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EP Fellows Curriculum: Arrhythmogenic Right Ventri ...
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Great. Well, thanks, Stubbe. And thanks, everyone, for signing in this morning to this new virtual world. And it's always fun to talk about AR&D. And I'm actually using this sabbatical to sort of re-gear up a new research theme that we're going to be working on, I don't know how much I'll tell you about it towards the end. Let's see how I've got it. Here we go. So anyhow, so I'll give you a little introduction to this program. We'll talk about everything to do with AR&D. But I'm going to start with a story. And I'm basically a clinically P guy. I like doing cases, like seeing patients. And I also find research sort of interesting. But I've never gotten an NIH grant. I get all my funding from donations from patients and just do it on nights and weekends. And all my focus has been sort of patient-based. But this whole interest in AR&D really started with this patient, Carrie Campanella Becker, who I saw in March of 1997. And I was seeing, she was referred to me by Tom Guarnieri, who used to be the head of EP here. And he had diagnosed probable ARVD and referred her to me for a second opinion. So she was a 35-year-old woman. She had had syncope. She was a big horse kind of person. Her physical was unremarkable, as Ron Berger likes to say, a stethoscope is just part of our uniform as an EP. So I can't tell you much more about that. But her family history was interesting, that her father died suddenly at the age of 36. And it turns out her father was a guy named Joe Campanella, who was a professional football player with the Baltimore Colts. And he died suddenly playing squash with Don Shula. And it was written off to a, quote unquote, a heart attack. An autopsy was never done. But that was interesting. So here is her EKG. You can notice the T-wave inversions, V1 to V4. And if you look in V1, even I would call this an epsilon wave. An epsilon wave has to be distinct from the QRS complex. So you drop a perpendicular from the latest QRS complex, V1 to V3 down. And it has to be after that perpendicular separated by an isoelectric interval. So I would call that a true epsilon wave. But we'll get back to that a little bit later on in the talk. But clearly, her EKG was abnormal. Her MRI, she had a big right ventricle. She had an EP study, a lot of inducible VT. I said, yes, you have a defibrillator. Tom had gone into private practice. I didn't want to steal any cases from him. So I told her to go back to Tom and get a defibrillator put in. And it turns out the patient elected to wait till the end of the summer to have the defibrillator implanted. And she didn't make it. She had sudden cardiac death getting off her horse about a month or two after I saw her. And it really was a catastrophe. And I remember taking that call as I drove up to northern Michigan to our summer place. So before you know it, I ended up seeing her youngest brother. Her youngest brother wasn't born when his dad died. He was born after his dad died. He's like the sixth or seventh Campanella in the family. And this is John and his wife, Kathy. And they had been newly married at that time. And John had some palpitations. Kathy was very nervous about marrying damaged goods. And they ended up coming to see me about, could he have this disease? So this is John's EKG. And you can see some T-wave inversions in V3 and V4 by phasic and V2. Not totally normal, but not classic for ARVD. But I thought this was a little suspicious. Did a Holter, was quiet, got an MRI, had some sort of slight evidence of this or that. Did an EP study, was non-inducible. And we tried to figure out, well, should he get an effibrillator? His dad died suddenly, his sister died suddenly. And the bottom line is we ended up putting an effibrillator, mainly because of this terrible family history and not knowing a lot back then. And I had talked to Frank Marcus, who really is the pioneer in ARVD. And he had told me, you should tell these people not to exercise. So I told him not to exercise. And now 22 years later, he's doing great. He's never had a defibrillator shock because his defibrillator has been replaced multiple times. He remains non-inducible. He has a couple of kids. And lo and behold, we identified the plaquephyllin 2 mutation in him. And that's the most common mutation you find in ARVD patients. So this is his EKG in 2016. And you can see the zero progression. Basically everything's been absolutely fantastic for John. So that's sort of a happy story. So back in 1997, the question was, we didn't know much about ARVD. How do you make the diagnosis? What's the natural history? Does the disease progress? And what causes it to progress? What should you do about exercise, medications? How do you risk stratifying people? Should everyone get an effibrillator? It was known, it was sort of familial, but no gene had been found at that point. And then obviously the big goal was to try to cure ARVD. So John and Kathy ended up, they were sort of smart people from pretty affluent families. So they went around the world seeing everyone working on ARVD. They flew out to Arizona, St. Frank-Marcus. They flew over to Padova, Italy, talked to Gaetano Tieni and Domenico Corrado. And they flew back to Baltimore and said, there's not much going on. I think we should get started a program to focus on ARVD. And I thought that was fantastic. And I felt terrible about that patient who I felt that I probably should have put the screws to her a little harder to get that defibrillator put in. And so I was hoping that they were rich and could write a big check, but it turns out football players in those days didn't make a lot of money. But we decided to start the program. Kathy started this website, ARVD.com. And with that, the program was launched. And one of the crucial things was getting some money. And John was smart enough to figure out that Jack Bogle, who founded the Vanguard Funds, had been transplanted for ARVD. So the next thing you know, me and the president of Hopkins University and the head of cardiology, Ken Boffman, are all meeting with Jack Bogle down at Hopkins. And he pulls out his checkbook, we had checked for a million or a million and a half dollars to start the fund, start the program. And he specifically said, I want you to use this money. Don't use it as an endowment, but spend it as capital to get the program launched. And with that, the program started. And the first person we hired was a genetic counselor named Julie Rutberg. And someone at church had recommended that we hire a genetic counselor. I didn't even know these people existed. And the second person we hired, our first research fellow was Harry Tandry, who is now one of my colleagues and I've been working with ever since then. And Jack just died last year of esophageal cancer, but he had a very long and happy life. And he's an amazing story. You know, he had showed up at Princeton. He went to Princeton as a scholarship student. It would wait on tables at the eating clubs and stuff like that. And then obviously became a fabulously successful investment banker, but I'm very grateful to Jack and his wife Eve for helping us get our program going. So we started the program. And the goal was to work with the whole international community to educate patients and physicians about this disease, to coordinate care of these patients and to learn new things. And last year we celebrated the 20 year anniversary of the program. We had a big symposium. These are the folks that attended from all over the world. And it was lucky it wasn't this year. The whole damn thing would have been shut down, but we had a great sort of celebration of sort of where we are now and where we're going. So let's talk a little bit about ARVD. So it's an inherited cardiomyopathy. It's characterized by progressive replacement of the right ventricular myocardium with fatty and fibrotic tissue. The key is really myocyte loss with fibrotic replacement. The fat is very nonspecific and fat in your heart really means sort of nothing. You can have fatty hearts. You can see fat in an MRI. It doesn't have much to do with the diagnosis. It's about myocyte loss and fibrosis. Arrhythmia is we know about, and it's a very arythmogenic condition. We also know there's a left dominant form or biventricular forms of the disease are quite clear now. This is a 32 year old patient. We transplanted for ARVD. You can notice the RV is blown out. The LV looks pretty good. There's some, you know, a little bit of sort of fat infiltration here, but again, look at the right ventricle with the myocyte loss. It's fairly striking. When you look at the history of the disease, you know, Gaetano Tani will tell you it was known, it's been known about in Italy for more than 200 years, but the group that put it on the map was Frank Marcus and Guy Fontaine. And Guy Fontaine also died last year, the year before a real pioneer in the EP world and just an unbelievably sort of eccentric, but genius guy. But Frank had a sabbatical. So he went over to work with Guy and Guy ran a big DC shock VT ablation program. Had been seeing these strange patients with this RV myopathy. And Frank wrote up that series. And this is the first sort of major paper on ARVD. And that paper was a beautiful paper, but it had one big mistake and that's this figure. So this figure shows the triangle of dysplasia. And they're trying to emphasize that ARVC impacts the inflow track right under the tricuspid valve, the outflow track and the apex. And I say it's a mistake because ARVD doesn't involve the apex. Only when your whole RV is dead does the apex involved with early disease, you never see apical involvement. And that's led to a lot of over-diagnosis, misdiagnosis. Because in those early days, people would look at the RV apex. It looks a little thin, maybe it's not moving normally as this ARVD and a lot of patients were over-diagnosed. Turns out the third leg of the triangles, the posterior lateral LV is the other sort of area that you look for. This is just shown here with a reference from 2013 when we put this together. So it's a pretty rare condition, but we say it's one per 5,000, but where that number comes from, it's really picked out of a hat. I think it's sort of made up. The point is if hypertrophic cardiomyopathy is one per 500, this is about 10 times less common than HCM. It's slightly more common than men and women. Men do worse than women because testosterone is a bad actor. We'll get to that. Comes to about 20% of sudden deaths and about 5% in the US. It's about the number three or four sort of cause of sudden death in young people. Now, this is a recent paper by Chris Samsarian looking at the cause of sudden death in young people in Australia. And you can see it's a more common cause of sudden death than HCM, even though HCM is 10 times more common. The other thing you gotta be aware of the diagnostic criteria, these were put together by Frank back in 2010. They're good, but they're imperfect. And there's been some efforts recently to update them because now it's 10 years later. And the world's sort of starting to think about that. And I would guess in about two years we'll be done with a new diagnostic criteria, but for now we're left with these. And you have the 94 criteria, the 2010 criteria. It lists, you have RV size and function, it's quantitative, biopsy, they give specific percent normal myocytes, T wave inversion, V2 and V3 is a major criteria. It's very easy to diagnose. If you have just V1 and V2, it's a minor criteria. Epsom ways are listed as a major criteria, but I'm gonna encourage you to ignore those and I'll go over that a little bit later. Single average EKG is still part of the diagnostic criteria, but we never do single average EKGs anymore. We found them to be very insensitive and nonspecific and basically no value. TAD, terminal activation delay, is the time from the tip of the S wave back to baseline. And that sort of replaced the single average EKG that cut off as 55 milliseconds as a minor criteria. Left bundle supraxis VT is a major criteria. If it's left bundle infraraxis, it's a minor criteria, more than 500 PVCs, and then some family history and genetic result criteria. So here's another EKG of an ARVD patient. T wave inversion is V1 to V3. And then look at this TAD, this is what I mean. The tip of the S wave back to baseline more than 55 milliseconds. You can see it, it's sort of sluggish getting back. That's the slow activation of the RV. You can see it here too. Some people would say this is an Epsom wave, but an Epsom wave has to be distinct within the QRS complex of V1 to V3. And if you draw a perpendicular from here up, this is within the QRS complex. You know, it's delayed activation, you know, but anyhow, so that's another EKG. You know, an MRI showing ARVD and Harry Tanju is sort of the world's expert in MRI reading. So it's important to remember that, you know, the MRI is one of many diagnostic tests. It's not the gold standard. It's the most common reason for over-diagnosis. And we've taken out about 25 defibrillators of misdiagnosed ARVD patients. I think we just published a recent series. But the reason, it's sort of embarrassing, you put a defibrillator and the patient comes and seizes for a second opinion, we take out the defibrillator. We had one patient who came down from Philadelphia with a newly implanted defibrillator. And we told him he didn't have ARVD and he was sort of horrified because he just got the $60,000 bill the day before. So he went out to the Cleveland Clinic to get a second opinion and, you know, they took the defibrillator out. So the most common reason for over-diagnosis and people aren't aware of the diagnostic criteria, they don't recognize that myocardial fat and wall thinning are not part of the diagnostic criteria. You may have quote unquote a thin wall that's not part of the diagnostic criteria. Fail recognition that RV wall motionalities may result from an RV free wall tether or a pectus. If you have an ARVD patient and they have a deep pectus, probably that screwed up MRI is because of crazy motion because of the pectus. You know, RV moderator bands, another reason. You know, and people are also, we're also focusing on the apex of the RV, thinking that was part of the triangle, not knowing it's not. And then that would make them think, oh, this must be an ARVD patient and they'd thrown a defibrillator. So let's move on to the genetic basis of the disease, which is a fascinating story. It starts in the island of Naxos, which is about a two to three hour ferry ride from Athens. I've never been there, but I'm planning to go there at some point. But anyhow, on Naxos, there was a couple, a physician couple, Nikos Protonaterius, who's now dead, he died of GI cancer, and his wife, Adelina, who he had grown up on the island. And when he graduated medical school, they went back there and set up shop. And they noticed these strange patients that would show up with this woolly hair, pomoplanta or keratoderma. They would say you can make the diagnosis by shaking their hand. And then clinically they'd show up with what looked like the ARVD that Frank and Guy had described. They had this Fabro fatty replacement in their hearts. They had all these arrhythmias. So it was, and this was termed Naxos disease. And they'd go to the beach and they'd see someone with his screwed up hair and funny palms. And they say, why don't you come on in for an evaluation? And they'd find this. Anyhow, it was a remarkable story of how they put this paper together. They actually hand delivered it to the British Heart Journal. They flew to London to deliver the paper because they were suspicious of the mail and sort of an amazing story, but they discovered this. And once they discovered Naxos disease, which is a disease of the skin and the hair, they'd say, well, that must involve desmosomes that got people thinking about desmosomal proteins. And then 14 years later, Godfrey and McCoy was a PhD student went to work with Bill McKenna. They got all the blood and they ended up discovering that plaquoglobin was the cause of Naxos disease. And once that was discovered, people said, well, what are the other desmosomal proteins? And they quickly, within five years, all the mutations were found. So that was 2000. 2002, desmoplacan was discovered. 2004, placofilin-2, the most common one was discovered. 2006, our group discovered desmoglan and that was confirmed by another group. So very quickly, all the desmosomal proteins were identified as causes of ARVD. And these desmosomes are the bolts that hook myocardial cells together. They're these linker proteins. Some are intercellular and some are intracellular and whatever. So as of now, we know you can find a mutation in about two thirds of patients. Placofilin-2 is the most common. And desmoglan, desmoplacan, desmocolan. Plaquoglobin is pretty rare. There's some non-desmosomal proteins you rarely can see. TMEM43 is the Newfoundland version of the disease. Very penetrant, very lethal. Rheonidin receptors have been identified in some patients. And then you have things like phospholamban, which is the founding mutation they have in the Netherlands that causes a condition that sort of behaves, looks like ARVD, but doesn't really behave the same. For example, exercise doesn't impact the phospholamban version of ARVD. Filament C and so forth. And these together probably represent about 5% of patients where you can find a mutation. So inheritance of these desmosomal mutations is presumably autosomal, dominant with age-related, incomplete penetrance, and variable expressivity. Patients could have multiple mutations, two mutations of one gene or multiple mutations in two different genes. And in general, if you have multiple mutations, you do worse. And in about a third of patients, they're gene elusive. We can't find a cause. So then we move on to what causes ARVD. And you have the simplistic cause that I like to think about. You have bad bolts or bad glue. You exercise too much. These desmosomes get stressed. They pull apart. They die, and you get fat and scar. That's the simple way of thinking about it. And then you have the way people like Jeff Safitz likes to think about it, the scientists. You have these desmosomal gene mutations. That causes nuclear signaling of Wnt and other nuclear signaling proteins. And that turns on apoptosis and fibrogenesis and adipogenesis and transdefination of myocytes. Turns out it's very, very complex. And people like Mario Delmar, Jeff Safitz have made a career studying this. And it's fascinating, but it's something a mere clinical EP guy can't fully comprehend. But I can't comprehend a lot about clinical presentation and follow-up, and we'll move on to that. So here's our first big series in 2005, 100 patients, 69 diagnosed while alive, 31 on autopsy. We called this paper a United States experience because prior to that, people thought this was a disease that only occurred in Europe. It was sort of like the virus. We thought it only was over there in China. But it turns out it's everywhere. And you can look at this. The average age of patients around 29, half are men, half are women. A lot are athletes. Show up with palpitations, syncope or sudden death. Some are asymptomatic. Now, this shows sort of a Kaplan-Meier curve. Symptoms correlate with VT, sudden death, less common, heart failure is late. But this disease doesn't occur before puberty. You never see anyone younger than 12 or 13 or 14. It's really around 13, 14, 15 that starts to show up with the average age of around 30. This is a transplant series we put together a number of years ago of patients who were transplanted. And the point of this slide is that patients show up and they end up getting transplanted about 20 years later. So the symptom onset was 24. The people that end up needing transplants usually show up at a younger age. And it's about 16, 20 years later that the heart fails, they end up needing the transplant. And they're transplanted mainly for heart failure, less for arrhythmias because we've gotten so good at handling arrhythmias with catheter flush. So recently we updated our experience to 1,001 patients and family members is working with our colleagues in the Netherlands who we partner with in a lot of our research. And it basically confirms what we showed in that first series. Patients show up, if you have a gene that you show up a little bit earlier than if you don't have a gene, the main manifestation or arrhythmias, heart failure and transplant occur late in the condition. We've also done studies on genotype-phenotype relationships. This is one paper of 577 genotype patients. Plaquephilin-2 is by far the most common. These are all patients with a mutation and all the other ones are pretty uncommon and they can be different types of mutations. So there are a couple of findings from this study. The first was that patients presenting with sudden death were younger than those presenting with sustained VTRs, asymptomatic patients. So if you presented with sudden death that were asymptomatic, you tended to be younger. There's sort of a hot early phase of the disease. Patients with more than one mutation presented earlier than those with a single mutation. So these are the patients with multiple mutations. LV dysfunctions related to genotypes. So if you look at the patients with LV dysfunction, phospholambam, desmoplacan are sort of the two where you see a lot of LV dysfunction. Plaquephilin-2, only 16% of LV dysfunction. So it's very much linked to what the genetic abnormality is. Number five, gender impacts phenotype. Presentation with sudden death is more common in men. Men are more likely to be programmed, probands are among those presenting alive, arrhythmia-free survival is lower than men. Farad Duru and the group in Zurich have done some nice work with testosterone and it turns out testosterone's a bad actor and if a higher level of testosterone, you have more active disease, higher risk of sudden death, and this accounts for men dying suddenly more than women. So we'll move on to management and I like to think about this five-legged stool. You gotta make the diagnosis, you gotta figure out if they need a defibrillator, you need to minimize the defibrillator going off, you gotta prevent progression, and then you have cascade family screening because you gotta think about other family members and diagnosing the disease early. So first, make a diagnosis. We've talked about that. The workup really is a history, a physical exam, an EKG, the single average EKG you can forget about. Holter's invaluable. Number of PVCs per 24 hours is very important in the diagnostic criteria. An echo or an MRI. Stress testing, not so much. We basically never do stress testing. There's a couple papers saying it can be of value, but generally we find these arrhythmias are not triggered on a stress test. It's sort of cumbersome to do and we find it adds nothing or almost nothing. Genetic testing when the disease is suspected and remember those task force criteria. So a couple new things or relatively new things. Our colleagues in Bordeaux are really remarkable with their creativity. And this is a beautiful paper they took where they took patients that had sort of ventricular ectopy PVCs, 412 patients, and they did a high-dose isoproteranol infusion challenge, 45 mics per minute for three minutes. And what they reported in this study was that patients with ARVD have this kind of response. They just light up like a Christmas tree with reams of VT, multi-morphic triggered automatic VT and the non-ARVD patients don't. They said this is a highly sensitive test for ARVC and sort of called attention to this as a diagnostic test. We've been doing it and they're absolutely right. You see this. We sort of think of it more as a prognostic test. You know, if you're gonna bring someone with possible ARVD, idiopathic VT to the lab for an ablation or risk stratification, always do this because it can provide you a better sense of what's going on. With typical idiopathic VT, you aren't gonna see this kind of response. So I think it's a very useful test. It's important not to miss the opportunity to do this. A few other comments on diagnosis because I didn't skip over it about the epsilon wave. So we recently did a study and I must have deleted it from the slide set where we took 10 self-proclaimed experts in ARVD and sent them 30 EKGs and said, is there an epsilon wave or not? And it turns out no one could agree. And then we met and we agreed on a definition and we did it again and it still was horrific. So then, you know, everyone's realized you only see epsilon waves in severe disease. And in severe disease, everything else is positive. So does the epsilon wave really add anything? So then we and a group in Norway looked at our databases and said, let's just delete epsilon waves from the diagnostic criteria and see how many patients go from diagnosis to be non-diagnosed. And basically it changed nothing. Meaning you only see the epsilon wave severe disease by then all the other parameters are positive. So it really adds nothing. So basically in your own mind, you shouldn't be looking for epsilon waves. You aren't gonna be accurate in figuring it out and it doesn't add anything. Just look at the other parameters, the Holter, the MRI, you know, the genetics, the family history, that kind of stuff. So the next question is, do you need a defibrillator and here are the variables that we think about, you know, history of sustained VT or sudden death, proband status, if you're the proband, the first effect in the family, you're much higher risk than your family member. Male gender, we've talked about that. In general, more severe disease means higher risk. Frequency on the Holter, more PBCs, higher risk. Cardiac syncope, exercise plans, results of EP testing. And then you gotta filter this into whether a patient, what their threshold is for defibrillator. So Aditya Bansal and our group put together a nice series a number of years ago. 84 patients have got a primary prevention ICD. And you can see, there's a reason we call it ARVD. You know, 60% of patients that are appropriate shock within five years, there's no other condition where you're gonna see these kinds of curves. And even for VTVF, you know, 30% by six years out, unbelievably arrhythmogenic, these patients. And the predictive factors were the results of EP testing. There's some debate about this. Domenico Corrado will say it's not predictive. We find it's predictive. The group in Zurich find it's predictive. You know, it's one more test. If you can start a VT, you know, that's a predictor in our mind. More than 1,000 PVCs is predictors. And the higher it goes, the higher the risk. Non-sustained VT separates them out. And proband status is very important. Family members are at much lower risk than the proband. So you can be much more selective and put in defibrillators in family members. Now, our latest big contribution to this is made by Julia Kajanteregni from Montreal, who came and worked with us for two years and put together this beautiful prediction model, sort of an app for risk in ARVC. And we worked with about five different ARVD registries to create a cohort of about 500 patients. And we looked at the predictors in our model were male gender, men higher risk, age. You're higher risk, actually, if you're younger than if you're older. Recent cardiac syncope is a risk factor. PBC count, you know, it's based, the higher the number, the higher the risk. Extended disease based on T-wave inversions. And the RVF, we didn't end up including the LVF in the model because we had basically no patients in the, almost no patients that had that parameter. So it fell out as a predictor. And through that, we have an app. If you go to ARVCrisk.com, you can put in age, number of T-wave inversions, number of PBCs, RVF, and you'll get a five-year risk. Now, this risk calculator is for all arrhythmias. It's not for VF or V, or rapid V flutter. It's for all VTs. So it sort of is overly sensitive, if you will, but it gives you sort of a general something, you know, number to start the discussion with a patient. So just want to make you aware of that. Then the question becomes, should you get a sub-Q or get a standard defibrillator? And we're currently doing a study of the sub-Q device. I think we have 49 patients enrolled. We need one more. So if any of you have put a patient sub-Q device in an ARVD patient, we'd love to have that patient join our registry and be part of this little study we can get across the finish line with 50. But, you know, the basic challenge is unlike hypertrophic cardiomyopathy, where you have big voltages and big signals, with ARVD, you get myocyte loss and you get shrinking of the QRS complex and shrinking of the signals. So the real problem is inappropriate shocks because of T-wave sensing. So we've learned that it's effective, meaning we have a fair number of patients, 50 who've gotten a sub-Q device and none have died suddenly, so it's effective. But we've had a number, you know, more patients got inappropriate shocks than with a standard device. And you have to balance that with the benefits of not having an endocardial lead. And in general, we've been using the sub-Q device sort of for primary prevention patients, even for 14, 50-year-olds, skinny little kids, where you want to avoid that lead. It's worked quite nicely. Once someone has, they're having sustained VT, not only do you lose the benefits of ATP, those are patients with more advanced disease, worse signals, you can still use it in those patients, but you got to be really circumspect and make sure they really pass all the vectors. Don't try to barely get them in by a little hair in terms of meeting the screening pairs when you put in the sub-Q ICD. So we like it, we're learning more, but, and it's great mainly for primary prevention, some secondary prevention, but just make sure the signals, you know, look good. Once you get it in, you want to minimize the shocks. So the main thing, and we're going to focus a lot on exercising, stop competitive and endurance sport, take beta blockers. We like giving patients ACE inhibitors if they have any evidence of structural disease. You could consider antiarrhythmic medications if occurrence, you know, and generally, you know, they have ARVD, they have a lot of actiV, you put them on a beta blocker, they still have a lot of actiV and non-sustained VT, then you think about sotalol or flecainide. You know, they don't respond to that, they start having shocks, then you think about catheter ablation, and we could talk more about that. So in terms of exercising, there's lots of data now saying you got to tell these people not to exercise. So we know it's a disease of the desmosomal dysfunction. We know these desmosomes are the glue that holds the heart together. We know when you exercise, the RV dilates and pressures increase threefold, so the wall stress in the RV goes up dramatically. The LV, there's less of an increase in wall stress. Most ARVD patients are high-level athletes. I mean, just yesterday, I was on the phone with a 14-year-old girl with newly diagnosed ARVD, and you know, classic story, she was a swimmer since she was like eight, doing three hours of swimming a day, you know, had practice, was feeling bad after practice, threw up, went home, threw up some more, started looking bad, called 911, of course, was in VT at 220 beats a minute. You know, and she's a 14-year-old with ARVD, EKG shows classic T-wave inversions. She has a plaquifilin-2 mutation, and you know, we see this all the time. Exercise is a common trigger of arrhythmias and sudden death. There's now about 10 different mouse model, exercise mouse models, and there's about 10 clinical studies showing how important this is. So this is the first major paper, one that my colleague Cindy James put together. 87 patients with a mutation, 56 endurance athletes, 31 not, and we took a lifetime exercise history. And what we found is the number of hours per year of exercise prior to presentation impacted whether they met diagnostic criteria. Again, all these patients had a mutation. So if you exercise zero to 134 hours per week, only about a third had the disease. The exercise, 510 to 2,600 hours per week, 85% had the disease. Or if you said, are you an endurance athlete, yes or no? If the answer is yes, 82%, no, 33%. And then that impacted their clinical course freedom from sustained VT and heart failure. If you weren't an athlete, you didn't get heart failure. And if you were an athlete, a lot more likely you'd get heart failure. If you weren't an athlete, you're less likely to have VT than if you are an endurance athlete. So then our next big study was to look at patients who didn't have a mutation. And we did the same study in them, although we used met hours instead of just hours because we want to normalize for intensity. And what we found was fascinating. If your gene elusive, no mutation, it took 6,700 met hours per year to get ARVC. Whereas if you had a gene, it only took 3,000 or a family history, it only took 3,000 met hours. So it's like the double hit hypothesis. If you have a mutation, less exercise added to that gets you the disease. If you don't have a mutation, some people have some predilection that with their super athletes, they get the condition. Now, this is a nice little study we did of PKP2 families where we took sort of a lifetime exercise history. Here's the proband, this is lifetime met hours like your odometer in your car. So the proband started at the age of 10 and is exercising like heck, gets sustained VT, gets diagnosed with ARVD, stops exercising. And here's his siblings who have the same mutation but didn't exercise. These are the AHA recommended exercise. So you look at that, it's unbelievable. Here's another family, here's the proband. Unbelievable amounts of exercise, had sustained VT, got diagnosed with ARVD. No one told them to stop exercising until they came and saw us up here. So here's the siblings, fat and happy. Just kidding about fat. They're only fat if they're eating too many pizzas. But here's their AHA recommended level. But I think this really tells the story. And then we recently, we just got this paper accepted where which was fascinating is we looked at patients with a mutation and we looked at all their exercise of those that got the disease and those that didn't get the disease. And this was fascinating because some patients, we hypothesized that if you did a lot of exercise and you had a mutation, you were gonna get the disease, full stop. But what we found was some people get away with it. All these patients don't have the disease but look how much they were exercising. So there's some factor that allows some people to get away with huge amounts of exercise. And we're now gonna focus a study doing a whole genome testing on these patients to figure out how were they so lucky where exercise didn't impact them. Whereas all these patients, it obviously did. So more work to learn. Another paper we looked at was exercise restriction. And basically what we found is that patients who reduce their exercise the most were 86% less likely to get an appropriate ICD shock than if they didn't. So that's an unbelievable powerful benefit of reducing your exercise dramatically. So for those of you who think you can keep exercising, you're misguided. So what's the role of catheter ablation? We talked about EP testing in a limited, you don't know if it's idiopathic BTR or ARVD in the beginning, go do an EP study. That will help figure it out, give them high-dose isoprel, idiopathic BT ablated. If they're positive with a high-dose isoprotel and they have five different morphologies, it's probably not idiopathic BT. Catheter ablation's obviously recommended if you're getting frequent ICD therapies. And in some centers, it's reasonable to do it first line if you have a good experience and outcome. And Stubbe can tell you how many BT ablations we do in ARVD here. I mean, my colleague, Harry Tandry does two or three a week, you know, and do EPI. So it's an extremely common procedure here, but it's pretty rare other places. If multiple BT ablations fail, what do you do? And I'll go over a sort of an interesting case history. This guy, Sam, Mobile, Alabama, super ultra athlete, 50 triathlons since the age of 11, he was 16. You guys figure that out, unbelievable athlete. So in March of 13, he felt lightheaded, collapsed in the pool at a VFRS, was resuscitated. He had some T-wave inversions looking like ARVD, but they thought this was long QT down there in Mobile, Alabama, they put a defibrillator in. He had some shocks, he had non-sustained BT, was sent here for management, we diagnosed ARVD. Look at the CKG, gorgeous, right? 16-year-old triathlete. Loads of ectopy, classic MRI, positive isoprel infusion test. So here he goes and does an ablation, this is sort of the other, where you tend to see the epicardial scar, non-inducible, discharged in a beta blocker, couldn't tolerate it. Had some PVCs, non-sustained BT, and we had recurrence within six months. So came back, he had another cardiac arrest, got multiple shocks, CPR for 16 minutes, hypothermia, came back, did another ablation, two morphologies induced, extensive ablation, negative EP study three days later, stress issues, some non-sustained BT. Had a shock a month later at a concert, non-sustained BT, started flecainide. What did we do, did we transplant him or do other things? So we said, well, let's send him up north to Penn. So he was sent up there, he went into BT, just entering the lab, Harry went up for this procedure to see what they were doing up there. Terminated with sedation, propovol, BT was induced, extensive endocardial ablation. They couldn't get into the epicardium because of scarring, so they opened his chest at a cryo of the RV. So here's the cryo picture from up there at Penn, and went all the way, beautiful. EP negative, VP study post procedure. BT returned, six shocks, we're running to catch a flight two months later, more BT. What did we do next, transplant or sympathectomy? He ended up getting a sympathectomy with Shiv Kumar, he went out to LA, and he's had no arrhythmias since then. I think he went out to Shiv, or maybe we did it, I forget, but whatever, it worked. So since then, we've done this in about 18 or 20 Averdee patients, we wrote up a little paper about it recently, and we've had very good results. So it's sort of a last thing before transplant, and we're starting to do it a little bit earlier, bilateral sympathectomy, but we're learning more, and Harry's trying to figure out a number of ways to do this. So next, I want to talk about progression. First, I want to convince you that this is a progressive condition, I know there's some in our field think it's not, but they're wrong. You just think about it, no one's born with a disease, shows up around puberty, so if it wasn't progressive, how could that happen? This is not a dysplasia, which is something you're born with, this is a cardiomyopathy which you develop, and it's not an acute event like a heart attack, it's a problem with intracellular connection that's ongoing. So we've done, we published a paper recently where we did echoes about five years apart, and guess what, over time, RV function goes down, LD function goes down, and it's progressive. And we're seeing this now, as we're seeing more and more patients who we've followed for 20 years coming in for their transplant. So if you're just looking for a year or two, you'll think it's pretty stable, but if you look over a two decade view, you'll get a pretty, very clear view, it's progressive, not in everybody, there's some John Campanellas in the world, like the first patient I presented, but for every John Campanella, there's another that's gearing up for a transplant. So this is another paper we put together looking at heart failure, so it turns out 49% of patients over time will develop heart failure symptoms. So again, it's a progressive condition, and this is just showing that. So how do you prevent progression? Stop exercising, walking, golf is good, sex is allowed for quality of life, but endurance sports is clearly out. What we don't know is, can you go walking, we think two to three days of light to moderate exercise is fine, we think weightlifting's better than running, what we think that getting more, doing more than that is probably not wise till we learn more. There's a new document out that HRS put out on this consensus document on arrhythmogenic cardiomyopathy, and this is a very ambitious document that Jeff and Bill led, and they've basically redefined arrhythmogenic, the field, by saying arrhythmogenic cardiomyopathy is a twitchy heart. If you have evidence of heart disease and you have arrhythmias, then you have arrhythmogenic cardiomyopathy and you should be evaluated or screened through an inherited heart disease kind of program, because a lot of these patients will have diseases now. So the idea is, do you have ventricular dysfunction? Yes. Is arrhythmia in the clinical presentation? Yes. Then the patient has ACM. Is another door disorder present? Yeah, so the things that fall into ACM now are sarcoidosis, Chagas disease, amyloidosis, sarcoidosis, myocarditis, and I think it's a way to sort of view people, but they're sort of taking a big tent approach, but arrhythmogenic cardiov is not really what we're talking about, ARVD, ALVD, you know, which are these desmosomal diseases. So it's sort of a ambitious sort of thought exercise, if you will. Now, before I draw things, well, let me just conclude, then I'm gonna tell you the latest thing we're working on due to the virus. So ARVD is a rare disease, but it causes more sudden death than hypertrophic cardiomyopathy. It's a disease of desmosomal dysfunction. Making the diagnosis is challenging. You gotta evaluate these patients carefully with non-invasive or invasive testing. We have a risk calculator to help guide decisions about defibrillator implantation, but family members, you're much less likely to need a defibrillator. Catheter ablation is important, you know, but it's not curative, it's palliative. ARVD disease, you know, it results in cardiac dysfunction. About half of patients with ARVD over time will get heart failure. We think ACE inhibitors is important. Exercise restrictions, very important for controlling arrhythmias, preventing progression. And we have this new term. Now, the final thing I'm gonna talk to you about is some new data that we're about to submit and sort of a new focus of the program. So the data that we're about to submit, a new paper is, over the time, we've seen a number of patients that were initially diagnosed with myocarditis. And then ultimately they were diagnosed with ARVD. We have 12 patients in our series. And most of these patients have a desmoplacan mutation, but they show up with a myocarditis, chest pain, troponin leaks, you know, and they're called myocarditis. And then two, three, four years later, it's clear they have ARVD, they have VT, they come in, they get whatever else. And desmoplacan seems to be the biggest player. But so that was sort of interesting. But one of the other interesting things we've been thinking about during the COVID shutdown is the overlap between ARVD and inflammation. And it's been known forever that about two thirds of patients with ARVD have evidence of inflammatory cells on an autopsy or a biopsy or whatever. And, you know, people have talked about hot phases of ARVD where patients show up, you're like this girl I saw the other day. When she came in, she had a troponin, a high troponin. And that continued for about two, three weeks post her initial presentation. She's a placofilin-2 patient. So she showed up in a hot phase where there's sort of active cell death going on. And over the years, we've seen a fair number of these patients where they come in, they have a troponin leak, they get worked up for ischemic disease, they don't have it, it turns out they have ARVD. So the real question is, you know, how big of a role does inflammation play in the natural history of ARVD, these sort of hot phases? And how does one track this, monitor this, treat this? So we're sort of gearing up our new research focus to sort of look at this. I think the exercise story we've really nailed, we've figured this out. And that's unbelievably important. But as that exercise figure shows, there's more to it than exercise. And I think inflammation probably is the next, you know, and we know autonomics is important. We got that figured out. So I think the next big issue that we've got to sort out is inflammation. So stay tuned, but we're gonna be, hopefully you'll see our paper soon that we're about to publish on this myocarditis stuff. And then we're gonna be putting out a series of papers and hopefully doing some prospective studies of this sort of inflammatory component of ARVC and trying to better understand that. So I'll stop there. Well, let me just go to my final slides of, I wanna thank my colleagues that are part of our program. You know, loads of people here at Hopkins work in ARVD these days. Our wonderful research fellows. And again, Harry Tangier was our first hire. What a genius we got with that recruit. And he's obviously the co-director of the program with me and has been fabulous. And again, we have wonderful genetic counselors here. We have three genetic counselors that are part of our full-time staff of our program. We're here to help. And we appreciate the opportunity to speak with all of you today in this online COVID world. Thanks so much and I'll stop. That was fantastic, Hugh. We have, thank you so much for that. We have a number of questions that have come through and a lot of them very good. Dr. Vassiwala from Loyola had a specific patient question. So I'm gonna just unmute him and let him ask. Thanks, Dr. Calkins, great talk. I have a patient actually, a 55-year-old female. So she has a 15-year-old son. She's actually part of the University of Rochester Hopkins registry. Genotype negative. The son who saw me in clinic because the mother is obviously very concerned. We did an MRI on him, shows RV enlargement. It's not massively blown out RV, but there's no late gallon uptake in the RV. EKG is totally normal. So her questions specifically are pertaining to screening for her son. How often should we screen? With what strategy? And any exercise recommendations? The guy's, the son is a avid hockey player, essentially trying to go for college level hockey. Yeah, that's a great question. So in terms of current recommendations, if the mom had a mutation and if the son had the same mutation, we're recommending that gene positive family members restrict exercise. You can eliminate the ARVD by telling that gene positive kid to go to art camp or acting camp instead of soccer camp when they're young. So that's one thing. In gene elusive families, we don't do that. And that patient to me doesn't sound like he has ARVD. I mean, the RV is big, but he's an athlete, but you gotta have just not only a big RV, you gotta have wall motion abnormalities. And it's almost unheard of to have ARVD and have a normal EKG. It's also unheard of, almost unheard of to have ARVD and have a normal Holter. So in terms of screening, we recommend like in family members like this, they should all be screened with an EKG. Initially it's an EKG, a Holter, and then a Echo, unless you have a really good MRI program, you could get an MRI. And then every, if they're active, then every year you repeat the EKG and the Holter. And every three years, the MRI or Echo. Someone like this who's exercising a lot, I would say every year you come in, get an EKG, get a Holter. And as long as those stay quiet, then every three to four years, recheck the MRI. Great, thank you. And then we had a question from Dr. Katz in New Jersey. Let me just find Mike on here. Here you go. Once again, Dr. Calkins, amazing talk. Thank you so much. I had a quick question. You told us an anecdote of a patient who was 14 years old. I was just wondering if you had any pointers or tips to differentiate malignant T-wave inversions from juvenile T-wave inversions. Yeah, I don't know. That's a very good question. And Frank Marcus has put together, he's written a number of papers about this. And obviously, this sort of 14, 15, the juvenile versus whatever. So it's certainly, you have to consider this, like in this 14-year-old girl, could these be juvenile changes? So that, so you have to sort of, once you're like 16, I think the juvenile changes you can sort of forget about. But 14, it's certainly in consideration. But in her case, the fact that she showed up with a VT and has loads of 10,000 PVCs, it's clear it's ARVD. But so I think in the little kids, you gotta be aware of that, that the T-wave finding is a little bit less specific. I wouldn't make it a major criteria on a 14-year-old. I sort of view it as a minor criteria. But again, you need results from multiple tests. And we think the most useful test is that Holter monitor. I mean, that really tells you so much about disease activity. And the risk correlates with number of PVCs. So if you have these patients and they're having 20 PVCs in 24 hours, this is not someone you gotta be concerned about. And you gotta think you got a wrong diagnosis. Whereas if you got 10,000 PVCs or runs non-sustained VT, this is something you gotta be losing some sleep about. But if you look, and I haven't written on this specifically myself, but I know Frank Marcus put together a beautiful paper about 10 years ago where he reviewed all the literature and he has all the statistics and numbers in there, but it's an issue, but you just look for these other parameters. And then just a couple more questions. So one was, could you more clarify how you're using isoproteranol to challenge these patients and how it's changing your management? And when you ablate them, what do you target during VT ablation? So in terms of isoproteranol, if we're bringing any time an ARVD patient comes to the EP lab, we'll take that chance to learn more and give them that high, we'll try to get them off beta blockers before they roll in. And we'll give them that, Stu, we can tell you, we'll give them the 45 minutes. You know, and it's usually oftentimes when in the cool down phase, they light up and then you gotta have Esmolol ready to shut it down fast. So we'll do it, we're sort of in a, trying to learn what it means. I mean, the group in Bordeaux said it's a very good sensitive diagnostic test, so they use it as a diagnostic tool. We sort of consider it to be a bit of a risk predictor, meaning if some isoprel lights them up and they're having reams of VT in the lab, that's gotta be a higher risk patient. So as we discuss, should you get a defibrillator or not? We'll look at the results of standard EP testing with a standard dose of isoproteranol. We'll look at the extent of structural heart disease. We'll look at the, you know, with sort of our risk calculator, if you will. You know, but in a patient who's sort of wondering, should they do it? I think this tends to have us push them towards getting the defibrillator, but we don't really know that for sure in terms of what it really means, there's no published data. In terms of catheter ablation, so Harry Tandrew does all of our VT ablations in ARVD patients. I don't do them, I just see the patients, but he does them all. And he's, you know, he's done like 150 or 200, and I have, I can, and he's sort of a wizard at doing this. He's actually never had a complication, has, you know, very good results, but it's not curative. He's had plenty of patients where he's doing a second or third, you know, one of these procedures, but he will give a high-dose isoprenol, Terenol baseline, and then also at the end of the study to use it as an endpoint for the ablation procedure. Are they non-inducible with program STEM, but also are they negative with the isoprenol infusion at the end of the procedure? So he finds it very useful as sort of an endpoint for the ablation procedure, together with ablating all areas of scar. He's very aggressive with endoepi, sort of aggressive substrate modification. Stuby, you've done a lot of these cases with Harry. Do you have any, you could probably answer that question better than me. Yeah, no, I think the one epicardial map you showed during your talk sort of highlights where the typical late activated regions are, where the scar is sort of high in the RVOT and down toward the basal lateral tricuspid valve. So often it was sort of substrate modification, a lot of ablating in those regions, and then as you said, doing the isoprenol challenge after the procedure to see if there was still a lot of multi-morphic PVCs or VT. Rarely there was some sustained VT, and you can sort of, you know, and train it and figure out where the circuit was. But a lot of times, you know, those are hemodynamically unstable, and so it's mostly a substrate modification strategy. All right, great. Maybe just one more, or a combo question here. The thought as to why the RV is more affected than the LV, and in patients who have biventricular involvement, is there any data on maybe using CRT in those patients? So in terms of why the RV is more, I mean, people will say because, you know, the relative wall stress goes up more than in the LV. You know, the RV, you know, pressures go from 25 to 75, and the RV dilates in response to exercise, whereas the LV thickens, and pressures may go from, you know, 120 to 180, but you don't triple blood pressure. So I think relative wall stress, and then sort of the way it's designed, not being symmetrical or whatever, so I think most people hand wave, and say it's some wall stress thing. The LV, I mean, what we know is if you look at, like, autopsies of people with severe disease, you know, both the RV and the LV are involved in virtually all patients eventually, you know, but some of these, you know, genetic abnormalities really affect the LV. You know, the desmoplacans can have an LV predominant form, and then they don't always fit the diagnostic criteria. So, you know, you have the T-wave changes, or T-wave inversions of V4 to V6 is sort of an LV criteria, and one of the major rewrites that needs to be done on the diagnostic criteria is to try to come up with diagnostic criteria for ALVC. In terms of resynchronization therapy, most of these patients get a right bundle. So, and generally, there's quite a, there's not much role for CRT therapy, but the one exception are some people have a totally dead RV, and we put in a CS lead, you know, for sensing, because the whole RV is completely washed out and dead. So that's really where it's come into play, but virtually none of these patients have a left bundle. So in terms of hemodynamic, it doesn't seem to, you know, be a big, big issue, and very, very few of our patients have a BIV device.
Video Summary
In this video summary, Dr. Hugh Calkins discusses arrhythmogenic right ventricular dysplasia (ARVD) and its diagnosis, management, and progression. ARVD is an inherited cardiomyopathy characterized by progressive replacement of the right ventricular myocardium with fatty and fibrotic tissue. Diagnosis of ARVD requires a combination of history, physical exam, EKG, Holter monitoring, and imaging such as MRI or echo. Genetic testing is also recommended if the disease is suspected. Risk stratification for defibrillator implantation is based on factors such as history of sustained VT or sudden death, proband status, gender, and results of EP testing and Holter monitoring. Exercise restriction is a key management strategy for ARVD, as exercise can trigger arrhythmias and progression of the disease. Catheter ablation may be considered for patients with recurrent arrhythmias. Monitoring for disease progression involves regular follow-up with EKGs, Holter monitoring, and imaging. Recently, there has been a focus on the role of inflammation in ARVD, and further research is being conducted to better understand this aspect of the disease. Overall, ARVD is a progressive condition that requires ongoing monitoring and management to minimize arrhythmias and prevent disease progression.
Keywords
arrhythmogenic right ventricular dysplasia
ARVD
diagnosis
management
progression
cardiomyopathy
genetic testing
defibrillator implantation
exercise restriction
inflammation
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