Circulation July 12, 2022 Issue

This week, please join author Ambarish Pandey and
Editorialist Linda Peterson as they discuss the article "Frailty
Status Modifies the Efficacy of Exercise Training Among Patients
with Chronic Heart Failure and Reduced Ejection Fraction: An
Analysis from the HF-ACTION Trial" and the editorial "Heart
Failure With Reduced Ejection Fraction (HFrEF): ‘The Importance
of Being Frail.’"


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast, summary,
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate editor director of the Pauley
Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn,
this week's feature article, Heart Failure Reduced Ejection
Fraction in Evaluating the Efficacy of Exercise Training. But
guess what? It appears it may be more efficacious in those that
have high Frailty Index scores, as opposed to those that may not.
But before we get to our feature discussion, let's grab a cup of
coffee and go through some of the other articles in the issue.
Would you like to go first?


Dr. Carolyn Lam:


I would love to, and this first paper is one that defines
epigenetic biomarkers of lifelong cardiovascular health exposure
and really contributes to our understanding of their roles in
cardiovascular disease development. First though, a little quiz
for Greg. So, Greg, what does DNA methylation mean to you?


Dr. Greg Hundley:


Well, Carolyn, DNA methylation. So, what I understand is these
methyl groups get involved with our DNA and actually affect
change over time that leads to phenotypic expression of, maybe,
new traits. But I don't know. Maybe I'm not quite up to date.


Dr. Carolyn Lam:


Oh, you're perfect. Indeed, DNA methylation is a widely
characterized epigenetic modification, which means exactly as you
said. It's a regulatory modification to our DNA induced by
environmental exposures and can affect gene expression. And this
is the topic of today's paper by Doctors Zheng, Hou, and
Lloyd-Jones from Northwestern University Feinberg School of
Medicine and their colleagues. So, what they did is they studied
blood DNA methylation at over 840,000 methylation markers
measured twice over five years in participants of the CARDIA
study. Epigenome-wide association analyses on a clinical
cumulative cardiovascular health score were then performed in
both CARDIA and compared in the Framingham Heart Study.


Dr. Carolyn Lam:


The authors identified 45 midlife DNA methylation markers
associated with clinical cardiovascular health metrics, such as
body mass index, blood pressure, blood glucose, and total
cholesterol longitudinally measured since young adulthood. The
methylation markers were located in genes involved in lipid
metabolism, insulin secretion, and cytokine production, which
could not be fully attributed to genetic factors. So, they
proposed and validated in summary a methylation-based risk score
to promote a personalized cardiovascular disease risk evaluation
beyond traditional cardiovascular risk factors.


Dr. Greg Hundley:


Oh, wow, Carolyn. Interesting, a methylation-based risk score to
promote personalized cardiovascular disease risk evaluation. Wow!
That's really exciting.


Dr. Greg Hundley:


Well, I'm going to go to the world of preclinical science, and
just like last week where we had a really nice article on
myocardial regeneration, this week, we've got another. And so,
Carolyn, early neonates of both large and small mammals are able
to regenerate the myocardium through cardiomyocyte proliferation
for only a very short period after birth. This myocardial
regenerative capacity declines in parallel with withdrawal of
cardiomyocytes from the cell cycle in the first few postnatal
days. No mammalian species examined to date has been found
capable of a meaningful regenerative response to myocardial
injury later than one week after birth.


Dr. Carolyn Lam:


Interesting. Now, I see that these investigators worked with
possums. Could you tell me why they did that, and what did they
find, Greg?


Dr. Greg Hundley:


Right, Carolyn. So, this work was led by Dr. Wataru Kimura from
the RIKEN Center for Biosystems Dynamic Research and their
colleagues. The reason they studied possums, so the marsupial
possum maintains cardiomyocyte proliferation and a capacity for
myocardial regeneration for at least two weeks after birth.
Remember we stated before, all the other mammalian species, it's
only one week after birth. So, this appears to be the longest
postnatal duration of such a capacity among mammals examined to
date, and AMP kinase signaling was implicated as an evolutionary
conserved regulator of mammalian postnatal cardiomyocyte
proliferation.


Dr. Greg Hundley:


And they additionally found that in a separate mouse experiment,
the authors noted that the pharmacological inhibition of AMP
kinase signaling was sufficient to extend the postnatal window of
cardiomyocyte proliferation in neonatal mice, so really exciting
work in the area of cardiomyocyte regeneration.


Dr. Carolyn Lam:


Wow, indeed! And I've learned now about possums. Thank you, Greg.


Dr. Carolyn Lam:


So, Greg, have you ever asked yourself, what is the frequency,
penetrance, and variable expressivity of dilated
cardiomyopathy-associated gene variants in the general
population? Well, guess what? This next paper addresses just that
in more than 18,600 UK Biobank participants who had undergone
whole-genome sequencing, ECG, and cardiovascular magnetic
resonance imaging.


Dr. Greg Hundley:


Wow, Carolyn, another really interesting study from the UK
Biobank. So, what did they find?


Dr. Carolyn Lam:


So, this study is from Dr. Chahal from the Center for Inherited
Cardiovascular Diseases Wellspan Health in Lancaster,
Pennsylvania and colleagues, and they found that approximately
one in six of adults with putative pathogenic variants in dilated
cardiomyopathy genes exhibited early dilated cardiomyopathy
features potentially associated with the genotype. And it's most
commonly manifesting with arrhythmias in the absence of
substantial ventricular dilation or dysfunction.


Dr. Carolyn Lam:


Among individuals with putative pathogenic dilated cardiomyopathy
gene variants, ECG or CMR-detected early features were nearly
four times more common than clinically manifest dilated
cardiomyopathy or early features. Over 90% of subjects with these
gene variants in dilated cardiomyopathy-associated genes did not
have a prior history of dilated cardiomyopathy, and the overall
clinical or subclinical penetrance of dilated
cardiomyopathy-associated single pathogenic variants was highly
variable between genes ranging from zero to 67%. And so, in
conclusion, a genotype-first screening approach for dilated
cardiomyopathy using a large genetic panel is currently not
suitable in the general population due to incomplete
understanding of the genetic architecture and reduced penetrance
of the associated genes.


Dr. Greg Hundley:


Very nicely said, Carolyn. Wow! Well, let's take a look and see
what's in the mailbag. And first, there's a Research Letter from
Professor Huguenard entitled, “Frequency of Screening Detected
Intracranial Aneurysms in Patients With Loeys-Dietz Syndrome.”
And our own Bridget Kuehn has a really nice piece on Cardiology
News.


Dr. Carolyn Lam:


Nice. There's also an On My Mind paper by Dr. Sattar, McGuire,
and Gill entitled, “High-Circulating Triglycerides Are Most
Commonly a Marker of Ectopic Fat Accumulation: Connecting the
Clues to Advanced Lifestyle Interventions,” and an exchange of
letters between Dr. Groothof and myself, Dr. Lam, regarding my
article on “Efpeglenatide and Clinical Outcomes With and Without
Concomitant SGLT-2 Inhibition in Type 2 Diabetes: An Exploratory
Analysis of the AMPLITUDE-O Trial.”


Dr. Carolyn Lam:


Ah, that was awesome. Well, thanks, Greg. I am so excited to get
to the future discussion that you queued us on so well, frailty
in heart failure with reduced ejection fraction. Here we go.


Dr. Greg Hundley:


You bet.


Dr. Greg Hundley:


Welcome, listeners, to this July 12th, 2022 feature discussion.
And we have with us today, Dr. Ambarish Pandey from University of
Texas Southwestern Medical Center in Dallas, Texas, and Dr. Linda
Peterson, an editorialist for this article from Washington
University in St. Louis. Welcome to you both. Well, Ambarish,
We're going to start with you. Could you describe for us
basically the background information that went into the
preparation of your study, and what was the hypothesis that you
wanted to address?


Dr. Ambarish Pandey:


Thanks, Greg, for having me on this, and thanks to Circulation
for publishing our article. Yeah, I think the premise for this
study stems from the longstanding known benefit of exercise
training in patients with heart failure with reduced ejection
fraction. Now, that was shown in the HF-ACTION trial, where
individuals with chronic stable heart failure with reduced
ejection fraction underwent exercise training, and there was
demonstrated benefit in quality of life and adjusted analyses.
There was a protocol-specified adjusted analysis that did
demonstrate improvement in some of the key primary endpoint.


Dr. Ambarish Pandey:


Based on these results, CMS has approved exercise training and
cardiac rehabilitation in patients with chronic stable heart
failure with reduced ejection fraction. However, despite this
mandate from CMS and generally well-accepted benefits of exercise
training in heart failure with reduced ejection fraction, the
uptake of exercise training has been pretty low, and there's a
lot of heterogeneity in the improvement in outcomes that is
associated with exercise training.


Dr. Ambarish Pandey:


So, we wanted to see whether frailty, which is a
well-characterized syndrome of reduced physiologic reserve and
impaired homeostatic tolerance to stressors and is common in
patients with HFrEF, we wanted to see how frailty modifies the
beneficial effects of exercise training in HFrEF. And based on
the existing literature and some of the prior works we have done,
we hypothesized that individuals who are frail and who have more
functional impairments are going to have more targets for
improvement in their functional status and thus would be more
likely to benefit from exercise training. And we looked at this
in the HF-ACTION trial itself and using the Rockwood Frailty
Index and the difference in primary outcome and treatment effect
of exercise among frail and non-frail individuals.


Dr. Greg Hundley:


Very interesting, so really sort of a look back in HF-ACTION
data. Describe a little bit more for us that study design, and
then specifically, what was the study population that you used to
test your hypothesis?


Dr. Ambarish Pandey:


Right. So HF-ACTION was a randomized control trial multi-centered
that was sponsored by NHLBI and was conducted in the early 2000s
and basically focused on chronic stable patients with heart
failure with reduced ejection fraction who have not had a
hospitalization in the past six weeks and have ejection fraction
less than 35% and class II to IV. And these participants were
randomized in one-to-one fashion to getting aerobic exercise
training followed by some home-based exercise versus the usual
care.


Dr. Ambarish Pandey:


And in our study, what we looked at was we looked at the effect
modification by baseline frailty status on the treatment effect
of exercise training. So, we calculated the frailty index, which
is a well-established measure of frailty using a Rockwood Index
Model, and we stratified patients by frail versus non-frail
status based on a Frailty Index cut-off of 0.21, such that higher
index identifies more frail participants. And then, we looked at
how the treatment benefit of exercise training on different
outcomes was differential across the frail and non-frail strata.
We looked at qualitative interaction, and we also looked at the
Frailty Index, so the continuous variable to assess the benefits
of exercise across the spectrum of frailty in the study
population.


Dr. Greg Hundley:


And so, before we get to your study results, how many patients
were in your study? Give us an idea of what was the range in age,
and then also the composition of sex? How many men? How many
women?


Dr. Ambarish Pandey:


Right, so this is really important because that's addressed to
the generalizability of the study. So, the study included around
a little over 2,100 participants. The mean age was 59 years. 28%
were women, and 32% were self-reported black individuals with
chronic stable heart failure. That was the demographic
distribution. The age was slightly younger than what you've
commonly see in observational studies with heart failure, and
that is largely because the study recruited patients who were
able to do exercise training and were able to do exercise tests
with peak VO2 and peak VO2 peak excess capacity assessment at
baseline and follow-up. So, that kind of selected for a slightly
younger population.


Dr. Greg Hundley:


Very nice. And so, what were your study results?


Dr. Ambarish Pandey:


So our study results are, indeed, pretty interesting. We
identified that around 60% of patients with chronic stable heart
failure with reduced ejection fraction who were in the trial were
actually frail based on the Rockwood Frailty Index Model. And we
observed that among the study participants, the exercise training
was associated with significant improvement in the primary
composite endpoint of all-cause hospitalization or death in frail
participants, but not in the non-frail or less fail participants.
And there was a significant treatment interaction, such that
baseline frailty modified the treatment effect of exercise
training for the primary composite endpoint.


Dr. Ambarish Pandey:


Now, this was largely driven by a significant reduction in
all-cause hospitalization among frail individuals who underwent
exercise training, and not so much by an effect on mortality. And
we did not see a significant difference in the mortality
component of the primary composite endpoint across frail versus
non-frail status participants. So, in a nutshell, baseline
frailty did modify the treatment effect, largely driven by
substantial reduction in the risk of all-cause hospitalization
among frail participants more than non-frail participants.


Dr. Greg Hundley:


And before we get to Linda in her interpretation of your study,
Ambarish, did you see the same effects in frail men, in frail
women? And also, what about in individuals that might be a little
older versus those that were perhaps younger?


Dr. Ambarish Pandey:


That's a really important question, and we were a little bit
limited to do further subgroups because we are dealing with
around, I think, 2,000 participants and we had frail, non-frail,
and we did not do a further subgroup stratification by sex or by
age. The age range was rather narrow. It's 58 years plus/minus 13
years, so we didn't really have a lot of older individuals above
75, something like what REHAB-HF Trial has shown in the news, a
recent trial.


Dr. Ambarish Pandey:


We couldn't address the question of whether the effect
modification was further modified by sex or age, so I think
that's the two-level interaction. But I think that is something
that would be interesting to test perhaps in a pool analysis of
multiple exercise training studies, which is something we are
considering.


Dr. Greg Hundley:


Thank you. Well, listeners, now we're going to turn to our
editorialist, Dr. Linda Peterson, from Washington University in
St. Louis, and, Linda, very provocative results here, heart
failure reduced ejection fraction. And certainly, we like to go
to things like cardiac rehab, but we're hearing this it seemed to
make a difference if you were frail versus not frail.


Dr. Linda Peterson:


Right, I think that's an important distinction here in this
article as Ambarish has so eloquently put forth, and it's
especially important because other articles have shown in looking
at the PARADIGM-HF Study and ATMOSPHERE it appears that one out
of two patients with HFrEF are actually frail. And so, the
magnitude of these findings and the importance of these findings
is highlighted by that study. And this frequency of frailty is
roughly double that of community-dwelling adults who are over age
90, so we're thinking of frailty usually as much older adults,
but in HF-ACTION, actually, the patients' average age was 60 in
the patients with HFrEF.


Dr. Linda Peterson:


So, there's almost an accelerated aging phenotype we're seeing
here in a large proportion of the patients who have HFrEF. I
think this has an enormous impact on a lot of the patients that
we're seeing with HFrEF, and we should be alerted to looking for
frailty and potentially screening for frailty. And I think
another highlight of this study is that it points out the
importance of frailty because frail patients have a 50% higher
risk of hospitalization and death, according to some other
studies, particularly one by Faray and their group and also by
Yang and their group.


Dr. Linda Peterson:


And so, it highlights the importance of getting patients who are
frail with HFrEF into cardiac rehab or getting them some sort of
aerobic exercise training. But paradoxically, frailty is also
associated with a lower likelihood of those particular patients
on getting into cardiac rehab and also getting on goal-directed
medical therapy. And that was shown by Phil Ades and his group.
So, I think the importance of these findings by Ambarish and his
group are to be commended, and they're very important for a large
proportion of our patients with HFrEF.


Dr. Greg Hundley:


Very nice. Well, let's turn back to Ambarish, and then follow up
with Linda. Ambarish, what do you see as the next study that
should be performed in follow-up to your study?


Dr. Ambarish Pandey:


I think that's a great question. And I think we are just
beginning to realize the magnitude of impact that frailty has in
the care of patients with heart failure. And this goes across the
spectrum of ejection fraction, both HFpEF or heart failure with
preserved ejection fraction and heart failure with reduced
ejection fraction. Indeed, the burden of frailty is higher in
patients with heart failure with preserved ejection fraction, and
they are more of the accelerated aging phenotype.


Dr. Ambarish Pandey:


And I think the next study basically should look at a targeted
approach to exercise training or category of intervention among
patients who are most likely to benefit from it, which would be
patients who have a high frailty burden or patients who have
HFpEF. I think they go hand in hand when it comes to frailty and
HFpEF. So, I think that's the next study to do is to see to what
extent we can actually identify and target exercise training in
the highest risk individuals who are most likely to benefit from
it because that subset of highest modifiable risk is indeed
identified by frailty and when you look at other subtypes by
HFpEF which has a lot of high frailty burden.


Dr. Greg Hundley:


And, Linda, from your perspective, what do you see as the next
study to be performed in this sphere of research?


Dr. Linda Peterson:


Yeah, I think this study really provides a springboard for future
studies in HFrEF, in particular. One, what hospital interventions
can be done in patients to get them moving more, and really
assess is there a possibility of different types of exercises to
get patients less frail even while they're in the hospital when
they're enroute to going home? And then also, how do we have
different mechanisms by which we can get more patients into
cardiac rehab? Clearly, our national average of getting patients
who qualify for cardiac rehab, which is a class I indication is
20% at best, and the aim from the AHA is 70%.


Dr. Linda Peterson:


There's a big gap there, so interventions looking at
implementation and getting patients to cardiac rehab or looking
at other types of aerobic exercise training, such as home-based
cardiac rehab for patients who don't have a cardiac rehab center
next to them, I think the field is wide open for different
studies to springboard off of these findings.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Ambarish Pandey
from University of Texas Southwestern Medical Center in Dallas,
Texas, and our editorialist, Dr. Linda Peterson, from Washington
University in St. Louis, for bringing us this research study,
highlighting that among patients with chronic stable heart
failure and reduced ejection fraction, that baseline frailty
modified the treatment effect of aerobic exercise training with a
greater reduction in the risk of all-cause hospitalization.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, we want to wish you a
great week, and we will catch you next week on the run.


Speaker 5:


This program is copyright of the American Heart Association 2022.
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, please visit ahajournals.org.