Circulation April 11, 2023 Issue

This week, please join author Kavita Sharma and Associate
Editor Svati Shah as they discuss the article "Myocardial
Metabolomics of Human Heart Failure With Preserved Ejection
Fraction."


Dr. Greg Hundley:


Welcome listeners, to this April 11th issue of Circulation on the
Run. And I am one of your cohosts, Dr. Greg Hundley, director of
the Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Peder Myhre:


And I am Dr. Peder Myhre from Akershus University Hospital, and
the University of Oslo in Norway.


Dr. Greg Hundley:


Well, Peder, wow. This week's feature discussion, very
interesting. We spend a lot of time, especially with our
colleague, Dr. Carolyn Lam, on heart failure preserved ejection
fraction. But this week's feature discussion, it's going to focus
on some of the myocardial metabolomics in this condition. But
before we get to that, how about we grab a cup of coffee, and
jump into some of the other articles in the issue? How about if I
go first?


Dr. Peder Myhre:


Let's go, Greg.


Dr. Greg Hundley:


Okay. So Peder, some believe that cardiovascular disease may be
the main reason for stagnant growth in life expectancy in the
United States since 2010. And so, the American Heart Association,
as you know, recently released an updated algorithm for
evaluating cardiovascular health. Life's Essential 8, and it has
a very nice score. So these authors, led by Dr. Lu Qi, from
Tulane University, aimed to quantify the associations of the Life
Essential 8 scores with life expectancy in a nationally
representative sample of US adults. And the team included 23,000
non-pregnant non- institutionalized participants who were age 20
to 79 years, who participated in the National Health and
Nutrition Examination survey, or NHANES, from 2005 to 2018. And
whose mortality was identified through linkage to the National
Death Index, from the period extending through December of 2019.


Dr. Peder Myhre:


Oh wow. So really, a validation of the Life's Essential 8. Greg,
that's so interesting. What did they find?


Dr. Greg Hundley:


Right Peder, as you say, very interesting. So here are some of
the data, and let's itemize them. So, during a median of 7.8
years of follow up, 1,359 total deaths occurred. Now, the
estimated life expectancy at age 50 was 27.3 years, 32.9 years,
and 36.2 years, in participants with low Life's Essential 8
scores, less than 50. Moderate, so Life's Essential 8 scores of
greater than or equal to 50, but less than 80. And then, high
scores, greater than 80. Okay? So equivalently, participants with
high Life's Essential 8 scores had an average of 8.9 more years
of life expectancy at age 50, compared to those with low scores.


Next, on average, 42.6% of the gained life expectancy at age 50,
from adhering to sort of that cardiovascular health, those
recommendations, was attributable to reduced cardiovascular
death.


Next, significant associations with the Life's Essential 8 score
and life expectancy were observed in both men and women.


Next, similarly significant associations of cardiovascular
health, Life's Essential 8, with life expectancy were observed in
non-Hispanic Whites and non-Hispanic Blacks, but not in those
originating from the country of Mexico.


So Peder, finally, in summarizing all of this, adhering to the
cardiovascular health lifestyle, defined by the Life's Essential
8 score, it was related to a considerably increased life
expectancy. However, because of the findings from the individuals
from the country of Mexico, more research is needed to be done in
some of these minority groups, and particularly, those of
Hispanic ethnicity, and perhaps other races.


Dr. Peder Myhre:


Oh, wow. Very interesting. And I would love to learn more about
this subgroup analysis in future studies.


So Greg, the next paper is about the hospitalization for heart
failure measures. Because contemporary measures of hospital
performance for heart failure hospitalization, the 30-day risk
standardized readmission and mortality rate, are estimated using
the same risk adjusted model and overall event rate for all
patients. Thus, these measures are mainly driven by the care
quality and outcomes for the majority racial ethnic groups, and
may not adequately represent the hospital performance for
patients of Black or other races. And in this study, led by
co-corresponding authors, Mentias from Cleveland Clinic and
Pandey from University of Texas Southwestern Medical Center, the
authors used fee for service Medicare beneficiaries from 2014 to
2019 hospitalized with heart failure, in hospital level 30 day
risk standardized remission and mortality rates were estimated
using traditional race agnostic models and the race specific
approach, with measures derived separately for each race
ethnicity group.


Dr. Greg Hundley:


Ah, very interesting, Peder. So what did they find from this
study?


Dr. Peder Myhre:


So the study included more than 1.9 million patients, comprising
of 75% White patients, 15% Black patients, and 10% patients of
other races, with heart failure from 1,860 hospitals. And
compared with the race agnostic model, composite race-specific
metrics for all patients demonstrated stronger correlation with
30 days readmissions. And that is correlation coefficient 0.78
versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black
patients. In concordance in hospital performance was for all
patients and patients of Black race was also higher with race
specific as compared to race agnostic metrics.


So Greg, the authors conclude that among patients hospitalized
with heart failure race specific 30 day risk standardized
remission and mortality rates are more equitable in representing
hospital performance for patients of Black and other races.


Dr. Greg Hundley:


Very nice, Peder. What a beautiful summary in a very elegant
study. Peder, myocardial insulin resistance is a hallmark of
diabetic cardiac injury. However, the underlining molecular
mechanisms for this relationship remain unclear. Now, recent
studies demonstrate, that the diabetic heart is resistant to
several cardioprotective interventions, including adiponectin and
pre-conditioning. The universal quote, unquote, resistance to
multiple therapeutic interventions suggest, impairment of the
requisite molecule, or molecules, involved in broad pro survival
signaling cascades. Now caveolin is a scaffolding protein
coordinating trans-membrane signaling transduction. However, the
role of caveolin-3 in diabetic impairment of cardiac protective
signaling and diabetic ischemic heart failure is unknown. And so
these investigators, led by Dr. Xinliang Ma, from Thomas
Jefferson University, studied mice fed a normal diet or high fat
diet for two to 12 weeks, and subjected them to myocardial
ischemia and reperfusion.


Dr. Peder Myhre:


Oh wow. What an interesting preclinical science paper, Greg. What
did they find?


Dr. Greg Hundley:


Right. So the authors found that nitration of caveolin-3 at
tyrosine 73 and resulted signal complex dissociation was
responsible for cardiac insulin adiponectin resistance in the
pre-diabetic heart. And this contributed to ischemic heart
failure progression. Now, early interventions preserving
caveolin-3 centered signal zone integrity was found to be an
effective novel strategy against diabetic exacerbation of
ischemic heart failure. And Peder, I think these very exciting
results suggest that this is a new area of research and further
experiments are warranted.


And there's a very nice editorial by Professor Heidenreich,
entitled “Pursuing Equity in Performance Measurement.


Well Peder, there's some other articles in this issue, and we'll
dip in this week to the mail bag, for a Research Letter from
Professor Hibbert, entitled “Utility of a Smartphone Application
in Assessing Palmar Circulation Prior to Radial Artery Harvesting
for Coronary Artery Bypass Grafting.”


Dr. Peder Myhre:


That is so cool. And we also have a Letter from Dr. Kim,
regarding the article entitled, “Detection of Atrial Fibrillation
in a Large Population Using Wearable Devices: The Fitbit Heart
Study.”


Dr. Greg Hundley:


Very nice. Well, how about we get along to one of Carolyn's
favorite topics, heart failure with preserved ejection fraction,
and learn more about myocardial metabolomics?


Dr. Peder Myhre:


Can't wait.


Dr. Carolyn Lam:


Today's feature discussion is on my favorite topic, heart failure
with preserved ejection fraction, or HFpEF. But today, what we're
focusing on is truly novel. We are looking at the myocardial
metabolomics of human HFpEF, very, very valuable data and
insights. We're so pleased to have with us the corresponding
author of today's feature paper, Dr. Kavita Sharma, who's from
the Johns Hopkins University School of Medicine, and our
associate editor, Dr. Svati Shah, who's, of course, from Duke
University School of Medicine.


So welcome Kavita and Svati. Kavita, if I could start by, please
put us and bring us all to the same level of knowledge, by
perhaps explaining in simple terms, what is metabolomics? And
what is normal versus perhaps abnormal metabolomics, in a known
condition, like systolic heart failure or heart failure with
reduced ejection fraction?


Dr. Kavita Sharma:


Sure. Well thank you, Carolyn, for the opportunity to chat around
this topic. And it's great to be with you and Svati this morning.
Metabolomics is a broad general study of essentially, all the
chemical processes involving metabolites, or small molecule
substrates, their intermediates, and even the products of
cellular metabolism. This can be studied in really, any organ
system, in any organ. What is really unique, I think, to this
particular paper in our project is that, it has yet to have been
defined or described in human HFpEF from the myocardial tissue.
We call this heart failure with preserved ejection fraction, and
inherent to that name in this complicated syndrome is that, there
is something probably wrong with the heart, yet we have not
really had much insight to what that might be from direct
myocardial tissue.


We are also still learning about what metabolomics looks like in,
for example, the heart failure with reduced ejection fraction
state. Though, there is more published in this space than in
HFpEF. From the limited knowledge that we have, it does appear
that heart failure with reduced ejection fraction hearts, and
this is certainly seen in the plasma, which is where most of
metabolomic studies have generated from, those hearts tend to
utilize various forms of energy banks, if you will. Whether
that's fatty acid oxidation, whether that is glucose utilization
or intermediates and so on. And our primary interest was to
understand, how do the preserved EF parts in patients fare in
comparison?


Dr. Carolyn Lam:


Oh, thank you so much, Kavita. That was beautifully explained.
And indeed, what's so special about your paper is, it's not just
circulating metabolites but myocardial metabolites. And you have
the control groups that are so important to study at the same
time. So patients with HFpEF, but also those with HFrEF and
versus controls. And thank you for establishing too, that if I'm
not wrong, fatty acid metabolism accounts for the majority of ATP
generation in the normal heart. Whereas, this declines a little
in the HFrEF heart. And now, I think we're about to find out what
happens in the HFpEF heart. So if you could explain what you did
and what you find.


Dr. Kavita Sharma:


Yes, absolutely. So we examined, again, tissue and plasma
metabolomics from 38 subjects with HFpEF. These are patients
referred to the Hopkins HFpEF Clinic. And so they have been
essentially, clinically evaluated, and have what we define as
HFpEF, based on hemodynamic testing. So a right heart
catheterization, often with exercise, that meets criteria for
diagnosis of the syndrome.


As you stated, we compared our HFpEF patient tissue and plasma
samples to samples coming from patients with HFrEF, dilated
cardiomyopathy, and non-failing controls. And the latter two
sources were a tissue bank from the University of Pennsylvania,
that is long-standing, where patients with endstage dilated
cardiomyopathy are able to have tissue banked at the University
of Pennsylvania at the time of explant prior to transplant. So
albeit, we are comparing to fairly advanced end stage dilated
cardiomyopathy, and control tissue comes from unused donor
hearts, essentially. So presumably, normal heart function
patients, likely in a brain death state, who for whatever reason,
the hearts were not utilized for transplantation. Again, not an
entirely perfect controlled state, but again, given the nature of
the work, the fact that it's myocardial tissue, the closest that
we have found we've been able to come to for a control
comparison.


We started out performing what we call quantitative targeted
metabolomics. We measured organic acids, amino acids, and
acylcarnitines in the myocardium. And that was totaling around 72
metabolites. And we did the same in plasma, so close to 69
metabolites. And our metabolomics work was actually completed at
the University of Pennsylvania. And so, I wish to credit Dr.
Zoltan Arany and Dr. Dan Kelly for their great collaboration in
this study.


Dr. Carolyn Lam:


That's wonderful. Kavita, if you could tell us a little bit more
about the patients with HFpEF. We understand it was end stage
dilated cardiomyopathy, HFrEF, and donor hearts as the controls,
but the patients with HFpEF, in relation to obesity, diabetes,
and how that may impact the interpretation of the results.


Dr. Kavita Sharma:


Sure. So these are HFpEF patients that are in an ambulatory state
outpatient setting. They have many of the comorbidities we know
are intrinsic today to HFpEF. Out of our HFpEF population, the
majority were women. So 71%, that's 27 out of the 38 we serve.
And we're very fortunate to serve a African-American enriched
population in Baltimore that's intrinsic to our center. And so,
over half of our patients were Black. The remaining Caucasian,
one non-Caucasian. Over half had been hospitalized, for example,
in the prior one year. So these are certainly symptomatic
patients. And all had NYHA II or greater symptoms.


We do have a rather obese cohort at Hopkins. And so, our median
BMI, for example, was 39, our mean is very similar. And the
majority have, as we see often in HFpEF, the majority with
hypertension, over half with diabetes. In fact, it was actually
70% or so. Rather few with coronary disease, and this is a trend
we're seeing in general in HFpEF in the present day kind of
common phenotypes, and about a third with atrial fibrillation. So
really, representative, I think, of this kind of cardiometabolic
as we call it, phenotype of HFpEF, that is the predominant
phenotype we're seeing, at least in North America.


Dr. Carolyn Lam:


Oh, that's perfect. And then, maybe just a few words about the
results before I bring Svati in for her thoughts. Thanks.


Dr. Kavita Sharma:


Sure, absolutely. So we conducted this study in a couple
different stages. We first started with performing a principal
component analysis and hierarchical clustering analysis, to see
whether the myocardial metabolites and the plasma metabolites,
respectively, would they distinguish these three patient groups?
So HFpEF from HFrEF and controls. And interestingly, in the
myocardial tissue, our PCA analysis and our hierarchical
clustering analysis show that actually, in fact, as few as 70
metabolites in the myocardium really distinctly differentiate
these three subgroups. The top contributors that separated HF
from controls, for example, and HFrEF, were mostly related to
amino acids, including branched chain amino acids and their
catabolites, as well as medium and long chain acylcarnitines,
which are byproducts of fatty acid oxidation.


When it came to the plasma metabolome, on the other hand, there
was far less distinguishing between the groups, and significant
overlap, both in PCA and hierarchal clustering. And really, the
take home there is that, the myocardial tissue and the plasma
were really quite distinct for the overall metabolite analysis.
But then, even as we broke it down by fatty acid oxidation, by
glucose metabolism, and even branched chain amino acids, we saw
this trend continue, that the plasma was quite distinct from the
myocardial tissue.


Now, which of the two is more representative of the disease
state? Which is the one that we should be paying more attention
to? I think that remains to be fully understood further. And of
course, it would be really nice to replicate these findings in
another cohort. But that is something that, I think, is a first,
that certainly, that we have seen and important for the
community.


Dr. Carolyn Lam:


Indeed. Oh, Kavita, we could go on talking forever, but I'd
really love Svati's thoughts. Why was this paper so special? What
does it tell us clinically with any implications?


Dr. Svati Shah:


Yeah. I just want to commend Dr. Hahn, Dr. Sharma, on this
incredible work. If you can just imagine how much painstaking
work this took for Dr. Sharma and Dr. Hahn. It's a very careful
phenotyping of HFpEF. These are true HFpEF patients. The ability
to get tissue, and to pair the tissue to the plasma, so that we
can really understand. When we measure things in the circulation,
and we think they're telling us about the heart, are they
actually telling us about the heart? So I really want to commend
this incredible work.


And Carolyn, I love talking about cardiac metabolism, because the
heart is an incredible organ, right? The heart is a metabolic
omnivore. It'll eat many different kinds of fuels, and a lot of
different things determine which fuels it uses. And as you nicely
outlined, Carolyn, earlier, in the normal heart, the heart
prefers to use fatty acids.


But what we are not completely certain of is, what happens in
HFpEF? So in HFrEF, we know that the heart switches to glucose,
which is not a great fuel, actually. It's actually, a
metabolically inefficient fuel. And so we know in HFrEF, that the
heart has this metabolic inflexibility. All of a sudden, it's not
an omnivore, and it's kind of stuck with certain fuels, which are
not very healthy for it.


But what Dr. Sharma and Dr. Hahn have shown, for the first time
really, is what happens in HFpEF? And so, I think it's really
cool that, actually, it just highlights how complex HFpEF is as a
disease. So they were able to show that in some ways, HFpEF is
similar to HFrEF, including that there's impairments in use of
these fatty acids, which is what the normal heart does.


But, they also show that HFpEF may be different than HFrEF in
many ways, including, because of these branched chain amino
acids. And that may be because of some of the clinical
differences that we know exist in patients with HFpEF, including
the obesity and diabetes, that Dr. Sharma nicely outlined.
Although, I want to point out, they were very careful about
trying to take these clinical factors into account when they
looked at differences in the metabolites.


So really incredible work, highlighting that the HFpEF heart also
has this metabolic inflexibility. It also is not a metabolic
omnivore like the normal heart is, but highlighting important
differences, potentially, between HFpEF and HFrEF.


Dr. Carolyn Lam:


Oh, Svati, thank you for putting that so clearly.


Dr. Kavita Sharma:


No, I think that was a really elegant summary of the findings,
Svati. And thank you for your kind words and support in allowing
us to share our work through Circulation. I really couldn't say
it better, but that's exactly what we seem to find is that, when
we look at various sort of stores or banks of energy resource,
what we really found is that these HFpEF hearts are energy
inflexible, as Svati said, that begins with fatty acid
metabolism. And so, when we look at, for example, medium and
launching acylcarnitines, what we find is that these are markedly
reduced in HFpEF myocardial tissue, quite similar to HFrEF.
Again, both of them reduced compared to controls. And again,
these are byproducts of fatty acid oxidation, and that is really
responsible for almost 80% of generally what we think of energy
metabolism in the normal state.


In the plasma, however, again, back to that theme where we don't
see that reproduced in the plasma, we find that HFpEF is actually
not too dissimilar from controls for certain medium and long
chain acylcarnitines, and then closer to HFrEF in some cases. And
interestingly, we compared our metabolomics study to our prior
report of our RNA sequencing paper, that was also published in
Circulation now two years ago. And what we found is that, there
is reduced gene expression of many of the proteins involved with
fatty acid uptake and oxidation, when we compare them to control
states. So the story is sort of, fits with what we have seen
previously, and when we focus in on this group of genes.


Our analysis of glucose metabolism though, did not include
glycolysis or glucose oxidation intermediates. We still found
that, majority of the TCA cycle intermediate, so succinate, for
example, fumarate, malate, were all reduced in HFpEF versus
control. It was really only pyruvate in isolation that was
increased in HFpEF myocardium, compared to controls. And again, a
number of genes implicated in glucose metabolism in general, we
found to be lower in HFpEF versus control, including gluten 1, or
SLC2A1, which is involved in glucose uptake.


So again, this theme of, we have patients with significant
obesity, many in the diabetic state, we would think that these
hearts would utilize these energy stores, but they don't seem to
be. And finally, we see distinct differences in the tissue and
branched chain amino acid pathways as well. There appears to be
some sort of a block between the branched chain amino acids, and
then sort of byproducts, as you continue down through ketoacids
and further. And we don't fully understand where those blocks
are, but that was certainly notable.


And then lastly, I'll say, one interest that we've had, and
really, what led to much of this work in the tissue, is to pursue
what we call deep phenotyping. Can these molecular signatures,
whether it's gene expression, or metabolomics, or what we're
working on now, which is proteomics, can these really help us
identify unique subgroups within HFpEF? And so, we've tried to do
that with the metabolomics, and we found that, using various sort
of clustering analytical methods, in fact, there is significant
overlap, as it turns out, within HFpEF, when it comes to the
metabolomic signatures. And we only found, really, two subgroups
within HFpEF. And even these two really did not have much that
distinguished them, beyond branched chain amino acids.


And so, this is the first time, at least that our group has seen,
at a tissue level, that there is actually a fair bit of
homogeneity now in the metabolomic signatures, compared to our
RNA sequencing work. And that may be reflective of now, this
increasingly cardiometabolic phenotype of HFpEF. And now, we may
be seeing signs of that at the clinical and at the treatment
level, where we have therapies like SGLT2 inhibitors, that are
showing benefit to what seems to be a much broader spectrum of
HFpEF, compared to prior therapies. So a lot of questions that
have been generated from the work, and we're looking forward to
exploring much of this in more detail.


Dr. Carolyn Lam:


And Svati, may I give you the last word? Where do you think this
field is headed next?


Dr. Svati Shah:


I think there's so much to do, and I think Dr. Sharma and Dr.
Hahn have highlighted how much work there is to do in this space.
We're brushing the surface and understanding cardiac metabolism
with this really important paper. But Carolyn, as you pointed
out, we really need to understand what happens to these patients
over time? What happens to, not just cardiac metabolism, but
molecular biology more broadly, in patients with HFpEF with these
various treatments? Including now, thank goodness, we have SGLT2
inhibitors as a therapeutic intervention for patients with HFpEF.
And in fact, we published in Circulation a few months ago, a
paper led by a very talented junior faculty, Senthil Selvaraj,
where we actually showed that these acetylcarnitine levels that
reflect fatty acid oxidation actually are changed by SGLT2
inhibitors, and are associated with changes in clinical outcomes
in HFpEF. So we really need larger sample sizes, being able to
look at these patients in a longitudinal fashion. But really,
doing what Dr. Sharma and Dr Hahn have done, which is careful,
careful phenotyping and multidisciplinary teams, so that we can
understand the molecular biology, as well as the clinical
implications.


Dr. Carolyn Lam:


Oh, wow. Thank you so much, Kavita and Svati, for this incredible
interview. I learned so much, and enjoyed it so thoroughly, as
I'm sure our listeners did as well.


Well, listeners, you've been listening to Circulation on the Run.
Thank you for joining us today, and don't forget to tune in again
next week.


Dr. Greg Hundley:


This program is Copyright of the American Heart Association 2023.
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.