BPG Webinar - Precision medicine in cardiomyopathy Why genetic testing matters more than ever edit So hello everyone and welcome to today’s educational webinar titled Precision Medicine in Cardiomyopathy, Why Genetic Testing matters more than ever. The webinar is brought to you by Blueprint Genetic, a genetic knowledge company committed to providing an innovative approach to genetic genetic testing and to ensure accurate and confidence in your clinical practice. My name is Taina Vuopio and I have the privilege of hosting today’s webinar. Please submit any questions you may have in the Qi box. You can submit them throughout the webinar and we will answer as many as possible at the end. Oh, we are excited to have Julie Hathaway as our speaker today. Julie received her Master of Science in Genetic Counselling from the University of Toronto. She’s board certified in both the US and Canada. Julie was introduced to cardiac genetics early in her career and this remains her main area of interest in the field. As a Clinical liaison at Blueprint Genetic, Julie provides both internal and external clinical support and education. In addition, she contributes to research and creates scientific content. Prior to this, she worked as a clinical coordinator and cardiac genetic counsellor and worked to establish the multidisciplinary BC inherited arrhythmic program. So thank you for being here today. Julie, please, thank you so much, Taina, for that kind introduction. And it’s a pleasure for me to spend the next 40 minutes or so talking to you about a topic within cardiovascular genetics, which is my favorite specialty, as Taina mentioned. And what I wanted to talk about today is about why genetic testing in cardiomyopathy is really more personal than ever before. Here are a few of today’s objectives want to go over and talk about how gene specific recommendations in cardiomyopathy management guidelines demonstrate really the importance of genetic testing for that affected individual. Then I also want to compare some overlapping features of both genetic and acquired cardiomyopathies, which can highlight some emerging clinical indications for genetic testing in the in this area. And then at the very end briefly talk about some recent advances in gene specific therapies for patients with cardiomyopathies. So as many of you know, genetic testing for patients affected by cardiovascular disease, including the cardiomyopathies, has been a published recommendation by societies around the world over the last number of years. The one that I was able to trace back to was, you know, starting in about 2011. And someone might correct me and say that it’s been earlier than that, but it they keep coming up as recommended recommendations for patients affected by these conditions. And historically, in the older guidelines, recommendations really emphasize the need for genetic testing to pinpoint and identify those people in the family of the affected individual who would be at risk to develop the condition, which as we know, these inherited cardiovascular diseases predisposed to sudden cardiac death. So if we can identify the genetic cause in the family, we can then pinpoint who is at risk and then establish some surveillance and any kind of treatment for those family members or ongoing surveillance. Like I said, however, over time, there’s been a shift towards how genetic testing results increasingly benefit the patient themselves, of course, also the family, but the patient themselves is what I want to talk about more today. And I think we can see this illustrated well by comparing similar images or tables from the 2011 expert consensus statement published jointly by Heart rhythm societies around the world, both from 2011 and then from 2022. And these outline the diagnostic, prognostic and therapeutic benefits of genetic testing for affected individuals. Obviously the more plus signs you see the higher the advantage or the, the stronger the advantage. And so looking just at hypertrophic cardiomyopathy in 2011 and in 2022, we see that the advantages or the strength of the recommendation or the strength of the benefit has really you know been quite the same over the last 10 years for genetic testing if for that particular cardiomyopathy. But we do see a noticeable change for both dilated cardiomyopathy and arrhythmogenic cardiomyopathy, where genetic testing is now evaluated as having a much stronger impact on the diagnosis, prognosis and therapy for these patients. And I’m hoping to show you some examples of that today. Before we do, let’s just do a very brief review of the well known genetic cardiomyopathies, a quick review of the normal function of the heart. We’ve got all the way on the left hand side, normal structure and function of the heart. At the top, you have the top chambers called the Atria. At the bottom you have the left chambers called the ventricles. The left side of the heart, The left ventricle is responsible for pumping the oxygenated blood to the rest of the body. This is the more muscle or stronger side of the heart and then the right side of the heart pumps deoxygenated blood from the sorry from the body into the lungs and it’s not as muscular as the left side. If you want throughout the presentation, I might say left ventricular or LV dysfunction or RV dysfunction, which just basically means abnormalities in the pumping function either mainly on the left side or on the right side of the heart. That first cardiomyopathy is hypertrophic cardiomyopathy or HCM compared to the normal heart. We can see thickened muscle in in that heart muscle on the left hand side, in the left ventricle. And in severe cases, that thickening can actually block the outflow of blood out of the heart, which we could call obstructive cardiomyopathy. Genetic HCM per SE is when this hypertrophy or thickened heart muscle is not explained by other conditions such as hypertension. And although the hypertrophic cardiomyopathy is, you know, one of the common classic genetic cardiomyopathies, it won’t be the star of the show today because I really want to focus on dilated cardiomyopathy, which as the name suggests, has that dilated left side of the heart, much bigger weakened muscle on that left side. And arrhythmogenic cardiomyopathy, which as we’ve, you know, learned more about these conditions. I understand that there’s a really important and more accurate way to describe arrhythmogenic cardiomyopathy and specifically by based on the structural and functional findings. So whether or not the the issue or the, the the problem per SE is coming from the right side of the heart. So your arrhythmogenic right ventricular cardiomyopathy, that’s one that we’ve probably come across in the past more very often. And then arrhythmogenic left ventricular cardiomyopathy because we are seeing that these that cardiomyopathies affect the left ventricle of the heart and they can be quite arrhythmogenic as well or a newly I’ve seen also non dilated left ventricular cardiomyopathy come up. So really thinking about arrhythmogenic cardiomyopathy and thinking about whether it’s the right or the left side of the heart that’s impacted is becoming increasingly important. And so just a little bit more about dilated cardiomyopathy. As I mentioned, this is dilatation on the left side of the heart in the left ventricle, sorry, the left ventricle, not the left side of the heart, which results in problems with the pumping function. And this is idiopathic if you want, if it’s not explained by if it doesn’t have a clear explanation like hypertension, coronary artery disease, valvular disease or etcetera. The primary mechanism involved in the pathogenesis of pathogenesis of dilated cardiomyopathy is really this impairment of myocardial contractility, the ability for the for the heart to contract and relax again. And in more severe cases this results in not enough blood circulating to the body. And if insufficient blood is if insufficient blood is pumped is not pumped out of the heart, it can begin to accumulate in the lungs and this can lead to symptoms of shortness of breath, fatigue, and eventual swelling as too much fuel fluid accumulates in the body, all signs of which can be referred to as heart failure. Dilated cardiomyopathy can also result in abnormal heart rhythms because the heart’s electrical signal is not conducted properly through that overstretched muscle and this condition can be seen pre all the way from prenatal onset to adults and is not that uncommon. As I mentioned, in the idiopathic cases, the yield of genetic testing is somewhere in the range of 20 to 40% and the presentation can be really variable. So patients can be asymptomatic, have a developing heart failure symptoms, can develop only arrhythmias, sometimes arrhythmias prior to any structural abnormalities that we see or pumping problems of the pumping function problems, stroke or importantly sudden cardiac death. If we talk a little bit about the genetics of dilated cardiomyopathy or DCM, which is incredibly heterogeneous, this image on the left hand side is inside the cardiomyocyte. 1 The genes implicated in DCM have all kinds of different functions, all of which when impaired lead to ventricular dysfunction and that loss of contractility. So these genes are involved in the structure and function of the sarcomere, which is that main contractile apparatus in the heart muscle allows that heart muscle to contract. And genes within the sarcomere we know are implicated in different types of cardiomyopathy through different disease mechanisms. We have genes that are involved in building protein, the ion channel proteins, we’ve got genes involved in nuclear proteins and so on, as well as we finally have some genes that are also implicated in that cardiac desmosome, which is that structure that holds the cells together. On the right you have a table of the most common genes associated with idiopathic or dilate, idiopathic cardiomyopathy or dilated cardiomyopathy. Titan is obviously the most common genetic ‘cause it was really, you know, relatively recently described over the last 10-15 years, maybe not that recent now, but it was really a game changer when it came to the identifying more genetic causes of cardiomyopathy. Sensitive accounts for such an important percentage. After that, you’ve got other genes that have important contributions and it’s worth mentioning that some of these genes like laminae, FLNCR, BM20, phospholamin and DSP are all genes can that are particularly arrhythmogenic forms of dilated cardiomyopathy. Arrhythmogenic cardiomyopathy, on the other hand, is a heart muscle disease characterized by fibro fatty myocardial tissue replacement specifically in the ventricles. As a result, and as a result, there is this predisposition to arrhythmias because obviously if you’ve got infiltration, as you can see on that little diagram, infiltration in the heart muscle that that cardiac conduction that generates the heartbeat can’t circulate well through that heart muscle and can predispose the heart to start beating very, very quickly. And if essentially may stop altogether. It was previously only thought to involve the right ventricle, but we now can see that it obviously can also impact the left ventricle or both bottom chambers of the heart. It can arise for several reasons. We have genetic underlying cause. We’ve got viral causes, autoimmune, inflammatory explanations, infiltrative diseases, and so on. The genetic testing yield in those cases where there isn’t an obvious explanation is about 50%. We tend to see this condition show up late adolescence and adulthood, early adulthood. And again, the presentation can be really variable, everything from asymptomatic patients to sudden fainting, often in response to exercise, dangerous arrhythmias and sudden cardiac deaths, a death or sudden cardiac arrest or sudden death. And we’re increasingly recognizing that exercise is a risk factor in this particular condition, which is a whole other topic and really interesting as well. The pathogenic variants of that cardiac desmosome that I already mentioned are the most common genetic causes of inherited cardio arrhythmogenic cardiomyopathy. Those cardiac desmosomes, like I said, hold those cardiomyocytes together and abnormalities in the protein components can lead to loss of adhesion or detachment of those cells under that contraction, which can cause inflammation, cell death and eventually fibro fatty replacement. Of these desmosomal genes, the most common one that we see in that strict ARVC affecting the right side of the heart is PKP 2, and then you’ve got the other genes listed there as well. I do want to point out DSP because although it’s listed under ARVC, we tend to see, as I mentioned before, the left side of the heart being implicated a lot more than the right side of the heart. You may have noticed as well that there are some of these genes that of course were also present in that dilated cardiomyopathy table that I showed you a little bit earlier. And of course, making a diagnosis for these cardiomyopathies is particularly important because we know they predisposed to sudden cardiac death. And although you know, perhaps we didn’t go into a lot of details about the clinical features of these different cardiomyopathies, they do have overlapping clinical features which can make the diagnosis particularly tricky. And as well, we know that there is overlap in the underlying genetic causes for these cardiomyopathies as well. One of those is DSP and I want to talk about that gene in particular a little bit more. So cardiomyopathy associated with DSP appears to be this distinct entity that’s actually specifically often named after the implicated gene because although it has overlapping features with other arrhythmogenic cardiomyopathies, it does. So it does have its own unique features. It, as I said before, it frequently involves the left side of the heart or the left ventricle and starts with this fibrosis really deep in the heart tissue prior to the development of any problems that we can see with the pumping function of the heart. It’s also characterized by these episodes of chest pain and elevated biomarkers that can be sometimes indicative of like heart muscle injury or ischemia that would without you know any presence of like obstructive coronary artery disease. So we call or you know, not we, but these episodes are called hot phases and these hot phases are characteristic of arrhythmogenic cardiomyopathies, but as I understand are seen a little bit more frequently in these DSP related cardiomyopathies. These episodes frequently affect younger individuals and are on the differential diagnosis for acute myocarditis. So it can be tricky to know exactly what’s going on. And these are particularly problematic because if you think about the inflammation that are caused by these hot phase episodes, it’s really sort of built up a perfect storm for a heart that’s already pre predisposed to really dangerous arrhythmias leading to sudden cardiac death. And so, you know, start to think that if there is, if DSP cardiomyopathy is unique, how are patients potentially managed a little bit different than other patients with other types of genetic cardiomyopathy. So data from a large registry including you know around 800 patients primarily from Northern European background were included in this particular network or registry over 26 or 26 institutions, over 9 countries. These patients with a likely pathogenic or pathogenic variant in DSP. And the purpose was really to see what was, what are the main features and could they could the researcher, clinician researchers identify risk factors that that could predict dangerous arrhythmias in these patients. And when they looked at this group of 800 patients, they saw that the prevalence of these ventricular arrhythmias were about was about 4% per year. And risk factors to predict these ventricular arrhythmias were things like female sex, prior arrhythmias and reduced left ventricular dysfunction. They saw that about 9% of patients had these hot phase episodes that I just talked about and those were a risk factor for ventricular arrhythmias and heart failures and heart failures. Excuse me as well. These patients presented with, you know, different diagnosis, about 40% with ARBC, 7% with dilated cardiomyopathy, 24 percent or so with this non dilated left ventricular cardiomyopathy and about 1/3 had no phenotype at all. So with that information, the group was able to generate what they’re calling ADSP risk score, which provides A5 year ventricular arrhythmia risk in patients with pathogenic or likely pathogenic variants in the DSP gene. And how they generate this five year risk factor for these patients is by considering some of those risk factors that I just mentioned that they identified from the paper. And with that they can, you know, determine what is the risk for the patient to have dangerous arrhythmias and then start to make decisions about management based on that risk. And DSP isn’t the only gene where there are specific risk factors that have been identified that are unique to the gene itself. Other examples include FLNC where age, male sex, non sustained ventricular tachycardia, sudden fainting, syncope, left ventricular ejection fraction, which is a measure of the pumping function of the heart can predict the risk of sudden cardiac death and major ventricular arrhythmias. This French study demonstrated that predictors of heart failure and other cardiac outcomes in patients with laminae variants included male sex missense variants in specific domains of the gene and a particular ECG finding called left bundle branch block. And these different factors were now, you know, validated in another cohort and another and a risk factor, sorry, a risk calculator. Or laminae for patients with laminae variants does exist now as well. And finally, the last example is actually with regards to a specific variant in a gene called phospholamin which is associated with both dilated and arrhythmogenic cardiomyopathy. A multi center cohort with this variant was studied to identify factors which again could predict sustained ventricular arrhythmias and these predictors were left ventricular function, premature ventricular contractions like extra beats on a Holter monitor and specific ECG findings. And again, a risk calculator was generated specifically for these patients. So if there are these risk calculators that exist for specific genes that are particularly arrhythmogenic, but that occasionally the presentation might be quite similar between genes with the particularly arrhythmogenic genes and genes that we’re going to eventually follow a more dilated cardiomyopathy course with a lower risk of arrhythmias. It seems really important to quickly and promptly identify which of those patients fall into the arrhythmogenic cardiomyopathy category versus dilated cardiomyopathy category because that management of those arrhythmogenic cardiomyopathy patients are, is going to be on those ventricular arrhythmias. And whether or not, you know, what sort of management strategies need to be taken there versus patients with dilated cardiomyopathy where, you know, potentially heart failure is going to be what is going to be the, the, the point of focus for management. And so transitioning from, you know, describing A cardiomyopathy based on, you know, dilated or arrhythmogenic cardiomyopathy may not be as helpful anymore. And naming the cardiomyopathy based on the gene that is actually implicated is actually potentially going to be a lot more informative. These six genes that I list here below are particularly arrhythmogenic, but again, in the early stages may not be able to distinguish the two. And these six genes are particularly important because they’re called out in recent management guidelines. And knowing that a patient has a specific variant in one of these high risk genes can have direct management implications. So this is a screenshot taken from the 2023 European Society of Cardiology Guidelines for the management of cardiomyopathies. And this recommendation outlines that the patient’s genotype should be considered in the estimation of sudden cardiac death risk in in dilated cardiomyopathy and that an ICD should be considered in patients with dilated cardiomyopathy with a genotype associated with a high risk sudden cardiac death. So one of these specific genes potentially in the without the presence of additional risk factors that were particularly considered in the cases of in other cases with when a patient doesn’t have those specific that specific area in that gene. So really tailoring recommendations based on the gene itself. Of course, I am not a clinician, so I’m not the, you know, I am not saying that’s, you know, making any suggestions about how your patients should be managed, but of just pointing out that I think it’s really interesting and important that these guidelines are highlighting this for folks to be aware of. And we’re seeing gene specific recommendations come out more and more. So this is a list of of management guidelines that have been published over the last, you know, 10 or so years, oldest at the bottom, more recent at the top. The very top is that European guideline that I just mentioned with regards to cardiomyopathy published in 2023. And on the right hand side you can see whether or not there are any gene specific recommendations in the guidelines. This image taken by the Australian group led by Jody Ingalls and if there is a green check mark it means that there are gene specific recommendations within that guideline. The earliest one that we see is the Heart Failure Society of America practice guideline with regards to cardiomyopathy. And as over time we can see that, as you know, we can see that more and more guidelines are including gene specific recommendations. So really important to be aware of those and hopefully that evidence that I showed you before about these risk calculators and how each gene is a bit unique highlights that importance. So now that we’ve talked about how genetic test results can have direct management implications for a patient and, you know, we didn’t even talk about the family members, I want to bring up whether or not there are other forms of cardiomyopathy which were not previously considered that could also have an underlying genetic etiology. And if so, does genetic testing have a place to also guide diagnosis, prognosis and therapies in those patients? So this is a classification of cardiomyopathies from, you know, 2006 published by multiple US based societies such as the American Heart Association. I’ve included only the primary cardiomyopathies here for our purposes today, but also within that included the acquired cardiomyopathies because those are the ones that I want to really focus on today. We probably only have time to talk about one of them and the one that I do want to focus on is this inflammatory cardiomyopathy. So like the name suggests, inflammatory cardiomyopathy is really a heart muscle disorder characterized by persistent inflammation leading to ventricular dysfunction, problems with the pumping function and remodeling, often evolving from acute myocarditis or infections. Acute myocarditis, sort of like sort of perhaps an infectious origin or immune, immune, immune mediated, excuse me. There can be several different causes for the inflammation. Like I said, there could be a viral infection, bacterial infection, autoimmune, drug induced radiation, chemo or what have you that can cause this inflammatory inflammation. And we can see this both in children and adults. The prognosis, as I understand, is influenced by the initial severity of the condition, the extent in which that inflammation is causing fibrosis and the underlying etiology. The those with a clinical presentation with rapid progression can sometimes see a recovery of heart function with proper support, whereas others can go on and present with heart failure picture and others with more of an arrhythmogenic picture that can be obviously quite dangerous as well. Myocarditis specifically is a cause of inflammatory cardiomyopathy. It really is just an inflammatory disease of the heart. Again, that can result as a consequence of infections or exposures. And it is, like I said, A cause of inflammatory cardiomyopathy. The diagnosis is made when a patient presents with clinical features as consistent with myocarditis. So for example, signs of a fever or illness, mild chest pain, arrhythmias, signs of heart failure. And they also present with findings on a specific biopsy or on cardiac MRI. And it sounds like of course these these features or presentations of myocarditis are reminiscent of the hot phases that we talked about earlier. As I think I mentioned earlier, when we this leads to inflammatory cardiomyopathy in some cases with about 1/4 of the cases having residual ventricular dysfunction, which looks like a dilated cardiomyopathy picture. 25% of cases are complicated by both heart failure and arrhythmias and 50% may have a completely spontaneous recovery. And something to consider as well is that about three to 12% of autopsies attributed to sudden cardiac death actually have features of myocarditis. So again, something important to keep in mind when we’re thinking about myocarditis as a as a cause of this inflammatory cardiomyopathy predisposing to ventricular arrhythmias, there’s acute myocarditis, chronic myocarditis, complicated myocarditis, which means that there are other features such as left ventricular dysfunction, ventricular arrhythmias and heart failure in the complicated versus uncomplicated type. And so knowing what we’ve reviewed so far, we can see that there’s some overlap between arrhythmogenic cardiomyopathy, myocarditis and inflammatory cardiomyopathy as well as dilated cardiomyopathy. So we’ve got this arrhythmogenic cardiomyopathy which is characterized by scarring and fatty infiltration, both of which can cause inflammation. We know that DSP cardiomyopathy has those is known for those hot phase episodes which are reminiscent of what you can see in myocarditis and especially the acute episodes. And then we know that myo episodes of myocarditis can then lead to inflammatory cardiomyopathy which shares its features obviously with dilated cardiomyopathy such as pumping dysfunction and heart failure. So given that, it seems possible then that there could be an underlying genetic predisposition for either dilated cardiomyopathy or arrhythmogenic cardiomyopathy that is particularly sensitive to inflammation with the right exposure and creating this particular vulnerable environment. And on the flip side, some sort of exposure or the right pathogen can cause the inflammation that’s just needed to sort of be that second hit to trigger the onset set of cardiomyopathy in a patient with an already genetic predisposition. So since there’s overlap, it’s, you know, and it all kind of, yeah, it all kind of a little bit overlaps and there’s a lot of similar features. It seems possible that there could be some of these myocarditis cases that might actually have that underlying genetic etiology. And in fact, if you look at populations with of patients with myocarditis, you do find pathogenic and likely pathogenic cardiomyopathy variants in an important proportion of them. Depending on the study that you look at, the yield is actually anywhere from 8 to 67%, which of course is a huge range. Those smaller cohorts with pediatric patients, more severe cases is going to be on the higher end of the yield. And then those aggregate studies with a more heterogeneous population will have that lower yield of genetic testing. And this slide is a summary of a number of studies that have been published that have looked at cohorts of patients at various stages of myocarditis, some of those who have a family history of cardiomyopathy. And this is taken directly from a great review out of the authors from John Hopkins in the US and Italy as well. And although you may or may not be able to see it, DSP does come up quite a bit as a genetic finding in these specific cohorts with myocarditis. So there are two quick studies that from the table that I want to highlight in a bit more detail. So the first is this one by La Taye ET al, which is a study from 2022. And in the European group, they looked at 2 cohorts of patients with acute myocarditis. One had over 201, had over 300 patients and they compared them to a healthy control population and that wasn’t nomad patients. These were patients that specifically had a cardiac MRI to confirm that they had normal cardiac structure and function. They I actually identified A pathogenic or likely pathogenic variant in a gene associated with either dilated or arrhythmogenic cardiomyopathy in 8% of the cases compared to less than 1% of the controls. And interestingly, the arrhythmogenic cardiomyopathy specific truncating variants we’re seeing more often in the cohort with that preserved heart function and those were most often these DSP truncating variants. Also more typical dilated cardiomyopathy variants were seen in patients that had pumping dysfunction and often in more in older adults. And that most common finding were variants in the Titan gene, which again, if you remember from the beginning is the most common genetic cause for dilated cardiomyopathy. And I think that there is value in considering that this is probably an underestimate of the yield, the actual yield of genetic testing in these patients because only a a subset of genes were evaluated and FLNC was not included there. And we know that there are papers that have reported on FLNC variants in myocarditis populations. The second study that I want to talk to you about is with regards to myocarditis and cardiomyopathy variance by Monda ET al, which was a meta analysis of eight observational studies of patients presenting with myocarditis. They split up these patients either in pediatric or adult patients and whether or not they had complicated or uncomplicated myocarditis. When we look at the population itself, there was 586 patients in total, 517 adults, 69 kids. Then they identified pathogenic or like the pathogenic variants in 85 patients for a yield of about 14.5%. You can see the breakdown of the different genes in this sort of busy diagram. But the main point to take back to take out of this is that over about 50% of the likely pathogenic pathogenic variants were in genes of the sarcomere, most commonly Titan, that sarcomere being that contractile apparatus in the heart muscle cell. We talked about that a lot in the OR a little bit at the beginning I should say when we talked about dilated cardiomyopathy. And then the second most common court sort of gene category was variants of variants in genes encoding that desmosome. So and DSP specifically being the most common genetic finding there. The yield of genetic testing was actually significantly higher in children compared to adults and higher in cases of complicated myocarditis versus uncomplicated myocarditis. And the breakdown of genes again was different in the complicated versus uncomplicated myocarditis. In the complicated myocarditis, we saw more of those sarcomere dilated type cardiomyopathy genes and in the uncomplicated ones we saw more of the desmosomal genes, specifically DSP. So I think, you know, this study has, I think generated a lot of buzz because of the data that has come out of it. Of course, every study has limitations and there’s a really good editorial that was published on this specific study outlining some of the limitations, but you know, more and more data is coming out about this. So it’s, it’s really interesting. And so if we think about, OK, so if we find genetic, genetic variants in patients with myocarditis, what does it actually mean? A retrospective international study compared risk of death, ventricular arrhythmias and recurrent myocarditis and heart failure in patients with acute myocarditis with and without those desmosomal variants, such as DSP and the group with the desmosomal variants and acute myocarditis had a significantly higher number of cardiac events compared to those without a genetic variant or desmosomal variant. Other reports of patients with myocarditis and DCM variants demonstrated that these patients tended to have the worst outcome, specifically a higher risk of arrhythmias and sudden cardiac death than those without DCM variants after an adjustment for age and sex. And then finally another outcome where with patients with myocarditis and cardiomyopathy variants show that they had a higher mortality risk than those without cardiomyopathy variants. And so these data would suggest that knowing again, whether or not a patient with myocarditis has an underlying genetic etiology is really important for diagnosis and prognosis as well. And so increasingly, genetic testing for all patients with myocarditis is being published in guidelines. Earlier in 2025, the American College of Cardiology specifically addressed genetic testing for myocarditis in their most recent expert consensus consensus statement stating that genetic testing should be a part of the work up. They do recognize that genetic testing can, you know, is not always accessible. So to potentially prioritize that testing for those with evidence of, you know, a genetic cardiomyopathy or hints of a genetic cardiomyopathy such as a family history. And then six months later, the European Society of Cardiology also published updated guidelines on the management of myocarditis and indicated that genetic testing should be considered in patients with definite myocarditis. Again, if there were features that was potentially more suggestive of genetic underlying etiology such as specific findings on MRI, recurrent disease, family history and so on. And so we can remember that knowing the precise genetic cause is critical, particularly if a patient has a variant in one of those high risk genes which we have seen for example DSP come up a lot in myocarditis because there are specific gene, gene specific management guidelines with regards to to treatment and potentially IC DS as well. So what genetic testing should be offered? Let’s watch this space. I haven’t seen any formal recommendations published to date. I’m happy to be corrected though. Reading a couple of papers on this and editorials, it seems that folks are recommending obviously the cardiomyopathy genes to be included, neuromuscular disease genes, potentially those neuromuscular diseases that present with a cardiomyopathy or that can have a cardiomyopathy as well as some immunology related genes. So interesting to see what comes of this and you’ll be very interested, very interested to see how things unfold. And so in the last few minutes of today, want to shift away from guidelines and and what we’ve talked about previously and talk a little bit about gene specific therapies, notably gene therapy clinical trials that are ongoing for patients with cardiomyopathy. And this just really adds one more reason for why genetic test results can have a significant an impact for affected patients. This image is from a great review by cardiomyopathy experts in the US and Italy. There are three main approaches to gene therapy that are outlined here today of in this image I should say, we’ve got the gene replacement strategy on the left, gene silencing on the middle and direct genome editing on the right. So gene replacement therapy, that first sort of image that you see there involves using an adeno associated viral vector to deliver a wild type cDNA in an attempt to increase protein expression. So this strategy is really being used for genes where hapl insufficiency is the disease mechanism. So patients who have these nonsense frame shift or or more generally speaking loss of function variants, we’re seeing trials with patients with MYBP C3. Variance PKP 2 DMD and LAMP 2 the gene silencing therapy is better suited for more of a dominant negative mechanism. It can involve delivery of a non coding inter interfering RNA to sort of silence the transcript that has that deleterious variant. And one sort of thing to consider with the gene silencing is that we need to make sure that we it needs to be ensured that the if one allele is completely silenced that sufficient protein is being expressed from a wild type allele to sort of maintain normal function. So that’s something to something to consider. And finally, direct genome editing specifically involves the potential to remove a small piece of DNA sequence that includes A variant and takes advantage of technology such as CRISPR and CAS 9. And thus far the trials that are utilizing gene replace so far like the gene replacement therapy is the strategy that I’ve seen being utilized in ongoing trials for patients with cardiomyopathy. And so this is a summary of some of the active gene therapy clinical trials. This list was published, you know, earlier this year, so may not be completely up to date already. From this particular paper, I’ve actually only included the trials for specifically for cardiomyopathy patients. And so far there is some outcome data for the trial out of Tenaya Therapeutics who developed TN2O1. You can see that they’re under therapy which is an adeno associated virus based gene therapy, sorry gene replacement therapy designed to deliver MYBP C3 to cardiac myocytes. Preclinical style. Preclinical studies for this particular trial show that the TN2O1 restored protein levels, improved hypertrophy and cardiac function as well as extended survival in those homozygous null mice. So some promising early results and then my peak is the first, first human trial to assess the safety and efficacy of TN2O1IN symptomatic adults with MYBP C3 associated hypertrophic cardiomyopathy. These patients are all patients with truncating MYBP C3 variants. We, they were assessed at one year and then at five years, 2 cohorts were receiving different amounts of vectors. So the trial is obviously continuing, ongoing. And the endpoints that say sort of looked at to to be able to see if it was making a difference was whether or not protein levels were increasing, whether or not there was a reduction of biomarkers, which were an indicator of myocardial injury. They measured the left ventricular mass, left ventricular wall thickness, and the ejection fraction. If we remember, we didn’t talk a lot about HCM today, but from the beginning, that thickened heart muscle. So the initial results from a Phase 1B2 trial was that TM2O one was actually well tolerated by the patients and they did see increased protein levels as well as reductions and stabilization of biomarkers as well as reductions of left ventricular hypertrophy measures. So some promising early outcomes. And although this is just for one particular trial, it’s encouraging to see that there are lots of trials popping up for various genes. And hopefully we can see more as time goes by. Gene therapy has not had an easy road, and hopefully this is continuing to go on the right path for these patients. And so that was a bit of a quick whirlwind into why genetic testing today matters really more than ever. And I’m hope I’ve demonstrated that for you firstly by showing that genetic findings are seen in more cardiomyopathy cases than we previously appreciated and that genetic testing is crucial for making specific diagnosis, leading to gene specific treatment or management and informing prognosis. Although there’s a lot of evidence out there that’s showing the importance of genetic testing, we do know that there are recent studies that have been published that has showed that these that genetic testing is really underutilized. So hopefully, again, the more that we can demonstrate the real gene specific tailoring that’s occurring, the more that we can get these patients tested and in through the right management. So genetic testing is in cardiomyopathy is really more crucial and more important than ever. And I thank you so much for coming today and for all of your attention. Happy to take any questions. Thank you, Julie. Excellent presentations. Yes. So then we go to the questions. OK, I’ll start with the first one, the last Blueprint genetic have any data available on what percentage of patients with myocarditis sent sent to testing in your laboratory have disease causing variants? Yeah. I, I mean, I wish that I did have data to share. Unfortunately, I don’t know that that’s something that I will be able to ever really demonstrate on our end as the laboratory because we don’t get consistent clinical information. So we don’t, we don’t know if patients do have myocarditis when they’re sent in for testing up consistently because it’s not always indicated on the requisition. And so we can’t keep track of that in sort of any kind of way, unfortunately. I wish that there was a way for us to be able to evaluate that because we could just add more, more information to the growing body of literature around this. But at this time, I don’t have any data to share and I’m I don’t know how I would be able to share that in the future. But I guess never say never. We just don’t have a consistent way of collecting those clinical diagnosis. OK, Then the next one, how reliable are calculators for the prognosis for patients? Oh, that is a great question. And I, I did mention throughout the presentation that I’m not a clinician. So I, I actually don’t know the answer to that question. I think that would be something that would need to be discussed. I mean, you can always shoot an e-mail to one of the authors that has generated the risk calculator or speak to someone who has expertise in rhythmic genic cardiomyopathies to determine how reliable those are. I know obviously everything has its limitations and the right, the right gene needs to be considered the right risk factors and whether or not these things get repeated over time. Unfortunately, I can’t answer that question because I don’t I don’t see those patients and I’m not a cardiologist, so I don’t do that risk assessment. But great question and hopefully you can find an answer. Yes. OK. Then the next month would would you do genetic testing for HCM or DCM at any age? That’s a great question. I mean, the guidelines would suggest that age would not be a factor that would preclude from offering genetic testing, obviously considering whether or not there are other explanations for the cardiomyopathy that you’re seeing. Also, we know that genetic testing is not always fully accessible, but if it is accessible and there is an opportunity to do genetic testing, obviously I’m not going to make any specific recommendations, but the guidelines would would absolutely say that patients with hypertrophic cardiomyopathy or dilated cardiomyopathy, genetic testing is a published recommendation. So I would look at the the guidelines to get some more information on that. But we do know that genetic test results can really make a difference. So, OK. And then the next one, patients with DCM phenotype and long HX of of hypertension, when should they be tested, tested if no suspicious if HX, so a patient with hypertension and hypertrophic cardiomyopathy. Yeah, again, unfortunately, I wish I could answer that question because I am not a clinician and I’ve just sort of summarized some of the information in the guidelines today. I think there’s probably some really solid information published about when to consider whether or not that that hypertension is a significant enough to cause HCM. Also you’d want to you know, consider whether or not there is any kind of family history that’s suspicious. You can always send your patient for genetic counseling and see or refer to A to a clinic or a multidisciplinary clinic that sees some of these patients with cardiomyopathies to really have once over a family history reviewed some in more information about the history to see if it’s suspicious. So that would be a suggestion that I would make would be to take a look and see if there would be a place to refer your patient if you’re if you’re not sure, OK. Is there a push towards this or VGS in CN patients based on the limitations of panel fennel based testing and high boost results with panels? That’s a great question. And I guess I mean just to tackle the US side of the question first. I think it, it really depends on you know, the lab that you’re choosing to have genetic testing, what their reporting policy is with regards to what variants are actually going to appear on the report. So I think there was, I think you know, panels are, are ones where we’ve got a specific defined set of genes and you know, by sending in a panel you’re asking the laboratory to report out anything that we think would be clinically relevant from that set of genes for your patients. And obviously the lab is not the clinician, right. So we’re going to, you know, tell you any, any variants that we think are could possibly explain the the presentation in your patient. And of course that’s going to what’s going to actually include it. Again, like I said, it’s going to depend on the laboratory that you choose. I don’t know if there’s really more of the USS then there is on exomes. I know there was a paper published on this and of course I’m drawing a blank exactly on what the outcome of of that was. But in terms of genome and exome for some of these patients, that’s a really good question. I haven’t seen anything specifically in the guidelines. I think some guidelines caution with using exome or genome for some of these patients, but I think there may be a place for it in some patients. For example, you’re really young kiddos who present with a very severe form of cardiomyopathy because those that differential diagnosis in such a young patient is really broad, right? So sometimes it’s hard for a panel to be curated completely up to date and up to all the possible presentations of cardiomyopathy. So potentially exome or genome, as long as it’s, you know, giving you a significant advantage over the exome that you’re using. Could there could be a place in some of these families also, if previous panel testing has been negative, you know, is there is there a use for exome or genome potentially for new gene discoveries? There’s also been a lot of work that has shown that some non coding variants are implicated in various types of cardiomyopathy. So whether or not the panel that the patient previously had, if you’re reconsidering retesting has non coding variants included, I think that would be important. So yeah, it’s a really interesting question and I’d be curious to know what clinicians out there right now are are considering when they’re deciding on exome versus a panel. That was a long winded answer. Yeah, thank you, Julie. So you’re welcome presentation and thanks for answering all all these questions and thank you for everybody for attending the webinar today. So the recording of the webinar will be made available and it will be sent to you by e-mail. So thank you again and I hope you have a great rest of the week. Thank you, thank you, Taina, thank you everyone. Have a wonderful day.
