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Circulation on the Run: April 30

  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20240426.766271

Dr. Greg Hundley:

Welcome, listeners, to this April 30th issue of Circulation on the Run. And I am one of your co-hosts, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm the other co-host, Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Peder, this week our feature discussion comes to us from the world of preclinical science. And listeners, it's really interesting. It's going to focus on atrial fibrillation in two components. One, activation of the NLRP-3 inflammasome. So that term we always hear referring to sterile inflammation. And then also clonal hematopoiesis. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue. Peder, maybe this week would you like to go first?

Dr. Peder Myhre:

I would love to. Because, Greg, my first paper is so interesting and it is about something that is close to my heart, the Athlete's Heart. And Greg, exercise-induced cardiac remodeling, which is also referred to as Athlete's Heart, can be profound. With dilatation of all cardiac chambers and a tendency to lower measures of systolic function. So this is the key here. Thus, there is a clinical overlap with dilated cardiomyopathy. And also, intense endurance exercise has been linked to an increased prevalence of fibrosis and arrhythmias, some of which might predispose to sudden cardiac death.

However, the significance of this reduced systolic function in athletes is unclear. And therefore, these authors led by André La Gerche from St. Vincent's Institute of Medical Research in Australia and collaborators aim to study the prevalence, the causes, and the consequences of reduced left and/or right ventricular ejection fraction in a prospective cohort of healthy, young, elite endurance athletes from five different centers in Belgium and in Australia. So in total, 282 elite athletes from sports such as triathlon, cycling, rowing, cross country skiing, distance running and swimming were included and underwent cardiac MRI and a dilated cardiomyopathy related polygenic risk score.

Dr. Greg Hundley:

Oh, wow, Peder. This is really an interesting research question. And, of course, as you know, I'm always interested in the studies that are incorporating cardiac MR. So this group is evaluating the hearts of triathletes, cyclists, rowers, and other distance athletes from both Belgium and Australia. So what did they find?

Dr. Peder Myhre:

All right, Greg, so let's go to the results. So first of all, 44 athletes, so that's 16%, had reduced systolic function either left or right. And that included 12 individuals, so 4%, with isolated reduced left ventricular ejection fraction. 14 individuals, 5%, with isolated reduced right ventricular ejection fraction. And 18 individuals, so 6%, with both reduced left and right. And now, the reduced ejection fraction was associated with a higher burden of ventricular premature beats. So that was 13.6% in those with reduced ejection fraction, versus 3.8%.

And athletes that had the reduced ejection fraction had a higher mean polygenic risk score compared to those without a reduced ejection fraction. And in fact, athletes in the top decile of the polygenic risk score, had an 11-fold increase in the likelihood of reduced ejection fraction as compared to those in the bottom decile. And Greg, finally, male sex and higher polygenic risk score were the only significant predictors of reduced ejection fraction in a multivariate analysis, that included age and even fitness.

So Greg, in conclusion, reduced ejection fraction either right, left, or both ventricles occurs in approximately one in six elite endurance athletes. And this is related to genetic predisposition in addition to exercise training. And there is a very nice editorial by Ben Levine from the UT Southwestern Institute where he really put this in context to previous findings.

Dr. Greg Hundley:

Very nice, Peder. Really interesting article for our listeners focusing on the Athlete's Heart. Well, next we'll transition to the world of preclinical science. And Peder, a main obstacle in current valvular heart disease research is a lack of high quality homogeneous functional heart valve cells. And so human induced pluripotent stem cells derived into heart valve cells may help with this dilemma. However, there are no well-established protocols to induce these human induced pluripotent stem cells, or HIPSCs, to differentiate into functional heart valve cells. And also, the networks that mediate this differentiation have not been fully elucidated.

So Peder, this team in association with corresponding author Dr. Nianguo Dong from Huazhong University of Science and Technology, generated heart valve cells from human-induced pluripotent stem cells, utilizing several sequentially activated signaling pathways. Transcriptional and functional similarity of these human induced pluripotent stem cell derived heart valve cells were compared to primary heart valve cells and they were fully characterized. Also, Peder, longitudinal single-cell RNA sequencing was employed to uncover trajectory, switch genes, pathways, and also transcription factors that contributed to this differentiation.

Dr. Peder Myhre:

Oh, wow. This is really groundbreaking research. So we're really trying to direct these pluripotent stem cells into the heart valve cells. So what did these investigators discover?

Dr. Greg Hundley:

Right, Peder. And so an efficient protocol was developed to induce these human-induced pluripotent stem cells to differentiate into derived valve endothelial-like cells, and a second population of derived valve interstitial-like cells. And after the six-day differentiation process, what was really interesting is that those valve endothelial-like cells really performed very similar to the cells from the valve comparators. Including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress.

And then the cells that went along the pathway to differentiate into interstitial-like cells, well, they secreted collagen, matrix metalloproteinases, and they differentiated into osteogenic or adiponectic gene lineages. So they were the structural component. So it was really fascinating research. You had one group of cells differentiating into the endothelial lining of a valve structure, and the other to that structural component based on collagen.

So Peder, in conclusion, this team is the first to report an efficient strategy to generate functional valve endothelial-like cells and valve interstitial-like cells. And also to describe this differentiation trajectory and transcriptional dynamics of how this all occurred. So another great article from the world of preclinical science. And it's followed by an excellent editorial from Dr. Wu entitled Empowering Valvular Heart Disease Research with Stem Cell Derived Valve Cells.

Dr. Peder Myhre:

Fantastic, Greg, thank you for summarizing that very important study. And now, over to what else is in the mailbag. So to begin with, we have an exchange of letters between Dr. Tsigkas and Jones regarding the article “Computed Tomography Cardiac Angiography Before Invasive Coronary Angiography in Patients with Previous Bypass Surgery: The Bypass CTCA Trial.” And then there is a Perspective piece by Dr. Mikael Delborg from Sweden on [entitled] “Adult Congenital Heart Disease.” And finally, there is a Perspective piece by Dr. Caren Solomon entitled “Fossil Fuels, Climate Change and Cardiovascular Disease: A Call to Action.” Very nice perspective pieces there.

Dr. Greg Hundley:

You know, Peder, and also in the mailbag, and for our listeners, there's a very nice Research Letter from Professor Tank entitled “Peripheral Oxygenation and Pulmonary Hemodynamics in Patients with Fontan Circulation During 24 Hours of Simulated High Altitude Exposure.” Well, Peder, and our listeners, how about now we transition to our feature discussion today, “Evaluating Atrial Fibrillation Through the NLRP-3 Inflammasome Activation.”

Dr. Peder Myhre:

Let's go.

Dr. Spencer Carter:

Welcome listeners to this week's feature discussion for Circulation on the Run. I'm your host, Dr. Spencer Carter. I am a cardiology fellow at UT Southwestern in Dallas. I'm joined by the first author for our paper today, Dr. Amy Lin, who is an assistant professor at UC San Francisco. I am also joined by our stat editor and physician scientist, Dr. Amanda Tong, also from UT Southwestern. Welcome to you both.

Dr. Amanda Tong:

Thank you.

Dr. Amy Lin:

Thank you. It's great to be here.

Dr. Spencer Carter:

So today we get to discuss clonal hematopoiesis of indeterminate potential, or CHIP, with loss of TET-2 and the setting of atrial fibrillation published in this week's issue of Circulation. This study sought to answer the question of how CHIP impacts the risk for atrial fibrillation. So without further ado, I'm going to ask Amy, could you walk us through some background for your study?

Dr. Amy Lin:

Okay, great. It's nice to be here, thanks for inviting me. This work started in the lab of my mentor, Dr. Benjamin Ebert. And we worked with some great collaborators in the field of CHIP and also atrial fibrillation. And this includes Dr. Peter Libby, Dr. Patrick Eleanor, as well as Dr. Pradeep Natarajan and Dr. David Myland. So these were great authors to work with and mentors to work with as well.

We know that CHIP, or clonal hematopoiesis of indeterminate potential, plays a major role in the pathogenesis of heme malignancies. But we also now know that it plays another role in cardiovascular disease. Particularly, increases the risk for MI, heart failure, stroke, peripheral vascular disease, et cetera. But less is known about its role in arrhythmias, in particular atrial fibrillation.

So I was particularly interested in this topic because we know that atrial fibrillation shares a lot of the same risk factors or origins of clonal hematopoiesis. One being that it's age-associated. Two, there is a risk for atrial fibrillation with atherosclerosis. And the third is that we know that increased inflammation is a process involved in CHIP, and that has also been shown to be part of the mechanisms for atrial fibrillation as well. So I thought it would be a really interesting path to pursue, and that's what we did.

Dr. Spencer Carter:

That is a super clever study. I think especially with CHIP already predisposing to other cardiovascular disease, it certainly makes sense to look at its role in arrhythmia. Now, I will tell you both, I'm not a basic scientist. Amanda already knows this. And so because of that, I'm so glad to have her here in order to help us work through the methodology. I'm sure a lot of our listeners may not be basic scientists as well, and so we're going to do our best here to translate this to plain English so that everybody understands. So let's move into the methods. We're going to discuss the study design and how we made everything work. And for that section, I'm going to defer to Amanda to get into some of the methodology with Amy.

Dr. Amy Lin:

Great. I'd just like to say that I'm also not an electrophysiologist.

Dr. Spencer Carter:

Fair enough. Fair enough.

Dr. Amanda Tong:

That's okay. We're definitely not going into that details. Yeah.

Dr. Amy Lin:

My co-author is Dr. Aneesh Bapat, so he did a lot of that work and really taught me a lot about the mouse models for electrophysiology.

Dr. Amanda Tong:

Yeah. So thank you so much. It's my great pleasure to be here today. And then, first of all, I really want to congratulate Amy and all the co-authors for this beautiful study. Spencer just mentioned, I think this study really further expands our knowledge on the role of CHIP in an increasing spectrum of cardiovascular diseases, from atherosclerosis to heart failure, now to arrhythmia.

So I think this is a beautiful study. It demonstrated, for example, using a combination of methodology from epidemiology studies all the way to basic science mouse models to validate the findings. So I was just wondering whether, Amy, can you briefly go through how you guys linked with your discovery from the epidemiology study perspective and all the way to how you validated your mouse models?

Dr. Amy Lin:

Yeah. So we used a very widely used cohort that we've used quite a bit in the past, which is the UK Biobank. It's over 500,000 patients from the UK that have both health data and genomic data. So from there we were able to show that individuals with CHIP, particularly a large burden of CHIP, and specifically those with large burden of TET-2 CHIP, had an increased risk of developing atrial fibrillation. It's a modest increase, but it's still an increase. And if you consider all the other risk factors that you have to account for, it's quite robust in that sense.

Dr. Amanda Tong:

Yeah. So how did you guys validate that finding using your mouse models?

Dr. Amy Lin:

Yeah, so we have a mouse model of CHIP. It is a transplant model where LDLR-deficient mice have received a bone marrow transplant from mice that have loss of TET-2 and it's hematopoietic lineages. So it is a very good model that we've used before in the past that show that with this loss of TET-2 in the hematopoietic lineages, there is an increase in atherosclerosis that develops in these mice. And there's also clonal expansion of these TET-2 loss clones.

So from our mouse model, we were able to show that mice with loss of TET-2 in its hematopoietic lineages, there is an increased propensity for atrial fibrillation. And we see that with an inducible aphid model. Mice are a very good model for atrial fibrillation in the sense that they're mice, and they're widely used. But mice actually don't develop atrial fibrillation. So you do have to actually induce atrial fibrillation, both in the electrophysiology model, but you also have to provide it with other metabolic or genetic changes that will allow for that atrial fibrillation to be observed.

Dr. Spencer Carter:

So Amy, I know you said you're not an electrophysiologist, which neither am I, but I am very curious as to how one goes about mapping a mouse heart. How does that work?

Dr. Amy Lin:

It requires a very meticulous and patient individual. It is very small, so the mouse heart is extremely small. And it's done ex-plant, so it's an ex-vivo model. So these are terminal experiments that are done. So very time-consuming, very meticulous, and yeah, it takes quite a bit of time to do. But very similar to how they would map out in humans as well.

Dr. Spencer Carter:

Time and tiny catheters.

Dr. Amy Lin:

Exactly.

Dr. Spencer Carter:

Sounds good.

Dr. Amanda Tong:

Yeah. It's one fringe. Yeah.

Dr. Spencer Carter:

One fringe. Wow. Yeah, definitely tiny. Okay. So I know we have alluded to some of the results as we were going through the methods, but I want to dive into them specifically now. So Amy, could you let our listeners know what the primary findings are for your study? And then after that we are going to get into implications, particularly clinical implications, and how this can affect the field going forward.

Dr. Amy Lin:

Okay. So I mentioned previously that our epidemiology studies show that individuals with CHIP, particularly large TET-2 CHIP burden, have an increased risk for developing atrial fibrillation. We wanted to replicate that in our mouse model. So we used the LDLR-deficient recipient mouse transplanted with bone marrow that have loss of TET-2 in its hematopoietic lineages.

From that model, these mice were fed a high-fat diet or a western diet. And then after about six to nine weeks on that diet, we performed the electrophysiology studies for inducible atrial fibrillation. So we were able to show that these mice with loss of TET-2 have an increased propensity for atrial fibrillation. And then when we look at the specific mechanisms for that, we see that their atrial effective refractory period actually shortens, as well as their right atrial action potential duration. And those are findings that you see and are associated with an increased risk for developing atrial fibrillation.

So we already know that one of the mechanisms of CHIP is increased inflammation, in particular NLRP-3 inflammasome activation. So we were very interested to know if within these mice in the atria, if there is an increased risk for or an increased expression of NLRP-3. So we're able to show that as well. Moving forward, we wanted to know what the specific role of NLRP-3 activation is in atrial fibrillation, particularly in our CHIP TET-2 mouse model.

First, we did an experiment that we looked at the loss of NLRP-3 in cardiomyocytes in our transplant models. These are LDLR-deficient and NLRP-3 deficient recipient mice that received a bone marrow transplant with hematopoietic loss of TET-2 and its controlled wild type. And we're able to show that we no longer see that increased risk of atrial fibrillation in mice that have a loss of NLRP-3 in its cardiomyocytes. Moving forward on that, we were able to use a small molecule inhibitor, which is specific to blocking NLRP-3 activation. And that also showed a decrease in AFib inducibility in our mouse model. And that's in the LDLR-deficient mice that received the bone marrow with hematopoietic loss of TET-2.

Dr. Spencer Carter:

So it sounds like NLRP-3 could be a potential clinical target?

Dr. Amy Lin:

Potentially, yes. So the actual molecule that we used is experimental. It was provided to us with our partners at Novartis. So there isn't a lot of clinical data that is published on this molecule. But there are cousins or other similar molecules of NLRP-3 blockade that exist. One is MCC-950, which is commonly used in the lab. And if we think of other downstream effects of NLRP-3 activation, one of the cytokines that's produced is IL1 beta, and we know that there are anti-IL1 beta molecules that exist, including canakinumab, which we've seen from the Cantor trial that can reduce atherosclerotic risk in patients who already have known CAD.

Dr. Amanda Tong:

Yeah, Amy. So I'm super interested in you guys actually discovered a genotype specific effect of the CHIP mutations, AFib. So specifically you guys found TET-2 instead of DMT3A, which is the most commonly mutated CHIP gene in, for example, in general aging population or CAD. So what's your speculation on the specificity of TET-2 associated the CHIP to the AFib phenotype you guys observed?

Dr. Amy Lin:

That correlated well with our epidemiology findings. So when we looked at the association risk for CHIP and atrial fibrillation, we found that it was highly associated with TET-2. But not associated with, as you mentioned, the most commonly mutated CHIP gene, DMT3A. And so we were able to show that in our mouse model as well. Mice with loss of DMT3A in hematocortic lineages with bone marrow transplanted into LDLR-deficient mice, did not have that increased propensity for atrial fibrillation. So that fit well together.

It's interesting because when we look at large cohorts, we do see that DMT3A is the most commonly mutated CHIP gene. If we go back to the Cantos trial and the sub-analysis, though, when they looked at that particular group, which again is a sub-analysis, and the sample size was smaller than what they would prefer, but we do see an increase in patients with TET-2 loss rather than DMT3A being the most predominant CHIP gene.

So I do think that there is a difference in the specific CHIP genes and their driver potential and their mechanisms. So for example, I think for cardiovascular risk and in atrial fibrillation risk, TET-2 plays a major role. It's not to say that there isn't a role for DMT3A. I think our mouse model did not allow us to pursue that particularly. But yeah, I think there is still a lot to learn and a lot to determine from our studies on CHIP and atrial fibrillation.

Dr. Spencer Carter:

Well, I think this represents a huge first step in terms of preventing AFib. Particularly related to this process. So I really do want to congratulate you, Amy, and all of your co-authors on an amazing study.

Dr. Amy Lin:

Thank you.

Dr. Spencer Carter:

Amanda, any additional thoughts on future directions?

Dr. Amanda Tong:

Sure. Yeah. So, actually, I would be really curious to hear Amy's thoughts on what's the implication for this current study to our future AFib management? For example, should we screen AFib patients for their CHIP status? And then what do you think the next step for follow-up studies?

Dr. Amy Lin:

Yeah, I mean, potentially it would be nice if we can screen patients with CHIP and determine what their risk is for developing, whether it's heart disease, atherosclerosis, and atrial fibrillation. So ideally there will be a process in the future where we can use CHIP as a biomarker for identifying patients at risk who would benefit from specific treatment that would target, say for example, inflammation and NLRP-3 activation.

So we know that from large studies that have been done looking at anti-inflammatories as a treatment for atrial fibrillation. There have been some wins and some losses. So it's very difficult for us to get a sense of whether or not anti-inflammatories are beneficial in the setting of management for atrial fibrillation or even prevention. So this might be a nice way to screen patients who would benefit better or more from these sort of treatments. And start along the path of a more personalized or targeted therapies for atrial fibrillation.

Dr. Amanda Tong:

Thank you so much for all the insights.

Dr. Amy Lin:

Thank you.

Dr. Spencer Carter:

Yeah, this certainly sounds like it has great implications for clinical practice. So again, congrats, Amy. Thank you so much for joining us. Amanda, thank you so much for your expertise, particularly in basic science, for helping us to dissect all of this.

On behalf of Greg Hundley, Peder Myhre, I'm Spencer Carter. We can't wait to have you join us for next week's episode of Circulation on the Run.

Dr. Peder Myhre:

This program is copyright of the American Heart Association 2024. The opinions expressed by speakers in these podcasts are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

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