Circulation September 21, 2021 Issue

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.