Circulation July 20, 2021 Issue

This week's episode features author Kieran Docherty and Associate
Editor Torbjørn Omland as they discuss the article "The Effect of
Neprilysin Inhibition on Left Ventricular Remodeling in Patients
with Asymptomatic Left Ventricular Systolic Dysfunction Late
After Myocardial Infarction."


Dr. Carolyn Lam:


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


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate, editor, director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, we've got an exciting feature this week involving
Neprilysin license inhibition and left ventricular remodeling in
patients with asymptomatic left ventricular systolic function
after they've sustained myocardial infarction. But before we get
to that feature discussion, how about we grab a cup of coffee and
jump in on some of the other articles in the issue? Would you
like to go first?


Dr. Carolyn Lam:


I'd love to, and I want to talk about transcatheter aortic valve
replacement, or TAVR, that we all know is really transforming our
management of aortic stenosis. Despite rapid improvements,
however, serious complications remain relatively common and are
not well-described by single outcome measures. So the purpose of
this paper was to determine if there was site-level variation in
TAVR outcomes in the United States using a novel 30-day composite
measure. And this is from Dr. Desai and colleagues from Hospital
of University of Pennsylvania. So they performed a retrospective
cohort study using data from the STS/ACC TVT registry to develop
a novel-ranked competent performance measure that incorporates
mortality and serious complications. Based on the associations
with one-year risk adjusted mortality and health status, they
identified for peri-procedural complications to include in the
composite risk model, in addition to mortality. And ranked
empirically, according to severity, these were: stroke, major
life-threatening or disabling bleeding, stage three acute kidney
injury, and moderate or severe perivalvular regurgitation.


Dr. Carolyn Lam:


Now, based on these ranked outcomes, they found that there was
significant site-level variation in quality of care in TAVR in
the United States. Overall, better-than-expected site performance
was observed in 8% of sites, whereas performance as-expected was
observed in 80%, and worse-than-expected performance was observed
in 11% of sites.


Dr. Greg Hundley:


Carolyn, really interesting comprehensive data. So how do we put
this all together? And what's the take-home message for us,
clinically?


Dr. Carolyn Lam:


Well, there are substantial variations in the quality of TAVR
care received in the United States, and 11% of sites were
identified as providing care below the average level of
performance. Further study is necessary to determine the
structural, process-related, and technical factors associated
with high- and low-performing sites. And all this is discussed in
a beautifully, beautiful accompanying editorial by Drs. Dharam
Kumbhani and Eric Peterson.


 


Dr. Greg Hundley:


Oh, fantastic. You know, Carolyn, those editorials are so helpful
in helping us put these new data in perspective. Well, my next
paper comes to us from the world of preclinical science, and it's
from Professor Vincent Christoffels from Amsterdam in UMC. So
genetic variants of SCN10A, encoding the neural voltage-gated
sodium channel NaV1.8 are strongly associated with atrial
fibrillation, Brugada syndrome, cardiac conduction velocities,
and heart rate. And these investigators studied the cardiac
expression of SCN10A and the function of a variant-sensitive
intronic enhancer previously linked to the regulation of SCN5A,
and coding the major essential cardiac sodium channel NaV1.5.


Dr. Carolyn Lam:


Wow, great. So what did they find, Greg? Sounds like a
first-of-its-kind study.


Dr. Greg Hundley:


Right, Carolyn. So genetic variants in and around SCN10A modulate
enhancer function and expression of the cardiac-specific NCN10A
short transcript, and the authors propose that non-encoding
genetic variation modulates transcriptional regulation of a
functional C-terminal portion of NaV .8 and cardiomyocytes that
impacts NaV1.5 function, cardiac conduction velocities, and
arrhythmia susceptibility.


Dr. Carolyn Lam:


Wow, that was a lot. So what are the implications, Greg? Could
you simplify it for us?


Dr. Greg Hundley:


Yes. Right, Carolyn. So three things. First, the authors
uncovered a novel alternative mechanism for how the SCN10A locus
regulates cardiac conduction. Second, their data implicate that
genetic variation-sensitive regulation of expression of NCN10A
short modulates conductivity of the heart, and can predispose to
arrhythmia in the human population. And then finally, Carolyn, in
deciphering the underlying mechanism of the increased NaV1.5
mediated current density by NaV1.8 short, the authors believe
their findings could ultimately lead to the development of novel
therapeutic strategies for particular conduction disorder.


Dr. Carolyn Lam:


Thanks, Greg. Well, this next paper is really interesting. It's
the first validation of the enhanced potency of human-induced
pluripotent stem cells-derived cardiomyocytes over-expressing
Cyclin D2, or CCND2, under the control of myosin heavy chain
promoter, and differentiated into cardiomyocytes. Now, that was a
mouthful, but so interesting, because Dr. Zhang and colleagues
from University of Alabama in Birmingham used infarcted pig
hearts, and transplanted these amazing cardiomyocytes, and found
that they were associated with proliferation of recipient heart
cardiomyocytes, epithelial cells, and smooth muscle cells, all,
at least partly, by paracrine activity.


Dr. Greg Hundley:


Well, Carolyn. Really an involved clinical design. So, what are
the clinical implications of all this research?


 


Dr. Carolyn Lam:


Well, first, I think the paper validated a novel therapeutic
strategy aimed at upregulating proliferation of recipient cardiac
cells using human-induced pluripotent stem cells-derived cell or
cell products. Furthermore, targeting the myocyte cell cycle
regulators, such as Cyclin D2, holds a strategic potential for
re-muscularization of an infarcted region.


Dr. Greg Hundley:


Very good, Carolyn. Well, how about we see what else is in this
issue? So I'll start first. There's a Research Letter by
Professor Marston, entitled 'Combining High-Sensitivity Troponin
with the American Heart Association/American College of
Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'.
Next, there's an ECG challenge from Dr. Feliciano, entitled 'An
Ominous EKG'. And then finally, there's a very nice exchange of
letters from Drs. Lang and Sattar regarding a prior publication:
volume status is the key in heart failure.


Dr. Carolyn Lam:


And finally, a very important perspective piece by Dr. Catapano
on omega-3 for cardiovascular disease: where do we stand after
reduce it in strength? Wow, that was great, Greg. But let's move
on now to our feature discussion.


Dr. Greg Hundley:


You bet.


Dr. Greg Hundley:


Well, listeners, we are on to our feature discussion today, on
this July 20 issue. And we're very excited to have with us Dr.
Kieran Docherty from University of Glasgow in Glasgow, Scotland,
and our own associate editor, Dr. Torbjørn Omland from University
of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's
start with you. Could you describe some of the background related
to your study, and what was the hypothesis that you wanted to
address?


Dr. Kieran Docherty:


Well, firstly, thank you very much for the invitation to discuss
our trial today on the podcast. The background of our trial was
that we are all aware that the development of left ventricular
systolic dysfunction following acute myocardial infarction places
patients at a subsequent increased risk of the development of
heart failure, and the process of progressive dilatation of the
left ventricle and a reduction in stroke volume, known as adverse
left ventricular remodeling, is the process which underlies this
elevated risk of heart failure. And many of the treatments that
have been shown to be beneficial following myocardial infarction,
such as [inaudible 00:09:24] , and angiotensin receptor blockers
and beta blockers, the benefit of these medications, in part, is
due to their ability to attenuate this process of adverse
remodeling. Now, our hypothesis was that it would be possible to
further attenuate, prevent, or delay the process of adverse
remodeling in patients at risk of heart failure following
myocardial infarction, by the addition of a Neprilysin inhibitor
to current standard of care.


Dr. Kieran Docherty:


Now, as we all know, a Neprilysin inhibitor in the form of
sacubitril valsartan when combined with an angiotensin receptor
blocker, has been shown to improve outcomes in patients with
symptomatic heart failure, with reduced ejection fraction in the
PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous
levels of natriuretic peptides, amongst a range of other
substrates for Neprilysin, including adrenomedullan, GLP-1, and
bradykinin. And our hypothesis was that adding in a Neprilysin
inhibitor, thereby increasing endogenous levels of these peptides
with potentially beneficial effects, such as reducing fibrosis,
reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have
an additive beneficial effect on left ventricular remodeling in
these high-risk patients with left ventricular systolic
dysfunction following myocardial infarction.


Dr. Greg Hundley:


Very nice hypothesis. So, how did you set up, Kieran, your study
design, and what study population, how many patients and whatnot,
did you include in your study?


Dr. Kieran Docherty:


Well, the first consideration when designing the study was
broadly, what group of patients should we involve? And the main
limitation was the indication for the use of sacubitril valsartan
in patients with symptomatic heart failure, so we did not feel
that we could include these patients. Therefore, our study
population included patients who had asymptomatic left
ventricular systolic dysfunction following previous myocardial
infarction. And specifically, we wanted patients who were at
least three months following my cardiac infarction. And the
reason for that was to try and exclude patients who had transient
systolic dysfunction or left ventricular stunning. And we
performed a screening transthoracic echo at this time point. And
if patients had an ejection fraction of 40% or less on echo, and
if they were tolerant of a minimum dose of an ACE inhibitor, 2.5
milligrams of ramipril BD or equivalent, and they were taking a
beta blocker, unless contraindicated or not tolerated, then they
were suitable for randomization.


Dr. Greg Hundley:


Very good. And what did you find?


Dr. Kieran Docherty:


So we find that in comparison with the ARB Valsartan, sacubitril
valsartan did not have any beneficial effects on cardiac
MRI-based measures of left ventricular remodeling. And the
primary end point of our study was left ventricular end systolic
volume index. There was also no improvements in biomarkers of
myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high
sensitivity to Troponin I.


Dr. Greg Hundley:


Very nice. And any pertinent issues relevant to, perhaps, some
subgroups, regardless of age or perhaps gender?


Dr. Kieran Docherty:


So in a post-hoc analysis, we performed an analysis of the
primary endpoint in patients who were below or at or above the
median NT-proBNP level, which is 238 p-grams per mil. And we
found, very interestingly, the suggestion of a benefit, in terms
of left ventricular remodeling with a reduction and systolic
volume index in patients who had higher levels of NT-proBNP
compared to those who had lower levels.


Dr. Greg Hundley:


Very good. Well, listeners, let's turn now to our associate
editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers
come across your desk. What attracted you to this manuscript? And
then how do you put the results of this study in the context with
other studies that have been published, particularly recently, in
patients with heart failure that have received sacubitril
valsartan?


Dr. Torbjørn Omland:


So, Greg, there were many aspects of this trial that made it very
attractive for circulation. I think the hypothesis was very
interesting, and also it is a very well-conducted study using the
reference methods for assessing left ventricular function, using
that for assessing the primary endpoint. And they also have a
broad array of secondary end points that also sort of provide
insight in potential pathways or mechanisms that can explain the
effect sacubitril Valsartan. So, that's also a very sort of hot
topic within the cardiology research currently, and we know that
the ACC, actually a much larger study, PARADISE-MI, was
presented. And we knew that this study was also very interesting,
because we knew when we received this manuscript, that another,
bigger trial that's sort of related would be presented at the ACC
at the late-breaking clinical trial sessions there the
PARADISE-MI study. But this sort of provided insight that nicely
complimented the results of that study.


Dr. Torbjørn Omland:


And I think as Kieran alluded to, we already have the very
impressive results from PARADIGM-HF is showing a very substantial
benefit in patients with chronic heart failure and reduced
ejection fraction. And then we have sort of the borderline
results from the Paragon trial, in those with preserved ejection
fraction, where it actually was a gradient from those with mildly
elevated, where there seemed to be a beneficial effect to those
with more normal EF, where there was no effect. So, this study
sort of provided new information, very relevant to the whole
field, I think.


Dr. Greg Hundley:


Very nice. Well, gentlemen, I want to turn back to you and ask
each of you, first Kieran, and then Torbjørn. Kieran, what do you
think is the next study that needs to be performed in, really,
this sphere of research?


Dr. Kieran Docherty:


As Torbjørn has already alluded to, PARADISE-MI kind of... It
fills the gap across the spectrum of heart failure. So in
patients who are at high risk of heart failure immediately
following myocardial infarction, that that group of patients were
studied in PARADISE-MI. And there is an echocardiographic
sub-study of PARADISE-MI, which we await the results for. And I
think that will be very interesting, because our patient
population was distinct from the group studied in PARADISE-MI,
namely the fact that the median time from MI was 3.6 years. So,
these patients were not in the throes of the neural humoral
activation at the time of acute myocardial infarction and prior
to the development of established my cardio scar and fibrosis.
And so, it may be that the addition of a Neprilysin inhibitor to
patients immediately following myocardial infarction may have
some benefits, in terms of attenuating or preventing ventricular
dilatation reduction and injection fraction that is observed. So
I think we await the echocardiographic results of PARADISE-MI
with great interest.


Dr. Greg Hundley:


Very good. And Torbjørn , do you have anything to add?


Dr. Kieran Docherty:


Yes. I found observations that actually, in terminal proBNP
measurements, could potentially identify a higher-risk group that
actually could benefit from the intervention. It was very
interesting. So I think we always speak about precision medicine
and cardiology, and I think this is sort of one avenue that we
should pursue and see whether we use biomarkers like NT-proBNP to
identify those patients who will benefit most from interventions
like sacubitril Valsartan


Dr. Greg Hundley:


Excellent. Well, listeners, we've heard a really interesting
discussion today. Another study investigating Neprilysin
inhibition in combination with angiotensin receptor blockers, and
basically highlighting that in patients with asymptomatic left
ventricular dysfunction following several years after myocardial
infarction, that treatment with sacubitril Valsartan did not have
a significant reverse remodeling effect just compared with
valsartan alone. Well, on behalf of Carolyn and myself, we want
to thank Dr. Kieran Docherty and his submission here to
circulation, and also our own associate editor, Dr. Torbjørn
Omland.


Dr. Greg Hundley:


And for all of you, we wish you a great week, and we hope to
catch you next week on The Run.


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.