to welcome you to San Diego. I'm sorry you caught us on one of the five days it rains in Southern California and the Heart Rhythm 2025, the 46th annual meeting of the Heart Rhythm Society. If you have not already done so please download the hashtag HRS 2025 mobile app from your preferred app store. This is how you can participate in the live Q&A that we will be holding at the end during sessions. Please scan the QR code on the screen to access this session's Q&A. When using the mobile app, log in with your HRS credentials. Please note that visual reproduction of Heart Rhythm 2025, either by video or still photography, is strictly prohibited. I'm Carol Ko, Joint Counselor at Providence in Orange County, California, and along with Kyla Dunn, Cardiology Genetic Counselor at Stanford Medicine Children's Health, we are going to be your chairs for this session. This is a joint HRS and National Society of Genetic Counselors session on optimizing genotype-informed approaches for rheumogenic cardiomyopathies, the latest in genetic testing, risk stratification, and exercise. Our first speaker today is the Genetic Counseling Manager at the Center for Inherited Heart Disease at Johns Hopkins. Her talk will explore building a pipeline for genetic testing, what is the optimal genetic counseling and testing strategy for ACMs. Please welcome Brittany Murray. Hi everyone. So I have a big topic to get start with, you know, kind of covering all of the pipeline for testing and genetic counseling, which I hopefully will emphasize to you are two separate things, an independent value, but we have quite a lot of content to get through, so I'll just jump right in. I don't have any disclosures. So many of you know in arrhythmogenic cardiomyopathy and many of the cardiac disease space, genetic testing is pretty much standard of care now. So we have come a long way where people are debating the value of genetic testing and it's pretty much widely accepted at this point. Some of our first guidelines were back in 2011 and now we have the most recent kind of broad reaching guidelines from Dr. Vilda in 2022 and the European Society of Cardiology guidelines in 2023, all emphasizing the value of genetic testing and genetic counseling in arrhythmogenic cardiomyopathy. So the usual practice for many, many years was very much, oh yes, of course, send genetic testing for family screening and prognostic and diagnostic confirmation in anyone meeting ARVC diagnostic criteria. Also in arrhythmogenic cardiomyopathy patients with a really, really strong family history of cardiomyopathy or sudden death, also, oh this is probably genetic, let's try to find the cause. But now genetic testing is really being used and even isolated cardiomyopathy cases that don't really meet these diagnostic criteria guidelines and this kind of broad-based cardiomyopathy genetic testing is now being incorporated into these newer guidelines. So this is a little bit of a point of contention but I thought we should explain it, right? What is arrhythmogenic cardiomyopathy? Because everyone kind of has their own definition and it probably depends a little bit on what continent you're on but for today at least we'll use the definition of arrhythmogenic cardiomyopathy defined by the 2019 Tobin HRS guidelines and that essentially if you have ventricular dysfunction and you have arrhythmia as the clinical presentation and there's not a known otherwise cause, this is arrhythmogenic cardiomyopathy. And this is broad. So yes, we have the classic desmosomal arrhythmogenic cardiomyopathy but this also includes conduction disease in lamin, SCN5A with cardiomyopathy, phospholamban, filament C is a huge culprit in arrhythmogenic cardiomyopathy nowadays, Desmond and others. So this is kind of the genetic arrhythmogenic cardiomyopathy we're talking about. And part of really the case that we're making for doing this more wide-based genetic testing even in individuals that don't have these kind of classic guideline-based diagnoses is because of the low penetrance and variable expressivity in all of the arrhythmogenic cardiomyopathies. Really you should be lowering the bar for suspicion of genetic cause in these cases and we're finding a ton of genetic causes even in more isolated cases. And this really shouldn't be surprising. In arrhythmogenic cardiomyopathies the penetrance can be as low as 30%. So the family history is really not reliable as a tool for suspecting genetic disease or not. And the age range can be widely variable. You know I have some PKP2 carriers that oh it's just grandma with AFib in her 60s and then you have the 15 year old that collapsed at the track meet that's the more obvious diagnosis. So the expressivity of these conditions can really make using the family history as ascertaining them more difficult. And in many case genetic causes of arrhythmogenic cardiomyopathy that you're going to see a much wider variability of presentation as well. So while the family history is extremely important for many many reasons it really the family history or kind of a specific diagnosis of ARVC should not be how you use to decide whether to have genetic testing or not. So this is also has become much more the case as we recognize the left dominant cases. So I was just joking about this case earlier. This is a family that I ascertained from some of our cardiomyopathy physicians many years ago. They are much more about genetic testing nowadays. But this is a really strong family history as you can see. And so the green is actually a transplant to the red cardiomyopathy and the gray sudden death. Each one of these six siblings had a different Hopkins cardiologist and they had all been told they had a viral cardiomyopathy. And that well this is a very rampant viral cardiomyopathy that in that family. And it wasn't until the guy down there at the arrow wanted to go to the Coast Guard and was being held out of the Coast Guard because of this family history that we were sent for genetic testing. And it did confirm that this is a pretty classic desmoplacan left sided arrhythmogenic cardiomyopathy of which the gentleman with the arrow was actually negative for the family mutation. And so he was then cleared to go into the Coast Guard. So especially desmoplacan and appreciating these sudden death risk in cardiomyopathy is a really really classic proponent of why we need to have genetic testing even the more left sided cardiomyopathies. And now one of the things that we're really recognizing is this myocarditis presentation. So it doesn't even necessarily look like a left sided cardiomyopathy. The LVF is often normal but they have these myocardial injury non arrhythmic presentations that meet you know Lake Louise criteria for myocarditis. And so in our recent big pooled together cohort the Desperados Network of desmoplacan variants which is a multi continent multi country registry pulling together all these desmoplacan cases led by our really great research fellow Alessio Gasparetti. We found that it's about one third of cases that have this myocarditis presentation. And so really you should be considering genetic testing in young and especially recurrent myocarditis cases as they're often genetic. And we've seen this in our clinic as well and replicated in two cohorts in the UK and in Spain showing that maybe 8 to 10 percent of all comers with myocarditis actually have an underlying genetic predisposition especially desmoplacan. And the difference and the importance is that the five-year mortality risk and really the sudden death rate is way different in these two populations. And this has led our practice at Hopkins for at least the last three to four years and then now the recent ACC guidelines from December that to start doing genetic testing in all comers with myocarditis. And so the ACC guidelines now and this is not meant to be read this really tiny workup flow but I just pointed out at that down at the bottom that they do recommend outpatient genetic testing for all comers with myocarditis as part of the workup because of the huge important management changes that catching these individuals. So your pipeline for genetic testing to wrap that up is those that meet diagnostic criteria obviously that those that meet the Tobin definition of ACM but also you know myocarditis all comers and any unexplained arrhythmia at young age especially with other abnormalities. So really broadening our base of who should consider genetic testing. Now I also promised I'd tell you that genetic testing and genetic counseling are not the same thing. As a genetic counselor as part of my bias you know share with you a little bit that that these things have unique benefits to them and they're not always equivalent and so this is our team at Hopkins just a quick picture. Genetic counseling in EP is also standard of care and so we really can perform can offer an appropriate testing strategy and up-to-date information. Very importantly what I spend most of my time doing when we're doing genetic testing in these wide swath of people who may have squishier phenotypes is interpretation of genetic test results. Family follow-up is a huge part of what I do and working with my EPs who I love something I know that they do not really have time to do tracking down family members and psychological care and this is why most of the big guidelines do recommend genetic counseling also for these patients as part of the genetic testing process. So as I said I love this data it's old data now from my Stanford colleagues and but really all cardio genetic counselors who have expertise in genetics are not taking that lab report that you get as face value. Almost all genetic counts cardiac specific genetic counselors are over interpreting and reinterpreting that lab report based on our specific expertise and importantly in a small but really important 15% of cases of the interpretation from that expert cardiac genetic counselor is going to differ from what the lab report says and this happens all the time. VUS reclassification is common in our practice we don't just take that lab report and leave it as it is. On the I guess left for y'all and aside this is actually a desmoplacan family where the probian ended up having a cardiac arrest was diagnosed as myocarditis and had a desmoplacan VUS that was disregarded. Fast forward her aunt then had a cardiac arrest and still to this day lives in a rehab facility because of a TBI from that arrest and maybe if we had done some family screening we could have caught things before then but then we were able to segregate that DSP VUS and prove and get it upgraded to pathogenic. On the other hand these are two brothers with a very similar phenotype what sorry first the father died suddenly and then the patient with the arrow presented with this kind of arrhythmogenic cardiomyopathy desmoplacan VUS then years later on family screening his brother has cardiomyopathy he does not have the desmoplacan VUS so we can downgrade that variant it is not causative in this family. So I wanted to just emphasize that that's routine that's strong that's what we see often is that these downgraded VUSs are not overacting on these variants that are on genetic testing. VUSs are common in cardiology and but if you look at the blue bar they are most often downgraded to benign. Another part of genetic counseling family follow-up and communication getting those family screening so another case example of the 48 year old diagnosed with ARVC family screening never really offered or emphasized years later his 14 year old died suddenly on the soccer field so family screening involvement with genetic counseling has been shown to improve these sort of outcomes. Also been shown to improve health related outcomes as well so we're getting some data as well and that the genetic counseling process itself not the genetic test the genetic counseling process does improve this concept of empowerment or improvement with adherence, patient-related outcomes, ability to see a future and tackle their disease and so we've seen this now in multiple studies showing this improved outcomes before and after genetic counseling. However you know genetic counselors are rare there's not enough of us and so we're really trying to figure out what the most appropriate way for genetic counseling is. Is it this heavy pre-test visit and then seeing patients after the fact with results quickly or is this post-test model where genetic test is a routine part of care and then we see them for the counseling heavy part with results is that more efficient? So then just quickly I'll mention that we have a randomized clinical trial that we do have funding for to really study what the most appropriate timing of genetic counseling is. We have an educational video that we're showing patients beforehand and then switching to have a more post-test heavy face-to-face visit and recruitment is currently wrapping up right now but the video test seems or the video pre-test consent seems to be acceptable in terms of knowledge and engagement and we're really going to see how the outcomes are in terms of adherence, the genetic counseling outcome scale in terms of empowerment and overall acceptability within this population. We're also trying to expand that and use this video to do more inpatient testing as well. So I'll end there and just saying that genetic testing is not only guideline recommended but very important in risk stratification and the genetic testing and genetic counseling are not the same thing and the data shows improved outcomes if your genetic counselor is involved in the care. And I'll just show our team there. I'm happy I think we're going to take questions at the end. Thank you so much Brittany. Thank you Brittany. And our next speaker, if you didn't get to catch her on Thursday, we're very excited to have her back, is a specialist in EP and cardiovascular genetics from Montreal Heart Institute and associate professor at Université de Montréal. Please welcome Dr. Julia Catran-Turini and she'll be speaking on how genotype outperforms phenotype in arrhythmic risk stratification for ACMs. Hello everyone. Thank you for being here early in the morning, especially those who are probably a little bit jet-lagged. So my role today is to tell you that genotype is important for risk stratification in ACM. I think many of you are probably already convinced but there are still a lot of things to do about that. So why do we care about risk stratification in arrhythmogenic cardiomyopathy? Well the whole question is who should we implant ICDs in? We don't want to live with the disease of having an ICD in complication but at the same time we don't want to miss sudden cardiac death, especially in young people who don't have other reasons to die. When it comes to risk stratification in genetic cardiomyopathy, two different approaches can be taken. First, the classical one, phenotype. And this is still what we do for hypertrophic cardiomyopathy. There's no gene-first approach, there's no inclusion of genotype in the different schemes that we have for risk stratification. In ARVC we have a phenotype-first approach and in many cases in non-ischemic cardiomyopathy, call it however you like, there's also a phenotype-first approach. But in past few years we've come to realize that some genes behave like diseases of their own and should have their own risk stratification. And this even culminated in certain cases into enough knowledge to have a specific risk calculator for some of these genes. So let's start with ARVC because this is the one we have the most information in. So for the past probably 25 years there has been a lot of work into trying to improve risk stratification for this disease and this culminated into in the past few years into the derivation and large validation of a risk calculator for arrhythmia and this disease, which is now one of the approaches recommended by the latest ESC cardiomyopathy guidelines in 2023. So why do everybody wants to do risk calculator? The whole point behind that is to try to improve risk prediction by taking as much as we can from prior literature and summarize it into one single number that we can use to take a decision but also use for shared decision-making with the patient and discuss amongst colleagues if we should implant an ICD in a patient. And there are a couple of key points we should keep in mind when trying to use these models. So first they work in the population they've been developed and validated in. The predictors that are in these models have to be possible to retrieve in large retrospective databases from many different centers so not everything can be in there. Outcomes is usually any sustained ventricular arrhythmia so not only sudden cardiac deaths but when you see event rates that look terrible well just remember that this is a little bit inflated and proper external validation is important. So the ARVC risk calculator has seven variables out of eight. So one was kicked out and it's left ventricular ejection fraction which did not make it into the model for ARVC. Young age, male sex, syncope, number of PVCs on the 24-hour Holter, number of leads with T wave inversion, non-sustained VT and RVEF are the predictors in this model. The population so it's a definite ARVC population so no not a gene first approach. Primary prevention patients only so not patients with a prior history of sustained ventricular arrhythmia. And now let's go into genotype because that's what interests us today. So the most common genotype was expectedly in the first two, well in the three studies with a higher proportion in the derivation and first validation study placophilin 2, 50% of patient approximately. Second most common is also expectedly desmoplakin which as you can see is is between 4 and 14 percent in the second validation study where there was less half less PKP 2 patient 21% versus 50% and desmogli and desmocolin were the third one. And the event rate was pretty high in the two first ones 5% per year while it was half of that in the second one. So when it comes to performance for these risk calculator we usually use two parameters calibration and discrimination. Basically discrimination is considered to be good at or above 0.70 not perfect but good and then just keep your eyes on the calibration which is basically the concordance between the prediction and observation. So the perfect result is this dotted line and you want to be on the line. So it goes pretty well for the derivation study goes pretty well for just seconds the first validation study and then the second validation study it didn't go so well there seemed to be overestimation happening in the overall cohort and the answer to that is in the genes. So in gene positive patient in this cohort the model works very well. In PKP 2 it works super well and when we take all the desmosomal patients together well it works well but not as good if we take just the PKP 2s and we remember that the second most common gene here is desmoplakin. Well in this specific cohort well as a departure from the two other ones they didn't work that well in the gene elusive patient and there might be reason explaining that. So let's go a little bit deeper into the genes the cohort included 118 patients with PKP 2 and 79 with desmoplakin which are pretty good numbers and on this figure you basically see I know it's a little bit small but the the predictors that stick in for these different genes and you see that for desmoplakin and PKP 2 it's pretty different. So you don't see the red at the same place. Left ventricular ejection fraction seems important for desmoplakin it's not for PKP 2 while many other ones are important for PKP 2 and are not for desmoplakin. So the next question is, does a risk calculator work for desmoplacan ARVC? And the answer is like, not very well. The C-statistic, as you can see, is .60, but when removing patients with left ventricular dysfunction, it improves, it's .75. So, kind of getting the idea in that maybe a specific prediction model based on the gene would be good. Second most common genes, and we often lump these two together because they have the same clinical features and the same mechanism, are desmoglion and desmocolin, which are three to five times less common than PKP2. They have a challenge in genetics because they don't are, as PKP2, only autosomal dominant disease. They can be recessive, but also there's a lot of compound hives, I guess, and digenic patients there. So, a more complex genetic background. So, just very, very recently, the largest cohort to date was published with 200 patients with ARVC. So, giving more information about this disease, but not specifically about risk stratification. And in sum, when looking at all the literature, we kind of see that they behave more or less like PKP2. There might be, however, an independent role for multiple variants. So, that I'm not sure what to do with, but more data would be needed to confirm. So, just to simplify things about ARVC, we can probably split genes into classical genes and non-classical genes. PKP2 is the super classical, the classical, the ARVC risk calculator works well. Desmoglien, Desmocolien, probably. Placoglobin is less common. Seems to behave the same, but I have less confidence in telling you that. While on the other side, I can tell you, it doesn't work for Desmoplakien. And the other ones, TMM43, the bad, newfoundland gene in Canada. Phospholamban, the bad gene from the Netherlands. Desmin and Filament C, which are all genes affecting the left ventricle. So, moving on to this next chamber of the heart, for which, for many, many years, we've used this kind of single, one-fits-all approach where we would implant ICDs with a single threshold of 35% rejection fraction. And kind of unfortunately, in 2016, this approach was challenged by a study showing no benefit of survival with ICDs in these patients with LDEF less than 35%. So, there's a lot of room for improvement and trying to define patients differently. And genes are a good way to do so because some of these genes are clearly at higher risk of ventricular arrhythmia than the garden variety genes associated with a non-ischemic cardiomyopathy such as Titan. So, the risk is higher and some predictors might work differently on these different genes. And it's interesting to see, you see here in Desmoplakien, for example, your risk increases when you reach 50% and below 50%, your risk remains high, but it doesn't go up again. So, kind of dichotomous use of ejection fraction, while in one of these studies on the filament C variant, well, there's no impact of left ventricular ejection fraction on ventricular arrhythmia, which I think is a little bit scary clinically-wise. So, for Desmoplakien, knowing that the risk calculator doesn't work, there was a specific risk calculator done for these patients. And large external validation is yet to come, but the model performed well in this sample. And interestingly, you remember that male sex is a bad thing for ARVC. Well, now it's female sex. So, this is completely different for Desmoplakien. Left ventricular ejection fraction less than 50% is in the model, expectedly. And the other good variables that we have for ARVC, non-system VT, PDC count, and the function of the right ventricle are in the model. There are other potential risk factors. Brittany told you a lot about myocarditis, which is a potential risk factor which was not incorporated in the model. The presence of late gadolinium enhancement is often a predominant feature that we have in these patients. I get this question asked all the time. I got an email this morning about risk stratification in such patients. So, it was tested in that model, but you have to remember these are different patients coming from different centers with just reports from MRIs with no granular data, no good quantification. So, this might change in the future if we look more specifically at DCMR. LMNA is also an important one. The second most common gene associated with non-ischemic cardiomyopathy after the Gordon variety titan has different predictors. One that is important to remember is the presence of atrial ventricular block, which kind of impact what we do with these patients, but is also a predictor of ventricular arrhythmia. And the combination of these factors and theirs increases the risk, and there's a specific risk calculator for that. This is a very busy slide showing the different genes with their different disease and risk stratification and their different predictors. But just to keep an eye on that, kind of tell us that there's no one-size-fits-all approach. The predictor change for different genes, their weight change. There are some pretty popular predictors, PVC count, the ventricular ejection fraction, but this really brings a very tailored approach. And for the first four one, we have more information, more data, but only validation for the first one with the risk prediction model. So, genes are important, but first there's a phenotype, and Brittany told you a lot about that. The first thing in knowing the genotype of a patient is asking for genetic testing. So, we have to remember and recognize these different high-risk features that should lower the threshold for genetic testing. And also, unfortunately, so we've come to be, we've come to be kind of very good at treating genes, and we're kind of happy when you have a positive result of genetic testing because we kind of know what to do with the patient. But we have to remember that, well, gene-negative patients still exist, and they still present a challenge. So, well, more to come, I hope, in the next few years. So, in conclusion, of course, genotype is important in risk stratification. We are coming up with different approaches for certain genes with specific risk calculation. And this is, I think, very good in international efforts because the patients that have a certain genes are quite homogeneous versus the gene-negative that might be different population depending on who you enroll in your big multinational cohort. A phenotype-first approach still exists and works. The ERVC risk calculator works most, performs better with certain very classical genes. Left ventricular cardiomyopathy, we still have to do that. And I think there's still a lot to understand for these gene-negative patients. Thank you very much for listening. Thank you to all who worked with us on the different risk calculator derivation validation efforts. Thank you. professor of medicine at Duke, where he sees patients in the adult cardiovascular genetics program, as well as the sports cardiology clinic. His talk today will take us through the latest evidence that genotype should inform shared decision making for exercise with arrhythmogenic cardiomyopathies. Please welcome Dr. James Daubert. Okay, well, thank you very much. It's a great pleasure to be here and enjoying all the other talks and working with colleagues up here. So, as you heard, I'm gonna focus in on the role of exercise as a predictor in these conditions, and there's some interesting old data and some interesting newer data that we'll get to. So I'll start with a case. This is a patient I saw at some point in his course, and he was, at that time, a pretty asymptomatic runner. Not a marathoner, but he ran regularly and was moderately active. His brother, some years earlier, had undergone heart transplant for dilated cardiomyopathy, and maybe there was myocarditis as a diagnosis, and no further family workup, as you heard, which used to be more common than it fortunately is now. So he came to attention because he had, and went to get life insurance, and fortunately or unfortunately, he had an elevated BNP and PVCs, and things went quickly downhill from there. He had a reduced ejection fraction, the PVCs, non-sustained VT, an abnormal MRI, a left bundle, and at that point, he was still a NYHA class one. He was found to have a lamin, LMNA mutation, a pathogenic variant, received an ICD, and over a couple of years, had worsening heart failure, VT, and underwent transplant, and he's doing well now. So we'll come back to him a little bit later. Starting again, as the other talks, with ARVC. That's where physical activity, exercise, sports, really became an important factor to consider in these patients. This is data from the North American Multidisciplinary Registry, headed up by Frank Marcus, who we lost a couple of years ago, unfortunately. And one of the senses in this paper is of particular interest is that 34% of the probands participate in competitive or professional sports prior to diagnosis, and an additional 36% of patients were active in recreational sports. A sub-study looked at, honed in on what type of exercise and found that competitive sports and high-intensity dynamic sports, soccer, running, bicycling, hockey, et cetera, were relevant to increasing the diagnosis. Much of our data from, about exercise and ARVC, in general, is from the strong work from the Hopkins Group, and they showed nicely that athletes were much more likely to reach a diagnosis and have significant disease, and if they didn't stop exercising, more likely to have an adverse outcome, with especially endurance athletes having a poor course. Why is this? Well, the right ventricle and the left ventricle are different. At least in humans, and the right ventricular wall stress with exercise increases much more, so it's less than left ventricular wall stress at rest, but maybe a little bit more with exercise, and for endurance athletes, this effect is even greater. Myocardial oxygen demand, as well, increases disproportionately in the RV compared to the LV, and I'll note that thoroughbred horses bred for many generations for exercise have thick RV walls, interestingly. There are studies in endurance athletes that show that the right ventricle can have transient dysfunction post-race that usually recovers, but the more severe the insult, the greater the change in RV function, and perhaps there may be lack of recovery in the long term. So you could imagine that the genetic risk combined with, the level of genetic risk combined with different degrees of environmental factors like exercise could reach the phenotypic expression, and in fact, in some series, the patients who were gene elusive did not have an abnormal gene detected had a much higher exercise history and sports participation history. Other mechanistic issues that are being worked out relate to PKPT2 mice with sarcoplasmic reticulum load, calcium sparks, hyperphosphorylation of phospholambin, an adrenergic mechanism that could be mitigated in these mice by membrane permeable beta blockers or ryanodine receptor channel blockers. Myocarditis, we've talked about this morning, and exercise can accelerate the disease and damage in that condition. In desmoglian mutant mice, endurance training worsens the effect and preload reduction can mitigate the effects in this animal model. And then other interesting work here, looked at gene expression in the milieu in the areas of inflammatory fibrotic niches in regions and found elevated levels of certain proteins. And in an animal model, this was related to interleukin B that could be mitigated by blocking that. And then lastly, from a mechanistic standpoint, catalytic antibodies can cleave desmoglian in the desmosome here and reduce cardiomyocyte in a cohesion and progression to ARVC. So again, sports, more of a signal than just overall physical activity for heart failure, VT, ICD interventions. And again, this is in ARVC, which is mostly placophilin-2, but a good bit of desmoplakin, gene elusive in desmoglian and colon. But what about the other genes that are less common, desmoglian and desmocolin? Well, there is an exercise signal in these and it's different whether they're single or multiple gene hits for these. The exercise effect is most prominent in the single gene types rather than the multiple pathogenic variant patients. Desmoplakin, also ARVC, but can present with LV cardiomyopathy, has not been found to be linked with exercise in this large series of DSP patients. But interestingly, some recent work found that episodes of myocardial injury, the myocarditis that you've heard about with this condition, appears to be triggered by endurance exercise. And this may be related to effects on the mechanical stress on the desmosome in these DSP-carrying variant patients. Well, perhaps the most severe ARVC phenotype from the maritime provinces in Canada, the TMEM43, is while male sex and other factors are predictive, exercise is very strongly predictive. A history of endurance or intense exercise by med hours is a strong risk factor for first appropriate ICD discharge or death in this series. Turning to left ventricular cardiomyopathies, lamin is a common one behind titan. And recent data is suggesting that there can be an important negative effect for exercise. Here with tertiles of exercise, there's a decreasing ejection fraction with greater exercise and outcome shown here, worse with exercise patients. On the other hand, phospholambin, which can present as ARVC or a left ventricular cardiomyopathy, is not associated with exercise, which is very interesting. And you heard it, phospholambin could be related to placophilin in some of the mechanistic models. But yet for carriers of this pathogenic variant, exercise was not associated with progression, nor for titan. Most common dilated cardiomyopathy, maybe not a classic arrhythmogenic cardiomyopathy, but athletes and non-athletes had a similar risk of having events if they carried a pathogenic titan truncating variant. Filamin C is another cause of arrhythmogenic cardiomyopathy that we've talked about this morning. A lot of scarring and VT. And while sudden deaths can be associated with exercise in this condition, there's so far no data that I was able to locate associating exercise, endurance exercise with progression of the condition. Also not strictly arrhythmogenic cardiomyopathy, but something in similar groups of patients, younger patients with mitral valve prolapse, arrhythmogenic mitral valve prolapse. And so far it doesn't appear that exercise is a predictor for progression or for arrhythmias in this condition. So to sum up, if we kind of divide things arbitrarily, ARVC or ALVC, and I've got a couple asterisks here for conditions that may lean a little bit leftward at times. You've heard that plaquafilin has the most strong effect for exercises being pathogenic for the condition. Desmoglien behaves similarly. TMEM, severe ARVC with some left ventricular involvement has a definite exercise relationship from the data we have so far. Probably plaquaglobin as well. And desmoplacan, interestingly not associated in data so far with exercise, but myocarditis episodes associated. So you have to wonder if you're getting myocarditis leading to delayed enhancement, scarring in the ventricle, that eventually there must be some relationship there. So not a strict breakdown on ARVC versus ALVC or desmosome versus nondesmosome because Lamin patients clearly are seeming to have an exercise relationship. In recent guidelines, European guidelines recommend against intense exercise for these patients, just like our patient who fortunately is doing well with his heart transplant. Maybe if he'd exercised less, he might have had less of a phenotype. And among the other left ventricular cardiomyopathies, we don't have a lot of data in all of them, but phospholambin and titan seem not to be associated with exercise. So what about recommendations? If patients have ARVC, they're advised against competitive sports and high intensity prolonged endurance exercise. And for those who are genotype positive, counseled that their risk of developing the condition may be exacerbated or increased by intense exercise. And how much exercise is too much? There's, of course, many, many questions back and forth with our patients. And one person's racquetball is probably different than someone else's, so this is always a challenge and a work in progress. But that's what I was able to find about exercise and ACM, so thanks very much for your attention. Thank you. Associate Professor Jody Ingalls is head of the Clinical Genomics Laboratory and director of the Genomics and Inherited Disease Program at the Garvin Institute of Medical Research. She's a cardiac genetic counselor in the Department of Cardiology at Royal Prince Alfred Hospital with more than 20 years of experience working with families with inherited heart diseases. Her talk explores the evolution of cardiovascular genetic testing and variant classification landscape. Please welcome Dr. Jody Ingalls. Thanks. I'll start, okay. Okay, the jet lag is real at the moment, but I'm really actually happy that so many people got up so early because I think the time zone thing is difficult for everyone at the moment with the slight differences. But I'm glad to be the final presenter in this session. I kind of got the really fun final talk slot where I basically just get to talk about the evolution of genetic testing. So I took that as being able to talk about whatever I want. But then I had a little bit of fun putting this slide together. So I started working as a genetic counselor in 2003 at the age of about five. And I've seen a lot of progression over that time, over that more than 20 years. And so I tried to just put some of those key points. I was gonna add actual years and a time scale to this, but it was too difficult to work out and it all ended up getting a bit squished in this. So from the time of the first cardiomyopathy and Long QT genes from the late 80s and early 90s, then we ended up with this sequencing being really, really expensive and slow and time-consuming. So the types of testing that we would do way back in the day when I started in 2003 were basically sending our patient samples to research laboratories around the world. And for us, that was the Seidman Lab at Harvard. And they would have postdocs doing Sanger sequencing, little segments of the genes, and it would take about two years and you'd get an Excel file with mutations back. Then at the same time, we started to identify that there were multiple mutations in some of our patients. And that was really cool. And we showed that they might be more severe. And so we kind of had this sudden, like you can't even imagine it now, don't stop sequencing when you find the mutation. You have to keep going. You have to sequence the entire panel. And so the entire panel was like five genes or something, but you couldn't stop and assume that you'd found the only variant. I guess over time, sequencing became a lot cheaper and more accessible. And so it was sort of the era of candidate gene studies where we would sequence, we would decide that a gene is interesting because it's associated with another gene and sequence a cohort of patients and then we'd be like, it's okay guys, it's fine. This variant's not present in 200 controls, which is mostly all the postdocs that had been through the lab. And so that meant it was a mutation. And that was kind of how things went for a really long time. And in this era, as sequencing became cheaper, we just added more and more genes to these panels. And so we got to a point where there were often more than 200 genes on some of these combined panels, which is again, it's the era of, I don't know how many of you have had reclassified T-CAP genetic test reports for hypertrophic cardiomyopathy patients, but it was a common gene. It is not an HCM gene, but it was commonly thought of as an HCM gene. Finally, we ended up with, it's one of those interesting things over the years, but the more you think you understand about genetics, the more you're basically going to realize that you don't know anything at all. And when some of these large population databases came online, like EXAC and NOMAD, we started to really understand that rare variation is common in the population. And that really put the brakes on a lot of variant interpretation and the way we actually understand how genetics causes these diseases. And it really changed things. I think that was the time when a lot of the downgrades happened. It was sort of the era of the VUS and the reclassification and so much reclassification. I can't even tell you how many times I've had that discussion with families. But now we have a much different approach. We are more targeted in what we test. But excitingly, I think the horizon for all of this is that genetic testing is still largely not accessible for a lot of patients. And yet, we can see on the horizon these gene-based therapies beginning to make it into the market. And as soon as that becomes more available, all of these patients are going to want genetic testing. And so I think sessions like this where we talk about how genetic testing is important is really needed so we can educate the community on why this is important. Just wanna highlight this recent practice resource, mostly because it took a really long time to get out. But it's a resource from the National Society of Genetic Counselors around genetic counseling and testing for hypertrophic cardiomyopathy. And this is meant to be a document that when we talk to new people working in a cardiac genetic counseling or genetic testing clinic about how you run this in a cardiac perspective, this is like all the little bits of information that you don't get from anywhere else, all in one nice little paper talking about proband testing, what type of testing to do, and what that means for the family. But I thought it would be useful if we just start with a gene report, because this is actually where a lot of people will interact or have some awareness of the fact that genetic testing happens. So this is, genetic testing, as we've heard, it's a class one indication in almost every inherited heart disease. This is the type of thing you get back when you do genetic testing. You know, your patient has a certain condition, you'll have a variant listed in a gene and a classification for that. So the types of things, like we've heard from Brittany already, genetic counselors don't or shouldn't just take these reports at face value. There's, you know, and over time, these things can change as well. So this is the type of thing that we look at. The first thing to look for is, is there evidence of a gene disease association? And this is something that we work out through a process of gene curation. And if you go to that GenCC website and type in your gene, you get a really good list of any gene disease associations that have been curated for that particular gene. And this is largely, you know, it happens in a few different frameworks, but in the cardiac world, ClinGen has been a big player in this. We've now curated disease genes for a number of the different cardiovascular diseases. We've got our previous work in hypertrophic cardiomyopathy on the left, the left, I think it's the left, and then the more recent DCM curation on the right. More recently, we've re-curated those hypertrophic cardiomyopathy genes. Interestingly, it's a disease that you would expect is not, you know, is largely fairly well understood. We had a lot of new genes and a lot of change in classification. So it goes to show this is a constantly evolving area. Second is we do the variant curation. And variant curation is probably something that you're all much more familiar with, whether you're familiar with the intricacies of it, but basically this is the process of going through and looking at the evidence for a particular genetic variant. And basically weighing up, is there enough evidence to say with confidence that this is the cause of a disease? Is there enough evidence to say with confidence this is not the cause of disease, and that's the likely benign and benign category? Or is there insufficient or conflicting evidence, and that's the uncertain category? So that's the basis of the variant classification framework. That would be like a full day lecture. So you'll all be glad to know I'm not gonna go into that in detail. Once you've got the variant classification, the next step actually is the clinical interpretation of that. And this is the bit that I think we used to kind of lump that into variant curation, but clinical interpretation is a different thing. You could have a pathogenic variant in the BRCA gene for breast cancer in this patient with hypertrophic cardiomyopathy, and that classification would be absolutely correct. It could be pathogenic, but it is not the cause of hypertrophic cardiomyopathy. And so clinical interpretation is, does that genetic finding make sense in that particular patient? And then finally, you have the implications for the patient and the family, and we've heard really nicely in this session already. Genetic testing is used obviously for the family, but also in a lot of other different ways. So why do we go to all of this effort? Primarily we go to this effort, and this is what we've been saying for 20 years, because it's a really powerful tool for the family in working out who is at risk and who is not, who can be released from all future clinical surveillance and who doesn't need to worry about passing this on. And that is the basis of why we do this and why this is cost-effective, because you can reduce the burden on the healthcare system, but also it's really important for the families because you can reduce the worry as well. This is a fairly complicated slide, but it basically illustrates, when we audited 20 years of our genetic heart disease clinic data in Sydney, we looked at the incoming clinical diagnosis of the patient and then the outgoing overall diagnosis that we made following genetic testing. And it's a really useful way to see that genetic testing really does help clarify diagnosis in a lot of cases. And this is two examples. This is two patients who came in with a diagnosis of apparent hypertrophic cardiomyopathy. One had a variant in filament C, which is actually a myofibrillar myopathy, and another had a variant in FHL1, which is X-linked and is an emery-dreyfus muscular dystrophy. Both of those patients need to see a neurologist for evaluation of their neuromuscular phenotype and have different inheritance risks, different clinical screening recommendations. So this is why this is important. Reproductive genetic testing is also important. Whether or not you agree with it is beside the point. This is an option that should be discussed with all patients so that they can get the right information about this at the right time. And then a final point on when genetic testing is uninformative. So, you know, I can't give a talk in cardiac genetics, you know, in 2025 without recognizing the fact that probably a large proportion of our patients have a polygenic etiology for their disease, and that things like hypertension and other, you know, environmental things likely contribute to their disease phenotype. And so when we don't find a genetic result, when we do clinical genetic testing, in those patients that fit that polygenic etiology, so often older, no family history, often less severe disease, that probably makes sense. But if they're not that category, if they're younger, and if they have a positive family history, they're the ones that we should be focusing on because they probably have variants in genes that haven't yet been worked out or affecting genes we know about in different ways. And this is a focus of what our team is currently working on nationally in Australia at the moment, going after those really interesting unsolved monogenic cases. Final slide, because we spend a lot of time talking about how useful genetic testing is, but our discoveries and things that we've built up and do in our population do not benefit the community equally at the moment. If I see a patient who's white European, the chance of finding a result that explains their disease is much higher. That means they get all the benefits of genetic testing that our patients who are not white will miss out on. They also have a much higher risk of misclassification, which can cause harm. So it's basically two to three times more likely to get an uncertain variant in those non-European people. And we've got a really nice example of this from our Oceanian population, where essentially we found a troponin T splice site variant that is, you know, present, absent in all of the population databases like NOMAD and All of Us and UK Biobank, but present in about 5%, 5 to 8% of actually ancestry matched reference populations, which are mostly research privately held populations. And this is a variant that actually is also found in some archaic genomes, goes back to some Neanderthal DNA that we managed to investigate. So we think it's about 130,000 years old, still basically absent in NOMAD. So it goes to show in different parts of the world, we have a lot of problems. So diagnostic yield is, you know, something that we're working on, but it's really not improving at the moment. I think we need a lot more research in this space. Genetic testing is not widely accessible to a lot of patients, and we need to do more, especially as therapies become important. And there's an equitable benefit to the population at the moment. So still a lot to do, but very useful when we're able to provide it to patients. Thank you. Well, we have a few minutes for questions. So please come up to the mic if you'd like to ask our wonderful panel. Hi, thank you so much. I think mostly for Brittany, but anyone, welcome to comment. I'm wondering if you counsel patients differently based on how they were ascertained. We have a biobank on our campus that is reporting out the ACMG secondary findings. And so when I see patients in clinic who are identified to have a pathogenic ARVC mutation, but they have zero family history, if you're telling them anything different. Is this on? Yeah. Thanks, Leslie. That's a really, really great point. I didn't really have time to go into this data today, but we do have data that those ascertained on secondary findings. So outside of arrhythmogenic cardiomyopathy, families do seem to have a much lower penetrance. So probably is some sort of other genetic modifiers that we're not identifying. But in those families with those secondary findings, because they seem to be based on our work with Geisinger, showing from the general population that they're penetrant so much less in those families, I do counsel them differently. And we have a paper I can send you from a few years ago showing that penetrance, for example, in PKP2 can be as low as like 6% in these families. So screening is much looser and we're also much more loose about exercise recommendations in those families. This question is mainly for Jody. And I'm Nadine, genetic counselor in Boston at Mass General. And I really love that you kept the ancestry as being like a relevant part of genetic testing and interpretation. Currently in the field of genetic counseling, I feel like we are swaying away from asking about ancestry. I have lots of opinions about that, but I also acknowledge like the questioning of ancestry in this social political landscape is tumultuous at best, yet it has scientific bearing and potential aid for gene-related genetic specific medications and treatment. So I'm wondering, how do you get ancestry? Is it part of some SNPs that we look at related to genetic testing? What should we be doing in the clinical space with our patients to keep ancestry as part of this while acknowledging the social barriers of that question? Yeah, that is a really good question. And probably it's the million dollar question. I have a lot of opinions on this as well. I actually don't see how you can do genetic testing if you don't know the ancestry and if they're represented or not. I mean, you don't know if anything is actually truly rare if you don't know their ancestry and if they're even represented in the population databases. So I actually think you have to ask it. And I think you just ask it from the patient and get their answer about... I mean, in our part of the world, it's different. One in 25 people in Australia are born overseas and we've got a lot of very unique and underrepresented indigenous populations. And I know that would be true in a lot of countries, but if you find something that's not really been seen in one of those patients, you absolutely cannot interpret if it's rare. And I think our example is terrifying because the number of patients that would have been told that this is a cause for their disease, it's so common. It doesn't answer your question because I don't know the answer, but I think we need to ask it. This country obviously has a lot more going on in terms of how charged that question is compared to mine. So I don't, for a second, know how to navigate that except that you absolutely need to know it. I usually find it's helpful to explain to them why you need that information and make it as medical as possible. I usually explain to my patients I need it for background variation purposes and it can reduce some of the charge around it while at the same time, however, it's complicated because many just don't know. And it is 9.01, but why don't we take one more question from Dr. James back there? Oh, mostly I'm just, I suppose this question is either for Jodi or Brittany. Jodi, I loved your timeline. You and I started around the same time. I was really enjoying that. So I'm gonna ask you to speculate into the future moving along on the timeline. If we think about the heritable cardiomyopathies, will we be integrating PRS testing into our standard genetic testing paradigm? What else do you see coming? Yeah, I totally agree. I mean, I think we have to. It's consistently showing that it's explaining some variation or some contribution of the phenotype. So we absolutely, if we're moving towards a precision medicine approach of fully explaining disease, then that has to be in there. As genetic counselors, we need to think about how we can communicate monogenic and polygenic risk at the same time. And that's something that the cancer field already do and we could probably learn a lot from them. But I think the other big challenge is, I mean, I've already talked a lot about ancestry. That is a huge issue. We actually can't all sit here and say, genetics is a really exciting thing that we offer our patients when it just really is not equitable across the population. The fact that even when we can do it in those populations and we get such variable results, so much more uncertainty, so much more risk of misclassification. It's just, we actually can't ignore that all of our research from here on will perpetuate that. Any use of AI models, anything will perpetuate that inequity. So literally I could go on about this for days, but I don't think we can ignore that. But yeah, it's an exciting time. I'm interested too. I'd love to know your thoughts on what you think comes next. We'll talk about it tonight. Well, thank you to all of our speakers and thank you all for coming to the session. Thank you.

Heart Rhythm 2025

genetic testing

arrhythmogenic cardiomyopathies

Brittany Murray

risk stratification

genotype-phenotype

exercise impact

ICD implantation

variant interpretation

personalized medicine