Hi, I'm Eric Pustowski and welcome to another segment of EP on EP. With me today is a former guest to the show, but he's always great to have back, Dr. Hugh Calkins, who's the director of electrophysiology at Johns Hopkins and has done work in our field in many areas. But today, Hugh, I'd like you to talk about ARVC. Great. Well, that's a topic I love to talk about, so thank you, Eric. I knew that. So, first of all, I just want to get terminology straight. Since I learned about this when I was a young guy in EP, it was always ARVC, and then you came up with this AC, arrhythmogenic cardiomyopathy, and I'm not really sure now what I'm supposed to call all these things. So could you clarify the nomenclature for this area? Well, ARVC is the initial disease that Frank Marcus and others focused on and that we have diagnostic criteria for, we know the most about. This latest document on arrhythmogenic cardiomyopathy, it was a consensus document that Jeff Tobin led. And the point of that document is if you have arrhythmias and you have evidence of cardiomyopathy, then it's sort of the big tent approach. You have, by definition, an arrhythmogenic cardiomyopathy, and you need to think about things like inherited heart disease, like ARVC would be one subset of that. I mean, cardiac sarcoidosis is an arrhythmogenic cardiomyopathy. So I think the term arrhythmogenic cardiomyopathy is really saying when you have someone with arrhythmias and a cardiomyopathy where the arrhythmias are a prominent part of how that patient presented, you can use the term arrhythmogenic cardiomyopathy and just include in your differential diagnosis these inherited cardiomyopathies like ARVC. But I think practically ARVC is what we always know and love. There's something called ALVC, which is left dominant ARVC, but it seems strange to call it ARVC that's left dominant. We're working on developing diagnostic criteria for ALVC that's a bit in flux, where really the world's major ARVC centers are putting their data together to come up with new ALVC diagnostic criteria that don't really exist yet. Domenico Corrado came up with some proposed criteria. We find they aren't terribly helpful in distinguishing cardiac sarcoidosis and other conditions. We're working on the next iteration of how do you diagnose ALVC and so forth. My only problem when that document came out was that it made it so general it took away the specifics. There is a difference between sarcoid and ARVC. It's like saying somebody's jaundiced. It's like, well, what's the cause of the jaundice? What I didn't like about it, I read the document, it's not like I had a problem with it, but I didn't like the fact that it made it everyone's AC. No, I mean, you've got to really dig down, correct, and find out what they really have. No, I think Jeff was sort of saying when you have an AC, then here's an AC clinic and you need to go down this kind of a, it's sort of the, he's trying to grab all these patients and then find the ones that are really the inherited heart disease patients that we really are mainly focused on. I agree it was an unusual document, but a very ambitious document and it's good we're having this discussion. Yeah, so I'll still be old-fashioned if you're okay with that. So let's talk about risk scores. You've spent years looking at these risk scores. Can you update us on what's going on with the risk scores? Well, I mean, I think we all know that there's risk scores have been developed for hypertrophic cardiomyopathy. Well, a number of years ago, six or seven of the major international ARVC programs got together to develop a risk score where we have a risk score for a risk prediction in an ARVC. And that was first published about three years ago. Julia Turegny was the lead author of that. And we got it out there, looked at five-year risks, seven different variables, easy to plop in, number of PVCs, cardiac syncope, T-wave inversion, and so forth. And so that's been out there for about five years and now we have that score, scoring system's been validated. Just earlier this week, we had a paper accepted with a completely different cohort validating that scoring system. So it's not only out there, it's been validated. So it's something for people to be aware of, ARVCrisk.com is where you can find it. And then the next criticism we got about that was it predicts sustained VT and all sustained ventricular arrhythmias, but we really care about VF and V flutter. I mean, Mark Josephson would have made this point that just sustained VT isn't going to necessarily kill you. So we developed yet another scoring system for VF and V flutter that was published last year. It's also out there. It hasn't yet been validated. But anyhow, people should be aware of these scoring systems, which helps the conversation when you meet a patient with ARVC and you're talking about five-year risk. So is that the same, would you say ARVC.com? ARVCrisk.com. Risk.com. Will that be in there if people want to look it up? Yes. It's online. You can go on your phone and there's a little app. So both of those characteristics. That's great. Useful information. Yeah. Let's pivot a little bit to genetics of this syndrome. Can you put it together for us? What do we need to know about the genetics of ARVC? Well, it's one of the amazing breakthroughs. When we started our program at Hopkins on ARVC 20 years ago, there wasn't a single pathogenic variant identified, and now we can find a pathogenic variant or mutation in about two-thirds of patients that meet diagnostic criteria for ARVC. So we've come a long way. And what we know is the big, most common one is plaquephyllin-2. That accounts for about two-thirds of patients. And then another very important one is desmoplacan is probably number two. And what we're learning now is that ARVC caused by plaquephyllin-2 presents one way, looks one way, has X amount of risk, and has a progression course that we sort of understand. Desmoplacan is completely different. The EKG can be completely normal. It can present as myocarditis with troponin leaks and chest pain. It has a worse course, higher risk, LV involvement. So now it's become, you know, you have ARVC, well, do you have desmoplacan ARVC or plaquephyllin-2 ARVC, or is it gene-elusive ARVC? And so we're getting more and more detailed information. Currently, we're putting together a series of over 500 desmoplacan ARVC patients from centers all over the world, just so we describe the clinical course, you know, clinical features, you know, of that subset of ARVC. So you said something I want to pick up on for clinicians. So if I'm seeing a patient who doesn't have any of the classic ECG findings, what are my clues to go look for something like that variety of ARVC? I mean, will they at least have the anatomic variety when I do a CMR or something? So, I mean, one, you have to be aware they can look different, and just because that EKG looks remarkably normal, I mean, if someone has, you know, a high number of PVCs, non-sustained VT, or they presented with chest pain and had a troponin leak, you need to be thinking about a genetic condition as the cause of this. We published a paper this year with 20 patients that initially presented with myocarditis that ultimately had ARVC, most commonly due to desmoplacan. So certainly, if you have someone with myocarditis, you should be thinking about a genetic condition like desmoplacan ARVC, and this is really where genetic testing comes in. So, again, let me stop you. So I would, just from experience, I would think things would light up on the left ventricle if you did a CMR to suggest myocarditis. Is this one of those varieties that's biventricular, or? Well, with desmoplacan, I mean, usually it's predominantly left ventricle involvement, but you're right that the MRI is extremely useful in picking it up, but it's really genetic testing that plays this huge role, that once you know they have a desmoplacan variant, you then know what the disease is, and in this series we're putting together, the 500 patient series, it's a gene-first approach, meaning to get into the series, you've got to have a desmoplacan mutation, and then we're going to describe the natural history of the phenotype and so forth. Let's say they don't have myocarditis. Let's say I have a patient who comes to me, EKG looks normal, echo is normal, and they have lots of PVCs. Often I'll just, depending on where the PVCs are coming from, I might not do a CMR, right? I mean, if it's a patient that's the worst of it, are you suggesting, and maybe not, but I don't want to put words in your mouth, that that may be a patient I should dig deeper and do some genetic testing? Well, presumably that patient, if they have a unifocal PVCs, you might bring them to lab, ablate them, and if they behave like a typical idiopathic VT and everything is normal, echo's normal, EKG's normal, there's nothing suspicious, well, fine, that's an idiopathic VT, but if you have PVCs from multiple morphologies where you get in there and you do EP testing and you have inducible sustained VT, which would be unusual with idiopathic VT, then you should say, well, maybe this is an arrhythmogenic cardiomyopathy and maybe this is related, then you'd get the MRI and you'd see some gadolinium enhancement, then you say, well, I'm going to order a genetic panel, and then all of a sudden you come up with a diagnosis. So that's fascinating new data. Anything new on the horizon with genetic manipulation of the disease to cure people? What's going on? The big excitement now is the whole notion of curing ARVC with gene therapy. So this year, there's a number of different companies that are working on this, and at this meeting, Tenaya Pharmaceuticals, which I think is based here in San Francisco, is reporting their mouse model treatment of plaquifilin 2-ARVC, where they use one of these adenosine viruses to get the new gene in there, and apparently it's a very positive study. So the whole concept that in hopefully the near future, we can cure or treat ARVC with gene therapy is amazing. That's cool. I was talking to Mike Ackerman about Long QT syndrome. They're working on the same thing with Long QT. Yeah, and I think Sylvie Pierori has got a model with CPPT, with genetic manipulation in an animal model, that I think at some point she told me they're hoping to do clinical trials. I don't know they're there yet, so I don't want to tell anybody something that's not true. Well, I know first comes the animal models, then comes the clinical trials. Hopefully next year or the next time we get together, we'll be talking about the first in man gene therapy for ARVC. That'd be great. Now, one thing to be aware of is that everyone's focusing on PKP2-ARVC, because it's the most common. That's where the money is. Currently, I'm not aware of anyone working on desmoplacan or these other mutations, but PKP2 is by far the most common, and so stay tuned, and we'll have more to talk about over the years to come. I'm going to end this with something that just is an important thing for clinicians, and I don't always know what the right advice is to people who want to do athletics. I know if you've got manifest disease, there are data that you can make it worse if you do a lot of exercise or competitive athletics. Forget the sudden death risk, just the disease can progress. But I've never known how I should approach somebody if you're doing genetic testing in a family, and they come up gene positive and phenotypic negative. Are there good data to say you should preclude a physical activity? Oh, there's very good data, and actually in this consensus document on arrhythmogenic cardiomyopathy, they make specific recommendations that if you're phenotype negative but gene positive, you're at risk for ARVC, and you should be counseled to avoid endurance and competitive athletics. Now, that individual may choose not to follow your advice, but the data is overwhelmingly strong from all over the world that exercise brings out the phenotypic expressive disease, and once you get the disease, continuing to exercise makes it much more likely you'll develop heart failure, need a transplant, have further arrhythmias. I'm going to stop you only because I understand that part of it, heavy duty exercise, but often it's a question of can a kid play school athletics? Do you really preclude any competitive athletics for someone who's gene positive? I don't know that there are data to support routine athletics. I don't mean endurance athletics. Well, there's a nice table in that document which shows the kinds of things you can- I know, ping pong and chess. You're walking and ping pong and sailing and whatever. But that isn't realistic for doctors. I mean, the main thing is you shouldn't be signing your kid up for a travel soccer team where year round they're doing five hours of- That makes sense. It has to do with intensity and duration, and you just want to avoid high intensity, long duration. But then it's all preferences and values and a parent's decision and so forth. Yeah, well, that's good advice. So, Hugh, as always, great job. Thank you for educating us. Thank you for this opportunity.

Arrhythmogenic right ventricular cardiomyopathy

ARVC

Nomenclature

Genetic testing

Gene therapy