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.