 Well, it really is an honor to be back here and to be acquainted with Dr. Willerson and talking with Dr. Stainback and Dr. Navarriho and meeting with Dr. Coulter. I see Dr. Delgado, so lots of familiar faces and had the pleasure of meeting with Dr. Lucianowski and Dr. Angelini this morning, and so I spent many days in clinic over in their office, so this is a special place and at the time I was here, 2001 to 2010, absolutely spectacular and hopefully you value the opportunity that you have here because the Medical Center cannot be rivaled anywhere else in the world and to have thought leaders like Dr. Willerson is an absolutely amazing opportunity, so it's really an honor to be here and I wouldn't be where I am today without the foundations that were developed in this very hospital, so thank you once again and it's a pleasure to talk to you. I want to speak a little bit about hypertrophic cardiomyopathy today. Some of this will be relatively basic, so I apologize for those of you that maybe it seems a little easy, but at the end I think you'll see some things that are very novel that will really be transformative I think in the way that we manage hypertrophic cardiomyopathy in a non-invasive way which is obviously very exciting. These are my disclosures and I do fair amount of consulting and so I wanted to show this slide just so everyone remembers you know the big statue outside and the hall so this was when I was a young attending I actually looked you know happy and I was walking around and doing good things so you obviously recognize the gentleman and the other white coat and the two people there my father-in-law who's a native Texan and his wife who's a native Texan so one day I was at work and they were in town they came up to see the place and my father-in-law said you know all my life I've heard about Dr. Cooley do you think that I could meet him and I said you know I have no idea we can ask so we walked up to his office and he was there eating his bowl of soup as he usually did and I said sir I know this is a completely unusual request but would you mind if we took a picture and he said absolutely not and so Susie Lanier took this picture so obviously a well-known figure in this institution and Dr. Cooley was just as nice and in the a perfect gentleman and honored this request which was completely out of the blue and my father-in-law has publicized this obviously you know throughout the world's like you know I know Dr. Cooley I know Dr. Cooley and so just an awesome place at that time and my very first circulation publication Dr. Cooley was a co-author and Dr. Lushanowski was a co-author and it was a special time Dr. Willerson was the editor-in-chief of circulation and this was just a thriving powerful institution and obviously it still is and so you guys are very fortunate to be here and I was very fortunate to have those opportunities so with that I usually like to start my lectures especially grand rounds lectures with a few questions and hopefully I'll be able to answer them for you as we move through so what is the reported prevalence of HCM in the general population so one in fifty one in five hundred one in fifteen hundred or one in ten thousand was a typical mode of inheritance from a Mendelian perspective is it autosomal dominant recessive x-linked or it's not genetically transmitted maybe that's a possibility systemic anti-quagulation should be strongly considered in patients with HCM and AFib true or false and then lastly this will be interested Dr. Angeline already knows the answer but patients with hypertrophic cardiomyopathy should be restricted from all competitive sports so keep those in mind so we'll go through this so as Dr. Willerson alluded to this is why I spend my time as genetically triggered cardiovascular disease specifically myopathies and aortopathies while I was here we had the good fortune of working obviously with Dr. Cicelli, Diana Milowitz so you know method the Houston is obviously a mecca and groundbreaking place for aortic disease but of the five types at least in the United States that we identify as heritable forms of cardiomyopathy or hypertrophic which we'll talk about today dilated LVNC which is where most of my research and clinical interests lie restrictives and then arrhythmogenic cardiomyopathy which was formerly ARVC but now we're understanding there's an ALVC in a biventricular so knowledge on that disease is evolving and this is kind of a takeaway slide if you can memorize this you'll know most of what you need to know for hypertrophic cardiomyopathy at least currently so the genetic triggers we'll talk a little bit more about but typically there's sarcomeric based so I know it's been a long time since physiology class I'll show you a cartoon about what I'm talking about rassopathy so that may not be a term that's familiar to you but that's things such as noon and syndrome Costello syndrome metabolic disease neurodegeneratives like Friedrich's and then mitochondrial disease which we have world experts here in the medical center on mitochondrial myopathies symptoms are quite variable we'll talk a little bit about that and obviously they're very different in a child than they may be in a 22 year old or even a 50 year old the current treatments beta blockade calcium channel blockers myctomy AICD I think are going to be maybe fading a bit once I show you some of the data that we have at the end and then as I said you know it is genetically triggered and it is a dominant mutation typically in the sarcomeric world and in most of the other syndromic forms of inheritance except for some isolated examples that we'll talk about there's obvious cellular derangements including calcium is handling and the survival and there's some nice data that the marines have published but in the contemporary world if you are managed in an hcm center of excellence quote unquote your outcomes can be that of the general population so it's very important that someone knows about hcm if they're going to manage your care so it's very genetically heterogeneous and and as you'll learn you know we try and keep it simple for now when we talk about genetics and disease and we always try and say you know this one gene is responsible for this phenotype right the more I do genetics I recognize that that's absolutely incorrect most of the time remember we're talking about one gene in the milieu of 25 000 genes and that doesn't include intronic data that's purely exons so it's oftentimes that it may not just be one gene but you may have multiple genes that are involved so that complicates things a bit if you try and do genetic testing but it's something that we still do and it's still a strongly recommended guideline based therapy or a strategy is to do that so we still pursue that but sometimes people may be completely asymptomatic and as you know many adolescent and young adult athletes the presenting symptom they have a sudden cardiac arrest so it's an important disease and I try and stress to my primary care docs this is a disease you do not want to miss if you have any concern refer them period because this could result in a catastrophic outcome and while here in Houston you know I would see people from all the professional teams and the collegiate level teams and it's a serious disease and it's a hard thing if you have to tell someone you can't play football basketball whatever the case may be but you really have to think about it in a very you know in a very thoughtful way you have to respect this disease it can be from infancy which is usually mitochondrial mediated up to middle age and we used to think classically that if you made it up to the age of 30 you would never manifest the phenotype of HCM which is actually not correct so I've actually diagnosed people who've had normal echocardiograms who manifested the phenotype in their early 50s so the idea of lifelong screening is something that I actually personally promote genetic causes are multiple and the penetrance can be variable so that's back to how do you present phenotypically so could it be that you have very mild asymmetric septal hypertrophy no obstruction and otherwise do well or could it be that you have severe obstruction you have concomitant atrial fibrillation all those things you can have very severe phenotypes and at the worst end of that spectrum is sort of our burnt out hypertrophenotypes that ultimately may require a transplant so it's a it's quite a variable disease which makes it interesting from my perspective obviously Joe and Ray recognize there are different morphologies that you can see on imaging and the prognosis is quite it's quite broad and much of it the underlying piece is that if you have isolated HCM and you're managed in a good center as I said you're going to do well but if you have concomitant mitochondrial disease or if you have concomitant Friedrich's ataxia or something like that then that obviously changes the the trajectory or changes your longitudinal possibilities for a long-term outcome clinical manifestations I think everyone is aware obviously diastology is an important consideration in HCM and as I said we do have maybe 10 15 percent of our HCMs go on to this burned out phenotype quote unquote which more of a dilated phenotype you can imagine the managements for that obviously is very different than someone who has HCM who's thick and has hypercontractal function sudden death is the thing we want to avoid the systolic dysfunction we've talked about and then obviously the inherent valvular abnormalities Mayo has made a strong living off of this about myectomy and concomitant valve interventions and chordal reattachments and those sorts of things so you have to be cognizant of that when you're looking on imaging so I want to bring this up just so everyone kind of understands the literature so I trained with Dr. Tobin as Dr. Willerson mentioned who doesn't agree with this slide so I'll tell you that ahead of time but there are some people that feel very strongly about this so so when you think about LVH and you're thinking truly about hypertrophic cardiomyopathy are they all the same regardless of their etiology so someone who you just put up the echo and Dr. Stainback says well that's obviously hypertrophic cardiomyopathy but then I say well the patient has Friedrichsetaxia is that really hypertrophic cardiomyopathy so if you talk to other leaders in the field like Dr. Seidman and Boston or others they'll tell you that that patient has an HCM phenocopy so they're not classically hypertrophic because they don't have sarcomerically mediated disease we think on the other hand it's sort of a final common pathway and the phenotype is the phenotype and we manage them the same way so it's just something to keep in mind and I'll talk a bit more about this with a specific disease in a few minutes but just be cognizant that when people talk about HCM they are typically talking about sarcomerically mediated disease and I'll show you more about that in a few minutes so one of your other questions about prevalence so the reported prevalence is one in 500 I can tell you as a practitioner that's an underestimate because we don't screen everyone right and many people are completely asymptomatic so they go through life and they may harbor that mutation have a very mild phenotype and never know about it so you know they're not going to get triggered for an echo unless someone's concerned about a pathologic murmur or unless there's a family history or an EKG abnormality so we are underestimating the disease as we are for all genetically triggered cardiomyopathies there is a slight male preponderance it can present at any time as we've talked about but those critical times are adolescents and early adulthood it currently accounts for almost half of our pediatric cardiomyopathies the inheritance or incidence I mean is about 0.47 per hundred thousand but it is a frequent cause of sudden cardiac death so you can't miss it if you see a newspaper headline about someone dying on a football field the soccer pitch this is the disease that's primarily responsible for that and then you get into other things like coronary anomalies myocarditis channelopathies but HCM is still the driver for most of that disease and it's really the classic Braunwald definition and Willerson definition if you look at the textbooks unexplained LVH so no systemic hypertension no end stage renal any of that sort of business and if you look under a microscope the disease is very distinctive so it's myocyte disarray so if you think about your myocytes they're organized in a very structured parallel fashion I consider HCM as if you had a bunch of pixie sticks if you remember what those are and you throw them on the ground they all kind of go like this right well that's kind of what these muscles look like under a microscope so you can imagine the ability to have adequate relaxation is inherently compromised so that's just something to think about from a basic science perspective phenotypically as you all know they're hypercontractal typically and when you see that contractility going down you need to pay attention to that patient they have reduced compliance and as I said they can present essentially at any age and the key word of all this is that it can be progressive okay and hopefully one of the things that you'll take away and we'll talk a little about the genetics is that this is a lifelong concern if you harbor the genetic trigger okay so that's why we do genetic testing because you never know when things are going to crop up and unfortunately many people will have a family history of HCM and you know the appropriate way to look at that is what's called cascade screening so that means we screen all first-degree relatives so parents siblings and children and unfortunately many of the children will they may see a cardiologist they may get an echo and it'll be normal not surprisingly and the cardiologist will say you're completely fine you never need to see a cardiologist again that is unequivocally the wrong answer so the main thing that you should take away is if they are at risk they do benefit from lifelong screening so remember that in your clinics they may have a normal phenotype now but in two to three years it may be completely different and we're talking about a disease that you could if you're monitoring correctly you can prevent a sudden cardiac death so keep that in mind echo I won't bother too much with all this I'm sure most of the audience is very familiar obviously we're paying attention to atrial size which factors in sometimes into risk factor calculations but extreme phenotypes you know obviously you can see from across the room but there are more subtle phenotypes that you have to pay attention to and this is a classic example this is you know a hypertrophic cardiomyopathy and I'll tell you you know and if I were to show this image to anyone they would say that's HCM and I would you know but the important thing is this is actually a patient with noon and syndrome so they had extreme septal hypertrophy so that's the other part of this if you have hypertrophic cardiomyopathy consider a broader differential so if they have a sarcomeric mutation that's fine you worry about the cardiovascular system but let's say they have noon and syndrome or they have you know if they are a Friedrich's what else needs to be done well there's a lot that needs to be done because there are other organ systems can be involved and they need appropriate screening and surveillance so keep that in your mind when you're looking at these patients for surveillance because it's not just about the heart necessarily it can involve other organs and systems as well and obviously this is just images depicting obstruction which is something that we obviously try and mitigate so most centers that I that I think are high level hypertrophic centers leverage two types of imaging so they're going to do echo and stress echo so they're looking for gradients that may not exist at rest but can be provoked with stress which is important because that leads you down some treatment pathways but also using CMR and so what in my time at Texas Heart Scott Flam was here and he's a world leader in cardiac MRI and we spent a lot of time talking about this disease with him but there are a lot of obvious reasons to do it that I probably don't need to tell everyone in the audience about our main thing is we want to characterize the myocardium and I'll explain more about that in a few minutes and there's no radiation so you know longitudinally you can continue to do this do this do this do this do this and it gives you a lot of data so this is the classic thing that's becoming a little more antiquated surprisingly enough but the idea of can we identify a surrogate of scar and we can using gadolinium and everyone in the audience is familiar with that so you look for late gadolinium enhancement the problem is gadolinium is increasingly found to have some potentially toxic effects so the exposure to gadolinium will probably continue to decline and potentially be taken away in the future by the FDA because it does lead to some residual staining in the brain and other areas and no one knows what clinically what that means so let's say I'm doing cardiac hemorrhage on a 20 year old that's a lot of gadolinium exposure over time people are going to say is that really safe or not and I don't think anyone knows the answer but there are data that are increasingly being reported so the question is well what can we do to get around that right what if I don't have to put an IV in and what if I could do it without any kind of contrast agent and it turns out you can so this is something that scott was working on a little bit while I was here but it's the idea of t1 mapping so you can easily you know upgrade your software system in your MRI suites to be able to do this and it really is very nice because you can do what's called pre-contrast t1 mapping and I'll show you some images in a few minutes but they actually are quite comparable to gadolinium administration and as I said it can be performed without contrast and this is interesting because it don't it not only gives you information about intercellular space but it also gives you information about the extracellular space such as edema or deposition so remember some diseases are not just about sarcomere some are deposition based disease such as pompe for example is a classic example and I'll show you one more in a few minutes so this these are some MRI images on patients with a variety of conditions so you can look at the top and you see normal post-MI diffused fibrosis or someone had significant AS replacement fibrosis also from AS and then on the far right is hypertrophic cardiomyopathy and you can see that native t1 which is in the middle those numbers go up so you started about 1100 which would be normal but as those numbers start to go up it's very consistent with myocardial pathology and you can see at the bottom the post-contrast t1s very much match up to the native t1 imaging so the idea do you have to give contrast is really in question you probably don't if you have the ability to interpret this well and these are some of the data we're starting to acquire on all of our cardiomyopathies but I think it has very special interest possibilities in the area of HCM and the one I want to draw your attention to is ECB so it's extracellular volume how can we calculate that and interestingly enough you actually can so you can do this on an MRI all you need is a concomitant hematocrit and that's pretty interesting and I'll show you why in a few minutes but up till now we really haven't been able to distinguish that sort of a characteristic when it comes to characterization so as in many of the diseases we deal with you get expansion of this extracellular volume and you can see this both in isolated systolic failure isolated diastolic or an accommodation which is you know quite common as you know and it's really regardless of the etiology and this this process actually offers prognostic information so we'll talk a little bit about risk factors for sudden cardiac death and it's typically based on LGE data now I'm talking about a completely different technology that we could leverage to risk stratify people with HCM and recently MR techniques have been developed to do this so this is an MR map of ECV and you can see the post mortems on the right and B and C and it's very well characterizing the extracellular space non-invasively and as I said all you need is a hematocrit and a calculator to be able to do this so this is kind of the next area of where we're going in cardiomyopathies in general and the data are there you just need a little bit of software to generate them but once again it's further characterizing what we would call the phenotype of HCM and these are some data that came out now these are on ischemic myopathy patients you can appreciate as your ECV changes as it goes up your mortality is strongly affected so if we could collect data and help leverage these data in the management of HCM I find that to be an exciting opportunity and we're doing it in a specific disease that I'll talk about in just a few minutes so genetics behind this disease evolve every day essentially new mutations are identified so we have a set number of genes but remember mutations can occur anywhere within those genes so you thought you come up with new mutations being reported at least potentially causative alleles that need to be verified as pathogenic mutations but it's an important thing because it gives us an understanding of mechanism and potential targets for therapy and it is Dr. Wilson said this is something that we spend a lot of time on so just to come back you know to general science back when you're in grade school you know the the peas and how are they inherited and traits that are passed down well HCM classically unless you have a mitochondrial disease or something else is typically autosomal dominant so what does that mean well as you remember it means if you harbor that mutation it's a 50-50 that you pass it on to your child and that 50-50 recurs with each child right so it's a coin flip every time every time every time so that's an answer to another question is that's the typical mode of inheritance for the fellows this is the thing you need to know for the boards is what are the typical mutations associated with HCM the most common is MYBBC3 next most common is MY87 or beta minus and heavy chain these comprise the majority of the cases that have HCM with a genetically identified trigger so remember that as we said nonsarcomeric genes are reported and then some of these genes are responsible for things like Pompeii we mentioned Noonan we mentioned and Fabray and this is a more detailed list of some of those genes and some of these proteins you're familiar with right troponin tropomyosin so you've heard these they're actually implicated in hypertrophic cardiomyopathy so obviously you use them as diagnostic tests and your stemmy evaluations and those sorts of things but they are very helpful when it comes to HCM understanding and then there are some these Z-disk genes which I won't spend too much time on but I want to come back to the nonsarcomeric piece these are the ones that are evolving so if you read you know Cirque Jack New England Journal there's a lot of focus on hereditary amyloidosis so specifically a thing called HATTR and that's mediated by transthyretin and actually the reason it's important because there are evolving therapies that can actually make a difference in that disease which you know can be a very difficult disease to manage so remember that so amyloid there's a potential possibility but the other one I want you to take a look at is a disease called Fabray and that's by galactosidase alpha and so that is also someone who can manifest with a hypertrophic phenotype so I want to spend a few time a few minutes on that because that's another board question that you're going to see so keep this one in mind so this is a progressive disease it actually starts in utero and it's a deposition based disease so it's basically the lysosomes if you remember back you know sort of the garbage cans of the cells if you will where you're depositing stuff digesting removing when those are dysfunctional bad stuff accrues essentially and that leads to cell lysis fibrosis different sorts of things and it's all driven by problems with alpha-gal so it's a very debilitating disease and you can imagine over time deposition is going to continue to accrue accrue accrue so you're going to manifest pathology and typically that's in the brain the heart and the kidneys so keep that in mind and they can be life-threatening complications and we manage a lot of the fabray patients in the country because there's just not a lot of knowledge about this in most cardiology practices and this is kind of the graph that shows you the progression of the disease and as I said prenatally it's already the deposition is already occurring but during childhood you'll start seeing some manifestations that are very nondescript so abdominal pain they suffer from anhydrosis so in houston they would do horribly in the summertime go outside they can't sweat so they can only play for a minute or two and they're back inside so those are classic childhood presentations and then you start getting tissue involvement specifically kidney so you start seeing proteinuria and then you start seeing cardiac involvement and i'll give you a slide in just a minute to talk about that which leads to premature death and most people if they did an echo and saw HCM really wouldn't think about fabray so they wouldn't say you have problems with anhydrosis they may not check your analysis those sorts of things but this disease matters and this gives you sort of a timeline of the disease that develops and cardiac dysfunction is the main one that's the leading killer in this particular disease we are wondering like well why am I talking about fabray well this is the only disease when we talk about HCM that actually offers a potential therapeutic strategy that could in some ways at least reverse part of the disease it's not curative it's not gene therapy but it can actually reverse some of the pathology that we see and that's in the form of enzyme replacement therapy so they're missing an enzyme we give it and then hopefully gets intercellular and actually functions the way that we want it to and so these are the things that you can see in fabray they can be cardiac they can be vascular so your your board question is probably going to be you know a 35 year old comes in with recurrent strokes and you notice hypertrophy on the EKG and the echocardiogram and there's a strong family history of similar so early strokes and they're also noted to be suffering from stage four CKD something like that think about fabray that's the answer okay if you see early stroke early hypertrophy hypertrophic disease and concomitant renal disease the answer is fabray so keep that in mind and the other part so this was back to what we do from a research perspective is that this we were talking about those t1 scores and the word normal is quote unquote this is the only disease that we know of where the t1s go down so you don't have to be a rocket scientist to look at the mr date and say i think that's probably fabray disease so that also makes it a little bit easier if you leverage that technology and this is that t1 mapping which you can pre down the left is normal and in the middle you can obviously see lighter colors some blues and yellow is very different than that circular green you can appreciate how that matches up with the late gadolinium enhancement by classic MRI imaging so just something for you to take away so when i see someone with hcm i'm typically concerned about two or three things so first is are they symptomatic okay so that's typically where management is geared and we'll talk a little bit about that second is i need to stratify them for sudden cardiac death risk because that's going to be the that's the main theme and that's what we really need to take care of and then other things that we need to be concomitantly they're potentially associated about 20 25 percent will develop atrial fibrillation about 25 to 30 percent have obstructive sleep apnea so there are other things that you have to think about to watch for down the road as you manage these patients and this is from bernie gers this is a guideline statement that's a little bit antiquated hasn't been updated in obviously in a few years but this is kind of the pathway of how we deal with patients and it really that first line is triggered by whether you have obstruction or not and it actually isn't just obstruction but it's typically obstruction associated with symptoms and that's when we talk about using medical therapies such as beta blockers or calcium channel blockers or disappearamide so that kind of gives you an idea about the flow and the continuation of that diagram is here if they continue to have symptoms and you've done all you can medically at least in the current era then you would consider other therapies such as myectomy or consider alcohol septal ablation so houston was a big driver of alcohol septal ablation over a thousand cases were done at Methodist so this was a large area for that and my argument's always been I don't really think we need it I think we can manage these patients medically so I've probably seen you know 3000 4000 hypertrophs in my career at this point and I've sent less than 20 for my myectomy whereas if I were at the Mayo Clinic everybody gets in my so it's just the difference in philosophy we feel strongly and my mentor in this Dr. Tobin felt strongly as well and Frank Smart who was here as well so that you can actually manage these patients medically and you can that's been our clinical experience and I'm going to show you some day that we can actually do a better job of managing them from a non-invasive management strategy so this is back to our other question participation competitive or recreational sports the answer is no you can look on the right for things that are low risk quote unquote that you can do but football basketball baseball all those things are out so typically we tell our patients avoid burst activity and avoid isometric exercises so anybody that's in the sport like football is going to be lifting weights not a good thing you already have a hypertrophy heart and let's put some increased afterload on that that is not a good thing long term so that's the answer to one of our other questions so we stratify in the US and I'll tell you about the European system in just a minute but these are the classically accepted ways to risk stratify someone for potential need of ICD okay so non-sustained VT which as you know sometimes is hard to document but in the current era with loop recorders is becoming easier and easier extreme lvh so typically greater than three centimeters a family history of sudden cardiac death typically a first-degree relative that is thought to be from hypertrophic cardiomyopathy unexplained syncope which is the one I get to deal with most of the time as which as you know is a difficult thing to adjudicate a hypotensive blood pressure response on exercise so typically obviously your blood pressure should go up but if you're manifesting obstruction your blood pressure is going to go down and then last one is the newest criteria where we leverage late gadolinium enhancement it's really about the volume of the lv that's occupied I think most people would agree that anything above 20% or so if the lv is occupied by fibrosis that is an independent risk factor for sudden cardiac death so this is the once again from from Dr. Gersh this is the sort of pathway that we that is recommended I can't say that I don't deviate from this occasionally because I do but this would be the classic approach and you can see the level of recommendation based on color coding this associated with the findings so and there are patients that don't get an ICD and honestly the overwhelming majority of our patients never get an ICD but you still have to reevaluate this every time every time they come to clinic you need to be redoing these tests and seeing have the risk factors changed while as typical European recommendations aren't always consistent with the US so Perry Elliott is a good friend and so he headed up the European sort of undertaking of risk stratifying hypertrophic patients and you'll see that many of these are similar one thing that's different though is the left atrial diameter so that's something that's a little bit different and age and so why do we care about age well interestingly if you have hypertrophic cardiomyopathy and you live so I saw a patient this week who was 75 and he was like should I get an ICD and I was like well in actuality your risks are going down as you get older so it sort of makes sense that you've lived with this disease your active quote unquote days are mostly behind you so is your risk really enough to warrant consideration of an ICD so that's a thoughtful discussion that you have to have but nicely enough Perry and his co-investigators provided us with a you know a very simple formula as you can appreciate but there actually is a website that will do this for you and you can plug in the the data and it will shoot out for you what they think the probability at five years will be for this particular patient from a sudden death perspective and this this is their their diagram regarding both primary prevention and secondary prevention secondary prevention is pretty easy you know someone arrests from HCM and they have a one-year or greater expected survival than they get an ICD the others are where you become a little more complicated and this idea of low risk intermediate risk and high risk I would say that that those lines are blurry if you do this long enough so these really well characterized little silos often don't exist in clinical practice so I personally take this with a grain of salt and so back to that you know we come back to the idea that really the population we're worried about are the kids and the young adults right those are the people that are dying a sudden cardiac death so I'm a part of an investigation called the primacy study so we had a question was could we apply these ESC guidelines that Perry had outlined and develop a calculator for kids so something similar but for a completely different population so we're doing all this right now and the data are actually quite compelling that we can so in children we try and observe the same sort of risk factors but a four-year-old wouldn't be expected to manifest a three centimeter septum right that doesn't you know from we use z-scores and pediatrics and so it's a very different thing when we're talking about how thick is too thick or what is extreme thickness in a young child it's a different cutoff so we have to think about that differently so we can't apply many of the standard criteria that we would use when we manage pediatric HCM so these are just some of the inclusion criteria and they're pretty straightforward but interesting as I say the data are interesting that it may work out the other thing is that there's been some repurposing of existing drugs in this disease so specifically ARBs and so we're a part of a trial that I'll talk about in just a few minutes but much of the pathology is related to TGF beta in this disease and so if we could interfere with that pathways or some way that we might disrupt some of the end organ problems that we see such as fibrosis and interestingly you can so most of the time if you think about HCM classically especially someone that's obstructive it is counter-intuitive to use an ARB or an ACE right because you're reducing afterload potentially changing the gradient but in these patients we've actually seen some compelling data so this is a study called Banish and it's being run by Carolyn Hull out of the Brigham and we're a part of this study but we're doing exactly that it's giving people with early evidence and relatively asymptomatic ARB and seeing what makes it seen if we see a difference or not and we actually are and this just depicts where we're impacting TGF beta and up there on the top left you can see that sarcomere that we were talking about a little bit but at a cellular level what are we really doing ultimately much of the disease is because of force and so if we can mitigate that in some way via an ARB we can disrupt the TGF triggering and ultimately hopefully impact the amount of fibrosis burden and then back to symptoms so I said that's the second thing that we worry about so this is the the cool part so this is cutting-edge science that we're very interested in so if you think about the mechanics from contractility you know you remember back to binding and you know grab and pull grab and pull sort of a thing what if we could interfere with that mechanism at the myocyte level and it turns out that we can so there's a drug called Mavicampton which is a small molecule that modulates striated muscles specifically myosin so it selectively targets myosin and it reversibly critical reversibly inhibits its binding to actin so by definition that would reduce force so the mechanism based on that we predicted well it could mitigate LV outflow tract obstruction and potentially could reduce hypertrophy if given long enough and this is back to the cartoon we were talking about and you can see representations of actin and myosin there and as I said all of these disease all of these proteins are implicated in cardiomyopathies whether it's a dilated phenotype a hypertrophic phenotype whatever the case may be and those junctions you see the desmosomal proteins are responsible for the arithmic genic cardiomyopathies just as an an aside so these are the data on Mavicampton and interestingly enough they're quite compelling and I don't want to spend too much time on this but this was a study in symptomatic patients with obstruction they were all greater than class two they had preserved ejection fraction and then there were some key exclusion criteria so we gave the drug for a period of time and then we stopped it during a washout period we had some very delineated endpoints mostly for this one it was a change in peak LVOT gradient at week 12 so they had been on therapy for that long but there were a lot of other endpoints that you can appreciate here and so it was a very small trial so you can imagine that's any statistician would tell you you're probably underpowered to accomplish anything which why I think the data even more compelling so this is what happened with LVO outflow tract obstruction is that you can see it either stayed the same or in many patients declined and when you drop the drug off it actually increased again so that's back to that reversibility endpoint this is also this the cumulative slide that once again you can see a nice decline with therapy and then a bounce back after you stop these are changes ejection fraction wise so you can appreciate there are some modulations of contractility and importantly we improved peak vo2 so that I think is a very important finding when we talk about symptoms quote-unquote with hypertrophic cardiomyopathy we improved disney scores and for many patients the majority of patients their functional class was improved and all of those you can see went back down after they stopped the drug so pretty strong argument that it was based on the drug looking at coax postulates or whatever you want to and then the anti-probian p's you see also declined and then went back up after stopping therapy and there were really no major safety events so that triggered the idea of well we need to do a larger study maybe we actually need to do two studies so that's what we're doing now is we're looking in patients both that have hcm with obstruction and hcm without obstruction so those two studies I'm going to talk about in just a few minutes but this is just sort of a summary that we really had good results that were statistically significant in a very small patient cohort which is very encouraging so that's what triggered these two trials are currently ongoing which are called explore hcm and maverick hcm so explorer is looking for 220 patients and we're still enrolling actively for this but we're looking for patients with obstruction and we're doing other things like rhythm monitoring and accelerometers and these are the inclusion criteria basically the main thing is that you need a significant gradient meaning 50 or more that's kind of the cutoff and the timeline as you can appreciate is not hugely dissimilar to what we did in pioneer and the primary endpoint is an improvement in their peak vo2s as well as a change in their new york art class based on those data that i was showing you and we also have nested a cohort that we're participating in where we do mr for many of the reasons that i explained to you earlier the other study is maverick which was in the patients with without obstruction which is actually completed enrollment and very similar outcomes they wanted to assess for safety because we hadn't looked at it in a patient with non-obstructive disease but many of the other objectives are very similar to explore so and once again this is a timeline so i don't want to bore you with this particulars of the study but what i want you to take away is this is a completely this is a paradigm shift in the management of hcm so that means we could take away beta blockers wrap them ill disappear might potentially and potentially take away the need for myectomy and or septal alcohol ablation with a oral therapy so that's pretty revolutionary and so we're very excited about this and we think that this held great promise for hcm so this is just that summary slide once again just to ingrain it into your mind so let's go back to our questions so what's the report of prevalence we talked about it's one in 500 but i would argue with anyone that it's probably one in 300 one in 350 but that those are the quoted data quote unquote what's the typical mode of inheritance it's typically autosomal dominance so that could also be a board question should you anticoagulate patients we didn't get a chance to talk about this but this is actually in the guidelines anyone with hcm and afib regardless of any kind of chads too vast or any other kind of scoring they all should be placed on systemic anticoagulation so keep that in mind when you see hypertrophic cardiomyopathy with afib and then should they play competitive sports unfortunately no and that's how I spend most of my time is telling people that they can't so in conclusion this is a clinically and genetically heterogeneous disease keep that in mind it could be very subtle or it could slap you in the face as i say you could see it from the parking lot it's a broad range of presenting symptoms but the majority of patients are asymptomatic so most of the patients that I follow are captured because of that cascade screening because a father died suddenly while exercising so I screened his siblings his parents and his children and we'll wind up finding other cases in many cases they have true pathology and i've had cases where they've passed out four or five times and their ER primary doctor said it's all vasovagal don't worry about it when actuality they were probably having a boarded sudden death events so that's how we acquire most of our patients with this disease targets for management obviously our our risk stratification I would say that's always at the top of the list symptom mitigation management arrhythmias and then treatment of resultant heart failure our risk continues to our understanding gets a little bit better and how we're going to sort of incorporate genetic data into that scoring system is an important question and as I said we can typically mitigate obstructive symptoms with medical therapy and with medicampim I think we'll be able to mitigate pretty much all of them a lot of focus and feeds on HCM we need more tools and we've talked about Valsartan does have some promise but these myosin modulators are really probably the next frontier when it comes to HCM management and as I said the overwhelming like 99 percent of the patients are going to do exceptionally well if they are managed appropriately very very few patients die of sudden death with HCM but it's always in a young person so it's a very impactful event so it's not like you're going to see lots of people in Houston dying from HCM but you will see a few and they're going to be publicized everywhere and it's important that you make sure you identify and manage those patients appropriately and we have numerous professional sports reports of this where they were being managed and told it was okay to play and then they die on the court there's a very famous one from Boston so you have to remember that and treat this disease with respect and if you have any questions send the patient to someone that you can actually has a familiarity with HCM and then lastly I would tell you that these are very good resources if you have a question about HCM they're a great way for your patients you know the first thing I tell any cardiomyopathy patient when they come to me is don't believe everything on the internet that's my first statement to them and it's absolutely true go to a reliable source and these sources are quite reliable so with that I want to thank you for your time it's been an absolute pleasure to be back at Texas Heart and I'd be glad to entertain any questions