Circulation July 13, 2021 Issue

This week is a Double Feature Circulation on the Run. Please join
author Patrick Serruys, editorialist Shamir Mehta, and Associate
Editor Emmanouil Brilakis as they discuss their article "Ten-Year
All-Cause Death According to Completeness of Revascularization in
Patients with Three-Vessel Disease or Left Main Coronary Artery
Disease: Insights from the SYNTAX Extended Survival Study" and
editorial "Achieving complete revascularization for multi-vessel
coronary artery disease." Then, please join author G. Michael
Felker, and Associate Editor Mark Link as they discuss the
Research Letter "Implantable-Cardioverter-Defibrillator
Eligibility after Initiation of Sacubitril/valsartan in Chronic
Heart Failure: Insights from PROVE-HF."


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, director of the Pauley Heart Center at
VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


So guess what, Greg, we have another double feature this week.
First, we need to talk about completeness of revascularization in
patients with three-vessel disease or left main coronary artery
disease. Always a question, and this time we've got insights from
the SYNTAX Extended Survival Study. And then, the next feature
talks about implantable cardioverter defibrillator eligibility
after initiation of sacubitril/valsartan in heart failure, and
these are insights from PROVE-HF. But before we get to that, I
suggest, as I pick up my coffee, could you tell us what some of
the papers you've spotted?


Dr. Greg Hundley:


Thanks so much, Carolyn. Sure. So I'm going to start from the
world of preclinical science, and the paper comes to us from Dr.
Vadim Fedorov from The Ohio State University Wexner Medical
Center. Carolyn, up to 50% of the adult human sinoatrial node is
composed of dense connective tissue, and cardiac diseases,
including heart failure might further increase fibrosis within
the sinoatrial node pacemaker complex, leading to impaired
automaticity and conduction of electrical activity to the atrium.
However, unlike the role of cardiac fibroblasts in pathological
fibrotic remodeling and tissue repair, nothing is known about
fibroblasts that maintain the inheritantly fibrotic sinoatrial
node environment.


Dr. Carolyn Lam:


That's true. So what did these authors do?


Dr. Greg Hundley:


Right, Carolyn. So these authors found that increased sinoatrial
node-specific fibrosis, with presence of myofibroblasts and
CILP-1, and periostin-positive interstitial fibrosis only in
heart failure versus non-heart failure human hearts. And
comprehensive proteo-transcriptomic profiles of sinoatrial node
fibroblasts identified up-regulation of genes and proteins
promoting stiffer sinoatrial node extracellular matrix in heart
failure hearts.


Dr. Greg Hundley:


And next, fibroblast specific profiles generated by the team's
proteo-transcriptomic analyses of the human sinoatrial node
provided a comprehensive framework for future studies to
investigate the role of sinoatrial node-specific fibrosis in
cardiac rhythm regulation and arrhythmias. So really very
interesting preclinical science, Carolyn.


Dr. Carolyn Lam:


Yeah. Makes me think of arrhythmias and heart failure very
differently, too. Thanks Greg. Well, for my next paper, we know
that dietary high salt is bad for us. It's associated with
mortality and morbidity. Serum sodium can accumulate at sites of
inflammation and affect the function of both innate and adaptive
immune cells. But how do changes in extracellular sodium actually
affect mononuclear phagocytes?


Dr. Greg Hundley:


Ah. Carolyn, this is really an interesting question, but how
would you even set this up or go about investigating this?


Dr. Carolyn Lam:


Ah, good question, Greg, and these investigators are really
smart. So first, let me tell you about the co-corresponding
authors, Dr. Kempa from Berlin Institute of Medical Systems
Biology at Max Delbrück Center for Molecular Medicine in the
Helmholtz Association, and Dr. Müller from the Experimental and
Clinical Research Center in Berlin, Germany. Now, guess what they
did? They used sea horse technology, pulsed stable
isotope-resolved metabolomics and enzyme activity assays to
characterize the central carbon metabolism and mitochondrial
function of human and murine mononuclear phagocytes under high
salt, in vitro.


Dr. Carolyn Lam:


And what they found was a disturbance of mitochondrial
respiration as the initial step by which high salt
mechanistically influenced immune cell function. While these
functional changes may help to resolve bacterial infections, a
shift towards pro-inflammation could accelerate inflammatory
cardiovascular disease. A further potential implication is that
mitochondrial functional analysis in monocytes and other immune
cells upon a high-salt challenge, could serve as a test for salt
sensitivity of immune cells in future.


Dr. Greg Hundley:


Oh wow, Carolyn. We don't often think about salt sensitivity in
immune cells. Really informative research. Well, my next paper
comes to us from the world of clinical science, and it's from
Professor Derek Chew, from the school of medicine, at Flinders
University, the Department of Cardiovascular Medicine at Flinders
Medical Center.


Dr. Greg Hundley:


Carolyn, this paper reports results from a multicenter
prospective, patient-level, randomized comparison of care
informed by unmasked zero to one-hour, high-sensitivity
troponin-T protocol, reported as less than five nanograms per
liter versus standard-practice, masked high-sensitivity, cardiac
troponin T-testing, reported at a value of less than 29 nanograms
per liter, assessed at zero to three hours, and followed
participants for 12 months. Participants included were those
presenting to metropolitan emergency departments with suspected
acute coronary syndromes, without ECG evidence of coronary
ischemia. And the primary endpoint was timed to all-cause death
or myocardial infarction.


Dr. Carolyn Lam:


Interesting experiment there. So what did they find, Greg?


Dr. Greg Hundley:


Right, Carolyn. So, while the use of the zero to one-hour,
high-sensitivity, cardiac troponin T-protocol expedited discharge
of patients presenting to the emergency department, with a
low-event rate at 30 days, an increase in death or myocardial
infarction was observed at one year in those with unmasked,
high-sensitivity, cardiac troponin T-concentrations. Next, among
those with intermediate cardiac troponin concentrations, where
care was informed by zero to one-hour unmasked, high-sensitivity,
cardiac troponin T-protocols, increases in revascularization and
reductions in noninvasive cardiac investigation were observed.


Dr. Greg Hundley:


So these changes in practice that result from the use of
rapid-discharge protocols, may be potentially associated with an
increase in all-cause death or MI, by 12 months among those
low-level troponin elevations. So in summary, Carolyn, this
research found that unmasked, high-sensitivity, cardiac troponin
T-reporting, deployed within a zero to one hour protocol, did not
reduce ischemic events over a 12-month followup, and changes in
practice associated with the implementation of this protocol may
be associated with an increase in death in MI among those with
newly-identified troponin elevations.


Dr. Carolyn Lam:


Wow, that's very, very interesting and clinically important.
Thanks, Greg. Well, let's do a little bit of a tour around what
else is available in this week's issue, shall we? I want to talk
about a Special Report that I was so privileged to contribute to
and was led by Dr. Gemma Figtree. And it's a Call to Action for
new global approaches to cardiovascular disease drug solutions.
There's also a Research Letter by Dr. Solomon on the prognostic
value of natriuretic peptides and cardiac troponins in COVID-19.


Dr. Greg Hundley:


Great, Carolyn. So I'm going to tell you about an exchange of
letters between Professors Correia and Chaitman regarding a prior
published article, entitled “Myocardial Infarction in the
ISCHEMIA Trial: Impact of Different Definitions on Incidence,
Prognosis, and Treatment Comparisons.” Also, there's a very nice
Case Series from Professor Shapira entitled, “In the Heart of the
Ancient Silk Road: Fever of Unknown Origin, Right Ventricular
Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has
a very nice On My Mind piece From Studying Heart Disease and
Cancer Simultaneously to Reverse Cardio Oncology.


Dr. Carolyn Lam:


So interesting. Well, let's get onto our double feature, Greg.


Dr. Greg Hundley:


Absolutely. Well, listeners, we are here for our first feature
discussion today and we have with us really, an very interesting
panel. First, Dr. Patrick Serruys from National
University-Ireland, Galway, Dr. Shamir Mehta from McMaster
University in Ontario, and our own associate editor, Dr. Manos
Brilakis, from Minneapolis Heart Institute. Welcome gentlemen.
Patrick, we're going to start with you. Could you describe for us
the hypothesis that you wanted to test.


Dr. Patrick Serruys:


Yeah. The hypothesis was that if the surgeon and the
interventional cardiologist doesn't achieve a complete
revascularization, there will be a penalty. The penalty is we
look at the all-cause mortality because that's really a unbiased
assessment.


Dr. Greg Hundley:


And then, tell us the design of your study for us.


Dr. Patrick Serruys:


So SYNTAXES, which is the extension of the SYNTAX study up to 10
years, had 1,800 patient, and then basically, we took a threshold
of eight. If you have a residual SYNTAX for more than eight, you
have an incomplete revascularization. We stratify for less than
four, four to eight, and above eight. And clearly, the group
above eight has a bad outcome, not only with PCI, but also with
surgery. The score is a little bit more difficult to establish in
surgery, because you don't have an angiography immediately after
the procedure.


Dr. Patrick Serruys:


And then as I said, if you do a complete revascularization by
PCI, and that's basically a residual SYNTAX score of zero, then
you have an outcome which is comparable to the surgical outcome.
What is interesting, if you have above eight, you have to think
twice and maybe refer that patient to surgery. It's difficult to
anticipate, but of course, bifurcation, total chronic occlusion,
small vessel, is the three major reason to have a residual SYNTAX
score.


Dr. Greg Hundley:


Very good. So Shamir, could you help us put these results in
context with other studies that have been performed in this
sphere of research?


Dr. Shamir Mehta:


Yeah, sure. I would be happy to. So the SYNTAX study was unique
in that they were able to look at the degree of
revascularization, and the key finding that PCI was comparable to
CABG surgery in terms of outcomes, when complete
revascularization was able to be achieved, is a very intriguing
finding. In cases where PCI was not able to achieve complete
revascularization, it was clear superiority of CABG surgery. And
so the question is in this study, this comparison, which is a
non-randomized comparison, whether or not there's any type of
external validity for these findings.


Dr. Shamir Mehta:


And, in fact there is. It's a timely publication, because
recently we had the 4,000-patient multinational COMPLETE trial,
which looked at the issue of complete revascularization versus
incomplete revascularization in patients with STEMI, and found
that complete revascularization with multi-vessel PCI, in
appropriately-chosen patients, reduced hard clinical outcomes,
including the composite of cardiac mortality and/or current
myocardial infarction. And it reduces it quite substantially, by
about 26%, and it's a highly-significant benefit.


Dr. Shamir Mehta:


I think the caveats to this finding are important, though.
Because in the COMPLETE trial, patients were not eligible for
recruitment, unless the interventional cardiologists felt that
all of the lesions were amenable to PCI. So complete
revascularization had to be achieved in the trial. And in fact,
over 90% of patients in the trial were able to achieve complete
revascularization. So that's absolutely key, and that brings up
the importance of having a heart team in evaluating these
patients.


Dr. Shamir Mehta:


The second point is that the SYNTAX score, Patrick had referred
to was relatively low in the trial, it was only 4.6. Meaning that
the lesions that were attempted were relatively straightforward,
meaning that there was a high probability of achieving complete
revascularization. So again, I think we're starting to see from
the randomized trials and from the observational studies, the
types of patients that may be suitable for PCI versus suitable
for CABG surgery.


Dr. Greg Hundley:


Very nice. Well, Manos, Shamir, what an outstanding description
in helping us put this paper in context with other research in
this space. Manos, I know you see a number of papers come across
your desk. Also, for you, what attracted you to this particular
study?


Dr. Emmanouil (Manos) Brilakis:


Yeah, thank you, Greg. And again, congratulations to Patrick for
a phenomenal study. I think the main strength of this analysis is
the clinical relevance. I think everyone is still debating this
question, is complete revascularization the goal in every
patient? And all of the data, as mentioned already, have several
limitations. Nevertheless, they move us a little bit closer to
understanding better on whom complete revascularization should be
used.


Dr. Emmanouil (Manos) Brilakis:


So the clinical relevance is one key. I think this paper does set
the stage well for a randomized trial. End of the day, we are
still not hundred percent sure if COMPLETE is the best for
everyone, because COMPLETE counts as a risk, and the risk is
going to be higher in those patients who have more complex
anatomy. But that study will give us the definitive answer about
which is the best way to go for each individual base.


Dr. Greg Hundley:


Very nice, Manos. So that's a great segue. So I'll turn to both
Shamir and Patrick, and ask them also, as well, what do you think
is the next study to be performed in this particular space?
Shamir, you first and then we'll finish with Patrick.


Dr. Shamir Mehta:


Well, I think the concept of complete revascularization has now
essentially been proven in multiple trials. And don't forget, if
you go back several decades, really the first proof was in the
context of CABG surgery. So really, this should be the goal in
patients with multi-vessel disease. The next large randomized
trial that is going to be starting very soon is the COMPLETE 2
trial where we are actually looking at the lesions
physiologically to see whether or not we need to revascularize
lesions that are physiologically significant versus anatomically
severe.


Dr. Shamir Mehta:


This is an important question because what it does is it has the
potential to reduce the number of lesions that we perform PCI in,
by about 50%. We are also looking at plaque composition in that
trial with optical coherence tomography. A very, very large
number of patients will be receiving that. So that will be trying
to target PCI to the actual pathophysiology of the disease, by
targeting unstable plaques to perform PCI on. I think this is the
whole next era of coronary intervention, where we are now
beginning to target our therapies to the actual pathophysiology
of the disease, which is a very, very exciting idea.


Dr. Greg Hundley:


And Patrick, do you have anything to add?


Dr. Patrick Serruys:


Yeah. I think, that obviously, you have to convert the anatomical
SYNTAX Score in a functional SYNTAX Score. You could do that with
the pressure wire and hyperemia of diastolic resting gradient.
You can also do that by QFR or FFR CT. So we are going in that
direction since a few years. The second point is that we have
been working on machine learning that, at some point, the
segmentation of the coronary segment, the assessment of the
narrowing is done. And then, the next step that we are doing
right now to is to convert that to the multi-slice CT scan.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Patrick Serruys,
from National University-Ireland, Galway, Dr. Shamir Mehta from
McMaster university in Ontario, and our own associate editor, Dr.
Manos Brilakis, from Minneapolis Heart Institute, really bringing
to us this paper that, in patients with complex coronary artery
disease, incomplete revascularization can be common after PCI.
And the degree of incompleteness can be associated with 10-year
mortality. And therefore, if it's unlikely that complete or
nearly complete revascularization can be achieved with PCI in
patient with three-vessel disease, maybe we should be considering
coronary artery bypass grafting.


Dr. Greg Hundley:


Well, again, let's get on now to that second feature discussion.
Well, listeners, we are now here for our second feature
discussion today, and we have with us Dr. Michael Felker from
Duke University, and our own associate editor, Dr. Mark Link,
from UT Southwestern. Welcome, gentlemen. And Mike, we'll start
with you. Tell us a little bit about the background pertaining to
your study and what hypothesis did you want to address?


Dr. G. Michael Felker:


Great. Thanks, Greg. So I think everybody's very familiar with
the concept of favorable ventricular remodeling in patients with
heart failure, that we know is something that happens when we
treat our patients with guideline-directed medical therapy, like
beta blockers, ACE inhibitors, MRAs. Interestingly, with the
introduction of sacubitril/valsartan and the landmark PARADIGM
trial, we had a drug where we had clearly a major outcome
benefit, but we actually had very little understanding about
whether that was mediated by remodeling.


Dr. G. Michael Felker:


And those questions led us to design the PROVE trial, which was a
single-arm trial of 794 patients, looking at whether or not
patients with heart failure and reduced ejection fraction who met
the FDA label for sacubitril/valsartan, the initiation of that
therapy will be associated with favorable changes in ventricular
structure and function, as well as favorable changes in
natriuretic peptide. The current paper's really trying to put
those results in a clinical context around some of the things
that we make clinical decisions about, in taking care of heart
failure patients in this case, whether and when patients qualify
for a primary prevention ICD.


Dr. Greg Hundley:


Fantastic, Mike. And so you've told us a little bit about the
study design, and did you have exactly the same number of
patients, or what was the study population for this sort of
substudy, if you will?


Dr. G. Michael Felker:


Yeah. So in PROVE, we enrolled people who had chronic heart
failure in the EF, less than 40%, because that's the FDA label
for sacubitril/valsartan. In this analysis, because we were
interested in patients who qualified for ICD therapy, we limited
our analysis to those who an EF plus or equal to 35%. Because, as
you all know, the guideline for primary prevention ICD is people
who have a EF less or equal to 35% after at least three months of
optimized heart failure therapy.


Dr. G. Michael Felker:


And so, one of our questions was in some patients start on
sacubitril/valsartan, what happens to their ventricle and how
many patients might favorably remodel? This is, obviously, a
question that comes up a lot clinically as more and more we're
switching people from ACE inhibitors, or ARBs, to
sacubitril/valsartan in line with the recommendation that's 1A
from the AHA guidelines.


Dr. Greg Hundley:


Fantastic. ell, we're all listeners waiting to hear your results,
Mike. This is very exciting. So what did you find?


Dr. G. Michael Felker:


I think our results were quite interesting. I mean, for one
thing, the patients that were enrolled PROVE were incredibly
well-treated at baseline, and they had had heart failure for
quite some time, and a average median time of over six years. So
this is not patients who are just recently diagnosed. A lot of
these are people that you might think, clinically, we're unlikely
to go on and have much favorable ventricular modeling, but that's
not what we found. We actually found that after the initiation of
sacubitril/valsartan, after six months, on average, we had a five
point increase in injection faction.


Dr. G. Michael Felker:


And by 12 months, on average, that was almost 10 points. So quite
a bit of favorable remodeling, even in these patients you might
think were less likely to do that. And we put that in the context
of ICD decision-making. By six months, 32% of the patients who
would initially have been eligible based on the guidelines for
primary prevention ICD, no longer met those criteria because
their EF had risen to greater than 35, and by 12 months, it was
up to 62% of those patients. So as we're thinking about
decision-making around ICDs, I think these data have some pretty
obvious direct clinical relevance to decisions we now make in the
care of our patients.


Dr. Greg Hundley:


Really interesting. So Mark, I know you get several papers coming
across your desk, and as associate editor, boy, I think I can see
why this paper was attractive to you. Tell us a little bit, how
do we put these results from this study into the context of how
we decide whether a patient should receive an ICD?


Dr. Mark Link:


Yeah. The current guidelines are to wait three months after
guideline-directed medical therapy, and then repeat the ECHO and
see if they still qualify. I think what this study shows us is
that patients can continue to improve after three months, and
that improvement is somewhat continuous, actually. Because at six
months, the improvement in EF was five percent, and at 12 months,
it was 10%. So I think that's what this shows, the context is, if
you have a patient who has a low EF and they are improving, but
still haven't quite made it to 35, let's say when they went from
25 to 30 in three months, I'd probably hold off and wait another
three months and repeat the ECHO again.


Dr. Greg Hundley:


Excellent. Well, Mike, Mark, I'm going to ask you question. And
we'll start with you Mike, and then go to Mark. What study would
you perform next in this space? Mike, you first.


Dr. G. Michael Felker:


So, I think it's important to recognize some of the limitations
of any study you do, including this one. So this was not a
randomized trial. PROVE was a single-arm trial, there wasn't a
control group. And the question about the ICD per se was not
pre-specified. It was really a post-hoc analysis. So as is often
the case, I think these are intriguing and highly-suggestive
results, but I think there's clearly an opportunity to confirm
them in perspective studies designed to answer this specific
question.


Dr. G. Michael Felker:


So you could imagine a trial where patients who are starting on
sacubitril/valsartan who don't have ICDs, get randomized to
waiting three months or waiting six months, or 12 months or
whatever the interval would be. So I think these are intriguing,
and that there definitely opportunities to develop confirmatory
results.


Dr. Greg Hundley:


Excellent. Mark, do you have anything to add to that?


Dr. Mark Link:


I think the big thing we would really like to know are
predictors, predictors of response and predictors of
non-response. And that would take a larger trial perspective, and
that would be very, very valuable. Because if you could have a
predictor of a non-responder, they would get an ICD earlier, and
predictors of responders, you might wait a while.


Dr. Greg Hundley:


Very nice. Well, listeners, we get rate studies here in
circulation, and you'll find this one as a research letter,
highlighting that in the substudy of the PROVE heart failure
study, that in patients with an EF less than or equal to 35%, the
introduction of sacubitril/valsartan improved EF to greater than
35%, at 62% of subjects at 12 months. Really an interesting
finding, and perhaps further randomized clinical trials as
suggested by both Mike and Mark here, are maybe warranted in the
future.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, we want to A, thank Dr.
Mike Felker and also our associate editor, Mark Link, and wish
you, as listeners, 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,
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.