborod: And essentially what we observed was quite remarkable, which is average pulmonary artery diastolic pressure at baseline was about 22 millimeters of mercury across the patient population, and in patients treated with empagliflozin, there was quite a rapid reduction in pulmonary artery diastolic pressure that we saw almost immediately within one week as compared with placebo. And that divergence of curves in terms of pulmonary artery diastolic pressure continued over the entire 12-week treatment period. And by the end of the treatment period, there was nearly two millimeter of mercury difference in favor of empagliflozin, with lower pulmonary artery diastolic pressure in patients with empagliflozin compared with placebo. And also interestingly, even after the treatment was stopped for an additional week, those curves continued to diverge, with even greater lowering of pulmonary artery diastolic pressure in patients that received empagliflozin. So, I think to our knowledge, this is the first evidence from a randomized clinical trial, randomized double blind placebo controlled clinical trial, that SGLT2 inhibitors, in this case, empagliflozin, have essentially direct the congestion effect towards a lower pulmonary artery pressure rapidly and with effect amplified over time. Dr Carolyn Lam: Yes. Congratulations and beautifully present it there. Now, if I could ask a few more questions now, because the things will come up there. What happened to the diuretic dose? Is this depend on diuretic dose? Are there any subgroups that appeared to benefit more? Dr. Mikhail Kosiborod: No, excellent question, Carolyn. So first of all, we monitored average daily furosemide equivalent dose continuously throughout the trial, and what we observed was that there was no difference in diuretic dose, essentially, between the two groups from a loop diuretic management standpoint. Now, remember this patients are getting frequent pulmonary pressures with diuretics being adjusted all the time. But if you look at what happens over time, that's one of the figures in the paper you see essentially the flat lines in both groups. And coupling that with the fact that pulmonary pressures continue to diverge for another week after the treatment was stopped, at least in my mind, suggests that this hemodynamic benefits as we observed with empagliflozin as compared with placebo was lowering of pulmonary pressures is likely not simply due to diuretic effect. It just cannot be explained only by diuretic effect. I think these findings are very much in line with the analysis that we had in DAPA-HF trial with the analysis that recently were published from EMPEROR-Reduced, showing that you just can't explain what you see with heart failure benefits with SGLT2 inhibitors simply by diuresis. Dr Carolyn Lam: Fascinating. Well, how about the question of diabetes? Dr. Mikhail Kosiborod: Yes. So in terms of subgroups, that you mentioned, we did do subgroup analysis. Now I will say that the subgroup analysis have to be interpreted with a great deal of caution in this trial, because the entire trial had about 65 patients, so it's a small trial. It was really powered to look at the entire patient population and look at the primary end point of the diastolic pressure. Nevertheless, as I mentioned before, we had half-and-half reduced and preserved EF and we did not see a statistically significant heterogeneity in the treatment effect when we look at patients with reduced to preserved EF, so that hopefully both for outcome trials in preserved EF heart failure, we'll see, of course, what happens with that. And in terms of diabetes we saw a bit greater effect in patients with diabetes as compared to patients without diabetes, in terms of pulmonary artery pressure reduction. Dr. Mikhail Kosiborod: But again, I would just strongly caution interpretation of those subgroups because certainly when we look at clinical outcomes in those DAPA-HF and EMPEROR-Reduced, we see no such difference. We see that the benefits, right, the hard clinical outcomes, benefits, are quite consistent regardless of diabetes status. I will say one other thing, which I think is really important. If you look at the pulmonary artery pressure trajectory in patients treated with placebo in EMBRACE-HF, you see that they actually go up over time. And this is in patients that have frequent monitoring of blood pressures, our own guideline-directed medical therapy are closely watched by predominantly heart failure cardiologists and their teams to make sure that they're well-managed. And despite that, you see this increase in pulmonary pressure over time, and that's just another reminder to us that heart failure is a progressive disease despite best available therapy. Dr. Mikhail Kosiborod: These patients deteriorate over time, which is why treatment, novel advancements, treatments like SGLT2 inhibitors and their effective implementation is just so important because we know the benefits occur very early. We saw one week here, when we start seeing separation of curves, certainly see a significant difference by 12 weeks with pulmonary pressure. But of course we know with clinical outcomes, we see within a few weeks of randomization, already a significant benefit in reducing CV death and hospitalization for heart failure, both in DAPA-HF and EMPEROR-Reduced trials. So I think that's a critical point for clinicians to keep in mind at the time of the death. Dr Carolyn Lam: Mikhail, those are just such important and practical take-home messages. Thank you again. In the last minute though, I just really, really have to go back to that very clever method. Could I just pick your brain? I mean, it's like a very clever population. This CardioMEMS population that maybe what's in the future plans? Give us a sneak peek! Dr. Mikhail Kosiborod: Well, Carolyn, very insightful as always. I really think of it as a novel platform for drug development and heart failure. I think this is the proof of concept. This is really the first time we did something in the heart failure space was with monitoring of pulmonary pressures that shows that drugs that work for hard clinical outcomes actually do something meaningful on hemodynamics. We've struggled for such a long time in heart failure to have a good surrogate endpoints that would be reflective of clinical outcomes. This may be it. It may be one of them. And I think EMBRACE-HF is a good concept proving study that can say, if you have a compound and you think that compound may be effective for heart failure. So of course the congestion is so important that we know correlates so well with clinical outcomes Dr. Mikhail Kosiborod: When we started to trial all the way back to late 2015, very few patients had this device. It's not lots of patients have this device. And testing novel treatments to try to understand will there promise in heart failure, and even making go-no-go decisions, in terms of drug development, I think is starting to become a potential future development, which we should at least seriously consider in the heart failure space. Dr Carolyn Lam: Wow, Bravo. And Mikhail, I mean. Okay, audience, listen, you heard it right here. This is amazing. Thank you once again for publishing with us and congratulations on the beautiful paper. Dr Carolyn Lam: And from Greg and I, thank you audience for joining us again today, you've been listening to Circulation on the run. Tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021.
Duration: 31 min