Dan Simon (Host): Hello, everyone. This is Your Science at UH host, Dr. Dan Simon. Today, I am here with our guest, Dr. Varun Sundaram, heart failure cardiologist at University Hospitals' Harrington Heart and Vascular Institute, the Deputy Director of the Health Services Research Center at University Hospitals and the Section Chief of Advanced Heart Failure at the Louis Stokes Cleveland Veterans Affairs Medical Center. Varun is also an Associate Professor at Case Western Reserve University School of Medicine. Welcome, Varun.

Varun Sundaram: Thank you, Dr. Simon. Pleasure to be here with you.

Host: So Varun, you've trained and worked across India, completed your residency and fellowship here with us at UH. Then, you went to the United Kingdom and ultimately returned to the U.S. as faculty at UH Cleveland Medical Center. Can you walk us through this journey, how you traversed this incredibly interesting path? We're so lucky to have had you come here. And what drew you to heart failure in general?

Varun Sundaram: So, I grew up in the southern part of India. And my father was an Internal Medicine doctor. So, he ran a small hospital and our house was in the same campus just behind the hospital. So, this setting kind of shaped my childhood where we would constantly see patients, sometimes even for help walking to our house and regular hospital intercoms in our home always going off throughout the day. That was part of our daily life as kids. And my older brother, who's five years older than me, also ended up becoming a physician. So honestly, I never thought of anything beyond medicine growing up. That kind of drew me to medicine.

And while in medical school, I was lucky to work with a nephrologist named Dr. Georgi Abraham, who had just moved back from Canada after a very successful academic stint. And he was the first one who introduced me to research. And he then sent me to Boston to work with Ajay Singh as a research fellow in Nephrology. And he actually opened up the doors for me in the U.S. And then, I moved to UH for residency and fellowship.

So when I started residency, I thought Nephrology was a natural choice because that's all what I knew. It was actually my brother who actually-- I don't know whether he brainwashed me or kind of like somewhat said that Cardiology is the way to go, and it'll be a great fit for me. And then, somewhat actually that was kind of like very pivotal in my switch to Cardiology somewhat. I had a subconscious hit, I think, after that. And while I got exposed to Cardiology in medical school from fantastic professors, especially namely one professor called Dr. _____ who would teach all medical students after 9:00 PM at night after a busy day of clinical schedule. I'm very grateful for that, for instilling interest in Cardiology.

What really happened was when I was in CICU during residency, and that was when I really got a hang of Cardiology and the hemodynamics, acuity and pace of it, you know, it was very gratifying. And when I started Cardiology, I mean, you were the chief then, and I thought I was going to be an interventional cardiologist. But your close colleague and friend, Dr. James Fang, when I worked with him, really actually that's when I got exposed to Heart Failure Cardiology first. And really, I thought that was the thing which I was most interested in. And until then, I was not really exposed to research in Cardiology.

But when I was a fellow and staffing a patient with an EP attending here, Dr. Jay Sahadevan, where there was a patient who was referred for CRT, and he had a cardiac resynchronization therapy, kind of a very wide QRS duration of 200 milliseconds. And I confidently told him, "Yeah, he should get a cardiac resynchronization therapy." And then he said, "Are you really sure?" And he brought up saying, "While trials had enrolled patients with greater than 150 milliseconds, they had not enrolled patients with very wide QRS and there's mechanistic reasons to believe that they may not benefit." That was actually the start of my true research interest in Cardiology. And then, the department was very supportive. And with the help, mentorship of late Dr. Waldo and Jay, I actually started doing research in General Cardiology. And I'm in my third year of research here, we get dedicated time as General Cardiology fellows of around six to eight months. I ended up spending time in Epidemiology and Biostatistics in the Harvard Training Program. But still, I was not sure whether research was my calling.

So, I went to the American Heart Association meeting to present as a fellow, and that's where I met with Professor John Cleland from U.K. who did the first CRT trial in heart failure and beta-blocker trials. After a long conversation, he just told, "Why don't you come? And then, we could work together." And that was a reason right after fellowship I ended up moving there. And I started as a clinical fellow in heart failure in England, then ended up doing PhD in Epidemiology. Subsequently, clinical trials, a methodology training. And then, once I got my first NIH grant, I moved back. And thanks to you, I stayed as a faculty during the time in UH, which really helped me to apply for NIH grants as a faculty here. And then, I moved back to UH. So, there are many people who have helped along the way. From India to Boston, Boston to Cleveland, Cleveland to London, and back to Cleveland. And each step and everyone has really been instrumental in kind of like shaping my interest or how I approach, say, even life in general and how I treat patients and how I approach clinical research in heart failure.

Host: Well, you know, Varun, it's so inspiring to hear your story. There are a couple of things that really stand out. One is how brave you were to leave India as a trainee and to really strike out an incredible journey, obviously, of going to Boston, but then coming here. And imagine how proud I am of you as one of your mentors, because you started as a resident. And now, you're a rockstar giving light-breaking clinical trials at international meetings. And so, we're going to get to that in a second. But it's really great to see your evolution over the past five to ten years, really amazing.

So, you have this interest in global heart failure epidemiology. And you've examined heart failure really across countries, how they're different between HFpEF and HFrEF and things like that. Could you give us some key insights from what you've learned about international differences in heart failure?

Varun Sundaram: Thank you again. And I think I'm lucky to be in a position to really understand that was a problem. And again, at that time, I had a unique opportunity to be in England and in Cleveland at the same time where I would be coming and going. So, what was striking to me-- as I mentioned earlier, I was a trainee in advanced heart failure in Royal Brompton and Harefield Hospital when I first moved-- is I would see heart failure patients in London, and then eventually take a flight here and come here and see patients in _____, same patients, same pathophysiology, but how differently they were managed. Strikingly different, right? From thresholds for admission to how they've been managed in the hospital and how they've been discharged, thresholds for discharge, procedural utilization, and the post followup care. So, this was across the Atlantic. I mean, it was striking difference to me for the same group of patients.

And around this time is when in the field of heart failure, we had a fallout in one of the major clinical trials called TOPCAT trial, which you know very well investigated the role of spironolactone in heart failure with preserved ejection fraction. And there were no treatments for heart failure with preserved ejection fraction until then.

What happened is the trial was overall neutral. But then, when a subgroup analysis, though hypothesis-generating, found that the patients in the U.S. had a much lower hazard that is reduction in heart failure hospitalization compared to patients who are randomized in Georgia and in Russia, showing a geographic differences in outcomes. It could be for many reasons. But this is something which was very striking, showing differing event rates, how patients are managed. All of this were different across countries.

And at that time, in England, I had a Cardiology trainee. I mean, he was a cardiologist in Japan, actually, Director of Cath Lab who was moving to heart failure and was from National Cerebral and Cardiovascular Central in Osaka. He was working with me with John Cleland. And he was telling me how differently they manage heart failure patients in Japan. So, all my clinical experiences across the Atlantic, both in the U.S. and U.K. simultaneously coming back and forth and the conversations with people from rest of the world, and the TOPCAT trial actually laid the foundation for my PhD work in Heart Failure Epidemiology, where first is we built a data science infrastructure of nationally representative samples-- not selected cohort, unselected cohort using electronic health records data from U.S., U.K., Taiwan, and Japan. It took a lot of time to go through data privacy regulations, but we got more than a hundred million patients of EHR data. And we developed harmonized data that is including similar diagnostic procedure codes and analytical pipeline so that we could compare apples versus apples across all these countries that is developed countries across three different continents and studied what the threshold for heart failure hospitalization is, how these heart failure patients are differing, how they were managed, and how different the outcomes were. And that was the basis for my global heart failure epidemiology work. And what we found was something which was really striking.

So, we think that we do way more procedures in the U.S. The results actually vary. Among patients who are hospitalized for heart failure on an average nationally, only 0.2% of patients in the U.K. had right heart catheterizations. It was 4% in the U.S, but 18% in Japan. They were getting every patient-- even at the repeated admissions-- they were getting right heart catheterizations. And one in five patients in Japan by getting coronary angiograms, regardless of what the prior status was. And the length of hospital stay, actually, U.S. had the shortest length of hospital stay, four days compared to Japan had 12 days. And this translated into difference in outcomes. And this was a big learning experience for us in the heart failure group. And we had many discussions over the years in this.

While we think the difference in event rates in trials do happen, we assume that it's all related to biology or treatment effects. It may not necessarily be, and that's what TOPCAT taught us. Despite effective randomization, there could be many reasons for difference in event rates. And in heart failure trials, we use time to first heart failure hospitalization as the outcome. The threshold is very different in each country. We learned it in Japan. They just admit people. The threshold is very different than what it is in the U.S. compared to what it is in the U.K. And when you use length of hospital stay, it's very different for different reasons as opposed to treatment effects. So, this has to be incorporated into the conduct of clinical trials and something that you really learned from the study. And it also formed the basis of my next formal training in clinical trials methodology, moving from epi to clinical trials. It's just formed the basis of how I operate in clinical research now.

Host: Let's shift gears for a moment to your hot research. You can't turn on the television without seeing commercials for Ozempic, Wegovy or Zepbound and Mounjaro, and you've had these explosive presentations about GLP-1 and GIP receptor agonists in patients, both in the atrial fibrillation space and in heart failure. So, tell us a little bit about how do these agents affect heart failure and atrial fibrillation.

Varun Sundaram: Yes. As you rightly pointed out, GLP is there in every news channel now. So, it's not just for obesity reasons, but being the cardiology group, we have been quite interested in the cardiometabolic space and especially me in terms of heart failure more so.

So, the first evidence, of course, in the field of heart failure came in patients with obesity-related heart failure with preserved ejection fraction, showing improvement in quality of life with the use of GLP-1 receptor agonist. But I do think there is an issue in the methodology and how we would interpret the results. Because in my opinion, it'll be extremely difficult. I've had this talk, you know, communication many times with the investigators of the trials. It's extremely difficult to effectively blind the GLP-1 trial.

So because patients know they're losing weight, some of them develop nausea, physicians know their own patients are losing weight, to give effective double blinding is very hard. And it becomes extremely important when we are measuring subjective outcomes like quality of life. And that's what the early trials of GLP-1 and obesity-related HFpEF actually studied, was quality of life. And the trials were not powered to assess heart outcomes, including heart failure hospitalization and mortality. And that's the knowledge gap which we try to address in the field, in the HFpEF space, where with pharmacoepidemiology approaches powered for heart failure hospitalization and mortality, and showed that there was a meaningful reduction in heart failure hospitalization and mortality, complementing the trial evidence on quality of life and some of the trials which are underpowered for heart failure hospitalization. That's in the HFpEF space.

But what is more important, what we think is in the heart failure with reduced ejection fraction, especially in advanced heart failure. So while we've been having GLP-1 and GIP trials in every field in medicine, this is one space where we have very limited evidence. And it's extremely important. What we believe is for the following reasons is early small trials, two trials in heart failure with ejection fraction, showed an increased signal towards mortality, heart failure hospitalization, and ventricular arrhythmias with GLP-1 receptor agonists.

The limitations of the study being they enroll both obese and non-obese population. So, it was not purely obese. And I think we were one of the largest recruiters for the trial when I was a fellow. The LIVE trial, I think, the previous heart failure director, Guilherme Oliveira, was actually the leading recruiter for the trial we had, and I was a fellow then. So, I remember that very well in 2013, 2012. And when you were the chief here and so we would be cathing many times during fellowship together.

 So, what it showed was a 46% increase in ventricular arrhythmia's heart failure hospitalization, and a signal towards mortality. And the mechanistic reasons is the cyclic mediated, AMP-mediated increase in heart rate. We give beta-blockers to reduce heart rate and reduce myocardial oxygen consumption, but GLP-1 kind of does the opposite and there's a dose-respose relationship.

So, this area has not been studied, with two trials showing signal of harm, and that's an area which we try to address, again using pharmacoepidemiology approach where we showed that it is safe at diabetes management doses. We don't know about obesity-related doses where you need randomized evidence that is safe in patients with clinically severe heart failure, and that's the one which we presented as a late breaker recently at the ESC meeting. But I think in HFrEF, we need more randomized trials at weight loss doses to address this critical need. Because many patients with heart failure and reduced ejection fraction have been prescribed with GLP-1 receptor agonists for diabetes and obesity reasons. So, we need to know if it's safe to do so, not just whether modifying obesity would improve heart failure outcomes from the efficacy standpoint. But it's very important because these medications are going to be used left and right in the community, and we have to know if it is safe to do it in the HFrEF space.

Host: So, one of the questions, I think, that's come up is that obesity is one of the main risk factors for HFpEF, right? There's no question about it. And that I think coupled with age are two of the big ones. What do you think the mechanism is of benefit in HFpEF? Do you think there are actual receptors within the heart that are active, or do you think this is all secondary to weight loss?

Varun Sundaram: So, that's a great question. Actually, the honest answer to that is we really don't know, but we can postulate from the trials. So, one of the criticisms, which, you know, in fact I asked at the late breaker session when the STEP-HFpEF trial was presented was the heart failure hospitalization rate was very low in the study population to 1.5-2%. That's like a primary prevention trial, so not truly heart failure trial. But what was interesting was that quality of life improvement, the Kansas City Cardiomyopathy Questionnaire Improvement, was almost eight points, which is like more than we have ever observed in any heart failure trial. We give SGLT2 inhibitors and Entresto does it to two to three points, so sacubitril. This is very high.

So, the question was whether was this improvement in quality of life related to modifying heart failure or were they related to modifying obesity? And as I mentioned earlier, it's very hard to blind this trial because patients and physicians know that they're losing weight and the intolerance, patients would know. They're reading everywhere, saying GLP can cause nausea, indigestion, all of it. So, the blinding becomes an issue. So which one of these two causes?

So, the thing is, because of the large effect size. I do think it was related to obesity, weight loss, but also what we observed was reduction in BNP. So, that actually supports that It is also mediated by modifying heart failure. And there are two proposed mechanisms. One mechanism is we have a pseudoconstriction physiology in patients with obesity-related HFpEF, where the epicardial fat actually causes some level of pericardial restraint. And the postdoc analysis from the most recent published SUMMIT trial showed reduction in epicardial adiposity, and it was a dose-respose relationship.

And the next thing is reduction in total body water. So because a total body water is 0.6 times that total body weight, so just reducing weight reduces the total body water. So, these are two proposed mechanisms from the heart failure standpoint. But to your question, we don't know if it's mediated by both. In terms of obesity related HFpEF, I don't think we can pinpoint that. It's only from heart failure, which some investigators do. But because of issues with blinding, I don't think we can definitively say that.

Host: Okay. Final question for you about your present late breakers. So, how do GLP-1s modulate the incidence of atrial fibrillation?

Varun Sundaram: Yeah. So, GLP-1 obesity-- so 50% of patients who undergo AF ablation in the United States are obese, be it with a body mass index of greater than 30. And despite advances in ablation techniques, one-third of them have recurrence within a year of ablation. So if we look, the average age of ablation is around 60 years. And the life expectancy is exceeding beyond 80 years. So, most of these patients are likely to survive for two decades post ablation. That means the need for recurrent procedures or repeat procedure is very high. So, we have to complement ablation techniques, not to replace ablation techniques.

And one mechanism, which is a driver of progressive atrial substrate remodeling, has been shown to be uncontrolled obesity. And GLP-1 presents a very promising. The problem now doing a complete randomized trial is ethical challenges, because we have to take patients with AF and obesity and randomize them to control group with prolonged non-exposure to GLP-1. I think we've missed the boat. So, it is just not because you have to do a trial with a longer period of time because you're modifying a risk factor, so it can be a shorter trial. And longer period, denying them GLP-1 with a body mass index of greater than 30. So again, this is one area where we use pharmacoepidemiology methods and big data to answer this question where we showed a 17 reduction in heart AF-related events, not just time of repeat cardiovascular ablation and hospitalization of the primary diagnosis of AF. And that's only evidence what we have in AF in GLP space. So, we believe that in patients who are going for ablations. We should use obesity as an indication to treat them with GLP-1 to reduce the recurrence of atrial fibrillation in this patient population. And that's another area of therapeutics in cardiometabolic space.

Host: Okay, Varun. So, looking forward in the next two to three years, what's the hot area for you? What's your new frontier?

Varun Sundaram: So, in the next two years, we hope to complete three projects. The first one is we've been funded by AHA to study more-- the American Heart Association-- to advance our work on GLP-1 receptor agonist and advanced heart failure. So, we're working with the Chair of Computer Science at Case to do in silico trial modeling to answer this question using electronic health records data here at UH. And that's one thing which we're looking at and where traditional trials are very difficult to do.

Then, the next thing is we are doing an investigator initiated randomized trial looking at the role of probenecid, a gout drug in heart failure with reduced ejection fraction. Preclinical studies have shown improvement in myocardial contractility, so proof of concept trial. We are looking at reduction in ventricular volumes.

And finally, we are revisiting the role, which we've been working for last almost 15 years since our fellowship to generate evidence, is to revisit the role of ICDs for primary prevention in heart failure with reduced ejection fraction at the background of modern medical therapy. This is because of declining rates of sudden cardiac death with modern medical therapy. Do we really need ICDs for everyone, especially those with non-ischemic heart failure?

Host: Well, Varun, I got tell you, I'm just absolutely impressed with your development. You are a model of the path from trainee to advanced fellow to an independent and bifurcated scientist who's now an associate professor and on their way to professor, and I couldn't be more proud of you. I'm so glad that we had the opportunity to talk today and that people could see what a leader you are in this very interesting global research space.

To learn more about research at University Hospitals, please visit uhhospitals.org/uhresearch. Thank you, Varun.

Varun Sundaram: Thank you so much, Dr. Simon, for all the mentorship for all these years and the ongoing support. Thank you.