And I have nothing relevant to disclose for this talk. So this is a slide actually from Barry. And what it shows is the five different categories of genetic abnormalities that can be seen in any disease. And they vary from no mutation identified to pathogenic. And the real problematic ones are the ones in the middle, the VUSs. Now, why would we use genetic testing in hypertrophic cardiomyopathy? And the biggest reason would be family screening or cascade screening. If you have a proband that has a positive genetic test, especially and probably only the pathologic ones, you can actually test the next of kin. And if they don't have that mutation, they do not need to proceed with family screening the rest of their life. And about 50% of individuals with familial HCM, that is more than one member in the family, will have a pathologic genetic mutation. So what other possible uses would genetic testing be for? One is genetic testing for prognosis. Does it predict sudden cardiac death? There was an early paper that showed TNT mutations predicted for sudden death. But what became clear is that was a specific TNT mutation, and that other TNT mutations did not have the same risk. So it really is a very limited usefulness in prognosis, with the possible exception that if there's a double hit, two pathologic mutations, there's probably a higher risk. And here's another use of genetic testing in hypertrophic cardiomyopathy, and that's preimplantation genetic diagnosis. So you can take an egg, retrieve it, start growing it, fertilize the egg, start growing it. At about day four or five, you can actually extract the egg, or extract a cell from that egg, and do genetic testing on that egg, and then only reinsert embryos that do not have that genetic disease. And voila, you end up with a baby. So the other way in the future means of genetic testing would be to correct the pathologic gene in the embryo. This is a far-flung field. It is coming to pass, though. There are lots of ethical issues with this. But in the future, it's conceivable that this would be another use of genetic testing in hypertrophic cardiomyopathy and other predominantly monogenetic disorders. So what about lifestyle? We all know that lifestyle makes a big difference to all of our patients and to hypertrophic cardiomyopathy. So, yes, motivation is good, weight control is good, mental health is good, stopping smoking is good, consciousness is good, wellness is good, and medical care is good. So I'm not going to talk about those because it's so clear that all of those are beneficial. But what am I going to focus on? And that's exercise, because that's not so clear. What is pretty clear is that patients with hypertrophic cardiomyopathy don't exercise as much as those without hypertrophic cardiomyopathy. This is a survey through the HCMA Foundation, and it was HCs or hypertrophs compared to an NHANES group, which is a normal population. This is not an athletic population. This is a normal population. And the people with hypertrophic cardiomyopathy did less vigorous work-related activities, they did less vigorous recreational activities, they did less moderate work activities, and they did less moderate recreational activities. So all of them were informed of their disease, and even though they probably weren't specifically told not to exercise, there was fear about the use of exercise in this population. So what is the paradox of exercise? We know that exercise can reduce the risk of metabolic syndrome, obesity, hypertension, mortality, suicide, you could go on and on. But there's also the potential that it could be an adverse remodeler of underlying cardiac disease, and there's also the potential that it could be a trigger for sudden cardiac death. And I'd like to illustrate the paradox of exercise with this video. So that's the paradox of exercise. I could show you data from a hundred studies that show you exercise as a preventive medicine works. It doesn't lower age, unfortunately, but lowers systolic blood pressure, diabetes, cholesterol, smoking, and in general, the more fit you are, the more you exercise, the better a preventive medicine it is. But there is some tantalizing data that maybe strenuous exercise can be harmful. And this is data not from any population of hypertrophic cardiomyopathy, but from a Swedish whale population, in that there appear to be those that are really strenuous that there may be a signal for increased death. There is actually very good evidence in RV dysplasia that exercise increases the risk of the phenotype, that is, the development of RV dilatation and the development of heart failure. And there's also very good evidence in RV dysplasia that it increases the risk of VTVF. And both of those things are true in mouse models and in human models. And it's been shown, at least in three human studies, that exercise in RV dysplasia not only increases the risk of phenotype and sudden death, but there's also a dose response, in that more vigorous exercise is worse than less vigorous exercise. Now, what about the data for hypertrophic cardiomyopathy? Here's a randomized trial from Michigan, from Charlene Day, that's gotten a lot of press, published in JAMA Cardiology a couple of years ago. And what they did is they took 136 patients with HCM, randomized them to usual activity group or to an exercise training group. Now, this was moderate exercise. This is not a high-intensity exercise study. And what they showed is those that were randomized to exercise actually had an increase in the peak VO2 compared to those randomized to usual activity. So hypertrophic cardiomyopathy patients do get the benefit of exercise with short-term exercise. But this was the more important thing, perhaps, and this was looking at the adverse events. The adverse events were no different between the two groups. And these adverse events included non-sustained VT, atrial fibrillation, other SVTs, syncope, or musculoskeletal injury. So a small study and, you know, only the beginning, but really one of the few studies of exercise in patients with HCM to evaluate both the risk and benefit. We recently reviewed this in Jack, and this is the summary slide or the central illustration. Currently, only low-intensity exercises are recommended by the ACCHA guidelines. The moderate-intensity exercise are the RESETS-HCM, which I've just presented to you from Charlene Day, and then there's a single-group intervention that's really an observational trial. There's very little evidence on high-intensity exercise. It's all observational, and it's all small group. So it's hard to say anything about observational data. Now, what about ICD patients? What about HCM patients with ICDs? Do they get, can they exercise? And here's the ICD sports registry that was published in 2013 that Rachel Lampert led, and there were 372 patients in this registry, and of those, there were 65 with hypertrophic cardiomyopathy. It shows you there, 65 with hypertrophic cardiomyopathy. But of this entire cohort, there were more shocks that were competition-related. And if you look at the number of shocks, 22 shocks competition-related, 14 physical activity-related, and only 11 in those that were not doing physical activity. And these were ventricular fibrillation, so these were concerning shocks in individuals. And this is the longer-term follow-up of that same study, and it shows you very similar things. Competition-related, there were 29 VTs, 12 VFs, and only a small fraction of this group was competitive. Physical activity-related was 15 VTs, 9 VFs, whereas at rest, 19 VTs, 14 VFs. So clearly a concerning signal here for the triggering of shocks, triggering of arrhythmias. And this is perhaps something I'm even more concerned about, and this is when you look at multiple shocks. So the first shock did not get them out of the tachycardia. And this is a series of ours from one of our hypertrophic cardiomyopathy series patients. And when you look at the individuals, of which there were 12 that had multiple shocks, running on treadmill, running in gym, unknown, swimming in a pool, swimming in a pool, swimming in a pool, swimming in a pool, playing flag football, unknown, jumping rope. So a lot of physical activity here in those individuals that got multiple shocks. And this was also seen in the ICD study in that the individuals requiring more than one shock for termination to sinus rhythm were largely doing physical activity, both competitive and practice. So what do the 2015 AHA guidelines on competitive athletes say about patients with HCM? And these are the most recent guidelines for HCM patients. They say that participation in competitive athletes for asymptomatic genotype positive, so they do not have the phenotype, they just have the genotype, that competitive athletes is reasonable. This is different than what the Europeans say because the Europeans say they should not participate in sports. However, patients with probable or unequivocal clinical expression and diagnosis of HCM should not participate in most competitive sports with the exception of those of low intensity. And that prophylactic ICD should not be placed in patients for the sole or primary purpose of permitting participation in high-risk sports, high-intensity sports. And this is actually very similar to what the Europeans say. And that is that avoidance of competitive sports is recommended in patients with HCM. And this is a class one, although level C, evidence. And level C means expert opinion, that it's not really based on randomized data. So in conclusion, exercise can be good for both those with and without heart disease. But there is no free lunch. The ventricular arrhythmias may be triggered, and that's especially true with RV dysplasia, CPBT, and long QT. There may be difficulty with terminating these arrhythmias in patients with ICDs. And there's also concern about ICD-lead where it's certainly reasonable in the short term based on the survey, but long term still may be an issue. And as in so many things in medicine, shared decision-making is key looking at the risk and benefits of exercise. Thank you. Mark, I'm not sure I heard you say that since you were talking about genetics, whether the sarcomere gene mutations predict what we're here talking about, sudden cardiac death or events. The question is about the sarcomere mutations and prognosis. And there's really no convincing evidence that a single sarcomere protein predicts sudden cardiac death. But dual hits, dual pathologic sarcomere protein abnormalities, there is a signal that they're at higher risk for sudden death. Okay, one question. Thank you for your presentation. So assume that you have disease-causing gene identified in the program. Do you still send the family members to genetic testing if they have already phenotype? It's hard to hear the questions up here because of the echo, but let me just make sure I understand. So gene-positive patient. There is a proband, gene-positive, and other family members with phenotype already. Do you still send them to genetic testing? If they're negative, they don't necessarily need a genetic consult, but if they're positive, they do. And there's probably good reason to send them to a genetic counselor, especially the proband, before any more testing is done. So, sorry, proband has the genetic test positive, okay? And there is a family member with the phenotype already. Do you still send this family member to genetic confirmation? I still don't, I'm not sure I understand. He wants to know whether genetic testing applies to positive family members with the disease, with LVH, whether it matters, unless they're probands to study next generation, of course. So if the proband is positive, then that's the benefit of when you can use genetic testing to test the siblings and the children. So I think I need to give an example. So you have a proband, hypertroph, phenotype positive, and gene test positive. And you have the disease-causing gene there. And then you check the sibling with echocardiogram. There is clear-cut hypertroph. Do you still send this sibling to genetic testing for confirmation? Is there any benefit? If they've got a positive phenotype and they meet criteria for disease, they've got the disease. There's no need. There's no need in that population for clinical diagnosis. Now, if you're going to check that person's kids, you'd probably want to check that person also before you went and checked the kids. But for clinical care of the patient, genetic testing is not useful. It's only useful for proband or for cascade screening and possibly if you want to do selective embryogenesis. Is your approach the same for ARVC as well? I wouldn't say that for ARVC. Every disease is a little bit different. There is some evidence for ARVC that the desmoplakin gene actually portends a higher risk to the patient than the plakofelin gene. So there is evolving evidence for ARV dysplasia that genetic testing may affect clinical care. No, I mean the genetic test is known for the family, but there is somebody, there is phenotype there already diagnosed as clinically ARVC. There is any additional benefit from gene test for this patient because you know the gene already from the proband. If you know the gene from the proband and you've got a clinical diagnosis in a sibling, yeah, you pretty much know what gene they have. Yes, thank you. Okay.

Genetic testing

hypertrophic cardiomyopathy

family screening

exercise

implantable cardioverter-defibrillators