Circulation April 13, 2021 Issue

For this week's Feature Discussion, please join authors Erik
Näslund, Mehran Anvari, Editorialist Philip Schauer, and
Associate Editor Ian Neeland as they discuss, in a panel forum,
the articles: "Association of Metabolic Surgery With Major
Adverse Cardiovascular Outcomes in Patients With Previous
Myocardial Infarction and Severe Obesity: A Nationwide Cohort
Study," "Bariatric Surgery and Cardiovascular Outcomes in
Patients With Obesity and Cardiovascular Disease: A
Population-Based Retrospective Cohort Study," and accompanying
editorial "After 70 Years, Metabolic Surgery has Earned a
Cardiovascular Outcome Trial."


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 in
Richmond, Virginia with VCU Health. Well, Carolyn, another double
feature this week and investigating the world of metabolic, or as
we also know, bariatric surgery and the impact of bariatric
surgery on cardiovascular outcomes.


Dr. Greg Hundley:


But before we get to that double feature discussion today, how
about we grab a cup of coffee and we jump into some of the other
articles in the issue. I'll go first this week, Carolyn. The
first article comes from Professor Andreas Schuster from
University Medical Center in Göttingen. Carolyn, as you know,
right heart catheterization using exercise stress represents a
key method for the diagnosis of heart failure with preserved
ejection fraction but carries the risk of that invasive
procedure. These authors hypothesized that real time
cardiovascular magnetic resonance exercise imaging with
pathophysiologic data at excellent temporal and spatial
resolution may represent a contemporary non-invasive alternative
for diagnosing HFpEF.


Dr. Carolyn Lam:


Wow, Greg, you know how I love talking about HFpEF? I actually
managed this paper. Could you just describe what they found? It's
so exciting.


Dr. Greg Hundley:


Yeah, Carolyn. Even the methods are interesting here, where these
authors created a situation where you're riding a bicycle and
obtaining an MRI scan at the same time. Let's get to the results.
The HFpEF stress trial, prospectively recruited 75 patients with
echocardiographic signs of diastolic dysfunction and dyspnea on
exertion with E to E primes greater than eight, New York Heart
Association class greater than or equal to two. To then, undergo
echocardiography, right heart catheterization and then this real
time pedaling a bicycle CMR exam at rest and during exercise
stress. And so what they found Carolyn, the real time CMR allowed
a highly accurate identification of HFpEF during physiological
exercise and qualifies, perhaps, as a suitable non-invasive
diagnostic alternative to the invasive procedures. So Carolyn, I
think these results will need to be confirmed in a multicenter
prospective approach, but really interesting innovation here, in
this particular study.


Dr. Carolyn Lam:


So Greg, the paper I want to talk about, actually, is the first
indicative critical role of cardiac macrophages in pressure
overload-induced cardiac fibrosis and dysfunction and reveal
macrophage micro RNA-21 as a key molecule for the pro-fibrotic
role of cardiac macrophages. Now, this comes from Dr. Engelhardt
from Munich, Germany, and colleagues who show that within the
myocardium, micro RNA-21 has the strongest expression in cardiac
macrophages. Where it is also the single strongest express micro
RNA among all micro RNAs. Targeted genetic deletion of micro
RNA-21 in macrophages of mice prevented their pro-inflammatory
polarization and subsequent pressure overload-induced cardiac
fibrosis and dysfunction. Analysis of intercellular communication
using cell sequencing identified the cardiac fibroblasts as the
primary recipient cell of intercellular signals that emanate from
activated cardiac macrophages and that are controlled by micro
RNA-21.


Dr. Greg Hundley:


Oh, Carolyn, really interesting findings. What are the clinical
implications?


Dr. Carolyn Lam:


Ah, glad you asked? What this implies is that interference with
the activation of cardiac macrophages represents a promising
therapeutic strategy in myocardial remodeling and dysfunction. In
fact, synthetic oligonucleotide inhibitors against micro RNA-21
are currently undergoing clinical testing against fibrotic
disease. This is really, really fascinating.


Dr. Greg Hundley:


Well, Carolyn, my next paper also comes from the world of basic
science and it's from Dr. Anke Tijsen from Amsterdam University
Medical Center, University of Amsterdam. Carolyn, as you know,
titin, the largest protein in human, forms the molecular spring
that spans half of the sarcomere to provide passive elasticity to
cardiomyocytes. Mutations that disrupt the titin transcript are
the most frequent cause of hereditary heart failure. These
investigators evaluated the role of titin and specifically a
class of circular RNAs for regulating splicing of key muscle
genes in the heart.


Dr. Carolyn Lam:


Fascinating. Tell us what do they find.


Dr. Greg Hundley:


Yeah, Carolyn. In this study, the authors found that the back
splice junction formed by circular RNAs creates a unique motif,
which binds SRSF10, to enable it to regulate splicing. And
furthermore, they show that one of these circular RNAs, cTTN1,
distorts both localization of, and splicing of, RBM20. Carolyn,
the authors demonstrate with this work that circular RNAs formed
from the titin transcript are essential for normal splicing of
key muscle genes by enabling splice regulators, RBM20 and SRSF10.
This shows that the titin transcript also has regulatory roles
besides its well-known signaling and structural function. So,
really interesting new work involving titin.


Dr. Greg Hundley:


Well, Carolyn, as we transitioned to the other articles in the
issue, I want to tell you about Dr. Maskoun. He has a
cardiovascular case series entitled, A Plumbing and Electrical
Problem: An Unusual Cause of Syncope.


Dr. Carolyn Lam:


I like that title. Well, there's also a perspective fees by Dr.
Lindman on unloading the stenotic path to identifying medical
therapy for calcific aortic valve disease, talking about its
barriers and opportunities.


Dr. Carolyn Lam:


Tracy Hampton reviews the literature and fascinatingly highlights
papers like how DNA base editing treats Hutchinson-Gilford
progeria syndrome in mice, how some researchers have identified
the protein involved in cardiac repair, which is the ZEB2 protein
and more information on mapping early heart formation in the
embryonic mouse heart.


Dr. Carolyn Lam:


We've got a research letter by Dr. Levine. This one is so
fascinating. It's about the cardiac effects of repeated
weightlessness during extreme duration swimming and how that
compares with spaceflight. Is that cool?


Dr. Greg Hundley:


Yeah.


Dr. Carolyn Lam:


Anyways, this was just such a power-packed issue. Now, let's just
go to our feature discussion. Shall we? I can't wait, Greg.


Dr. Greg Hundley:


You bet.


Dr. Greg Hundley:


Well listeners, we have got another exciting feature discussion
today on this April 13th issue. We have with us Erik Naslünd from
Karolinska Institute in Stockholm, Ari Doumouras from McMaster
Institution in Ontario, Canada, Ian Neeland our own associate
editor from Cleveland, Ohio, and Phil Schauer from Pennington
Biomedical Research Center-LSU. Welcome gentlemen. Let's start
with you today, Erik. Could you describe for us, what was the
hypothesis that your study wanted to address and what were your
study population and design?


Dr. Erik Naslünd:


Well, what we want to study was if metabolic surgery affects the
outcome in patients with previous myocardial infarction. And in
Sweden, we are lucky that every Swede has their personal
identification number, which is connected to essentially anything
that we do, including all healthcare and we then have several
registries. One is in a metabolic surgery registry, and then we
also have one for cardiovascular disease called SWEDEHEART. What
we did was, we went into these registries and we found patients
who had undergone metabolic surgery. And then, we went to the
SWEDEHEART registry and we looked at those patients who'd had a
previous myocardial infarction. And then, we were able to get a
match cohort, the same BMI and so on, in the SWEDEHEART registry.
We were able to compare these two. We got a cohort then of
roughly 500 patients who'd had metabolic surgery without a prior
myocardial infarction and 500 who'd had a myocardial infarction.
We then, assessed to see what the outcome was.


Dr. Greg Hundley:


Very nice. And can you describe for us your results?


Dr. Erik Naslünd:


Yeah, what we found was... Our main outcome measure was in the
major adverse cardiovascular event and we found that, that was
lower in the group that underwent metabolic surgery. We also then
looked at death, which was also lower. We also looked at the risk
for new onset of heart failure, which was also reduced. We also
then assessed the risk for a major complication of the surgery in
the group that had undergone metabolic surgery. We compare that
to our surgical registry and we found that that was essentially
the same. There was not really difference in terms of outcomes in
terms of severe complications after the surgery.


Dr. Greg Hundley:


Excellent. Now, Ari, you also have a study that is involving
bariatric surgery or metabolic surgery. Could you describe for us
your hypothesis and your study population and design?


Dr. Aristithes Doumouras:


Yes. Thanks, Greg. Our hypothesis, first and foremost, was very
similar to Erik's that patients who underwent metabolic surgery,
who already had a history of heart disease when compared to a
group that didn't receive bariatrics or metabolic surgery would
decrease the future cardiovascular risk through a MACE outcome.
Our secondary hypothesis we had, that was that those with heart
failure would actually have a greater effect of metabolic surgery
because of the decrease in obesity compared to those without
heart failure or patients with ischemic, just ischemic heart
disease with no heart failure.


Dr. Aristithes Doumouras:


The setting of the study was Ontario, Canada, where we have a
centralized bariatric surgery network called the Ontario
Bariatric Network. Like Erik, in Ontario, we're able to have
multiple databases that are connected. They have one unique
identifier for each patient. And so we looked at all patients who
underwent bariatric surgery in Ontario during a timeframe. To
note, we have a very large private system. Most bariatric
surgeries, more than 95%, happen in the public system so we're
able to track a lot of our bariatric surgery patients and don't
lose a lot. We tracked all of our bariatric patients and matched
them, on a one-to-one ratio, with very similar patients who also
had heart disease and access to cardiology care, access to family
physician care and followed them over 10 years. And so the design
was a retrospective matched cohort in this way, comparing these
two groups.


Dr. Greg Hundley:


Thank you, Ari. And Ari, what did you find?


Dr. Aristithes Doumouras:


Once again, like Erik, we found that there was a lower rate of
MACE outcomes in the patients who underwent metabolic surgery and
the absolute values were actually quite high. The absolute risk
difference between the two groups was 8% and actually that went
up to almost 19% in patients with heart failure. There was no
action causing interaction between ischemic heart disease and
heart failure, so they were the same. And the risk was about 40%
lower for future MACE events in the surgery group.


Dr. Greg Hundley:


Wow, a large difference. Ian, as an editorialist for Circulation,
the American Heart Association, you see a lot of papers come
across your desk, what attracted you to these two manuscripts?


 


Dr. Ian Neeland:


When I first read these excellent papers, I thought that first of
all, it was globally diverse. One study was in Europe, the other
one in North America. And nevertheless, they showed strikingly
similar relative risk reductions in MACE. One of them showed
between 40 to 50% and so did the other. That was one really
striking thing, was the consistency of a risk reduction despite
being globally diverse with different systems in each country.
Second of all, the absolute risk reduction was astounding.
Assuming you could translate the absolute risk reduction to a
clinical trial, to real-world experience, you're looking at a
number needed treat between five to 12 for MACE, which is
astounding and much greater than many of the evidence-based
therapies we have today. The magnitude of the findings were
striking and the ability to generalize globally were really
interesting.


Dr. Greg Hundley:


Thank you, Ian. Well listeners, we also have an editorialist that
can help us put all of this in context of what we known
previously about bariatric surgery or what we are calling
metabolic surgery. So we're going to turn to Phil. Phil help us
put the results of these two studies in the context of
cardiovascular medicine specialists or even family practitioners,
internists that are managing patients with cardiovascular disease
that happened to be morbidly obese.


Dr. Phillip Schauer:


Yeah, Greg. Well, these are both outstanding observational
studies. And congrats to Erik and Ari and their teams for putting
these studies together. Now, what's unique about these studies,
is that I think these are the first to actually look at metabolic
surgery for secondary prevention. Now, there are nearly 30
studies looking at metabolic surgery as primary prevention. These
are all observational. They're not prospective randomized trials,
but they all show, nearly all of them, show mortality reduction
and MACE event reductions. These two studies are the first to
show that metabolic surgery is good for secondary prevention.
This is really important because I think, up till now,
cardiologists have been very reluctant to refer patients to
metabolic surgery. Patients who've already had a heart attack
because of the least perceived operative risk and surgeons have
been reluctant to operate on these patients. And both Erik and
Ari have showed that the perioperative risks were remarkably low
for this population, operative mortality way below 1%.


Dr. Phillip Schauer:


And so within a very short period, within a year or two, the
mortality reduction, by far, supersedes any perioperative risk. I
think this is really very good news. We now have quite a large
amount of observational data in the primary prevention side.
These two studies, nearly identical, showing mortality, MACE
event reductions, as Ian pointed out, 40 to 50%. That's a lot.
That rivals almost anything else out there in terms of mortality
reduction, whether it's an SGLT2 inhibitor, a GLP-1, or a statin,
I mean, people dance in the street when you see a five and 10%
reduction. With surgery, it looks like we're seeing 40 to 50%.
So, this is remarkable news but we do have a little more work to
do. Perhaps we can talk about that, your next question.


Dr. Greg Hundley:


What a great lead-in Phil. So listeners, striking results with
this surgical intervention for patients with cardiovascular
disease that have morbid obesity. Erik, let's start with you, but
we'll go through all of our expert panelists here. Erik, what do
you think is the next study that needs to be performed in this
sort of area of research?


Dr. Erik Naslünd:


Well, I mean, the obvious answer to that is that we need to do a
randomized control trial to verify these results. That's the
number one. Number two, I think, we also need to tease out, if we
can, which are the most suitable patients. And is there a
difference between the most commonly performed metabolic surgery
procedures. That's where I would suggest that you need to do
next.


Dr. Greg Hundley:


Ari, how about you?


Dr. Aristithes Doumouras:


I agree with Erik. I think everyone's going to say the same
thing. That I think a randomized trial is the next step when
looking at bariatric surgery and the role of secondary
prevention-based patients, as these are all observational
studies. And they just need to be confirmed. We're starting on a
pilot study for this exact randomized trial at our institution
and obviously looking for more partners later on, but yeah,
that's definitely the next step in the process for sure.


Dr. Greg Hundley:


Ian, what would you like to add?


Dr. Ian Neeland:


No, I definitely agree an RCT is needed. I think one that
combines both primary and secondary prevention patients is
important to try to understand that the difference. One could
imagine that secondary patients may actually derive much greater
benefit than prime prevention patients given their baseline risk.
And if one can show that the operative morbidity, mortality is
low in both populations, as both papers showed observationally,
then I think there's a lot of benefit there. I also think it's
important to try to randomize people to different procedures, to
really try to understand is it the gastric sleeve? Is it the
bypass? And which one has greater benefit in the setting of a RCT
as well as how do the risks and safety outcomes differ between
those two in the real-world RCT setting.


Dr. Greg Hundley:


Very nice. Well, Phil we've heard randomized trials, maybe also,
do we need longer follow-up?


Dr. Phillip Schauer:


Yeah, Greg. In the title of my editorial, and I hope that the
listeners actually do read it, is after 70 years, metabolic
surgery has earned a prospective randomized trial, and it's true.
This field is 70 years old, there's not a single prospective
large randomized controlled trial. There are quite a few small
studies that were powered for biomarkers, but not hard clinical
end points. We need this and it is doable. For example, for
coronary artery bypass surgery, there's over a hundred
prospective randomized controlled trials. So we definitely need
this type of study. It needs to be long follow-up, probably five
years or more. As Erik and Ari pointed out, it should have a
mixture of primary and secondary prevention.


Dr. Phillip Schauer:


I'll share with you right now, I'm working with a group in the
US. Along with Steve Nissen, a very noted cardiologist, Bob
Eckel, who's currently the president of the American Diabetes
Association and a number of other experts. David Aterburn, Sonia
Thomas, who are working together to try to develop a study. The
question is who will fund this? And frankly, we've been talking
to various funding organizations. And frankly, we need the help
of the cardiology community to help us support this. This
information is very important.


Dr. Phillip Schauer:


If I may say one more thing, it's interesting the entire field of
obesity treatment, everybody who has obesity gets treatment to
cause weight loss. Yet in 2021, we do not have data that shows
that weight loss actually reduces morbidity and mortality. The
closest thing we have is a look ahead trial, and it looked at
weight loss via a lifestyle intervention. After 10 years, they
got 6% weight loss, 6% weight loss is not enough. With metabolic
surgery, we can get 25 to 30% weight loss. So we need to do this
study, not just to show that metabolic surgery is effective, but
to show that weight loss itself could actually reduce morbidity
and mortality. And frankly, it's not just cardiovascular. The
second most common cause of death in these studies is cancer. And
that's the other interesting thing that should be looked at.
Hopefully, we can get organizations like NCI to come in and
support this initiative.


Dr. Greg Hundley:


Thank you. Well, listeners, what a wonderful discussion today,
really a feature symposium. And we want to thank Erik Naslünd,
Dr. Aristithes Doumouras, Ian Neeland and Phil Schauer for their
time and expertise and sharing that with us today. Especially on
this topic of bariatric, but now maybe more commonly called
metabolic surgery, where these two studies have been
demonstrating efficacy of these procedures now in patients with
cardiovascular disease and even those post myocardial infarction.


Dr. Greg Hundley:


On behalf of Carolyn and myself, I want to wish you another great
week ahead and we will catch you in that next week, on the run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021.