Hi, this is Eric Pustowski and welcome to another segment of EP on EP. It's a delight to have as my guest today, Dr. Mina Chung, who is involved in a large way in her career, translational science, and the head of the genomics project with atrial fibrillation at the Cleveland Clinic. Did I get all that right? Yeah. Sort of. That's good. Sort of. Okay, so we're going to talk genomics of atrial fib, and clear up something for me as just a plain old EP guy. I often see patients who have a fib, let's say they're in their 40s or 50s, and I take out family history, and I found out mom who's 79 had a fib, and now she's got a pacemaker. Is that part of the thing versus, let's say, you hear about families where there's four or five people younger who have a fib? Strict. How do you view that? Oh, you know, if you take a careful history and include things like stroke and atrial fibrillation, there's a very high likelihood you'll find an association there in a patient. In earlier days, there were a lot of studies looking at the familial AF, but along with development of finding out that the pulmonary veins can be sources of triggers, around that time, we recognized that AFib was very heritable, and there were these large genome-wide association studies that were done, and now there are over a couple hundred loci on the DNA that are associated with AFib. The top one, you can see with just like 100 patients in our lone AF cohort, which is amazing because normally when you do these studies, you need thousands, tens of thousands, a lot of patients to see the signal. This is a really strong signal, and it's near a gene that happens to be involved with formation of the pulmonary veins. No, come on. Seriously? Yeah. I mean, there's a huge ... That's very interesting. Yeah. I did not know that. That's interesting. So, do you think ... I've wondered for many years about this whole pulmonary vein thing. I think we're lucky to have found it. Actually, it goes back, if you want to look at basic literature, it was actually studied in a paper in Nature, but of course, that got lost to the EP community, showing that pulmonary veins could have automatic activity, and then, of course, the pioneering work of Michel Hasseger. Sure. But why the pulmonary veins? And another thing ... Why do you have to ablate all four of them? We'll get to that. All right. Let's stick with genetics first. So, the thing that I find strange about it is, the vast majority of automatic foci, as I've seen in my career as a rhythmic foci, tend to get less as you age. Right? They get less. So, why is it that pulmonary veins become rapidly firing more commonly in older ... Is there any genetic tie in there? That's the key question. The paradox, right? So, if we're born with a predisposition to AFib, okay, then why don't we get it until you're 40s, 50s, 60s, 70s? So, it turns out that that gene, PITX2, in some animal studies, in knockouts, it's shown to suppress a left atrial sinus node program, so ... Really? Yeah. So, it's expressed mostly in the left atrium. Just think about your associations with AFib. Obesity, getting older, a lot of stressors, a lot of cardiovascular ... Hypertension. Hypertension. Right? So, we took some of these genetic studies to the next step in trying to figure out what the connection is between those genetics and getting AFib. And we, along with David Van Wagener and our CT surgeons, we collected a big human atrial tissue bank of left atrial appendages. So, we could then look at the next step from DNA to mRNA transcriptomics. And to see what ... First of all, when you do the genome-wide association studies, you don't know that gene, but to see if those variants are associated with gene expression. And we could also look across the transcriptome to see what's affected. So, with that, we'd done a lot of work on inflammation and oxidative stress, and I thought, oh, this is not going to be that interesting because it's going to be ... We're going to see those things upregulated. And so, I thought, oh, okay, yeah, we'll go ahead and spend the big bucks it took to do these studies. To do it. And to my surprise, what we saw were a downregulation of some of those. And so, we have this ... We have ... And then, there were some pathways that were really interesting. The proteostasis, protein handling, the inflammation ... So, our model is kind of a dual-hit model. You may be ... A dual-hit model. A dual-hit model. Almost like cancer, right? Okay. You're born with a predisposition to AFib from your genetics, and it's not until you get older when we overwhelm our metabolic stress responses, our other oxidative stress responses, and you develop obesity, all these things, overwhelm our cells' ability to keep AFib, those triggers in check. And then, as you develop stress and obesity, all those things make it more likely for those triggers to come out later in life. Mina, you've raised some really interesting questions. Do you have any plans, or are you engaged in clinical trials to look at these? Yeah, we're doing this clinical trial called TRMM-AF. So, it turns out that one of the things that's come out of our genomics work is a focus on this enzyme called AMP kinase. And this is a master metabolic regulator, stress regulator, in the cells. And it looks at ATP-AMP balance. If we use it up a lot with rapid AFib, for example, rapid stimulation, it has pathways to increase the amount of ATP. So it's really involved in the balance of metabolic stress. And it turns out that certain things like diet, exercise, they have good effects on AMP kinase and metformin. Really? Yeah. So, we're doing a... When you say good effects, you mean it would be sort of anti-AFib, in a sense? That's what we're hoping. Yeah, that's a hypothesis. Okay. So, we're doing a clinical trial in patients who have pacemakers or defibrillators so that we can record the atrial burden on a day-to-day basis and activity. And it's a two-by-two trial of lifestyle risk factor modification and metformin, or both. Yeah. That's interesting. Control. But having counseled people, including myself for years, to lose weight... It's hard. At least in Indiana, it's really hard. So, my guess is you're going to get a lot more out of the metformin group. I think you're right, unfortunately. The COVID pandemic has really hurt and made it really hard to recruit and for people to come in and participate in those programs. So we'll have to see. As things are ramping down, we hope, with the pandemic, we're ramping up again. So we'll see what happens. Well, that's exciting. It's a very important problem you're studying. Now, I know you've told me in the past that this is totally going maybe a little away from the main topic, but we ablate all four pulmonary veins, or at least we try to. You sort of have a view that maybe we don't have to. No, I think we do. Oh, you do? That would be great. No, no. I always... Because it always puzzled me in terms of why your early studies showed that if you just ablate one, the focus in there, it doesn't really work. It's not like going in and ablating WPW, one pathway, you got it and you're done. We've had to do much more. So it seems like it was a more systemic problem. So I think it really goes along with the genetics and genomics that we find with maybe some dysregulation of that left atrial sinus node program. When you isolate and you record those dissociated... Maybe that's our... Well, to go along with that, one of the observations I've made over the many years I've been in this business is that a person could do well for two or three years, and then they come back and you go back in and you see three veins that are reconnected. Now, they didn't reconnect three years later, they reconnected quickly. So my philosophy, just to tell you how simple a guy I am sometimes, I look at the veins as volcanoes, and volcanoes can be dormant or they can be active, and if you get lucky and have complete isolation of the one that's really active at that moment, then later on, another vein can sort of become a troublemaker. But we know that it doesn't take a year for a vein to reconnect. So I think we're sort of sometimes led down the golden path. We sort of misconstrue and we say, oh, look, there's a new source three years later. I don't know that that's true. I think that it was probably, like you said, a potential source, maybe for some reason. So that would go back to your genomics issue. Have you found, I know it's kind of early, have you found differential effects in different veins, different parts of the veins or something? Well, I don't know about different veins, but we have done a regional look at the transcriptomics that we haven't published yet. But to your point, it's very interesting that there's reconnection, and it can be later, and you know what? I tell my patients, your heart has a remarkable way, your body has a remarkable way of healing across what we do to it. And if you look at transplant data, people, they have a remnant of their atrium, they have a new heart there. You can get, down the road, atrial flutters and the remnant that find their way across that suture line. So you can grow across it. And I did a literature search a number of years back to see how early that could happen, and I found two years. So this can happen. What makes us think that it's not going to happen with pulmonary vein isolation? And in fact, one of the other times I've been wrong in my career, I thought, oh, wow, we found this locus that's near something having to do with the pulmonary veins. We could use this as a biomarker to who should get pulmonary vein isolation. But you know, having the variance in that is associated with higher risk of recurrence. So that's actually interesting because Dr. James Martin has done a lot of really great work on PEDX2, and he's taking it a whole other way. It has something to do with cardiac regeneration as well. And so I don't know if there's some dysregulation that happens because he has this model where if you have a newborn rat, a neonatal rat, you cut off the apex of the heart, it regenerates. But if you have PEDX2 deficiency, it doesn't. So it's hard to know. It's going the wrong direction, but you don't know which way these things are going. So a lot we don't know. Yeah. Well, it's a fascinating discussion. Just for the clinicians, we're not ready for doing some genetic testing. Is that correct or incorrect? I mean, if you have a patient, there's no reason to do a genetic panel for AFG. Yeah. I mean, it's so cheap to do nowadays that you're probably going to come up with people who have these loci at 4Q25 or the other AF genetic loci. I would just say it's hard to predict who long-term, but for that kind of a person, maybe it's worthwhile with these wearables that they just basically do something for that long-term. Or maybe, if I can opine, let's say mom has it or dad has it, and then you do the family and you find somebody else has whatever this gene is, maybe you can counsel them on lifestyle changes at that point. That's right. For sure. Great point. Make sure, in particular, there's a reason for you to go on a diet and eat healthy. Exactly. Exactly. Maybe. Yeah. But you're not going to use it. I don't think it's as strong. It's not like long QT and things, right? Right. Right. It'd be more kind of on the fringes right now, maybe? Is that fair to say? Perhaps. Yeah. Yeah. I mean, there may be some high, high-risk people that you might want to consider doing. Yeah. But we need the clinical trials to show that doing genetic testing actually impacts outcomes. Right. Mina, thank you so much. Thank you. It was great. Thanks for joining us today. Bye.

genomics

atrial fibrillation

PITX2 gene

clinical trials

metformin