Circulation December 21, 2021 Issue

Please join Guest Host and Associate Editor Mercedes
Carnethon and author Christine Albert as they discuss the article
"Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on
the Risk of Atrial Fibrillation in Randomized Controlled Trials
of Cardiovascular Outcomes: A Systematic Review and
Meta-Analysis."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to The Journal and its editors. We are 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, VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, today's feature paper is such an important question
clinically. It's something I've asked myself and so I cannot wait
to discuss it in greater detail. It refers to the effect of
long-term marine omega-3 fatty acid supplementation, and the risk
of atrial fibrillation in randomized controlled trials of
cardiovascular outcomes. So it talks about a systematic review
and meta-analysis published in this week's issue.


Dr. Carolyn Lam:


All right. Okay. You got to wait in suspense, as do I, and let's
discuss other papers, very important papers in today's issue too.
I'd like to start with a bit of a quiz. So Greg, for converting
atrial fibrillation, is the anterior-lateral or anterior
posterior electrode position better? What's your guess?


Dr. Greg Hundley:


Oh, wow, Carolyn. That's interesting. We put these pads on and we
kind of just follow the directions on whatever the particular
device says. Interesting question. It's a guess, Carolyn, it's a
guess. Antro-lateral?


Dr. Carolyn Lam:


Smarty pants. Well, let's see. Frankly I didn't know the answer.
It's just such an elegant question, isn't it? To answer in a
study. And this is exactly what Professor Løfgren from Randers
University Hospital and Denmark and colleagues did. They
performed a multi-center investigator initiated open label trial,
where they randomly assigned 468 patients with atrial
fibrillation scheduled for elective cardioversion to
anterior-lateral versus anterior-posterior electrode position.


Dr. Carolyn Lam:


The primary outcome was the proportion of patients in sinus
rhythm after the first shock. And so drum roll. The primary
outcome occurred in 54% assigned to an anterior-lateral electrode
position. And in 33% assigned to an anterior-posterior electrode
position, a significant risk difference of 22% in favor of the
anterior-lateral electrode position.


Dr. Carolyn Lam:


Cheers, Greg. There were no significant differences between
groups in any safety outcomes and the superiority of the
anterior-lateral electrode position was statistically significant
both after the initial low energy shock and after a final high
energy shock. So this study really suggests a practice change in
the standard approach to electrode positioning for cardioversion
in favor of anterior-lateral electrode position.


Dr. Greg Hundley:


Very nice, Carolyn. Very nice. Well, I'm going to come at you
using your heart failure expertise and ask you a quiz here in
just a second. But first I want to introduce this paper from Dr.
Javier Barallobre-Barreiro from King's College London. Okay,
Carolyn, here's your quiz. Do you think that the extracellular
matrix fibrosis contributes to LV dysfunction in heart failure
patients?


Dr. Carolyn Lam:


Absolutely.


Dr. Greg Hundley:


Very nice. I think, of course, you are correct. So Carolyn,
remodeling of the extracellular matrix is a hallmark of heart
failure and this team's previous analysis of the secretome of
mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and
metalloproteinase with thrombospondin motifs 5 as one of the most
abundant proteases. So ADAMTS5 cleaves chondroitin sulfate
proteoglycans such as Versican. The contribution of ADAMTS5 and
its substrate Versican to heart failure is unknown.


Dr. Carolyn Lam:


Ah, so what did the authors find, Greg?


Dr. Greg Hundley:


Well, first Carolyn, there was a methodologic advance here. Left
ventricular tissues from 86 heart failure patients and
non-failing controls were analyzed by quantitative mass
spectrometry, constituting the largest proteomics analysis on
human heart failure today. And so what did they find?
Accumulation of proteoglycan Versican was regulated by ADAMTS5,
that disintegrin and metalloproteinase with thrombospondin motifs
5, and was associated with the reduction in proteins involved in
intercellular communication. And Carolyn, interestingly,
proteoglycan accumulation in ischemic heart failure was
attenuated by beta blocker administration.


Dr. Carolyn Lam:


Oh, that's very interesting. Could you put that all together for
us? What's the clinical implications, Greg?


Dr. Greg Hundley:


You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast
constitutes an important component of cardiac fibrosis after
ischemic heart failure, just like you stated at the beginning
with your quiz answer. This contributes to impaired cardiac
function and besides their negative chronotropic and inotropic
effects, beta blockers may modulate extracellular matrix
remodeling.


Dr. Carolyn Lam:


Wow, nice, Greg, thank you for that. I've got another original
paper and it deals with the very important topic of endothelial
to mesenchymal transition. Now it has been reported that cardiac
endothelial cells contribute to a substantial proportion of
myofibroblast through this process called endothelial to
mesenchymal transition. Lineage tracing studies have demonstrated
that myofibroblasts are derived from expansion of resident
fibroblasts rather than from transdifferentiation from
endothelial cells.


Dr. Carolyn Lam:


However, it remains unknown whether endothelial cells can
transdifferentiate into myofibroblast reversibly or would these
endothelial to mesenchymal transition genes just transiently
activated in endothelial cells during cardiac fibrosis? So these
authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong
University School of Medicine, Dr. Lui from Price of Wales
Hospital and Chinese University of Hong Kong, as well as Dr. Zhou
from the University of Chinese Academy of Sciences in Shanghai
and their colleagues.


Dr. Carolyn Lam:


What they did is they used the dual recombination technology to
generate a genetic lineage tracing system for tracking
endothelial to mesenchymal transition in cardiac endothelial
cells and their genetic fate mapping results basically showed
that although mesenchymal gene expression was activated in
cardiac endothelial cells throughout the endothelial to
mesenchymal transition in the developing heart, the endothelial
cells do not transdifferentiate into myofibroblasts, nor do they
transiently express some known mesenchymal genes during
homeostasis or fibrosis in the adult heart. Resident fibroblasts
that are converted to myofibroblast by activating mesenchymal
gene expressions are in fact the major contributors to cardiac
fibrosis.


Dr. Greg Hundley:


Ah, Carolyn, very interesting. So can you put this together? What
are the clinical implications?


Dr. Carolyn Lam:


So what it really says is that it's the resident fibroblasts that
are converted to myofibroblast by activating mesenchymal genes.
These are the ones that represent a major therapeutic target and
really unraveling these mechanisms, driving endothelial to
mesenchymal transition in such a detailed way, provided new
insights into therapeutic development to target cardiac fibrosis.


Dr. Greg Hundley:


Wow, Carolyn. You know, two really good preclinical science
articles speaking to us about myocardial fibrosis.


Dr. Carolyn Lam:


Well, there are other papers in today's issue too. There's a
Perspective piece by Dr. Christopher Lamb on “Liver Cirrhosis and
Hepatocellular Carcinoma After the Fontan Operation: Reaching
Clarity in the Face of Uncertainty. And this is paired with a
Research Letter by Dr. Toshio Nakanishi on incidents and expected
probability of liver cirrhosis and hepatocellular carcinoma after
the Fontan operation.


Dr. Greg Hundley:


Very nice, Carolyn, and I've got an “In the News” piece from
Bridget Kuehn entitled “Centering Equity in Cardiovascular Care
as Michelle Albert Lays Out a Roadmap for our Profession.” Well,
Carolyn, how about we learn a little more about those long term
marine omega-3 fatty acid supplementations and the risk of atrial
fibrillation?


Dr. Christine Albert:


Oh, I can't wait. Let's go, Greg.


Dr. Mercedes Carnethon:


Thank you so much for joining us for today's episode of
Circulation on the Run. My Lame is Mercedes Carnethon, Professor
and Vice Chair of Preventive Medicine at the Northwestern
University Feinberg School of Medicine and Associate Editor at
Circulation. And I have the great pleasure today of having a
conversation with a long time friend, Dr. Christine Albert from
the Department of Cardiology at the Smidt Heart Institute at
Cedars-Sinai Medical Center in Los Angeles.


Dr. Mercedes Carnethon:


And today I've got the great pleasure of hearing directly from
Christine about a wonderful original research piece that is being
featured in Circulation about the effect of long term marine
omega-3 fatty acid supplementation on the risk of atrial
fibrillation in randomized controlled trials of cardiovascular
outcomes. And the exciting innovation of this piece that we'll
dig into is what we're learning from the systematic review and
meta-analysis that Dr. Albert and her team carried out. So, thank
you so much for joining us today, Christine.


Dr. Christine Albert:


Well, thank you, Mercedes. It's really great to be here.


Dr. Mercedes Carnethon:


Great. Well, I'd just like to launch with you telling us a little
bit about the study, what you found, why you decided to conduct
this meta-analysis and review.


Dr. Christine Albert:


Yeah. Great. So my first author, Dr. Baris Gencer and I decided
to do this because we actually had participated in a randomized
trial called the Vital Rhythm Trial, where we actually randomized
people to omega-3 fatty acids and atrial fibrillation, and found
a slightly elevated risk, but it wasn't significant. And at that
time, a number of other articles came out saying that there
really was an increased risk of atrial fibrillation.


Dr. Christine Albert:


So we wanted to put together the data to see what the combined
data, our data, that's been published before, on this sort of
long term treatment with omega-3 fatty acids and atrial
fibrillation. As you may know, there have been studies that have
looked at short term treatment, and specifically for atrial
fibrillation, and did not find benefit. So this is why we went
ahead and did this study. And what we did is we were able to find
seven randomized trials that collected data on atrial
fibrillation that had randomized people to omega-3 fatty acids
over an average of about five years of follow up between all the
different trials. And we found that when you combine all these
trials together, you actually see that there is a slightly
elevated risk of atrial fibrillation in the participants that
were randomized to the omega-3 fatty acids.


Dr. Mercedes Carnethon:


Thank you so much for that summary, Christine. I think the
findings themselves surprised me. This is not my primary area of
work, but we hear so much about supplements and their benefits
that I thought it was really telling to actually have these data
coming from a large number of studies, and particularly large
studies that suggest that there is a risk to benefit ratio that
we need to consider. How would you recommend that clinicians
weigh this evidence that you've generated today?


Dr. Christine Albert:


So I think that it's got to be individualized. There are benefit,
as you said, of these omega-3 fatty acids. And I think it's just
awareness, awareness that this potentially is a risk. If you have
a patient on omega-3 fatty acids and they start to have atrial
fibrillation, there could be a link. Also when you talk about it
with patients, I think it's reasonable, especially with the
higher doses, we can just discuss that this is a potential side
effect. Does it prevent you from using it? I don't think so. I
think you have to look at what is, again, as you said, the risk
benefit ratio for the individual patient. And as I alluded to, we
did do a dose analysis and we found that the risk was primarily
seen, and it was higher, in those that were given more than a
gram of omega-3 fatty acid a day.


Dr. Christine Albert:


However, I will say that the trials are very different when you
take a meta-analysis, it's really hard to say, "What is the cause
of the differences between trials?" You know, these trials that
had the higher dose, the reduce it trial that used just a
purified EPA was very different than the dose of the medication
that was used in vital, different than the type of medication
that was used in strength. And as you know, there's the whole
debate about the placebo and reduce it versus strength. And so
there are other differences, but one thing that is pretty
consistent is that most of the point estimates are on the side of
harm. So there is the thought that I think this is potentially
very real and we should be considering it when we use these
supplements.


Dr. Mercedes Carnethon:


You know, that's a really nice summary which really launches me
into two subsequent questions. The first would give you the
opportunity to speculate beyond the findings in your particular
study, and this is one of the benefits to me of this Circ on the
Run podcast, because you, of course, produced excellent science
and weighed all of your findings based on what you found. But can
you tell me, based on your experience, could you speculate about
what you think the mechanism of elevated risk of atrial
fibrillation is, particularly with those higher doses?


Dr. Christine Albert:


Yeah, no, it's interesting. You know, if you look at the
epidemiology for this, Mercedes, it was totally inconsistent.
When I postulated doing the vital rhythm trial, I actually have
to be honest with you, I thought that there might be an increased
risk, because when you look at some of the data of what these
omega-3 fatty acids do, they increase vegal tone, they lower
heart rate. They can actually slow conduction. So potentially
those electrophysiologic actions might, might allow atrial
fibrillation to emerge in people who are susceptible.


Dr. Christine Albert:


On the flip side, all of those things might be good for
ventricular arrhythmias. So you see, if you look at the
literature, there's benefits for…sudden death and epidemiologic
studies and in some of the randomized trials, but then when you
look at atrial fibrillation, at least the short terms, really
didn't show a benefit. And again, that point estimate was more
towards harm.


Dr. Christine Albert:


And then when you look at epidemiologic studies, looking at fish
consumption, there's actually a lot of studies that suggest that
people who eat more fish get more AFib. So it is really
paradoxical. And we know as electrophysiologist that atrial
arrhythmias and ventricular arrhythmias are not the same, we give
drugs to prevent atrial arrhythmias that then cause ventricular
arrhythmias. So it is interesting. And I think it's something
that hopefully some of our translational scientists will help us
to figure out.


Dr. Mercedes Carnethon:


All those contradictions are so challenging, but you were
certainly speaking my language in describing the hypothesized
mechanisms. It calls to mind, back in the day, in your early
research on sudden cardiac death that I was citing as part of my
dissertation work in epidemiology. So thank you for that.


Dr. Christine Albert:


Yeah.


Dr. Mercedes Carnethon:


You know, the second question that builds off of that is I
thought that the figure where you display the heterogeneity by
the dosage of omega-3's really underscores the argument that you
were just presenting. What I was wondering is, did you happen to
study heterogeneity by any other characteristics, particularly
sex or age?


Dr. Christine Albert:


That would be fantastic to be able to do, unfortunately, because
it's a summary level meta-analysis, we really can't do that. And
that's one of the things that we'd love to do in collaboration
with some of these authors if they would like to do that, is to
really get that sort of paid participant level data, so we could
do those kinds of analysis.


Dr. Christine Albert:


But what we did do is sort of separate out studies that had like
confirmed AF, studies that had incident AF versus recurrent AF,
so things where the studies were completely different, we were
able to look for heterogeneity and we didn't find anything that
suggested that there was heterogeneity on that basis. But there's
a number of things that I would love to look at and age is
definitely one of them, and also sex. And actually looking at,
which would be really interesting, is to look at the omega-3 or
EPA and DHA levels in these individuals. And again, I think each
study has sort of tried to do it on their own and you can't
because there's just not enough data. So putting all this data
together would be great to have a better understanding of what's
going on.


Dr. Mercedes Carnethon:


Oh, it sounds speaks to a number really thoughtful future
directions for this work. One of the benefits of me being able to
speak with you today in my role as a guest podcast host, but I
was also the Associate Editor for the piece and was really
excited when it came in. The discussions that we had amongst the
editors about this were really very stimulating and raised a
number of questions that led to you responding and making some
modifications and explaining certain things. Could you tell our
audience, why did you select trials over a certain size? You
know, quite often we do meta-analyses in order to pull together
smaller studies, but why did you choose larger studies?


Dr. Christine Albert:


I think it was so that, there were two criterias, one was larger
and one was long term, because we felt that the smaller studies
had been merged together previously and we wanted to have at
least some data on atrial fibrillation. One of the problems I
think that I think I want to emphasize a little bit here about
research in general in cardiovascular disease is that until now,
most studies hadn't really measured atrial fibrillation, and I
think it's really important. And I think you can see, you can
find off target effects of some of the agents that we use for
cardiovascular disease on atrial fibrillation. So for instance,
the Statin Trials, everybody said, "Oh, well statins might lower
atrial fibrillation," but then nobody measured atrial
fibrillation, so we never knew. And then people went back and
tried to measure it as a side effect or something that has all
kinds of biases to it.


Dr. Christine Albert:


So I think that what is exciting about this work is that both
reduce it and strength and vital, pre-specified that they were
going to look at atrial fibrillation. And so if we do that, we
may actually find other agents that are beneficial, not just
harm, but beneficial, like the SGLT2 inhibitors, there's lots of
hypotheses. So the reason that we did pick the bigger trials was
that we wanted to find trials that really kind of looked at
atrial fibrillation, had enough power to look at atrial
fibrillation and then over a long term, a follow up to gather
enough events.


Dr. Mercedes Carnethon:


Again, it has been such a pleasure to hear directly from you. I
really hope that our listeners today and our readers of The
Journal will dig into this in the same way that we have as
editors and really appreciate the thoughtfulness with which
you've presented this outstanding work. So I want to thank you so
much, Dr. Albert for joining us today.


Dr. Christine Albert:


Thank you for having me.


Dr. Mercedes Carnethon:


I guess I will sign off now. This is Mercedes Carnethon from the
Northwestern University Feinberg School of Medicine and Associate
Editor for Circulation.


Disclaimer:


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.