Circulation May 11, 2021 Issue

This week is a Double Feature Circulation on the Run. Please join
authors Alexander Benz and Lars Wallentin as they discuss their
article "Biomarker-Based Risk Prediction With The ABC-AF Scores
in Patients With Atrial Fibrillation Not Receiving Oral
Anticoagulation." Then, please join author Timothy McKinsey,
editorialist Thomas Gillette and Associate Editor Sergio
Lavandero as they discuss the article "HDAC Inhibition Reverses
Preexisting Diastolic Dysfunction and Blocks Covert Extracellular
Matrix Remodeling" and the editorial "HDAC Inhibition in the
Heart: Erasing Hidden Fibrosis."


TRANSCRIPT BELOW


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 Dr. Greg Hundley, Associate Editor, Director of the Pauley
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, I cannot get enough of our double features, and this one's
really nice because it's a clinical feature and a preclinical
feature, and both are just phenomenally interesting. The first is
about the ABC-AF scores. In case you don't recognize it, well,
then you just have to listen. Very, very important information on
biomarker-based risk prediction in patients with atrial
fibrillation, not receiving oral anticoagulation. Then we've got
a really interesting paper talking about HDAC inhibition and
diastolic dysfunction. Interested? Well, listen up.


Dr. Carolyn Lam:


First, let's talk about some of the papers in today's issue,
shall we? I want to start, Greg. You grab your coffee. I need to
talk about this first one, which really provides the first
extensive genetic and phenotypic landscape of a very important
condition, peripartum cardiomyopathy. This is from Dr. Arany and
colleagues from Perlman School of Medicine, University of
Pennsylvania. What they did is studied 469 women with peripartum
cardiomyopathy, who were identified from several US and
international academic centers. They acquired clinical
information and DNA samples. Next-generation sequencing was
performed on 67 genes and evaluated for the burden of truncating
and missense variance.


Dr. Carolyn Lam:


What they found was that women with peripartum cardiomyopathy
bear a significantly high burden of loss of function variants in
a number of genes, including familiar ones like TTN, FLNC, DSP,
and BAG3. The identity and relative abundance of these variants
were remarkably similar to that seen in idiopathic dilated
cardiomyopathy, indicating that the genetic predisposition to
peripartum cardiomyopathy and dilated cardiomyopathy may be one
in the same. Now, while peripartum cardiomyopathy patients with
the TTN truncating variants presented with lower ejection
fraction. No significant differences in the rates of recovery
were seen.


Dr. Greg Hundley:


Really interesting, Carolyn. Clinically, what are the
implications today as we see these patients?


Dr. Carolyn Lam:


Well, I think the most important one is that genetic counseling
and testing should, perhaps, be considered for women with
peripartum cardiomyopathy, following the guidelines for dilated
cardiomyopathy. What about you, Greg?


Dr. Greg Hundley:


Very nice, Carolyn. Well, my paper evaluates the role of
inflammation and outcomes in patients that sustain
out-of-hospital cardiac arrest. It comes to us from Dr. Martin
Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac
arrest patients who remain comatose after initial resuscitation
are at high risk of morbidity and mortality due to the ensuing
post-cardiac arrest syndrome. Now, systemic inflammation
constitutes a major component of the post-cardiac arrest syndrome
and interleukin 6 levels are associated with this severity. The
IL-6 receptor antagonists tocilizumab could potentially dampen
inflammation after post-cardiac arrest. The objective of the
present trial was to determine the efficacy of tocilizumab to
reduce systemic inflammation after out-of-hospital cardiac
arrest, A presumed cardiac cause, and thereby potentially
mitigate organ injury.


Dr. Carolyn Lam:


Oh, wow. Interesting, Greg. what did they find?


Dr. Greg Hundley:


Carolyn, they had 80 comatose out-of-hospital cardiac arrest
patients and they were randomized 1:1 in a double-blind,
placebo-controlled trial to a single infusion of tocilizumab or
placebo, in addition to standard of care, including targeted
temperature management. The primary endpoint of the study was
reduction of CRP response. This was achieved by tocilizumab, as
there was a significant treatment-by-time interaction. Systemic
inflammation was reduced by treatment with tocilizumab, as both
CRP and leukocyte levels were markedly reduced. Now, myocardial
injury was also reduced, documented by reductions in CK-MB and
troponin T. However, there were no differences, Carolyn, in
survival or neurological outcome. So Carolyn, it looks like for
those that survive an out-of-hospital cardiac arrest and do
experience neurological recovery, there could be cardiac
benefits.


Dr. Carolyn Lam:


Wow, very interesting. I cannot imagine how difficult it must've
been to perform such a trial. Thanks, Greg. Well, the next paper
demonstrates a new mechanism underlying diastolic dysfunction,
and provides theoretical and experimental evidence to explain,
perhaps, the ineffectiveness of conventional nitric oxide
enhancement trials for HFpEF. And you know, that's my favorite
topic.


Dr. Greg Hundley:


Wow, Carolyn, really interesting. Can you summarize it for us?


Dr. Carolyn Lam:


Sure. Well, first of all, this comes from Doctors Eom and Kook
from Chonnam National University Biomedical Research Center in
Korea. These authors used two animal models of diastolic
dysfunction, the salty drinking water, unilateral nephrectomy
with aldosterone, or SAUNA, model, and a mild transverse aortic
constriction model. They also looked at human heart samples from
patients with left ventricular hypertrophy.


Dr. Carolyn Lam:


Together, in very, very elegant experiments, they showed that
neuronal nitric oxide synthase was upregulated in diastolic
dysfunction, which increases S-nitrosylation and cardiomyocytes,
and its pharmacologic inhibition, as well as genetic ablation,
alleviated diastolic dysfunction. Now, specifically, protein
S-nitrosylation of histone deacetylase 2, or HDAC2, played a
critical role in the development of diastolic dysfunction and
nitric oxide reduction and the following protein denitrosylation
may provide a novel therapeutic strategy for HFpEF.


Dr. Greg Hundley:


Very nice, Carolyn. Well, my next paper comes from Dr. William Pu
from Boston Children's Hospital and looks at reactive oxygen
species-mediated CaM kinase 2 activation, and how that
contributes to calcium handling abnormalities and impaired
contraction in the Barth syndrome. Carolyn, mutations in
tafazzin, a gene required for biogenesis of cardiolipin, the
signature phospholipid of the inner mitochondrial membrane,
causes Barth syndrome. Carolyn, remember that Barth syndrome
occurs primarily in males, is associated with cardiomyopathy, a
low white count, and recurrent infections, and also skeletal
muscle myopathy and short stature. Cardiomyopathy and the risk of
sudden cardiac death are prominent features of the Barth
syndrome, but the mechanisms by which impaired cardiolipin
biogenesis causes cardiac muscle weakness and these arrhythmias
are poorly understood.


Dr. Carolyn Lam:


Oh, Greg, thanks so much for not quizzing me on that one. I was
trying to remember what Barth syndrome is, and thanks for the
review. Okay, so what did they find?


Dr. Greg Hundley:


Right, Carolyn. The investigators identified a molecular pathway
that links tafazzin mutation to abnormal calcium handling and
decreased cardiomyocyte contractility. This pathway may offer
therapeutic opportunities to treat Barth syndrome, and
potentially other diseases with elevated mitochondrial reactive
oxygen species production.


Dr. Carolyn Lam:


Thanks, Greg. Nicely summarized. Well, let's go through what else
there is in today's issue. There is a Perspective piece by Dr.
Singh, entitled The Morbidly Obese Patients with Symptomatic
Atrial Fibrillation: Why are we Holding Back on Bariatric
Surgery? There's an On My Mind piece by Dr. Wenger on the
incremental change versus disruptive transformation: COVID-19 and
the cardiovascular community. There's also a research letter by
Dr. Phillip on cardiovascular evaluation after COVID-19 in 137
collegiate athletes, and it's the results of an algorithm-guided
screening. A very interesting piece.


Dr. Greg Hundley:


Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an
exchange of letters regarding the article Anti-Inflammatory
Actions of Soluble Ninjurin-1 and the Amelioration of
Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally,
Dr. Rob Califf has an On My Mind piece, entitled Avoiding the
Coming Tsunami of Common Chronic Disease: What the Lessons of the
COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really
excited. Another double feature Tuesday. How about we turn our
attention and move toward those articles?


Dr. Carolyn Lam:


Yep. Something for everyone in this one. Let's go. Today's
feature discussion will sound somewhat familiar if we're talking
about the ABC scores. Now, remember that stands for age,
biomarkers, clinical history scores, and they're the scores that
we use in patients with atrial fibrillation receiving oral
anticoagulation, or at least that's the data we have so far. But,
what are the utilities of these ABC scores in patients not
receiving oral anticoagulation?


Dr. Carolyn Lam:


Well, guess what? That's what today's feature paper is all about.
I'm so pleased to have with us today, the first author, Dr.
Alexander Benz, from Population Health Research Institute,
McMaster University in Canada, as well as Dr. Lars Wallentin,
he's a senior author from Uppsala University in Sweden. Welcome,
gentlemen. Alex, if I could start with you, please. A very
interesting question and not so easy to answer, could you please
tell us a little bit about the background to your study, what you
did, and what you found?


Dr. Alexander Benz:


Sure. Thanks for the opportunity to speak here. The ABC scores
have now been shown to outperform clinical risk scores in the
setting of patients with AFib receiving oral anticoagulant
therapy. But so far, nobody has ever looked at the performance of
these scores in patients who are not treated with oral
anticoagulant therapy. So here we validated the ABC stroke,
bleeding, and death scores in patients with AFib who were not
receiving oral anticoagulant therapy. We chose the ACTIVE A and
AVERROES trials, where patients were randomized to receive
antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for
the validation study. We ended up studying the scores and over
4,300 patients who were receiving either aspirin, which were over
3,195 patients, or aspirin plus clopidogrel in about 1100
patients, in these studies.


Dr. Alexander Benz:


Now, we found that the ABC stroke score was superior to the
CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding
score was also better than the currently recommended HAS-BLED
score for the assessment of the risk of bleeding, yielding an
overall C-index of 0.73. And finally, the ABC-AF death score
yielded a C-index of 0.78, which I think is remarkable.


Dr. Alexander Benz:


Now, as these scores were derived from patients receiving oral
anticoagulant therapy, we're not surprised to see that the ABC
stroke score underestimated the risk of stroke in this
population. And very similarly, the ABC bleeding score
overestimated the risk of bleeding in these patients receiving
antiplatelet therapy. So these scores, the ABC stroke and
bleeding scores, were recalibrated for our prediction of absolute
event rates in the absence of oral anticoagulant therapy.


Dr. Carolyn Lam:


Thanks, Alex. That was a beautiful summary. Now, Lars, if I could
ask you, please, could you really highlight to all of us, what is
the key thing about validating these scores in patients with
atrial fibrillation, but not receiving oral anticoagulation?


Dr. Lars Wallentin:


I think what people like to have is an estimate of the risk of
stroke and the risk of bleeding. If you start them on oral
anticoagulation and that has been difficult, we only knew this
based on the risk scores on patients that were on treatment. But
if we now are using this score, which are also well-calibrated,
we can really estimate the absolute risk of a stroke. Let's say,
3% without oral anticoagulation, then how much is it lowered by
oral anticoagulation down to 1%? And we can do this on an
individual level, because there is a variability between patients
and we can identify the risk for an individual patient without
treatment, and the risk on treatment, and that can be balanced
then against the risk for bleeding on treatment and without the
treatment. And thereby, you can get the precise estimate on the
risk-benefit ratio for the individual patients.


Dr. Lars Wallentin:


This is a precision medicine approach, which we think will
provide a better treatment with better outcomes for the patients
than we have had before. Also, death can be, of course, involved
at the final net benefit, with and without treatment. Therefore,
we think this is a great step forward, and this cannot be
implemented in the real life because we have used biomarkers that
now can be available in the routine laboratories. These are
NTproBNP and troponin, which are available in all hospitals, and
a new marker, GDF-15, a marker that's related to the bleeding
risk and that is currently launched by Roche Diagnostics as a new
tool. So I think this is a realistic future to improve
treatments.


Dr. Carolyn Lam:


Dr. Lars, I have to tell you, all us editors fully agreed as
well, that this is a great contribution, filling an important gap
in the literature so far in a very clinically important question
when we face the patient who hasn't started anticoagulation. So
really, again, thank you both for this study and for publishing
with us. A couple of questions, though. It does require these
extra biomarkers that come with some, what can I say, cost of
needing to measure them if they're not already measured. Could
you give us some idea of how much the scores add to what we're
used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know,
maybe Alex?


Dr. Alexander Benz:


Sure. I think one downside of the widely-accepted and also often
useD clinical scores is that they rely on Arbitrary
categorization and dichotomization of clinical variables, and
with biomarkers, we have the great advantage of having a
continuous tool to assess the risk of outcomes here. And as Lars
mentioned, these are mainly the cardiac biomarkers NTproBNP and
cardiac troponin, as well as the GDF-15, or growth
differentiation factor 15. We think that biomarkers reflect a
powerful tool to also reflect underlying subclinical disease,
which is very important, I think, in this stratification, and
this is probably where much of the superiority of the
biomarker-based tool stems from.


Dr. Carolyn Lam:


Right, thanks. Back to what Lars had said about more precision,
which is exactly what the whole of cardiology is, I think, moving
towards as well, but it was very, very clever to look for the
studies ACTIVE and AVERROES. Hard to think of the population in
which you tested this. But weren't the blood samples in these
studies very old? Did you then have to remeasure those
biomarkers? Were they reliable?


Dr. Lars Wallentin:


Yes. These were old samples that were taken at entry into the
ACTIVE and AVERROES trial. The investigators in Canada were
really very clever to save the sample, but the samples have been
saved for a decade or more since then. But fortunately, these
assays are very stable over time, so all of them, and therefore
the results are reliable. The levels are very similar to the ones
we get in the real-life setting for samples as the one we have in
ARISTOTLE and RE-LY, where the scores were derived. So this seems
to be, I think, also an advantage that this can be used for
stored samples, and fresh samples.


Dr. Carolyn Lam:


Thank you for addressing that so nicely. We're running out of
time sadly, but I would love to hear, maybe as final remarks,
what you think are the overall clinical implications and perhaps
the next steps for important studies that need to be done. Maybe
I could ask Alex to start first and then Lars can finish?


Dr. Alexander Benz:


Well, I think the next steps in the ABC score program will depend
on potential integration or a combination of scores, which then
may guide physicians in whom to treat or even whom not to treat.
Withholding anti-platelet therapy in certain very low-risk
patients, that's what comes to mind. I know that Lars and his
colleagues are performing a randomized controlled trial in Sweden
where they're testing the ABC scores in clinical practice against
the usual care with the clinical scores. Maybe, Lars, you want to
elaborate on this.


Dr. Lars Wallentin:


Yeah, I think the final step is, of course, a prospective
randomized trial showing which are the real benefits. We are
randomizing 6,000 patients to conventional care versus precision
medicine-based care using the ABC risk scores. Outcomes are death
and stroke and bleeding. I hope that we will find usefulness of
this also in a prospective trial, which will be the final piece
of evidence, of course.


Dr. Carolyn Lam:


Wow, Lars, that is amazing. Thank you so much for sharing that
with us. First time on Circulation on the Run. Well, audience,
I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now,
hold on tight, we're going on to our next feature discussion.


Dr. Carolyn Lam:


Oh, I can't wait to get onto this feature discussion. You see,
it's actually going to reveal a potential new way to target
diastolic dysfunction. My absolute favorite topic. It's a basic
science paper. It is incredible. You're going to hear all about
its clinical translational potential and significance, and from
none other than the corresponding author, Dr. Timothy McKinsey
from University of Colorado School of Medicine, and editorialist
of a beautiful accompanying editorial, Dr. Thomas Gillette from
UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor
from University of Chile, San Diego. Thank you so much for being
here. Tim, could I get you started off? Recognizing there are a
lot of clinicians listening out there, this is an incredible
paper. HDAC, I think for some, it will be the first time you've
been hearing such a word. Please, please, could you break it down
for us what you did and what you found?


Dr. Timothy McKinsey:


Sure. Thanks, Carolyn, and thanks for inviting me to do this.
It's really a pleasure. HDAC, that stands for a class of enzymes
called histone deacetylases, and those are also known as erasers
of acetyl marks on chromatin. So they're really famous for the
regulation of epigenetics or gene expression. But we found that
HDACs do a lot of other things in the heart too, by deacetylating
both histone and non-histone proteins, and we're just really
interested in the therapeutic potential of inhibiting HDAC
enzymes for the treatment of heart failure. And, in so doing, we
assess their ability to reverse existing diastolic dysfunction in
a mouse model of kidney disease and hypertension.


Dr. Carolyn Lam:


You know what, Tim, I really liked the way you very carefully
said that. A mouse model of diastolic dysfunction with preserved
ejection fraction, that I think, previously, a lot of people with
just very loosely used the word HFpEF for such a model, but I
really, really appreciate how carefully you worded that. Could
you tell us a little bit about the model and what you found?


Dr. Timothy McKinsey:


Sure. Yeah, we've been really careful not to call it a model of
HFpEF, because it isn't a model of heart failure. It really is a
model of isolated diastolic dysfunction and preserved ejection
fraction. It's a model that's been used in the literature in the
past, where you perform a uninephrectomy in mice, so remove one
kidney, and then implant something called DOCA, which is an
aldosterone memetic. And over time, these animals develop
systemic hypertension that results in cardiac hypertrophy and
diastolic dysfunction.


Dr. Timothy McKinsey:


We were perplexed because we couldn't see any fibrosis in the
model. But when we did a deep dive into fibrosis using more
sensitive methods than are traditionally used, we did uncover
what we're calling hidden fibrosis. We believe that HDAC
inhibitors, our data suggests that HDAC inhibitors, can actually
block the formation of hidden fibrosis that leads to diastolic
dysfunction.


Dr. Carolyn Lam:


Very nice. If you could just give us a one-line on how will you
find this hidden fibrosis?


Dr. Timothy McKinsey:


We got stuck on that for years, because we did all the
traditional assays to measure cardiac fibrosis, mainly
picrosirius red stain, and we didn't see anything. But we were
fortunate to team up with some really talented collaborators,
including Maggie Lam here at the University of Colorado, who is
an expert at using mass spectrometry to study cardiac remodeling,
and also Luisa Mestroni and Brisa Peña who use atomic force
microscopy to look at tissue stiffness. When we teamed up with
those investigators, first with Maggie we found that, sure
enough, when we used her sensitive mass spec assay to look at
extracellular matrix protein expression in the heart, there was
really a profound increase in ECM protein expression in this
mouse model, even though the staining for fibrosis was negative.
That told us that there was this underlying hidden fibrosis.


Dr. Carolyn Lam:


Oh, that is really interesting. And so it is that form of
fibrosis that was actually reversed, perhaps, by the HDAC
inhibition, and that's what you showed. Would that be accurate to
say?


Dr. Timothy McKinsey:


Yeah. So the HDAC inhibitor really had this profound ability to
block that ECM remodeling, the hidden fibrosis, to the point
where initially we thought it was an artifact. We thought maybe
there was a mix-up of samples. It wasn't a mix up. It's just that
the compound, this inhibitor of HDAC enzymatic activity, really
has this amazing ability to block the formation of hidden
fibrosis.


Dr. Carolyn Lam:


Oh, wow. Wow, Tom, I really, really loved your editorial where
you put all of this in context and talked a little bit about the
translational and clinical potential. Could you maybe share your
thoughts here? I love the title by the way, Erasing Hidden
Fibrosis.


Dr. Thomas Gillette:


Thanks. Thanks for that. Yeah, first of all, Tim, it was a really
great piece of work, and it's actually really exciting because
when we think of this diastolic dysfunction, and really it's the
development of HFpEF, I think, that a lot of people are... It's
the single most critical unmet need in cardiovascular medicine,
is the treatment for HFpEF. That diastolic dysfunction, it's
really that stiffness that Tim was measuring with his atomic
force microscopy and those changes in ECM that really seemed to
be critical, at least in that model.


Dr. Thomas Gillette:


And we know from other models as well that these underlying
changes in fibrosis and stiffness, perhaps in the ECM, play a
really important role, not only in the diastolic dysfunction, but
also if you think about in strain as well, because I know in our
models of HFpEF and this mouse model of HFpEF, we have the
two-hit model published that Gabrielle, a Allie developed with
Dr. Hale in Nature. It's that strain that we could measure that
really seems to correlate well with the heart failure phenotype.
And so it begs the question, has he caught a very early change in
the ECM that's really critical to the development of this
pathology? And is there a way that we could detect it early on in
patients? Is there a way we could measure that in patients and
really get a sense of who's progressing and how they're
progressing?


Dr. Thomas Gillette:


Then there's a second point, and I mentioned a little bit in the
editorial, I didn't go into it too deeply, and that is, it's
really intriguing what this might mean for the development of the
disease, because the matrix not only is involved in stiffness,
but it's also a reservoir for growth factors, it helps recruit
inflammatory cells, and inflammation plays a huge role in HFpEF.
And so it begs the question, how many of those changes may
proceed a lot of that pathology as well?


Dr. Carolyn Lam:


Wow, Tom, I really couldn't agree more. I made a big deal earlier
about agreeing with Tim, calling this a diastolic dysfunction
model rather than HFpEF, but I completely agree with you that the
implications are for the development of HFpEF, and it needed the
begs, the question of how many patients actually have this hidden
fibrosis? And we know that in patients with HFpEF, there is a
stage of advanced fibrosis where we feel patients don't respond
to treatment as well. So have we caught an early phase that may
be clinically applicable? I really loved the way you worded that.
But finally, with Sergio, could you put it all together and what
the editors thought of this paper? Why you invited Tom to write
this editorial? And perhaps what next steps are?


Dr. Sergio Lavandero:


Okay, Tim, this is really a fascinating work. I have a long road,
because in Italy, you develop the most important new concept. The
new concept, the hidden fibrosis. The second important,
originally, most of the HDAC inhibitors were developed for other
diseases, originally for cancer. So now we have more data that,
probably, this compound can apply to other diseases like
cardiovascular disease. It was difficult to convince at the
beginning some reviewers about the concept of hidden fibrosis,
because it's not traditional. But finally, we asked to another
expert to, "Okay, why don't you explain, please, this new
technique?" For the future, Tim, what do you think? How can we
evaluate hidden fibrosis in patients?


Dr. Timothy McKinsey:


Ideally, and you would have a non-invasive approach to assessing
hidden fibrosis in patients. Obviously I know myocardial biopsies
could be analyzed using the mass spec approach and atomic force
microscopy, but not everyone is going to want to get a myocardial
biopsy. So ultimately, we would like to correlate data that we
obtain with biopsies, with circulating factors to see if there is
a non-invasive surrogate circulating factor that correlates with
the existence of hidden fibrosis. I think that would be very
powerful clinically.


Dr. Sergio Lavandero:


What do you think the specificity of this research, because maybe
it's too broad? What do you think?


Dr. Timothy McKinsey:


Yeah, that's a great point. There's a negative impression of
general HDAC inhibition, because people just can't believe that
you could inhibit a large number of HDAC enzymes throughout the
body and not kill someone. But you can. And in our models you can
use pretty low doses of these HDAC inhibitors and see efficacy.
But obviously, the holy grail in this field would be to identify
specific HDAC isoforms that regulate specific disease processes.
So we have an active area of investigation where we're trying to
tease apart the roles of different HDACs in the heart, with the
ultimate goal of finding the HDAC or a subset of HDACs that
regulate in fibrosis. Then you could selectively inhibit those
and perhaps have a safer drug than a general HDAC inhibitor.


Dr. Carolyn Lam:


Thank you, once again. This is an amazing discussion and really,
really an example of just the kind of papers we love publishing
at Circulation. So novel and with such translational potential.
Thank you, Tim, again, and Tom and Sergio. Thank you, audience,
for joining us today. From Greg and I, you've been listening to
Circulation on the Run. Don't forget to tune in again next week.


Dr. Greg Hundley:


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.