Circulation January 31, 2023 Issue

Please join Guest Host Maryjane Farr, authors Sarah
Franklin and Stavros G. Drakos, as well as Associate Editor
Hesham Sadek as they discuss the article "Distinct Transcriptomic
and Proteomic Profile Specifies Heart Failure Patients With
Potential of Myocardial Recovery on Mechanical Unloading and
Circulatory Support."


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
cohosts. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center in Duke National University of Singapore.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre, social media editor from Akershus
University Hospital and University of Oslo.


Dr. Carolyn Lam:


Peder, today's featured paper is very, very important in the
heart failure world. It is such a deep dive into the
transcriptomic and proteomic profile that specifies heart failure
and the potential of myocardial recovery with mechanical
unloading and circulatory support.


Dr. Peder Myhre:


Can't wait for that feature discussion today, Carolyn.


Dr. Carolyn Lam:


But you have to wait because I insist on telling you about yet
another really important paper, of course in my favorite subject,
heart failure with preserved ejection fraction or HFpEF. Now you
know that exercise intolerance is a defining characteristic of
HFpEF and a marked rise in pulmonary capillary wedge pressure
during exertion is pethepneumonic for HFpEF and it's thought to
be a key cause of the exercise intolerance. Now if that is true,
acutely lowering the wedge pressure should improve exercise
capacity, right? Well, don't assume this because to test this
hypothesis, authors led by corresponding author Dr. Ben Levine
from UT Southwestern evaluated peak exercise capacity with and
without nitroglycerin, which was used to acutely lower pulmonary
capillary wedge pressure during exercise in patients with HFpEF.


Dr. Peder Myhre:


Oh, that's so cool. What an amazing research question and
Carolyn, you're the best to summarize this. Please tell us what
did they find?


Dr. Carolyn Lam:


Well, they studied 30 patients with HFpEF and get this. They
underwent two bouts of upright seated cycle exercise dosed with
sublingual nitroglycerin or a placebo every 15 minutes in a
single blind randomized crossover design. So really well done.
Wedge pressure, VO2 and cardiac output were assessed at rest with
20 watts exercise and at peak exercise during both the placebo
and nitroglycerin conditions and the principle finding of the
study (singing) acutely lowering pulmonary capillary wedge
pressure during upright exercise with nitroglycerin in HFpEF did
not improve peak exercise performance. So peak VO2 was
practically identical with a 1% difference despite a 17% drop in
peak wedge pressure. Peak cardiac output and peak peripheral
oxygen extraction were unchanged, again, despite the drop in peak
wedge pressure suggesting that oxygen delivery and utilization
were unaffected. Exercise performance variables including peak
wattage, peak ventilation and peak RER were unchanged, suggesting
that again, reductions in peak wedge were insufficient to improve
exercise tolerance.


All these results suggest acute reductions in wedge pressure are
insufficient to improve exercise capacity and provide convincing
evidence that a high wedge during exercise by itself is an
epiphenomenon perhaps rather than a primary limiting factor for
exercise performance in patients with HFpEF. Now of course this
is incredibly interesting contrary to hypothesis and so please
read the paper. The discussion is very rich.


Dr. Peder Myhre:


Oh wow, Carolyn. That is such a great paper. I can't wait to pick
it up and read it from start to finish and now Carolyn, we're
going to look into research within cardiovascular disease from
COVID-19 and we have learned so much and so quickly about
COVID-19 and its effects on the heart and we have really come a
long way from the first case reports reported in the beginning of
the pandemic and this paper, which comes to us from corresponding
author Professor JP Greenwood, really adds important knowledge to
this field. The COVID heart study was a prospective longitudinal
multi-center observational cohort study of patients hospitalized
with COVID-19 and at elevated serum troponin levels across 25
hospitals in the UK and these investigators aim to characterize
myocardial injury, its association and sequela in convalescent
patients following hospitalization with COVID-19 utilizing
appropriately matched contemporary controls.


Dr. Carolyn Lam:


Ooh, important stuff. So what did they find?


Dr. Peder Myhre:


So these authors included in total 519 patients comprising 342
patients with COVID-19 and an elevated troponin, 64 patients with
COVID-19 and a normal troponin and 113 age and comorbidity
matched controls without COVID-19 and the frequency of any heart
abnormality defined as left or right ventricular impairment, scar
or pericardial disease was two full greater in patients with
COVID positive and troponin positive, so 61% compared to the
control groups and that is 36% for COVID positive and troponin
negative and 31% for COVID negative and comorbidity positive and
the myocardial injury pattern was different for these patients
with COVID and an elevated troponin more likely than controls to
have infarction and micro infarction. But there was no difference
in non-ischemic scar and using the late MRI criteria, the
prevalence of probable recent myocarditis was almost 7% for those
with COVID and elevated troponin compared to only 2% for the
controls without COVID-19 and myocardial scar is but not prior
COVID-19 infection or troponin was an independent predictor of
MACE.


So Carolyn, these authors discussed their findings in light of
previously reported studies and these authors identified a lower
prevalence of probable recent myocarditis than previously
described and a higher proportion of myocardial infarction and
this newly described pattern of micro infarction following
COVID-19 and Carolyn, there is a brilliant editorial really
summarizing this by Dr. Stuber and Baggish entitled "Acute
Myocardial Injury in the COVID Heart Study Emphasizing Scars
While Reassuring Scarce." I really recommend everyone to pick
this up and read the editorial as well.


Dr. Carolyn Lam:


Very clever title. Thank you. For the last original paper in
today's issue, it focuses on the crosstalk between sterile
metabolism and inflammatory pathways, which have been
demonstrated to significantly impact the development of
atherosclerosis. Authors today are featuring and focusing on 25
hydroxy cholesterol, which is produced as an oxidation product of
cholesterol and belongs to a family of bioactive cholesterol
derivatives produced by cells in response to fluctuating
cholesterol levels and immune activation. So these authors with
co-corresponding authors, Dr. Suárez and Fernández-Hernando from
Yale University School of Medicine, they showed beautifully that
first, 25 hydroxy cholesterol accumulates in human coronary
atherosclerosis. Next, that 25 hydroxy cholesterol produced by
macrophages accelerated atherosclerosis progression and promoted
plaque instability by promoting the inflammatory response in
macrophages and also via paracrine actions on smooth muscle cell
migratory responses.


Dr. Peder Myhre:


Wow, that is so interesting, Carolyn. What are the therapeutic
implications of these findings?


Dr. Carolyn Lam:


Yes, I'm glad you asked because it was summarizing a lot of work
in those findings with the very important implications that
inhibition of 25 hydroxy cholesterol production might therefore
delay atherosclerosis progression and promote plaque stability.
So this study actually opens a door to explore the role of 25
hydroxy cholesterol as a target to control inflammation and
plaque stability in human atherosclerosis.


Dr. Peder Myhre:


Oh, that is so important. Thank you so much and there is more in
this issue as well, Carolyn. We have another issue of Circulation
Global Rounds and this time we're going to France in a paper
written by Dr. Danchin and Bouleti. We also have an exchange of
letters by Dr. Yang and Dr. Schultze regarding the article, "Deep
Lipidomics in Human Plasma: Cardiometabolic Disease Risk and
Effect of Dietary Fat Modulation" and an ECG Challenge by Drs.
Manickavasagam, Dar and Jacob entitled "Syncope After
Transcatheter Aortic Valve Implantation: Pace or Not."


Dr. Carolyn Lam:


Interesting. There's a Frontiers paper also by Dr. Dimopoulos on
“Cardiovascular Complications of Down Syndrome: Scoping Review
and Expert Consensus,” a Research Letter by Dr. Kimenai on the
impact of patient selection on performance of an early rule out
pathway for myocardial infarction from research to the real
world. Nice. Well let's carry on to that feature discussion on
heart failure, transcriptomics and proteomic, shall we?


Dr. Peder Myhre:


Can't wait.


Dr. Maryjane Farr:


Welcome everybody to Circulation on the Run. We are so pleased to
be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from
the University of Utah. My name is Maryjane Farr and I am the
heart failure section chief at UT Southwestern and Digital
Strategies editor for circulation. Myself and Hesham Sadek will
be talking with them about their new paper and circulation called
"Distinct Transcriptomic and Proteomic Profile Specifies Heart
Failure Patients with Potential of Myocardial Recovery Upon
Mechanical Unloading and Circulatory Support." Just briefly, Dr.
Stavros Drakos is the director of cardiovascular research for the
division of cardiology at Utah and co-director of the Heart
Failure Mechanical Circulatory Support and Heart Transplant
Program. Dr. Sarah Franklin is associate professor of medicine at
the University of Utah whose lab has a specific expertise in the
applications of proteomics to heart disease. Welcome, Stavros and
Sarah.


Dr. Sarah Franklin:


Thank you.


Dr. Stavros Drakos:


Thank you. Thank you for having us.


Dr. Maryjane Farr:


This paper is exciting for clinicians. It's exciting for
translational scientists. Hesham, why don't you start digging
into this paper and tell us one or then the other of you tell us
what this paper is about, what's the background and let's get
into the science. Let's go there and then we'll pull back and
look at some of the big picture stuff. Hesham.


Hesham Sadek:


Well, thank you. So I've been fascinated by the field of cardiac
recovery for some time now and obviously Stavros is as an expert
and one of the leaders of that field and what struck me about
this is that we are starting to see some distinct molecular
signature of patients that can experience recovery as opposed to
patients undergoing the same procedures with the same profile
that do not manifest evidence of myocardial recovery and
specifically, the study was conducted very rigorously and the
signature was very clear in that they saw primarily interest for
someone like me who's interested in cardiac regeneration, a
signature of cell cycle in the patients that experience recovery
as well as ECM signature which could suggest reverse remodeling
and also there's some evidence that ECM might impact
cardiomyocyte and myocardial regeneration. So my interest in this
for selfish reasons is primarily that this supports the
hypothesis that perhaps there is a molecular signature of
regeneration that occurs in patients that experience myocardial
recovery with LVAD.


Dr. Maryjane Farr:


So Stavros, let's start with you. Give us the reason why to do
this study. You mentioned some of the background. It'd be great
to sort of talk for a moment about re-stage heart failure and
then how it brought you to this study.


Dr. Stavros Drakos:


Thank you, Jane. So again, thank you for the opportunity to talk
about the findings and the implications of this study. I like the
way you are asking us to look a little bit at what led to this
study and as you mentioned, the re-stage is a multi-center study
that was performed in six US sites which showed in a reproducible
fashion now given that we had single center studies from all over
the world suggesting that, advanced heart failure is not an
irreversible process that has to lead to end stage, an
irreversible disease and what a re-stage demonstrated was that
there is a subset of patients which if you select them based on
clinical characteristics that we derived from other studies that
were performed previously, you can achieve reverse remodeling,
essentially a bad heart looking much better by every clinical,
functional, structural characteristic in up to 50% of the
selected patients. That's what re-stage showed.


So having this finding now in a multicenter study, what made this
study very timely was to be able to understand what drives this
remarkable response. What are some of the mechanisms, as Hesham
said, that we can if uncover take advantage of and expand this
paradigm and enhance it and achieve reverse remodeling and
recovery of even more patients and even go earlier in the disease
process. So that's kind of how I would link the clinical findings
that preceded this study with the motivation to perform the study
and the implications of these findings for the ongoing
translational and basic science research.


Hesham Sadek:


I'd like to ask a question here. So Stavros, do you think it's
too early to sort of redefine the term reverse remodeling in this
context to include perhaps some evidence of regeneration? Is
there evidence of regeneration in this field or that's too
premature to say?


Dr. Stavros Drakos:


I think the data are directing us towards the direction you just
mentioned. I think that we can begin talking about it and
planting the seed. We do have other evidence from work that you
and others have performed indicating that this indeed is one of
the mechanisms that drives this phenomenon and I think that the
findings, especially in the cell cycle that we identified add to
and contribute even more to that body of work that you and others
have done. At this point, I will turn it to Sarah who can talk a
little bit more about the findings related to the cell cycle that
we identified in our study and I think that these may complete
the answer to you, Hesham.


Dr. Sarah Franklin:


Yeah, I would love to comment. I think it's a really interesting
phenomenon and really in these patient samples we were trying to
understand molecularly what the difference is between individuals
that respond positively to therapy and individuals that receive
the same exact therapy and do not respond positively. So these
are termed responders and non-responders and in our analysis we
combined two platforms where we could molecularly interrogate
what's different in these two tissues and try to see what is
differentiating these populations. So what's consistent and
reproducible different in responders and non-responders on a
molecular level and in both the transcriptomic data and the
phospho proteomic data, we saw clear patterns with cell cycle
regulation and extracellular matrix or focal adhesion molecules
and the interesting thing about cell cycle is cardiomyocytes have
typically been thought to exit the cell cycle not long after
birth and we see some interesting phenomenon either in humans or
mice where we can have nuclei that have either multiple sets of
chromosomes or multiple nuclei and there's some differences that
have been observed in the nucleus with regards to disease, so
hypertrophy, heart failure.


So the molecules that we've identified, we saw a large difference
in proteins involved in cell cycle regulation. Now the
interesting thing is not all of those molecules are increasing or
decreasing. We see a combination of molecules that are increasing
or decreasing. But I think the other thing that's interesting is
that these molecules, even though we are seeing changes in
expression or changes in phosphorylation, exactly how that
contributes to either cell cycle or cell cycle reentry or just
nuclear function and transcription of proteins or genes or DNA
regions is still what we need to continue to study. So exactly
how these changes in proteins or transcripts related to the cell
cycle, how they are exactly contributing to the physiological
improvements that we're seeing is something that still needs to
be investigated but is really important that that is a highlight
of this study and as Stavros mentioned of previous work.


Dr. Maryjane Farr:


Stavros, tell us the design of the study.


Dr. Stavros Drakos:


Okay. So this study was performed in 93 patients that were
prospectively enrolled in the Utah transplant affiliated
hospitals here in Salt Lake City between the University of Utah,
Intermountain Medical Center and the VA and these people came
from all over the mountain west, the surrounding states of Utah
and through our VA, through the state, from all over the west and
south, from Alaska and Hawaii to Texas and we think it's a very
representative population of our country's patient population and
then we followed prospectively these people with serial
echocardiograms so we can tell who will respond as Sarah said
before, which essentially means which hearts are going to get
better by echocardiographic criteria functionally and
structurally, the dimensions of the heart shrinking and the
ejection fraction improving to more than 40% and the dimension
shrinking to normal range and then we compare these people, the
subset of patients that have responded to the majority of
patients actually that they have not responded. As we know these
are advanced end stage patients and there is only a subset of
those that they will favor respondents.


As we said earlier, these subset can increase if you go
selectively and pick these patients based on baseline
characteristics. So then we analyze the tissue we got from these
people when the LVAD went in, which is the core of the apex of
the heart and compare that to the tissue we receive when the
patients got transplanted and we got the whole heart. So in the
meantime, as we just discussed, we phenotyped these people so we
knew who were responders and non-responders and then we went back
in the lab and tried to marry two basic processes, analyzing the
transcriptome and the proteome and by doing that we were able to
see some overlapping changes between the transcriptome and the
proteome and we felt that by doing this overlapping analysis, we
will increase the likelihood that what we are seeing, exponential
mechanistic drivers will be the real mechanism and not just
associations that you can frequently find when you do studies in
humans and that's kind of a rough, brief summary of the design.
Sarah, would you add something to that?


Dr. Sarah Franklin:


No, I think that's a great overview of it. I think what excites
me about it is that this was first clinically observed that these
patients were recovering and so I think the exciting part is the
hypothesis was that there was some molecular underpinnings that
could molecularly define these patients that were responding or
not responding and so with that hypothesis we then carried out
these analyses hoping that we would see a difference and we're
very excited. It's very successful in that we found very clear,
molecular differences that are reproducible between these patient
populations.


Dr. Maryjane Farr:


So obviously there's lots of implications. Let me start with one
very simple clinical one and that is, so based on some of the
differences in the signatures and pathways that you saw for the
next patient who needs LVAD therapy and you're trying to predict
in some way whether they may be a responder or a non-responder,
could you look at a biopsy sample and try to make some sort of
prediction based on some of your findings so that they can choose
a VAD over a transplant? That's a very clinical question and then
I guess the second question is would it have to be a left
ventricular myocardial sample? So are the differences? What do
you think about that question? Or it's just too much too, far
beyond? This is obviously a mechanistic study. But I'm just
asking.


Dr. Stavros Drakos:


No, that's a great question and I'll start and Sarah can add
later. So obviously it will be great if we can have a practical
way to predict before the intervention who are the people that
they will respond and that's one of the motivations for this
study. It was not just to find the mechanism so we can make this
phenomenon better and enhance it and find the mechanism, create
new therapies. It was also the practical approach that you
suggested, Jane, and I think that yes, this adds to the clinical
predictors that we have already identified from other studies and
yes, we could theoretically take the tissue and do this analysis.
Is this the most practical thing we can say to the patient to
biopsy the heart, right? It would've been better to be able to
identify a biomarker in the plaque and we've done that. We
started in other studies, identifying what's going on in the
tissue and then going targeted in the blood and that's how we
identified two cytokines and a two cytokines model, interferon
gamma and TNF alpha being predictive as circulating biome.


In this study we identify changes that can also inform future
studies of biomarkers in the blood. But if we had a way to easily
get the tissue and analyze the genes, yes, we could have done
that as a predictor as well. The practical issue is that asking a
patient for a biopsy just to predict the response to therapy may
be something that most patients and most clinicians will consider
way too advanced and complicated, right?that's why more work
should and could be done to identify circulating biomarkers or
other modalities that can help us interrogate what's going on in
the heart related with these findings. But not that we cannot
also do what you said. It's just more complicated. I don't know
if Sarah would like to add to this.


Dr. Sarah Franklin:


I'd love to. I think that's a great overview. I think the only
thing that I would add is that there are a number of conditions
whether in the heart or otherwise in the body that you can use a
single biomarker and it can be very predictive of conditions.
Heart failure is so complex that often individual biomarkers are
not sufficient enough to cover an entire population and all the
nuances that can go into heart failure symptoms or syndromes and
I think the exciting part about this study is it is one of the
largest cohorts of patients that have been examined in this
manner, which is exciting, but also that we have a multi-factor
panel that is made up of multiple biomarkers that with the number
of individuals that we examined is completely predictive of all
of these patients.


So these biomarkers are consistent and reproducible across all of
these patients between responders and non-responders regardless
of some of the nuances in the heart failure that they have and so
it's very exciting because it's possible that a multifactorial
panel could be much more applicable and last the test of time
more so than an individual biomarker. I think the one other thing
that is exciting like Stavros mentioned is that we did initially
identify these in the left ventricle and it will be really
exciting to see how far these biomarkers can be used if they can
be used in potentially other aspects of the heart or blood, which
obviously is less invasive and so that's not something that we've
applied this panel to yet, but I think is a really wonderful
extension of now saying, can we also identify some of these
biomarkers in the blood which would be less invasive even if it's
a fraction of them. That would still be wonderful.


Dr. Maryjane Farr:


I have so many clinical questions. But Hesham, what questions do
you have?


Hesham Sadek:


Yeah, so the elephant in the room here obviously is that the
variable is that these patients have an unloaded heart and there
is evidence that unloading can reverse some of the changes that
occur after birth with increasing ventricular load and initiate
cascade of molecular events that may allow myocytes to
proliferate. So this begs the question, is there a difference in
how these ventricles of patients that recover versus those that
do not recover see load? Are we able to measure load
appropriately and is there a difference in load between these
patients and if so, can this be improved or detection or
measuring unloading or the degree of unloading clinically, can
this be improved?


Dr. Stavros Drakos:


No, that's a great question and it provides the opportunity to
talk about some of the things we can do on the clinical arena to
further enhance this phenomenon. Yes, there are ways that we can
use to tailor the mechanical unloading that we can provide in
order to enhance this phenomenon. One way, and that's a study
that we are proposing, is to use sensors, pressure sensors that
can guide the way you function the machines, the devices, right?
The way you remove part of the load and these sensors, some of
them are clinically approved like cardioments and then without
doing invasive procedures you can follow chronically how these
patients are being unloaded and how the heart is responding to
this unloading. We know that a lot of LVAD patients, despite
doing clinically well, we know this from snapshot evaluations in
right-heart cath studies, they are not optimally unloaded. They
are feeling pressures left and right are not always optimized and
so by doing this kind of prospective assessment of the mechanical
unloading, you can tailor what you offer and the hypothesis
generated is that by doing that you may be able to recover even
more people.


You can do this as we said, with approved sensors like
cardioments or with other sensors that they are under
investigation. You can also do more invasive stuff like PV loops.
Of course these will require cathing these patients, which is a
little bit more complicated. But it will provide more accurate
assessment and it will also interrogate how the heart is
improving and provide to you in-depth investigation and in-depth
insights on also how the recovery process and the reverse
remodeling process is being, I would say, digested by the heart
and translated to functional response instead of just looking at
it with an echocardiogram or the findings of a right-heart cath
and these are studies that others have performed and have
published and we know that they can give you a real good look
into the systolic and diastolic function of the heart and how
this is changing and improving down the road. So yes, that's the
short answer. We can do that and we can tailor the unloading and
potentially that's the hypothesis, maximize the effect that we
saw here.


Hesham Sadek:


So this begs the question, maybe two questions here. One, is
there evidence that patients who recover not from this study only
but from other studies, is there evidence that patients who
recover are more unloaded than patients that do not recover and
the second question is: is it time to standardize assessment of
mechanical load in patients with LVAD, especially those that will
undergo or would be considered for recovery?


Dr. Stavros Drakos:


Yes. So that's a great opportunity to share with our audience
what we know and what we don't know in this field in relation to
your question about whether we know what is the optimum degree of
unloading and the answer I think is that we need to know and
understand more. What do I mean by that? There's this idea that
the heart as every other organ after being unloaded and not
working for some time may it lazy, may get atrophic and may need
some rehab like the skeletal muscle when we put it in the cast
and get atrophic and we need to rehab it when we remove the cast.
So you can imagine that the LVAD and the unloading that provides,
which in many cases may take over a significant part of the
function of the heart may need gradual reloading as a second
phase after the first phase of unloading and that's something
that we've done. We have an ongoing study on this and also others
have published that it may be beneficial.


Of course, it needs to be validated and investigated further and
to discuss about the degree of unloading in the first phase and
what is the optimum degree of unloading, I would say even there,
there is room for us to understand better what's going on and I
think that we can investigate with ongoing studies right now
whether full unloading versus partial unloading and measure the
pressures using these sensors can translate to better changes
functionally and structurally. I think that's something that is
very doable and it would be very beneficial. What was the second
part of your question, Hesham?


Hesham Sadek:


I was asking whether it's time to start standardizing some
measure of unloading if these patients are planned for recovery?


Dr. Stavros Drakos:


Yes, and that's what we are doing. In all of these people, we
report from the get-go what is their recovery score based on the
intermixed ICARS derived score and when we have patients that
they have high likelihood of recovery, we monitor them very
closely and clinically what we do is just looking at the echo and
whenever we do a right heart cath for clinical reasons. But in a
prospective research study we could do more than just looking at
the echo and occasional right heart cath and using the sensors we
just discussed previously, you can tailor the unloading and begin
prospectively unloading them in a more I would say well monitored
wave. Yes.


Hesham Sadek:


So this is unloading or device specific parameters. Now are there
patient specific parameters with regards to type of heart
failure? So we talked initially about whether there's an element
of regeneration specifically when it comes to cell cycle. But
many patients with non-ischemic cardiomyopathy for example, don't
have large scars and don't have lot of myocytes as the underlying
cause of cardiomyopathy. Would you foresee that there is
different mechanisms, for example, in these patients that don't
have myocyte loss, that perhaps maybe it's not cardio myocyte
proliferation and not regeneration?


Dr. Stavros Drakos:


Yes. So I think that the differential responses we get based on
the heart failure theology warrant further investigation. Sarah
and I have discussed that and actually we are following on our
findings with larger number of patients so we can tease out these
and I'll let Sarah talk a little bit more about it in a minute.
But to answer the clinical part of this question, we don't know
yet whether different parts of heart failure should be prescribed
different modes of unloading. But the way you described it of
course invites the hypothesis that of course different
substrates, different injuries of the heart, as you said, it's a
completely different failing heart if you have a big scar there
versus a patient who has a mode of heart failure, another type of
injury and would this be treated better and more effectively in
terms of reverse remodeling by applying a different mode of
unloading? That's things that we need to investigate further. But
Sarah, would you like to comment on the potential on the effect
of the different heart failure theologies on some of the findings
we saw?


Dr. Sarah Franklin:


Yeah, definitely. So I think it's a really interesting question
and in this analysis we included ischemic and non-ischemic
samples in the patient populations and really we're just
stratifying them based on responders and non-responders. When we
start layering additional levels onto that, then we're
effectively kind of reducing the potential numbers. So if we have
25 responders and we start breaking that down into ischemic and
non-ischemic to see if there's another layer of biomarkers there,
we actually did that we did not include it in this study. It's
something that we're working on to add that. But we do reduce the
number overall of patients in those two populations. So it would
be fine to share that we were seeing stratification between
ischemic and non-ischemic. But we did not feel like the numbers
might be high enough within the responder and non-responder
categories that warrant including that in this manuscript. So
it's very intriguing that just responders and non-responders
alone stratify as well as they do.


They separate based on these biomarkers and it looks like it will
also be possible in the future for us to even separate these
samples further based on similar or additional biomarkers based
on more specific factors in the etiology. So I think that will be
another really exciting next step for future research.


Hesham Sadek:


My final question would be maybe a little bit broader than LVAD
population, but definitely informed by this study. The term
non-ischemic cardiomyopathy, do you think it's too broad and too
vague for us to use in this setting because this encompasses many
different types of cardiomyopathy that really are not nuanced
enough by this definition.


Dr. Stavros Drakos:


Well, Jane was smiling while you were asking this question
because we all as heart failure clinicians need to accept that it
was not a good idea to name all of these different diseases
non-ischemic cardiomyopathy when we did it or when this happened
many moons ago. As you said, Hesham, and I couldn't agree more,
these are completely different diseases. We need to understand
them better and I think that the way we treat nowadays, chronic
heart failure, many years down the road when people will look
back, they will consider it a little bit, I would say, surprising
that we were treating all of these the same way.


We need more studies like the one we just did, that they will
have enough numbers and that's when the issue becomes that you
need enough numbers to be able to tell the differences between
all of these non-ischemic cardiomyopathy types, theologies and if
you go upstream, motivated and inspired by findings like this, we
hope that we will be able to identify how to go and do a root
cause analysis and treat these diseases, not down, down,
downstream the same way, but going upstream, finding what really
went wrong and treating them earlier in the molecular or other
pathophysiological mechanism pathway that led to the heart
failure and so yes, it was a bad idea to do that. But of course
sometimes we do things because we don't understand it better,
right? As one of our keynote speakers here in the recovery
symposium said a few years ago, Jay Khan, the founder of Heart
Failure Strata of America, some things look complicated until you
understand them. Then when you understand them, they look simple.


So here we don't really understand non-ischemic cardiomyopathy
and how all these theologies lead there and I think studies like
these can help us really inform the field better. But we will
need, as Sarah said, more numbers.


Dr. Maryjane Farr:


So that was a great conversation. I wanted to just raise one last
thing and that is what's so interesting about this cohort
relative to re-stage heart failure is these were older patients
and for re-stage heart failure, I think the average age was 35.
So you would imagine there might have been one etiology for
cardiomyopathy, uncontrolled hypertension or peripartum. But for
cohorts in their fifties, there's probably an accumulation of
different insults over many years time and so I thought that was
particularly interesting from the point of view of that you were
probably dealing with, again, a mixed bag of pressure overload,
volume overload, maybe a genetic underpinning, whatever the life
trajectory of some of these patients were and then lastly, the
decision to try to go to recovery rather than to transplant,
which would be the real world experience of why this wet pathway
than the other. These are people truly in their fifties where
they may have one or two surgeries in their lifetime left and so
it's the relevant population that you're studying and so I'll
leave it at that. That's a comment rather than a question, I
think.


But I think for heart failure clinicians, this is why the bench
to bedside piece is so relevant to understanding this because it
actually does change clinical practice, even if the mechanistic
pathways may take still many more years to truly understand. It
helps understand what's possible from an accrued clinical
decision-making level.


Dr. Sarah Franklin:


Jane, if I might just comment on that, I actually think that's
one of the most exciting parts about this dataset is that, as you
mentioned, these patients have complex diseases. They are older.
But yet we are still able to see consistent and reproducible
differences between the patient populations that respond and
don't respond and to me that suggests that at the end of the day
there are consistent differences or reproducible or consistent
molecular changes in cardiac tissue and in response to stress and
I think that that gives us hope that we could potentially not
only predict who would respond or not respond, but that as we get
better at understanding the differences, that there could be
potential therapeutic targets or therapies that would still be
beneficial regardless of the complexity of the heart failure.


Dr. Maryjane Farr:


Okay. So Sarah, Stavros, thank you so much for spending time with
Hesham and myself and look forward to EUCORS--I'm allowed to say
that.


Dr. Stavros Drakos:


Of course.


Dr. Maryjane Farr:


Thanks so much. Bye.


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.