Sep 20, 2021
This week's episode features author Benjamin Levine and Guest Editor Walter Paulus as they discuss the article "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage-B HFpEF."
Dr. Greg Hundley:
Well, welcome listeners. This is the September 21st podcast for Circulation on the Run. Sadly, I'm without Carolyn today, but I am your host today, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Our feature discussion today is really interesting. It's from Dr. Ben Levine, and he's evaluating the utility of exercise training and actually trying to reverse abnormal left ventricular myocardial stiffness in individuals that have stage B, it's a very early heart failure and preserved ejection fraction. But before we get to that, let's grab a cup of coffee and we're going to work through some of the other articles in this issue.
Dr. Greg Hundley:
So the first one comes to us from Göran Bergström from University of Gothenburg in Sweden. He and his team used coronary computed tomography angiography or CCTA to determine the prevalence, severity and characteristics of coronary atherosclerosis and its association to coronary artery calcification scores in a general population of greater than 25,000 individuals all aged 50 to 64 years and without known coronary heart disease. It really comes to us from the Swedish CArdioPulmonary BioImage Study or SCAPIS. Well, Carolyn would ask me that is a really large study, and what did they find? Well, let's get to the results.
Dr. Greg Hundley:
So using CCTA to detect silent coronary atherosclerosis, the investigators showed that any coronary atherosclerosis was actually quite common, 42% of individuals and significant stenosis of greater than 50% was less common, only 5% of individuals. More severe forms were rarely found, only 1.9% in this very large, random sample of middle-aged individuals.
Dr. Greg Hundley:
Now disease onset was delayed by 10 years in women and a higher prevalence of coronary atherosclerosis was observed with higher age and accumulation of risk factors. Interestingly, CCTA detected atherosclerosis increased with an increasing coronary artery calcium score. All those with a high CAC score of greater than 400 had atherosclerosis and 45% had significant stenosis. 5.5% of those with no coronary artery calcification had atherosclerosis and 0.4% had significant stenosis. So although there was a strong association with high coronary artery calcium scores and significant stenosis, atherosclerosis was not excluded in those with zero coronary artery calcification especially in those with high baseline risk.
Dr. Greg Hundley:
Well, our second article comes to us from the world of preclinical science and it's from Dr. Nathan Palpant from the University of Queensland. So the article pertains to ischemia reperfusion injury, and it's one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Now during cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6 to 6.5, and the resulting tissue acidosis exacerbates ischemia injury and significantly impacts cardiac function.
Dr. Greg Hundley:
So the authors today use genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a or ASIC1a, we'll call it from now, in cardiac ischemia reperfusion injury at the cellular and whole organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of ischemia reperfusion injury were used to test the efficacy of ASIC1a inhibitors as pre-imposed conditioning therapeutic agents.
Dr. Greg Hundley:
So what did the authors find in this study? Well, they demonstrated for the first time that acid-sensing ion channel 1a or that ASIC1a mediates cardiac ischemia reperfusion injury. The authors identify that ASIC1a inhibition is a novel therapeutic strategy for preventing acute injury response to myocardial ischemia reperfusion injury.
Dr. Greg Hundley:
So what are the clinical implications of this research? Well, first there are currently no drugs in clinical use that prevent acute injury response to myocardial ischemia, despite many promising candidates identified over decades of research, all of which ultimately failed in subsequent clinical trials. Second, the identification of new therapeutic targets for preventing the injury response to myocardial ischemia reperfusion injury would therefore have profound implications in cardiovascular medicine. Therefore, the results of this study reveal that ASIC1a inhibiting drugs, they're safe and they have potential applications in heart transplant and myocardial infarction with potential use in other clinical scenarios where myocardial ischemia reperfusion injury is a risk such as those that undergo cardiac surgery.
Dr. Greg Hundley:
Well, our next article comes from Robin Choudhury from the University of Oxford. Have you ever wondered why cardiovascular risk and diabetes remains elevated despite glucose-lowering therapies? Well, these authors hypothesized that trained immunity in response to elevated glucose accounts for diabetic hyperglycemic "memory", we'll call it, in relation to atherosclerosis. So accordingly, the author sought to determine if hyperglycemia-induced disease relevant changes in monocyte and macrophage function and whether these changes persisted after restoration of normal glucose, thereby implying fundamental reprogramming. So the team combined studies of cellular function, metabolomics, transcriptomics and epigenomics to define how hyperglycemia altered metabolism to modulate long-term activation through epigenetic modifications.
Dr. Greg Hundley:
Well, what did they find? First, hyperglycemia induced a trained immunity in bone marrow progenitor cells by inducing persistent epigenetic modifications. Second, hyperglycemia-induced trained immunity persisted after differentiation into those macrophages. Finally, hematopoetic stem cells transplanted from mice with diabetes to euglycemic mice promoted exaggerated atherosclerosis. So therefore, the findings of this study may explain the resistance of macrovascular complications of diabetes to conventional glucose-lowering treatments.
Dr. Greg Hundley:
Well, in the mailbag this week, there are some other articles. Professor Huang has a Research Letter entitled, “Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.” Dr. De Caterina has an In Depth article on coronary artery anomalies. Finally, Professor Merid has a Perspective piece entitled, “Digital Redlining and Cardiovascular Innovation.”
Dr. Greg Hundley:
Well, listeners, what a great group of articles, and now we're going to turn to that feature discussion with Dr. Ben Levine.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today and we're very fortunate. We have with us, Dr. Ben Levine from UT Southwestern in Dallas, Texas and also Dr. Walter Paulus from Amsterdam. Welcome gentlemen.
Dr. Greg Hundley:
Ben, we'd like to start with you. Could you describe for us a little bit of the background related to your study and what was the hypothesis that you wanted to test?
Professor Benjamin Levine:
Sure. Oh, nice to talk with you, Greg. As you know, our lab has been very interested in the effects of both aging and physical activity on cardiac mechanics. To cut a very long story short, what we know is that sedentary aging leads to stiffening of the heart. We also know that HFpEF, heart failure with preserved ejection fraction, is a disorder predominantly of the aged. I don't know about you, Walter, but I've never seen any lead masters athlete HFpEF.
Professor Benjamin Levine:
What we've shown is that if you regularly exercise over a lifetime that the heart can preserve its youthful compliance and flexibility. But if you wait until somebody is older, meaning over 65, 70, regardless of how hard or intense we train, the heart seems to lose its plasticity. It can't actually get that much better. But if we start in late middle age, it turns out that you can actually reverse some of the adverse effects of sedentary aging. So we said, "Okay, we know what the dose is, how much exercise you need to do. We know what the sweet spot in time. Now how do we find those people who are most likely to go on to develop HFpEF in whom getting them on a regular exercise program might help forestall this very challenging syndrome."
Professor Benjamin Levine:
So as part of an AHA-funded strategically focused research network and prevention, we identified a group of patients who had left ventricular hypertrophy, but evidence that they were on the wrong path. Their biomarkers were elevated. They have an elevated NT-BNP or a high sensitivity troponin. We did a right heart catheterization and we looked at their cardiac stiffness using a technique that we've done now for the past 25 years or so, and showed that indeed those patients' hearts are clearly stiffer than healthy, but otherwise sedentary middle-aged individuals.
Professor Benjamin Levine:
So our key question was what happens if we put them on a long sustained high intensity exercise program? Can we reverse the effects of sedentary aging superimposed with hypertension, left ventricle hypertrophy and elevated biomarkers?
Dr. Greg Hundley:
Really interesting, Ben. So describe your study design for us. How are you going to set up? It sounds like a very elaborate experimental setup here. Then also, maybe just define for us your study population. Did you have men and women or-
Professor Benjamin Levine:
Yeah, we started by going to the Dallas Heart Study. We're blessed here in Dallas by having this room access to our remarkable population where we know a lot about them. So we picked people in late middle age of all races, both sexes, and we reached out to the members of the Dallas Heart Study if they had left ventricular hypertrophy by echo or MRI and were of the right age range. We enriched that database by going to an EKG database and looking at the Ecolab database, trying to find people who did not have heart disease already. That was important. They couldn't have had a heart attack. They couldn't have had heart failure. They couldn't have had infiltrative disease. They had to be generally healthy except had left ventricular hypertrophy.
Professor Benjamin Levine:
We screened a lot of patients to get there, I have to acknowledge that, almost 4,000 of them or so to get the small number who were interested in doing a one-year exercise training program. But as we eventually got a good solid number that because we use such high resolution techniques, we were able to define the key outcome variable, which is cardiac stiffness.
Professor Benjamin Levine:
Briefly in our lab, we put a right heart catheter in to measure wedge pressure. We use 3D-echo to measure volume and then we use something called lower body negative pressure to unload the heart. It's almost like standing up progressively or tilting upright and then we give them a rapid saline infusion, 200 mls a minute. So a lot of saline, 15 and 30 mls/kg. We can get the left atrial pressure from about three or four up until about 18 to 20 and define the entire physiologic range of left ventricular filling. We look not just at the wedge pressure of course, but the transmural pressure.
Professor Benjamin Levine:
John Tyberg and his colleagues in Canada have shown clearly that the pericardial pressure is pretty close to right atrial pressure. So transmural pressure, which is the distending pressure of the heart, is left atrial minus right atrial pressure. We use that as the input into a pressure volume relationship.
Dr. Greg Hundley:
Very nice, and then what did you find?
Professor Benjamin Levine:
Well, what we found is after demonstrating that these patients with LVH and elevated biomarkers have increased stiffness, what we found quite remarkably actually was that we were able to reverse that by a year of training.
Professor Benjamin Levine:
Now when I say training, I mean, we do use the optimal approach to training that we've demonstrated in our lab. We didn't just pick one thing, get on a bike, do that for 30 minutes three times a week, right? These were sedentary people so we built them up slowly over about seven months. We added frequency, we added duration, we added intensity.
Professor Benjamin Levine:
I am enamored by the four by four in old Norwegian ski team workout, which is four minutes at 95% of max followed by three minutes of recovery repeated four times. We added interval training and long slow distance battle lasting about an hour on the weekends and a little bit of strength training, too.
Professor Benjamin Levine:
So what we consider the ideal prescription for life, four to five days a week, one long session, one high intensity session, two or three moderate intensity sessions and a little bit of strength. We did it for a year. It took a lot of effort. We had dedicated trainers. We gave them all heart rate monitors. Each person had a trainer to follow them.
Professor Benjamin Levine:
We did have a control group. We randomly assign them to a group that did stretching and yoga and mindfulness and a little bit of strength training, which makes people feel better. But we know from experience, it doesn't make them fitter and doesn't change their cardiac compliance.
Dr. Greg Hundley:
What happened with the treatment group?
Professor Benjamin Levine:
Oh, they got much more compliant. They got as compliant as if they had been training most of their lives. It was quite remarkable, actually, frankly, better than we expected it to be. We check the data multiple times by multiple people to make sure that this was a real finding. We really reversed much of the effects of the adverse effects of sedentary aging plus LVH. We hope that if that would be sustained over more than a year, years of long training study, there are very few training studies that go that long. But it's not a lifetime and at least we've set the stage for the concept that if this were to be sustained over a lifetime that we think it could forestall HFpEF.
Dr. Greg Hundley:
Very nice. Well, Walter, I know serving as a guest editor for us at Circulation and we're most appreciative for you doing that task. What struck you about this particular article and really enticed you to want to help us move it toward publication?
Professor Walter Paulus:
Well, I felt that the article was very visionary. Of course, as it comes from Ben, I didn't expect anything else. But what struck me were two points.
Professor Walter Paulus:
First of all, he looks at patients which we would label type B HFpEF. Most of our efforts have always been focusing on sick people, stage C HFpEF, stage D HFpEF. Now Ben was so clever to go to an early stage, and I believe that many of the so-called neutral outcomes in therapy for HFpEF are related to the fact that we actually address patients population who is quite far out on its natural history. So I think this was the first point to me. He, Ben, was addressing a population at the early stages of HFpEF.
Professor Walter Paulus:
The second point that struck me was that the variable he was looking at is in my opinion the key variable in HFpEF. It's the main reason I appreciated that this is the disease of myocardial compliance of left ventricle stiffness, and then very nicely addressed the stiffness of the heart as its primary outcome. This is something what we miss in all the pharmacological trials. I have always been curious when are we going to see the pharmacological trial whereby somebody is going to evaluate a compound in terms of its effects on left ventricular stiffness on myocardial compliance.
Professor Walter Paulus:
So these were for me two very salient features and very visionary in terms of treatment of a HFpEF population. Also, a couple of things that need to be clarified for me and I did. The patient's entry criteria were very demanding, has been also already said. I have the feeling that if you have LVH and then you will try NT-proBNP to be elevated and all your required troponins to be elevated, it's probably be very hard to get such a patient population and that may be then the only remark that could come up toward an extent in such a patient population still reflective of everyday health.
Dr. Greg Hundley:
Very good. Well, Ben, coming back to you, what's your next study?
Professor Benjamin Levine:
Well, we have a large program project grant, Greg, funded by the NIH, looking at the mechanisms of dyspnea and HFpEF. We're now just entered our third year. We're looking at a strategy to try to lower cardiac filling pressures acutely to see if that improves exercise tolerance and reduce dyspnea. We're looking at peripheral mechanisms of oxygen uptake and utilization and vascular control. We're looking at autonomic function, sympathetic nerve recordings, regulation of the sympathetic nervous system. We have a group focused on pulmonary mechanics, particularly on the effects of obesity.
Professor Benjamin Levine:
Our team with Tom Sarma is our recruitment core expert and one of the Circulation editors and is really the lifeblood of our study and leads our effort. We have Paul Fidel from UT Arlington who's leading our peripheral function studies, Qi Fu from UT Southwestern leading our autonomic group, and Tony Babb also from Southwestern in the pulmonary division leading our pulmonary mechanics.
Professor Benjamin Levine:
So we're entering this phase where we're trying to say, "Are there other components?" We know myocardial stiffness is a key factor, but what else in patients with the already manifest HFpEF is causing them to be so short of breath and can we change that?
Professor Benjamin Levine:
So that's what we're doing next, Greg. I think that if you ask what is the next step from this study, I think it has to be population-based and pushing the concept that exercise is medicine. When you find patients who have hypertension in general, and most of these had hypertension or diabetes, I mean, Walter has led this field and in emphasizing these comorbidities and what they do to the heart and the vasculature and the rest of the body, we have to catch people early. We can't wait until they have full-blown manifest HFpEF. We have to get them to include exercise as part of their personal hygiene.
Professor Benjamin Levine:
I know that that's a major effort from the American Heart Association. But I think that for the long-term health of our population and preventing this disease that is so difficult to treat when it's firmly established, we have to as cardiologists and as a healthcare system, we have to start by including incentives for reducing healthcare costs to get people to use exercise as part of their personal hygiene and daily life.
Dr. Greg Hundley:
Very nice. Walter, from your perspective, what do you see are the next studies that need to be performed in this sphere of research?
Professor Walter Paulus:
Well, I will be very curious to see how many patients would actually go on to develop HFpEF in their life. It should be as if Ben's hypothesis holds, then the control group probably would have an access development of HFpEF compared to his exercise training group. I think that would really extend to study from above, from a mechanical observation to a clinically, epidemiologically more relevant endpoint. So I think that to me would be the first question, how many patients will evolve to clinical HFpEF.
Professor Walter Paulus:
Second point I would be very intrigued in is, are there SIP groups in the patients who have a positive response to exercise? For instance, what happens with the different ejection fractions? Because we are very intrigued at present in HFpEF that at high ejection fractions nothing seems to work. Sacubitril was notable at high ejection fractions. Empagliflozin was also neutral to ejection fractions. What would happen with exercise? Do the patients who present with the 70% ejection fraction at the angio study, do they still have a positive response? This would be a game change because this would then be the only intervention that is able to cure the HFpEF with high ejection fraction. These are some future projects that come into my mind.
Professor Benjamin Levine:
Let me just add that we have studied and put patients with HFpEF on a yearlong exercise program with not as much effect as we would like. I think that's one of the things that pushed us to getting earlier into the course of HFpEF, as Walter said earlier.
Professor Benjamin Levine:
Ambarish Pandey and Jarett Berry, also from UT Southwestern, of course are very interested in this effect of fitness at different points in the lifespan, our fitness test, for example, measured in mid-life and what means for heart failure later. I think it's hard to do the kind of studies that we do and follow patients for 20 years to see if they're going to develop heart failure, and that's where I think being creative and looking at the studies that incorporate an assessment of fitness and that follow people over time will be very informative. I hope with me, Walter's hope and hypothesis that these patients are less likely to develop HFpEF. We've got to get in there early.
Dr. Greg Hundley:
Very good. Well, listeners, we want to thank Professor Benjamin Levine from UT Southwestern in Dallas and also Dr. Walter Paulus from Amsterdam for bringing us this really interesting study, indicating that in patients with LVH and elevated cardiac biomarkers, sort of the stage B HFpEF that one year of exercise training reduces left ventricular myocardial stiffness.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I 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.