Circulation May 24, 2022 Issue

This week, please join author Sanjiv Shah, Editorialist
Evangelos Michelakis, and Associate Editor Justin Ezekowitz as
they discuss the article "Latent Pulmonary Vascular Disease May
Alter the Response to Therapeutic Atrial Shunt Device in Heart
Failure" and Editorial "Atrial Shunt Devices in Patients with
Heart Failure and Preserved or Mildly Reduced Ejection Fraction
and the Pulmonary Circulation: Promises and Concerns."


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.


Dr. Carolyn Lam:


Greg, I love today's featured article. It's all about heart
failure with mildly reduced and preserved ejection fraction,
talking about device therapy and the response to therapeutic
atrial shunt device. Now, this is a very interesting discussion
of how specifically selecting patients based on latent pulmonary
vascular disease may hold some answers, but we're going to keep
everyone hanging here. You've got to, got to listen to the
discussion. But first, we'd like to tell you about some of the
papers in today's issue. And I think Greg, you've got one to
start us with, right?


Dr. Greg Hundley:


Absolutely. Carolyn, thank you so much. Well, this first paper
comes from Dr. Eliot Peyster from the University of Pennsylvania.
And Carolyn, the aim of this study was to leverage computational
methods for analyzing digital pathology images from routine
endomyocardial biopsies, to develop a precision medicine tool for
predicting cardiac allograft vasculopathy, years before overt
clinical presentation.


Dr. Carolyn Lam:


Ooh, interesting. Again, precision tools. So what did they find?


Dr. Greg Hundley:


Right, Carolyn. So there was a clinical predictive model that
achieved modest performance on the independent test set, with
area under the receiver operating curve of 0.7. But
interestingly, a histopath- predictive model for predicting
cardiac allograft rejection achieved good performance, with an
area under the receiver operating curve of 0.8. Most importantly,
however, a model, incorporating both clinical and histopathologic
features, achieved excellent predictive performance, with an area
under the receiver operating curve of 0.93.


Dr. Greg Hundley:


So in summary, Carolyn, these authors found that prediction of
future cardiac allograft vasculopathy development is greatly
improved by incorporation of computationally extracted histologic
features. Their results suggest morphologic details, contained
within regularly obtained biopsy tissue, have the potential to
enhance precision and personalization of treatment plans for post
heart transplant patients.


Dr. Carolyn Lam:


Aw, that's cool. Makes so much sense, but yet so novel. Thanks.


Dr. Carolyn Lam:


Well, for the paper I want to talk about, we are going to talk
about dapagliflozin. Now we know the SGLT-2 inhibitor,
dapagliflozin, improved heart failure and kidney outcomes in
patients with Type two diabetes with or at high risk for
cardiovascular disease, in the DECLARE–TIMI 58 trial. In the
current paper, authors, led by Dr. Wiviott from the TIMI study
group, aimed to analyze the efficacy and safety of dapagliflozin
stratified, according to baseline systolic blood pressure.


Dr. Greg Hundley:


Ah, so an interesting question, since SGLT-2 inhibitors are known
to reduce blood pressure. And given the concerns regarding the
safety of SGLT-2 inhibitors, in patients with low to normal
systolic blood pressure. So Carolyn, what did they find?


Dr. Carolyn Lam:


Nicely put Greg. So in patients with type two diabetes with, or
at high risk of, atherosclerotic cardiovascular disease,
dapagliflozin reduced the risk for heart failure hospitalizations
and renal outcomes, regardless of baseline systolic blood
pressure, with no difference in benefit for reduction in heart
failure or renal outcomes, among patients with blood pressure
from the normal range, all the way to severe hypertension.
Moreover, there appeared to be no difference in adverse events of
volume depletion, acute kidney injury, or amputations, across the
levels of baseline blood pressure. So these results indicate that
dapagliflozin provides important cardiorenal benefits in patients
with Type two diabetes at high risk, the independent of baseline
blood pressure.


Dr. Greg Hundley:


Oh, very nice, Carolyn. Well, my next paper comes to us from the
world of preclinical science, and it's from professor Jeffrey
Towbin and colleagues, at Le Bonheur Children's Hospital. So
Carolyn, as we know, arrhythmogenic cardiomyopathy is an
inherited genetic disorder of desmosomal dysfunction, and
plakophilin-2 has been reported to be the most common disease
causing gene when mutation is positive. Now in the early
concealed phase, the arrhythmogenic cardiomyopathy heart is at
high risk of sudden cardiac death before cardiac remodeling
occurs, due to mis-targeted ion channels and altered calcium
handling. However, the results of pathogenic plakophilin-2
variants on myocyte contraction in arrhythmogenic cardiomyopathy
pathogenesis, really remains unknown. So Carolyn, these authors
studied the outcomes of a human truncating variant of
plakophilin-2 on myocyte contraction, using a novel knock-in
mouse model, as well as evaluation of human subjects.


Dr. Carolyn Lam:


Oh, interesting. So what were the results from this plakophilin-2
knock-in mouse model?


Dr. Greg Hundley:


Right, Carolyn. So serial echocardiography, a plakophilin-2
heterozygous mice revealed progressive failure of the right
ventricle, but not the left ventricle, in animals older than
three months of age. Now next, adrenergic stimulation enhanced
the susceptibility of plakophilin-2 heterozygous hearts to
tachyarrhythmia and sudden cardiac death. Contractility
assessment of isolated myocytes demonstrated progressively
reduced plakophilin-2 heterozygous RV cardiomyocyte function,
consistent with right ventricular failure, measured by
echocardiography.


Dr. Greg Hundley:


And the next, Western blotting of plakophilin-2 right ventricular
homogenates revealed a 40% decrease in actin. In contrast,
plakophilin-2 heterozygous left ventricular myocytes had normal
contraction and actin expression.


Dr. Greg Hundley:


And finally, Carolyn, Western blotting of cardiac biopsies
revealed actin expression was 40% decreased in the right
ventricles of end stage arrhythmogenic cardiomyopathy patients.
So in conclusion, Carolyn, during the early concealed phase of
arrhythmogenic cardiomyopathy, reduced actin expression drives
loss of RV myocyte contraction, and that contributes to
progressive RV dysfunction.


Dr. Carolyn Lam:


Wow. Thanks, Greg. Well, also in today's issue, there's an
exchange of letters among Drs. Whitman, Ibrahim, and Løfgren,
regarding physics at the heart of the matter, referring to the
article, “Anterior–Lateral Versus Anterior–Posterior Electrode
Position for Cardioverting Atrial Fibrillation.”


Dr. Greg Hundley:


Right Carolyn. And also in the mail bag, there's an On My Mind
piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing
Winter Olympics, The Spotlight On Cardiac Metabolism.”


Dr. Greg Hundley:


Well, how about we get onto that feature article, and learn a
little bit more about atrial shunts, and how they may be helpful
in heart failure with preserved ejection fraction?


Dr. Carolyn Lam:


Ooh, can't wait.


Dr. Greg Hundley:


Well, listeners, we have a very interesting feature discussion
today related to hemodynamics pertaining to interatrial shunt
devices, in those with and without pulmonary hypertension. And we
have, gosh, a repertoire of speakers today. We have Dr. Sanjiv
Shah, from Northwestern University in Chicago, Dr. Evangelos
Michelakis, from Edmonton Alberta, and our own associate editor,
Dr. Justin Ezekowitz, also from Edmonton Alberta.


Dr. Greg Hundley:


Well, Sanjiv, we're going to start with you. Describe for us,
some of the background pertaining to your study, and what was the
hypothesis that you wanted to address?


Dr. Sanjiv Shah:


Great. Thanks, Greg. Thanks for having me today. Well, the
background of our study is that, it was a subgroup analysis, or a
secondary analysis, of the REDUCE LAP-HF II trial. Now this trial
has been in the making for over 12 years, almost 13 years. It
started out as an idea that was David Celermajer. David is a
pediatric cardiologist in Australia, who had this idea that, in
mitral stenosis patients, it's well known that, if there's a
concomitant secundum ASD, a congenital secundum ASD, in these
patients with mitral stenosis do better. They have a way to
unload the left atrium, and distribute that blood to the systemic
veins and the right atrium, the right side of the heart. And so
could this be helpful in quote, diastolic, heart failure or
HFpEF?


Dr. Sanjiv Shah:


And so, I started working with him about 12 years ago. This
started out as a concept. It was studied in animal models, and
then in humans, in open label studies, and then, in a first
randomized controlled trial. Where we showed, that an intraatrial
shunt device, an iatrogenic ASD, so to speak, put in humans with
heart failure with risk preserved EF, results in a lowering of
exercise pulmonary capillary wedge pressure. And so based on that
data, we designed a pivotal trial, a Phase III trial, the largest
trial of its kind, of heart failure with preserved and mildly
reduced ejection fraction, to see if interatrial shunt device
would improve outcomes. And we published that trial earlier this
year in the Lancet. Unfortunately, it was a totally neutral
trial. And when you have a neutral trial in any condition, but as
we see often in HFpEF, the question is, was it neutral overall?
Or was there a subgroup that benefited? And what we found in that
trial was that, there were three predefined subgroups that came
out that seemed like there was a difference.


Dr. Sanjiv Shah:


First, there was a sex difference. Women did better. Men did
worse with the device. Then, there was right atrial volume. Those
with bigger right atrial volumes did worse. If you had a smaller
right atrial volume, you did better. But the most significant
interaction and subgroup was exercise pulmonary artery systolic
pressure.


Dr. Sanjiv Shah:


If the pulmonary artery systolic pressure was greater than 70 at
20 Watts of exercise, so just with a little bit of exercise,
those patients did worse. And if PA pressure stayed low, the
patients did better. And so we sought to further explore this to
say, "Okay, what's exactly going on?" In a post hoc analysis,
what's going on with the pulmonary vasculature during exercise,
and how does that differentiate how patients potentially respond
to the device? And that's what we hope to figure out.


Dr. Sanjiv Shah:


We hypothesize, that if exercise pulmonary vasculature resistance
is lower, then the shunt can actually work, and blood can flow
from the left to the right, into the lungs, and the right heart
doesn't get too overloaded. And we know, that the normal response
of the pulmonary vasculature is to vasodilate with exercise. And
so, if patients had retained that response, the ability to do
that, that they may benefit. And so, we sought to figure that out
with this subgroup analysis.


Dr. Greg Hundley:


Sanjiv, it sounds like a really elegant, well thought out
hypothesis. So what was your study design? And describe your
study population.


Dr. Sanjiv Shah:


Yeah. This was a randomized controlled trial. And so this was 626
patients enrolled at 89 centers across the world. And it was
really, heart failure with mildly reduced, so an EF of greater
than 40, or preserved EF, and 93% of them had HFpEF. And what was
unique about this trial is that we, this is the first trial
really, that confirmed that these patients actually had heart
failure, with mildly reduced or preserved ejection fraction. Most
trials say, well, you have to have an elevated BNP, and you have
to have some sign of structural heart disease, and maybe, a
history of heart failure hospitalization. In this trial, every
single patient had to undergo rigorous noninvasive
echocardiography. And then, on top of that, they had to undergo
exercise invasive hemodynamic testing. And people thought that it
wasn't possible for 626 patients, but we did it. And every single
patient had had an exercise pulmonary capillary wedge pressure
greater than, or equal to, 25. And so this really was HFpEF. So
it's a randomized trial.


Dr. Sanjiv Shah:


And then, beyond that, we did a subgroup analysis. So we looked
on various subgroups, focusing on exercise PVR, and we really
looked to see the effect on three outcomes. Number one, a
hierarchical endpoint, a combination of cardiovascular death,
ischemic nonfatal stroke, recurrent heart failure
hospitalizations, and the KCCQ. And then the other two outcomes
were just the individual recurrent heart failure
hospitalizations, and the KCCQ. We looked at all of these, and
tried to figure out if there are certain subgroups that benefit.


Dr. Greg Hundley:


Great detail. So Sanjiv, what did you find?


Dr. Sanjiv Shah:


Well, we found that, there's this group of patients, that during
exercise, the pulmonary vascular resistance at peak exercise
stays above 1.74 Wood units. Now that seems like an arbitrary
number, but in fact, in older individuals that are healthy, when
you exercise them, the PVR upper limit, the exercise PVR upper
limit, is about 1.8. So we're right about the upper limit of
where the PVR should be. And if it was above that, the patients
actually did worse with the shunt device. They had a lot more
heart failure hospitalizations. Their KCCQ got worse, didn't
benefit. And if they were below that threshold, meaning they
were, sort of compliant pulmonary vasculature, and it stayed
compliant, or they vasodilated effectively with exercise, then
they benefited from the device. And what we call this concept of
exercise-induced pulmonary vasoconstriction, or inability to
vasodilate, is latent pulmonary vascular disease.


Dr. Sanjiv Shah:


And so, if you have that latent pulmonary vascular disease, your
win ratio is 0.6. That means you do worse. And if you don't have
this pulmonary, this latent pulmonary vascular disease, your win
ratio is 1.31. And that means, you do better with the device. And
we saw very similar findings with the KCCQ. We saw similar
findings with the recurrent heart failure hospitalizations.


Dr. Sanjiv Shah:


And the final thing is, we found that, we looked at various other
subgroups, and it turned out that if there was no latent
pulmonary vascular disease and no history of pacemaker, which we
found was kind of associated with sex and right atrial volume,
those patients, for about 50% of the group, actually did the
best. And that was what we called, the responder subgroup.


Dr. Greg Hundley:


Thank you, Sanjiv. Well, listeners, we're going to turn now to
our associate editor, Justin Ezekowitz. And Justin, you have many
papers come across your desk. What attracted you to this
particular manuscript?


Dr. Justin Ezekowitz:


So Greg, this paper kind of stood out for a number of different
reasons, as I sent you. You're to be congratulated for a variety
of reasons. But the number one is, pursuing the data from a
neutral trial overall, to understand who might benefit and who
might be harmed from a pretty novel device and way to treat
patients in such a scale, that's not being done like this before.
So it stands out by just the magnitude of number of right heart
catheterizations, number of patients enrolled, number of
procedures done. And all of those things really lead to us to be
able to understand the area much better than I think we can in a
human population.


Dr. Justin Ezekowitz:


Where this sits with other devices that are very similar, is hard
to really know, if all devices are going to be the same or
different, but your population is quite unique is if they're not
all end stage, but they're sick enough to get into your trials.
So there's this population we treat actively. And I wondered if
you could touch on that continuous nature. And so for readers,
there's this beautiful figure, which shows a continuous nature of
exercise PVR. And I wonder if you could touch on that. Is this
mid group, the group that we should target for our future
therapies like this, or this needs further study?


Dr. Sanjiv Shah:


Well, I think it needs further study. I think the listeners
should be aware that this is a post hoc analysis. We did
pre-specify exercise PA pressure. This is one trial. But it makes
a lot of sense, pathophysiologically. What we're doing here is
we're shunting this excessive LA, overloaded LA, shunting the
blood from the LA to the RA and into the pulmonary vasculature.
Well, if that pulmonary vasculature can't accept that increased
flow, the patient's not going to do well. And how can we simulate
that? Well, we can simulate it with exercise. As the patient's
pedaling on the bike, on the cath lab table, there's increasing
blood flow to the pulmonary vasculature, and we're seeing what
happens with the pulmonary vasculature. Does it vasodilate, does
it not? And so, I think that's why we were excited about this
finding.


Dr. Sanjiv Shah:


I do think that, there are at least seven other companies making
shunt devices, interatrial shunt devices or therapies. And I do
think, they need to pay attention to this and really look at
this. Not all trials are doing exercise and basic hemodynamics,
that needs to be done, I think. So it'll be really interesting to
see.


Dr. Sanjiv Shah:


Now, one thing I will say is that, and I've written about this,
this is a really interesting trial. Because the BNPs were lower,
and so you would think, okay, these are patients that are less
sick. And yet, their heart failure hospitalization rate was at
least one and a half times higher than pharma Phase III trials.
KCCQ was way lower, like 30 points lower. So there are these
patients out there that are really sick, and they're the ones
that I think, are where their life, their sort of quality of
life, their outcomes, are being driven by the HFpEF. And that's
what we found in this trial.


Dr. Greg Hundley:


Very nice. Well, listeners, let's turn now to our editorialist,
Dr. Evangelos Michelakis. And Evangelos, two questions. How do we
put the results of this substudy, really in the context of the
main trial? And then secondly, do you have any, with your
expertise in endothelial function, and understanding the
mechanisms of pulmonary hypertension, can you describe what you
think might be operative as a mechanism here, and why Sanjiv
observed these positive results in some patients?


Dr. Evangelos Michelakis:


Thank you. So the first point is that, I have to also repeat,
that it was a remarkable achievement to do all this right heart
catheterization on a treadmill in the cath lab. It's a very
complex procedure. And it is, they have to be congratulated, the
authors, for actually doing this. There is no question that, like
Sanjiv said, ongoing trials for future trials will need to
include the hemodynamics in the trials, before and after the
procedure.


Dr. Evangelos Michelakis:


So another important thing is that, the authors brought up this,
they called it latent pulmonary hypertension, we could call it
latent pulmonary hypertension, or probably, early pulmonary
hypertension, as an entity. Now that entity, it's newer in the
heart failure field. It's not that old in the PIH, the pulmonary
interior hypertension field, since it used to be in the
guidelines for this disease, that exercise pulmonary hypertension
was a diagnostic criterion for that. Because the idea is that,
exercise pulmonary hypertension reflects early pulmonary
hypertension. So you needed to intervene with therapies early.


Dr. Evangelos Michelakis:


Now, I'm not sure that this is a fact. But it is very likely that
these patients, in Sanjiv's trial, that had the early, that had
the sort of enhanced response with exercise, did have at least,
endothelial dysfunction in the pulmonary arteries. Not only
because this population has a number of endothelial risk factors,
diabetes, smoking, you name it. But also, there are newer
problems like SNPs polymorphism mutations, that will recognize
more into the pulmonary arterial hypertension field, to be more
unique to the pulmonary circulation.


Dr. Evangelos Michelakis:


But the reason I say that is that, the reason that you dilate
with exercise, is mostly because of your pulmonary arterial
endothelial cells, secreting vasodilatory factors. And also,
allowing previously closed capillaries to open up with increased
flow. However, the problem is that, if you have pulmonary
arterial endothelial cells in vitro, and you expose them to high
flow, like in this case, you can actually change their identity.
Turn them into cells that are not endothelial cells anymore, are
proliferative pro-inflammatory, and they can actually cause
structural pulmonary circulation damage.


Dr. Evangelos Michelakis:


Also, there are animal models and people working in PAH and ASD,
where they've shown that, if you have, if you're given
endothelial toxin in animals, and then, you do an aortocaval
shunt, then you get really severe pulmonary hypertension with
structural disease, that is not even reversible if you remove the
shunt.


Dr. Evangelos Michelakis:


So from this trial, the conclusion that patients with pulmonary
hypertension should not get the device, is very clear. And
probably, the ones with exercise pulmonary hypertension. My
theoretical concern is, for those that don't have exercise
pulmonary hypertension, or those that do have it, could they get
worse after a number of years, and have structural pulmonary
vascular disease? And unfortunately, we didn't have a follow up
right heart catheterization to prove that, whether this is right
or wrong. Which is a thing, is the most important thing to do in
the future. So mimic the protocol for this trial from now on, but
also add a follow up right heart catheterization, perhaps not
just in a year, but longer. In other words, enough time to allow
the structural pulmonary remodeling get established, but also,
affect the right ventricle, these things don't. So maybe in a few
years. It's a very demanding thing for these protocols, but I
think, that's what needs to be done before we say this device can
actually be beneficial for those patients, or for some patients,
or not hurt others.


Dr. Greg Hundley:


Very nice. And so, a great segue, Evangelos, into what we think
the next studies may need to be performed in this particular
sphere of research.


Dr. Greg Hundley:


So Sanjiv, in just 30 seconds, could you share your thoughts
first, and then we'll circulate back to Justin, and then finish
up with Evangelos. Sanjiv?


Dr. Sanjiv Shah:


Yeah. I think the key thing is, to do a confirmatory trial. And
that's what we're aiming for, is to do a confirmatory randomized
sham-controlled trial, but focus in on these patients with an
exercise peak PVR of less than 1.75, around there. And I think,
that'll help answer the question. The Qp/Qs we get with this
device is 1.2 to 1.3. So I don't think it's a high flow. And we
actually have open label studies, where we've gone out to three
years, with repeat invasive hemodynamic testing, echocardiograms,
and we've had patients who've been implanted for seven years.
We're not seeing, at least at that point, any sort of worsening
of pulmonary vascular disease, or RV function, or anything like
that. And so, it remains to be seen.


Dr. Sanjiv Shah:


The last thing I'll say, which I think is provocative, in the
field of HFpEF, all pulmonary vasodilator drugs have failed. And
though, we only measure pulmonary vascular resistance at rest.
And what we saw in this trial, is that some patients have a high
PVR and it comes down. Some people have a PVR that stays low, and
is low and stays low. Some people have a low PVR and it goes up.
You know? So I think what we need to think about in the field of
PH‐HFpEF, is more exercise genotyping, to determine what's the
dynamic exercise PVR? And maybe, those with exercise elevation of
pulmonary vascular resistance are the ones that respond to
pulmonary vasodilators. So that's another thing that I think we
can think about taking away from this trial.


Dr. Greg Hundley:


Thank you, Sanjiv. Justin.


Dr. Justin Ezekowitz:


Yeah. So my thoughts are mimicking Sanjiv's. But one of the
things that we desperately need is, ways in which we can
noninvasively assess the exercise PVR, so that we can think about
the large scale interventions that might come down the road, if
interventions such as this work well. Because the noninvasive
scans will really help us look at broader populations. Those are,
that don't make it into trials, and those that aren't
traditionally in our studies of HFpEF. So I think, that's another
area where we can really grow the field, and then, grow our
knowledge.


Dr. Greg Hundley:


Very nice. And Evangelos.


Dr. Evangelos Michelakis:


So, yes. Of course, like everybody said, we need trials that will
have a follow up right heart catheterization, at least address,
if not both, like the investigators did. But because the big
question is, are these patients having an earlier stage pulmonary
hypertension or not? These patients that the authors called,
latent pulmonary hypertension, we need to phenotype more their
endothelial cells, or their disease. And in the absence of
biopsies, the only way we could do that, is perhaps, with
molecular imaging, or at least, in some small populations. Or
with analyzing pulmonary arterial endothelial cells in the blood,
and their molecular phenotype, to see if they are a distinct
group, which I suspect they may be. So further genotyping of this
exercise induced pulmonary hypertension in this population, will
be important as well.


Dr. Greg Hundley:


Thank you. Well, listeners, we've had a great discussion today,
from Dr. Sanjiv Shah, from Northwestern University in Chicago,
our editorialist, Dr. Evangelos Michelakis, from Edmonton,
Alberta, and our own associate editor, Dr. Justin Ezekowitz from
Edmonton, who brought us this study, demonstrating that in
patients with heart failure and preserved ejection fraction, or
heart failure and mildly reduced ejection fraction, the presence
of pulmonary vascular disease, uncovered by invasive hemodynamic
exercise testing, identifies patients who may worsen with atrial
shunt therapy. Whereas, those without pulmonary vascular disease
may, at least in the short term, benefit. And of course, as
Evangelos has pointed out, the long term findings really warrant
further study.


Dr. Greg Hundley:


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


Dr. Greg Hundley:


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.