C. Anwar A. Chahal BSC, MB, ChB, MRCP (UK), PhD, FACC, FESC joins Georgia Heart Institute as a Cardiovascular Grand Rounds speaker during the CME lectures for 2023. Dr. Chahal is the Clinical Director of the Inherited Cardiovascular Diseases and Consultant Electrophysiologist at WellSpan Health. Dr. Chahal also serves as a research scientist at the University of Pennsylvania, Mayo Clinic in Rochester, MN, Honorary Consultant Cardiologist at Barts Heart Centre in London and Senior Fellow at Royal Papworth Hospital in Cambridge, United Kingdom. Dr. Chahal discusses cardiovascular genomics and the role of precision medicine in the prevention of cardiovascular disease. To receive CME credit for this presentation, please visit the survey link.
Good morning, everybody. Welcome to Georgia Heart Grand rounds. We're so glad that you can join us this morning. We have an exciting program for you today before we get started. I'd like to recognize that grand rounds is provided to you by Georgia Heart Institute with the generosity of grants from our industry partners. The planners have disclosed no relevant financial relationships with commercial interests to claim cmi credits for today. Be sure to take our survey at the end of the program. If you're viewing online, the link will be posted into the chat. If you're here in person, you will receive the Q R code at the end of the session. So be sure to grab one. Also, be sure to sign in. If you didn't sign in when you get here, sign out because if you don't sign in, then it's like you were never here and it's difficult to claim credit, so be sure to do that. Um And now I would like to ask Dr Sam Body to come up and introduce our guest speaker, Dr Hall. Good morning, everyone. Um I tell you when you, when you start uh with a big Thanksgiving feast and you're really, really hungry. This is what we've got in front of us this morning. Um We've got an amazing speaker that I want to take a minute and just read his bio. Um But then obviously he'll kind of take us to the next level. And I was, I was saying several of the fellows up here, this is really the future, this is where medicine is going and you're gonna see um that it's actually here today as Dr Hall will tell us. So Dr Anwar Anwar Alcohol is a clinical and translational scientist originally from the United Kingdom um where he completed medical school, internal medicine residency at King's College Hospital. Um One of the premier places there um and fellowship in general cardiology, advanced imaging and inherited cardiovascular diseases at ST Bartholomew's Heart Center and University College London. These are really top places I went to medical school in England. So I'm familiar with some of this um as part of his clinical investigator program, he completed a phd and an American Heart Association funded postdoctoral fellowship at the Mayo Clinic. He trained in cardiac electrophysiology at University of Pennsylvania. Since 2020. He's led an independent research group investigating cardiomyopathy, these arrhythmias sudden death syndromes, combining state of the art imaging with electrophysiology for deep phenotype ng. Um and with high high throughput genomic studies. And he'll explain to you what that is is the founder and clinical director of the Center for inherited cardiovascular diseases and consultant, cardiologist and electro physiologist at Well Span Health in Lancaster, Pennsylvania is a research adjunct faculty at the University of Pennsylvania, and a research scientist at the Mayo Clinic and an honorary consultant at ST Bartholomew's Heart Center in London. So we've asked Anwar um to share with us what cardiovascular genomics looks like and precision medicine today. Um And I think that you'll find out that, you know, we don't, we shouldn't all be treated the same, the same problems, low ejection fraction, sarcoidosis, amyloid, arrhythmias, sudden cardiac death, we can get to the root of the problem. We can understand the genetics and we can modify that. So I can tell you that 5, 10 years from now, if Dr Joel has his way, they're gonna be these incredible centers of precision medicine and we certainly are a huge fan of that and would love to learn more. So, Anwar without further ado, please come up. Good morning, everyone. I'm just gonna ask Billy, can you hear me find their super? Well, thank you very much for the kind invitation to present today. I've no um C O I or R wi learning objectives. We're going to cover these three key things. We're going to go through some cases and apply guideline recommendations for what we would do for sort of genetic testing. Hopefully, we're gonna impart onto the importance of cascade family screening, using clinical and genetic testing and how that actually changes when curveballs arrive and we end up going back to the patient and then to the family and, and back again. And then I want to give you a very brief overview of precision medicine, precision health, including jean first screening strategy. So we'll go through some cases and then at the end, we'll go over some of the research that we're doing. Okay. So we'll do some definitions because I'm, I know I'd like to dive straight into it. But my colleagues tell me, listen, it was a long time ago when people did genetics. Um So we'll cover some of these aspects and then we'll do the cases in the research and then we'll, we'll hopefully close out with some summaries that are good conversation starters. Okay. All right. So what is precision medicine? Um Lots and lots of definitions out there. Many words become part of our vocabulary and we use them, we sort of know what they mean and they're difficult to pin down. Um And there's words such as individualized, bespoke, personalized, all these get used together. Um But they actually mean slightly different things okay. It became very popular when in 2015, President Obama announced the Precision Medicine Initiative, which we'll, we'll talk about. But some people will say, look, it's a form of medicine that uses information about a person's own genes or proteins to prevent diagnose or treat disease. And that's the N C I N H N C I definition oncology, in case you didn't know really catapulted the way forward with clinical genetics far exceeding other specialties, including our own in cardiovascular, other definitions that have come out. So it's an evidence based approach is what the H A says that uses innovative tools and biological data science to customize disease prevention, detection and treatment and improve the effectiveness and quality of patient care. So that's slightly different from what the are saying. Um NIH all of us and the National Institutes of Health again, redefining some of these definitions that we have. That one thing I want you to take away is personalized, does not equal precision. Because if you talk to any of the more senior faculty, they'll tell you we've never done a one size fits all. We always personalize the treatment. So we want to draw that distinction from, from precision medicine. Okay. His picture of President Obama in his state of Union address in 2015 when he announced that he is launching this precision medicine initiative. And it's a bold new research effort to revolutionize how we improve health and treat disease. And the mission statement which I'm just going to read out to you is to enable a new era of medicine through research, technology and policies that empower patients, researchers and providers. I prefer clinician to work together towards development of individualist care. Okay, so again, you're seeing some of these words that are interchangeable, but the key words that jump out are really that we want to combine research technology and we actually want patients involved, we want researchers involved, we want clinicians involved. And instead of being in silos, we get together and say, right, how can we transform care now for the future? And I'm going to show you that some of these things are actually already here. As part of that, there was a commitment of $215 million of investment that will go into the NIH and the NIH all of us program was announced the NIH all of us program is a fantastic resource that plans to recruit one million individuals and 25% of whom need to be non white. So most of the sort of bio banks, bio repositories out there have a heavy slant towards white populations and do not represent the other human beings that make up our societies today. That's something they want to change. Sometimes you might hear it called us Bio Bank. Um And that's really because the UK Bio Bank started in 2008 initially faced lots of problems and difficulties but has now just become an amazing resource for researchers out there that has truly democratized data. So the US version of that is NIH, all of us and what it plans to get right is double the number of patients versus U K Bio Bank, but also include non white populations. And I think they'll do that very well. And they're going to do things like integrating things like your activity monitor in your iphone or your smartphone that can then tell people you know what your sleep wake cycles surveys that are being done. So it's, it's absolutely amazing. All right. You heard the term atomic? Okay. Um There's lots of comics out there that's personal, there's genomic, there's pharmacogenomics, proteomics meta below Mick. Um There's the microbiome which we were discussing last night very briefly at dinner. Um So what they really mean is look if you hear that term OEM. So instead of just a gene or genetic, when its genomic, you're saying all of the genes essentially. And when you say proteome, We have the technology now to be able to do these high throughput things. Instead of just looking at a single protein or a couple of proteins, you can actually look at someone's entire signature of proteins and you can do it in like $200. So problems no longer become getting this information together. The problem now is what do we do with the data and how do we integrate them? Because you may have an expert who's a proteome expert who say, I don't know metabolism or genomics, our microbiome. And that's a problem because again, we're just in silos and we need to get out of that. There's even a pollutant which I actually quite like. So that's all our polluting molecules out there combined together and you can actually measure this stuff so people can go around and measure the air quality, for example and see what exists in your pollute um locally. Alright. So the I want you to really remember this. Now, this slide here, what we're saying is think of where we're headed is that we've got all of these aspects. Now we can do a transcriptome. If you take a heart biopsy, you can actually run to see what are the RNA signatures within there. So in other words, you know what gene expression, okay, because all the genes are not on all of the time. And then you want to know what proteins do you make and are they defunct or not? Right. So you want to know the overactive, underactive, have they lost certain functional characteristics? And then you want to know how does that affect metabolites? And then you can go back to the person and look at what's called the Phanom. So that means all your phenotype put together and it's actually very sophisticated tools now that allow you to go through someone's electronic health record and actually build a phenom ICC profile. So this is a way if you read some of the papers about this, you'll start to say, why are they jumping from one to the other? Because now we can and actually open up the door to areas that we may not have looked at. But the other cool bit of these data analysis approaches. Now, in that we're able to say, okay, we're collecting all this information, but I really want to know what their sleep cycle. Okay. What's their diet like? So you can merge all of these things into people's electronic health records and you can use ai machine learning tools try to help you get the signal from the noise. Okay. Data is no good on its own. You want information in that data, that's what matters. There's piles of data out there and being collected on all of us all of the time. A lot of it is not helpful, right? But if you're clever, you can look to see what sort of book somebody buys, what sort of political affiliations they may have and you can even manipulate an election by targeting those people and saying, hey, these issues are important for you. How can we take it another way? So people are using our data out there. We just gotta get smart how we do that in medicine. Okay. Central dogma. Alright. You all got your coffee's already okay. Let's go over this. I obviously love this, the central dogma of biology and you know, my inspiration for all of this, I'm just going to declare it upfront. You know, I'm a big Trekkie and growing up, I watched the next generation and I was just sharing that with my Children recently and the ship Doctor Dr Beverly Crusher, one of the episodes actually is able to sequence someone's entire genome and figure out what's gone wrong with this alien that's been hacking them. And that was actually my in inspiration said this is amazing. It's the code book of life. It's what I want to do. I was sharing this story with my Children. I was like, no, no, honestly, I'm telling you, I remember, you know, at home in England and this is, this is what happened. I was like, wow, look at the power of this stuff. So for me now, you know, as an undergraduate to see the human genome get, get done to where we are now is just absolutely fascinating. So I love the central dogma of biology. Okay. Essentially, it says we've got D N A, it's a code book of life, it's a universal code book, right? So if you go to plan to go to animals, we're all using essentially the same code, right? Um It might be then transcribed into RNA and then that RNA is translated into proteins. And then we have all these post translational modifications, those proteins have structural components and functional components. We have 23 chromosomes, right? One pair of sex chromosomes and then 22 oughta soames. So that's some of the language you're gonna have to get used to as we get more and more into genomic and precision in heart and vascular when you hear those terms thrown around Okay timeline. So I was saying to you look um the biggest thing here is that we've gone all the way from understanding, you know, DNA, the structure of DNA, the Watson and Crick model of the double DNA helix. And then how we've actually gone to 2001 when the human genome was done and I was an undergrad then just blown away by that. But of course, that was only, you know, one individual at the time. Now, we've got to a point where if you look on the right here with Moore's Law, which really says that essentially it's related more to try to transistors rather than computing power rather than genomics. But we've taken the principles and that basically says that at some point when you have a major day discovery, the time to get to the next step in the major discovery gets shorter and shorter and shorter. So actually, we're able to develop and discover things far faster than we could. So one example might be, for example, making the vaccine for SARS COV two, it took scientists across the world 89 months to actually get a product out there, which would have taken years previously. So this principle applies and it applies to genomics in that we're able to do $1000 genome right here. Right now, I can order it for patients right here right now. The big problem is what do we do with it? And this is where you need to understand this really important figure that depicts the overall relationship between penetrates and the probability of a variant causing disease. So here's a little frequency. Okay. So it's very rare and it gets more common on the X axis on the Y axis here. What we're saying is that the effect size, meaning it has very little impact to very high impact. How do we organize all of this? And some of the science of all of this is particularly fascinating because as you all know, Mona's psychotic twins are genetic clones, they are nature's natural clones that exist out there, almost identical. And the reason I say that is sometimes that can be germline mutations that can take place that can make them subtly different, but they generally have the same nuclear chromosome and also usually the same mitochondrial genome as well. But what's fascinating is that twins don't always get the exact same disease. They don't die at the same age And they die of different causes, which really says, well, Okay, that's how a natural experiment there to look at what happens to a clone. What was different about Mona's exotic twins also raised in a very, very similar way. The environment is usually very, very similar. So what could it be that is therefore changing that you can look at these exotic twins which are 50% similar just like any other other siblings would be. And the environment is similar. But what we realize is that you know if we think of Gregor Mendel and his famous experiments with peace and where we get where we get dandelion disease. Mono genic disease from things don't really hold up to that model as easily. Okay. And that's the idea that you've got this sort of rare alleles that cause Mandelli in disease over here with a high effect size and penetrates. Well, that's mono genic disease, but that's only the small chunk of most disease out there. Most diseases, palla genic multiple variants that interact together with a low effect size to come together. One of the analogies that I particularly like is that sort of genetics loads the gun and the environment, your lifestyle, what you do afterwards, your epigenetic and all the rest of it decides on whether the trigger is pulled and when that trigger is pulled, which I think is a very nice analogy to get it because sometimes we say, look, mandolin diseases are just saying with psychotic twins, you can find the penetrates can still be different and it means there's other things going on that we don't yet understand. It's a very, very important concept. This because the other thing it tells you is that you see, if you have a rare and its deleterious that usually there is death of the organism if it's so deleterious and that death of the organism should happen in utero okay or very early in life. So in other words, that person can't now reproduce to pass on that big difference with one of our Mandoline disease and cardiovascular is its adult onset and it tends to be more dominant. So you only need one bad copy versus the wild type copy to actually cause disease. But people are able to reproduce and pass that on. So really, really important concept versus almost lethal, severely deleterious aerials. Okay. Alright. Pedigree symbols, I won't dwell. This have really left this just so you have some extra reading but family trees are very important. Okay. We have the square symbol for male. We have the circle for female. Somebody who's affected is shaded in black, somebody's hetero sickos is half shaded. If you're diseased, you put a line through it. But we draw these complex family trees and here the thing to remember is that we go by sex. So the NIH definition of sex chromosome or gender is everything else. And we don't really get into that in biology because you know, quite quite frankly, it would be very hard for us to be able to deal with all of those complexities of human gender, applying that to biology. So to keep it simple for us who are dealing with this, we actually deal with biological sex there. And then if the sex is unknown, you can put a diamond shape in there. Okay. So what are the modes of inheritance is very quickly have mentioned that also more dominant which can be early or late onset, most, most cardiovascular diseases, late onset um someone recessive disease. And by that, we mean you need to bad copies. Um and that will then give disease. Um this idea though that someone recessive where you only have one bad copy and that bad copy therefore means you're a carrier is generally what's what's taught out there. So, cystic fibrosis is a good example of that where many European ancestry, individuals actually carry that. But the chances of having a child are actually quite small because you'll have to get to bad copies aligned in that next offspring, excellent dominant and excellent recessive. So the X and Y chromosome, the Y chromosomes remember physically shorter than the X chromosome and where those aliens exist on the X chromosome, there's no counterpart on the Y chromosome to match that. So if you have a matching counterpart and there's only one, a little that's affected and its dominant and that's excellent dominant. But if it's recessive, you either need to bad copies in a female or in a male for that particular gene, one copy is sufficient because you have no counterpart, the Y chromosome shorter and then maternal, otherwise known as matrilineal or extra nuclear is the mitochondrial genome. And you'll all remember when the spermatozoa join the over. Um what actually happens there when the nuclear material combines is that the mitochondria outside of the head of the sperm and the only the head will actually enter. So the rest of the tail and all those other components, the motors that cause the swimming are all left out. The mitochondrial genome is not paternal e inherited. Okay. So you only get it from females and that's where you may have heard that term. Um The two important terms in population genetics out of Africa theory. Okay. And the IV mitochondria. So, what do we mean by that? Well, the genetic data show as we come from a single female, no doubt about it because it's only matrilineal mitochondrial and it doesn't matter what racial or ethnic definitions that we impose on the world, right? So our models that we put and project out say you're this category of human being, you're this one, our mitochondrial genome is incredibly conserved and aligns with us having one single original four mother, I will say rather than for father. Okay. Alright. Other really important terms. So you'll hear these branded around especially if you use an inherited service. And sometimes I think we struggle with like what's the difference between penetrates expressivity and what happens with both. So if you look here, you've got some, some of these eggs, let's say that are shaded in purple or white. And what you're saying here is that when you're less than 100% penetration, not everybody expresses the disease. So if everybody expressed that all these would be purple, right? So very few diseases that are 100% penetrate and that's a really important concept because if you carry the gene, what it's saying is you might not actually have the disease. That's something to think about. What does that do? Then if you genotype somebody in your genotype family members and they are part of the lucky ones who are never going to express disease. How does that impact them? Because there's a law here, the genetic information, nondiscrimination act that protects you against genetic discrimination. So think X men mutants and how their outcast, right? Um People don't want that happening to other human beings because no fault of your own, you inherit the genes that you get and you get the mutations that we were, you know, our D N A is changing in all of us, you know, somatic cell lines change and cancer is fundamentally a genetic disease and that's what happens, right? You didn't have it necessarily at birth, but people then develop enough hits to be able to lead into unregulated cell proliferation, which is what cancer is okay. So how does, how do we deal with that? Will Gina here protect you? So for essential insurance, health, life, health insurance, motor vehicle insurance, home insurance, it doesn't affect it. So they can't discriminate on that luxury insurance, life insurance, disability travel that there's actually doesn't protect you on that. So it can affect people's ability to get things like life insurance. And it's really important because there are cases where people have just gone and ordered the genetic test in good faith without counseling of about this. And then they've gone. Well, I carry exactly what my mother has and you said got some more dominant one. Bad copy is enough. Yes. But you're telling me I'm healthy, everything's fine. Yes. So I'm kind of okay. And now, you know, 40. So yes, I think you're going to be okay, try to get life insurance and their declined or charged extortionate premiums. So this is a very, very important concept of penetrates okay. And then the next thing is variable expressivity. Okay. So hear what you're saying is seeing is the different shades of lavender and purple. That are that what you're saying is that if phenotype is changing and in some people, it can be particularly severe, it can affect other parts of the heart or outside of the heart. This is variable expressivity. So for example, if we look at hypertrophic cardiomyopathy, most do not go skeletal muscle problems. But once you get into the syndrome IQ and non Sarko Merrick, you know, the expression of those genes can be highly, highly variable throughout the body. And then here at the bottom, you're saying, well, actually the reality is you have variable penetrates and you have variable expressivity and that's what makes it really hard to see the patient in front of you and the family. And that's why we talk about phenotype and re phenotype. Okay. This is there for your reference. If you want some additional reading material, strongly recommend that you pull these up some really good statements that have come out from the H A R. Also some very good statements that have come out through the Heart Rhythm Society, the European Heart Rhythm Association, E S C I reckon, you look at those and then the American Council Medical Genetics and genomics have published some really, really important documents and HFS A Heart Failure Society of America's published some on cardiomyopathy led by Ray Hershberger. Okay. So let's dive into some cases and get your brains firing. And let's say I just selling you a load of, you know, stuff that's not helpful or does it actually make a difference? So let's go with a case. 68 year old female. She has a history of hypertension diabetes. She has sleep apnea, she's got CPAP machines. She swears, she uses it. She refused to get vaccinated. She got COVID and she has a witness collapse which collapsed with loss of consciousness without warning. Her husband evaluates and notes that she's grunting and he really pointed this out to me grunting. That was a weird thing. So I checked her pulse, there was no pulse. So I moved from the sofa to the floor and I started CPR did it within two minutes and he got sick and she was alert and actually sat up. She was neurologically intact. The ambulance crew was called, they arrived and they notice that she's got sinus rhythm with this particular E C G she's taken to the, er, and admitted she has troponin is done, which are normal. So we know it's not a heart attack. Okay. She gets a CT triple rule out. Very nice. No, P, no aortic dissection and no significant coronary artery disease. Fantastic. If you can get it okay. She gets an echo shows some concentric LV, H, some diastolic dysfunction and I'm called, hey, what do you think is actually going on? And A C T I will say it didn't really play this, but she does have some consolidation in her lungs from her COVID that she's actually recovering from. And we also do a CT head just to make sure she's not had a cranial event. Let's just look at the CCG. Anybody want to have a go at this, please. Please, please go for it. I've highlighted it. Sorry. Very good. Yes. So the cuties prolonged. Okay. And the other thing you'll notice here, put the highlighter over here as well. This is a narrow PVC. Okay. Would you all agree with that? That's a PVC. Look at the T wave versus A T wave here. Okay. Now, look over here at the T wave. Okay. So it's more than just a prolonged Q T. She's actually having pvcs and she's having this phenomenon. Anyone know what that is? Please go for it. How would you describe that? If you look at the 12 V D C D and the T wave wave keeps changing re polarization abnormality. Is it a systemic T wave Alternations? That's T wave alternates? Okay. Macro T wave alternate. So you can only measure T wave alternatives with dynamic E C G recording. You can do micro T wave alternatives. So if you do a really good halter, you can actually measure that out. This is Macro and actually in the long Q T world, this is a really bad adverse prognostic marker. So we asked her a little bit, huh? What's your family history? And she has a son who had an aborted sudden death when he was 18 years old and he carries this SCN five A mutation that's definitely pathogenic. And he has an I C D and he also got atrial fibrillation at the age of 39 required an ablation. And he's also had lots of shocks for polymorphic VT. So we asked a little bit and she said, well, you know, I was told, I'm okay, I'm 60. I'll be okay that have not shown anything so far. And I, I don't have the cogs of when she was first evaluated, but let's assume they were normal. Um What more could we have done here? Could we have actually done genetic testing? And we did, and it confirms that that actually she has the same variant and she was always told her T waves were abnormal because she got hypertension and hypertensive heart disease. That's not, that's not unreasonable. Okay. To put that together. And then while we're working her up, you know, doing all of this, she has this right in front of us and ends up getting shocked. But that PVC is back. Okay. We check the potassium at 3.7 magnesium is normal. How do we control that? Now? So here, now we have to apply E P. We give her I V s and we give her some magnesium. Magnesium is brilliant for torso. Okay. It probably doesn't really help in anything else. I'm wearing my EP hat. Magnesium for a fib, I'm not convinced, but magnesium for torso is actually really good. Put them on a drip and it will help stabilize things. But we've got this right bundle, right inferior lee directed PBC. That's narrow, that suggests it's from the conduction system, from the particular system. She has three more arrests in front of me. Okay, despite doing all of this and the I V s model is now causing bradycardia. And at this point, we're sort of like, well, how are we going to control this? Which is now V T storm? So we actually decided to put in uh an ai pacemaker and overdrive pacer put the S model on correct her electrolytes and then hopefully we should be able to get her out of the hospital. So actually what we did then was transition onto needle and we stabilize the VT storm, she got this dual chamber I C D implanted, we ai over dr suppressed, er but A Q T was still incredibly long. So here's now where we applied precision medicine. We know that she carries an SCN five A sodium channel five, a gain of function mutation for long Q T three regardless syndrome is kind of the opposite. When the SCN five A is involved, that's a loss of function in SCN five A. So we know she's got Q T long QT syndrome three. She's got macro T wave all turn and she's got incredibly long T way Q T interval of sort of 5 66 100 we can't use all the drugs together under control. How can I get a Q T shorter? Because our goals are to make it less than 500 milliseconds. I can't let her go home. She'll just keep getting shocked. So here what we did, we gave him axity. So we actually knocked her sodium channel out. So having that genetic information helped us to know that she's gained a function. If you knock that sodium channel out, you make the Q T better. And I hope I can show you here. And not only did we make the Q T better, we're a pacing her, but we've made that T wave stable now. And I saw her as an outpatient. She got a little bit of hair loss and we thought it might be Maxillary. And so what we actually then did was put her on fleck inside with Oxytocin, which are not FDA approved, but they're really, really highly specialized and she's had no further shocks. We've controlled her Q T interval. It's a really nice case where, you know, genetics have made a big difference in terms of what we were going to do and really important clues within their, about what's going on. And it's a real world case that I'm sharing with you is that she had everything else L V H hypertension and sleep at, they don't walk in like a board review exam. You know, 18 year old with SCN five A and what do you do? This is real life and how we make a difference with it. Let's do it another really nice case. 46 year old female presented with palpitations. It was human dynamically tolerated metamorphic beatty that we actually saw no Cinco P, no pre syncope. And then she also had these pvcs with a 17% burden intrinsic sinus CCG was normal. Her T waves are normal, echo was normal. She had a pre procedural CMR. I just got the stilt here that showed the RV was a little bit dilated that the ejection fraction was normal. There was no regional wall motion abnormalities, there was no late gadolinium enhancement of the L V or the RV and there was no fatty infiltration. So we decided to take it to the lab and get rid of these pvcs that are bothering her and sort out this VT. And actually what we found is that these are left bundle inferior lee directed with a V five transition. In other words, are coming from the right ventricular outflow outflow tract on the septal region. Um And then she goes into VT in the case and of course, we start the ablation within 10 seconds, it's terminated, which for any P is like heaven doesn't happen often. Okay. So we get very excited about that. Then we thought, you know, why does she actually have this? If this is just outflow tract BT, that's actually one of those safe VTS um that you don't need an I C D four, right? We talk about VTS structurally abnormal and structurally normal, structural normal heartbeat. E is a very good outcome or does it, that's really the question, these assumptions that we have made based on retrospective observational data. So we, we decided to do a voltage map. So what you see here is the right ventricle um from different projections. Here's the outflow tract and here's the mitral valve, sorry, the try custard valve coming in. You see all the way here at the apex purple, here is healthy, red is unhealthy. Both the bipolar and the unit polar voltage maps here were grossly abnormal. So let's just, just piece all that together now. Okay. You got someone with the T, the RV is a little bit dilated. Okay. And actually get into the history. She's actually an ex marathon runner, so she's got a little bit, maybe athletes heart is what we were thinking. Um E F is normal. There's no regional wall motion abnormalities, but she has this vi T and it's mainly coming from sort of the outflow tract area. Okay. Is it just outflow tract B T or is it a R V C? I'm sure that's what you're all thinking, right? This is probably a R V C and that's what we wanted to know about. How do you know that? So you do a voltage map and it's telling you this is grossly abnormal. Okay. We decided to do genetics on it. We actually found a change in P K P T which is the most common variant seen in rhythm eugenic cardiomyopathy, but it was reported as a variant of uncertain significance. So when you get genetic test results back, they come back in one of three ways, they're reported as the variant. And that's a new way for saying mutation, all the expense stuff. We don't want to offend anyone. So we actually call it a genetic variant, okay. And then we have to classify that variant and we call it benign Or we call it pathogenic or likely pathogenic or we call it a variant of uncertain, unknown significance. And thus is the term that we use. So if you hear that term out that that's what they mean? Okay. So thus in PKP- two, what can we do about this? And then the big questions that come up, what are we going to do? Should we implant an I C D? Should we screen family members? So huge Hopkins has built this A R V C risk calculator from the Hopkins group where you can plug in all of this stuff. Let me just draw your attention here. It says do not use this for people who do not meet the task force criteria for A R V C. Does she meet the criteria? RVS essentially normal structurally? No, she doesn't, okay. Has not dropped. She doesn't have regional wall has sinus rhythm is normal. She does not have any T wave inversions at all. Okay. She has no epsilon waves, right? Her T A D time is short, it's not prolonged, but she has these abnormal voltage maps and she has this vi T so she doesn't meet criteria. So you can't really use that calculator in the end. It's a judgment call. And we said look that P K P two, maybe at this, we may have with the advent of the technology, we've got quarter patient so early in the journey of a rhythm, a genic cardiomyopathy because the cases we hear about in the clinical iceberg are the ones who have survived a cardiac arrest or have very advanced structural disease. You know, it's quite rare to get advanced structural disease. My very first case of R V C I saw was actually a lady who was a, was a Gurkha and ST George's London who had such severe RV, dysfunction actually ended up with really bad renal failure and ended up getting a heart transplant. I saw the tip of the iceberg there that got me into a R V C but the majority do not have that overt structural abnormality. They had this period where there's this concealed phase and then this very early phase where the disease changes and something happens, they might report things like myocarditis type episodes, right? And they may just get these pvcs, they haven't syncope ized on the disease spectrum. We're seeing it so early. How do you know she's not going to be a R V C five years from now and then you apply the risk calculator and it says yes, she does have it. You could probably argue to give it it. So we made the justification that she's got mono more fit bt even though it's stable to do it for secondary prevention. We gave her a sub Q I C D okay. Here it is. Eight months later, she decides to do this okay. And then she basically ends up getting a shock and it saves her life, right? So on balance, look, it was a judgment call is what I'm saying. And these are the challenges that we actually face. I'm actively surveying her and I am screaming her family members. And what we're trying to say is, is this going to turn out to be a R V C if I was a betting man, I'd say, give me a few more years and she'll meet the criteria, but it's kind of stupid to wait for the criteria to be met when you have a patient in front of you and you need to know what to do with them. And I don't want to implant I C D s and everybody because that's not precision is it, that's a one size fits all. And sometimes we treat ourselves right? Makes you feel better that you gave them an I C D and that you can sleep easy at night. But the reality of it is we have to be judicious in our use. And here I think what we're going to show once the family members all come for evaluation is that P K P two is probably going to get reclassified from A V US into pathogenic. But that's the work the inherited program now has to do, which doesn't generate many RV US except for the family members being screened. OK. K Street. This one is a quick ish one but 28 year old male referred for sports pre participation screening has frequent pvcs endorses remote history of unexplained syncope, physical examination. He has a mid systolic click and the mid late systolic murmur has an echo and the echo shows mild LV dilatation for 50% and embargoes mixer metis mitral valve and see if we can play that Billy. They played before, didn't they? Okay. We definitely tested these earlier guys and they all played fine. So I'm not sure what's going on there. But anyway, you have to trust me here that there's a jet of em are there that you see at the top here? Okay. And this is a Bar Lows valve and these are the pvcs that we're getting. These pvcs are coming from the papillary muscles. Okay. And there's okay. Clinical questions then. Alright. Should we repair the mitral valve? Okay. Patient has excellent exercise tolerance, CS 50%. It's moderate M R by the usual criteria, normal pulmonary pressures. Should we do more history? Should we do an M R I should do a zero patch. Should we follow up in six months? These are real questions that you would all face. Is there a right or wrong answer? I think it's totally reasonable. Um You know, you could justify either way to do what you're going to do. But here's what we did. We did a whole episode. There were episodes of non sustained BT and we became worried about something called the rhythm, a genic mitral valve prolapse. And we decided to put him through an M R I scanner and the M R I scanner here that, that you see on the still just here. There's something I want to draw your attention to, that wasn't obvious on the echo that we picked up on the M R I. And you can indeed see it on, on, on eco as long as you get the views, something called M A D or mitral annular disjunction. What that means is the mitral valve Manulis and the true LV, myocardial are actually separated and this is something that's an adverse sign. Let me show you the late God sequences here. Here's the septum inter ventricular septum is pretty thin, young, healthy guy otherwise, but look at this white stripe in the middle. He's got mid myocardial late gadolinium enhancement. So then he's referred to E P. Hey, what should we do about these pvcs? And what more can we do about it? And so we said send it to the inherited clinic and we do what we do best. We take a family history and guess what? There's all these family members who actually have mitral valve prolapse and non ischemic cardiomyopathy, potentially from the leaky mitral balance, right? Or there's something else going on. And we said, let's do a genetic test here. Genetic testing came back positive for a frame shift and a truncating variant in laminate, laminate A is one of these high risk genes. I'm going to show you in a minute and then we find all these other family members are actually affected. So, going back to the clinical questions, what should we actually do here here, we've got all these features put together, right. We've got mitral annular disjunction. We've got this thing called Pickle House Science. When you do tissue Doppler imaging, what you're getting is rapid changes here and it looks like a German helmet. Okay. Um And then we've got all this scar and then we've got this gene. Should we implant an I C D? Well, let's look at what the guidelines show us. So, on the left here, we've got the 2017 H A 2019 Heart Rhythm Society on a Rhythm, a genic cardiomyopathy. And then here the most recent CSC guidelines, um suffice to say that they all now recognize that if you've got a laminate mutation and your EF is near normal, you should actually seriously think about putting in an I C D. They don't talk about mitral valve prolapse. But I want you to just, you know, I want to be sort of put the cat amongst the pigeons here. We were talking about this at dinner last night. What is a rhythm, a genic mitral valve prolapse and who is high risk? And I just showed you these are all the risk factors that tell you somebody is at high risk and you should think about putting in a defibrillator. Um But what about genetics? So this case, we've actually written up and we have a small series now that we're putting together where we've actually looked for some of these genes and the main mechanisms of the genesis in mitral valve is actually physical. It's traction. It's that mitral valve, leaflet Cordy pulling on the papillary muscles that causes this PVC that can trigger VF or VT but also sustained traction on that papillary muscle can then lead to scarring within there. Okay. So this is a kind of like this is what I enjoy about this, our conversations. Um Last night, we how do we connect the dots? Because most mitral valve prolapse doesn't do that. Most is benign. Most has a really good outcome. Okay. Case four, I'm gonna, I'm gonna whiz through this 21 year old African American descent B M I 30 has some sleep apnea. Cesar uses CPAP comes into the er with palpitations. The 12 V DC G is below what you see a fib. Agreed good. We start the delta and of course what happens when the season starts? The car devotes himself? It's not the delta. Okay. Don't believe that is literally when you connect it and you just cardio birds. I wish it was that powerful. Alright, so the 12 V DC G here has gone back to sinus rhythm. Any major abnormalities? Would you all agree that sinus rhythm, normal R wave progression? Good QRS voltages, the T waves look fine. Agreed I would pass out as normal but we did an M R I. Okay. We don't have any imaging guys here. Do we want to have a stab at list. Okay. So again, I'm sorry, the movies aren't playing, going to restart that. Billy may need a hand here, please. Just to restart this, this whole frozen, my mouse is frozen as well. So while Billy's fixing that essentially, this is a normal M R I at the bottom left, we did a T one look locker sequence and that was normal and then the signs are all actually normal and there's no late gadolinium enhancement. So, question for you all is then what about a f in athletes and younger patients? It's just not none of it's playing. The mouse is getting stuck as well. Yeah, I think the laser is gone now. Alright. So basically if, if you've got a young guy in front of you, that's not an uncommon thing that we see. What do the guidelines now tell us? Okay. Well, if you're, if you're an athlete, you can get a fib if you've got sleep pattern and that's untreated, you get a fib, if you're overweight, you get a fib. Okay. Guidelines have changed for genetic testing. Now, we used to say it was a class three recommendation. Do not do genetic testing in somebody with atrial fibrillation that got changed last year. The Heart Rhythm Society and published that to say that actually we know there's all these genes where we get a fit. The thing I want you to remember is somebody gets, some people get tacky cardiomyopathy right there. E F drops that LV can dilate you, get them back to sinus rhythm that ef recovers and all of that, why does that not happen to everyone is the question that you should ask? Right. Well, I'm going to propose that some of them actually have a genetic cardiomyopathy. They don't tolerate it as well. And that's what we're now realizing. So tighten the number one gene that we see in dilated cardiomyopathy is now the number one mono genic gene that we see in a f what do the guidelines tell you under 45 or they have a really strong family history, actually just do the genetic testing. So we decided to follow the guidelines and did it and guess what we found, we found T tr okay, which causes amyloid. So this African American gentleman has the exact same common that's seen in the African American population for T tr but he has not shown any features of amyloid thus far isn't just part of the amyloid process, the atrium being affected early, potentially it. So we're now going to follow him more closely rather than there. There, there's your medicine and will will deal with that in due course. Okay. I'm going to skip through this case just in the interest of time and I'm going to fast forward to say I can't play any of the images. Um Essentially this case had obstruction and shared this case with you before at the symposium last year. What I want you to understand is here, genetics played a massive difference in how we manage this case because it actually turned out that this woman had Anderson Fabry disease and we genetically tested, we excluded all psycho Merrick genes. We found that she has a variant in G L A which causes fab raise, but it was came back as one of those V US again here. The cool thing that we did, we actually evaluated her Children. One of her sons has symptoms. One of her sons does not. We did the gla gene test and the son who's affected has the same variant that she has and the son who's unaffected does not have that variant. And then we measured serum alpha one galactose today's levels and they were normal in her. They were abnormal in her son. What does that tell us that tells us that this is X chromosome lionization, which basically means with females, both X chromosomes are not expressed at the same time. One will get switched off, but which one gets switched off is quite random. And it depends on that cell line starting from the Z go all the way down to the multicellular organism. It's random which one happens. So in women, if the wild type allele is switched off and the G L A, that's the abnormal one is now on. Actually, they'll show disease. So in London, the number one, the number two cause of conduction system disease in females after Sark oid is actually Fabregas is what we found. And people say to me including eminent places here, but there's no L V H. You don't need the L V H. You can just have subtle conduction system abnormalities. But the beautiful thing here where we took metabolism and linked it to the gene was we measured alpha one gal in her son. But you can't do that in a female because overall their alpha one gal levels are totally normal because they have enough activation and inactivation to make sure that that balances out. So here we then got this V US reclassified as likely pathogenic. So her Children, when we screen them, her son is now eligible and has actually started a precision therapy. So enzyme replacement therapy is what is on and it's not affected his heart so far his son does not, her son does not need an I C D or anything like that. So we're really pleased that we've been able to prevent disease progression in her son. Okay. Alright, I'm gonna skip through this very, very quickly. Um 54 year old female Hispanic ancestry basically has a DCM. She gets by the I CDI. Okay. Um She has atrial flutter fib, she gets a belated, we organize an M R I and we get all this horrible imaging artifact, but we do get some LG and we can see that the septum here and here is actually scarred Okay. Again, this is real world images that I'm sharing with you. So we run a gene panel and to our amazement, it comes back as positive as prodigy to G two is one of those things that causes hypertrophic cardiomyopathy. But important things of what the genetics did for us, we excluded known DCM genes, we excluded known Sarko Merrick jeans and we excluded amyloid and fabrics. And this prodigy to gene that we identified as the candidate were essentially saying that this is actually advanced prodigy to cardiomyopathy. So here we did family screening of daughter one, she was pregnant at the time. Her BCG otherwise looks normal. Her son who came and did the E C G and then her other daughter, we did the C G look at this grossly abnormal L V H with pre excitation. So we had a bet in our clinic and we said, who do you think is going to be gene positive? Right? And guess what? The genetics was negative in this daughter? This one declined but I reckon is negative. And then we tested this daughter and sadly, she's positive. Now, the amazing thing is she's 29 she's fit, she exercises. She's one of these people who does this whole peloton thing and you know, hold its high intensity exercise. We put her in a cardiopulmonary exercise testing. It's totally normal vo two max was great, but this is what her echo shows is. I don't think it's going to play it again? Okay. But would you implant an I C D? What sudden death calculator shows? I feel like I really need to show you this. So I'm just going to play it in this mode. There's a lot of effort gone into bringing you this case. Look at this for hypertrophy. I showed my wife and she was like, where's the bloody blood go? I was like, well, there, there you go. There's no room for it whatsoever. Okay. And then we actually did some late God sequencing and look at all this scar scar scar. What I want you to take away here. Oh, really? My apologies. Okay. Just go back on see if you can play that. I just tried that and it wouldn't project actually, I really wanted you guys to see this. Okay. This is an amazing case. Anyway, getting back to the mother presented with a non s scheme that she was dilated. She had a baby I C D, right? Um Essentially she has what's called burnt out HCM phenotype. I've tried to get her pictures from 2009, because I have a feeling she had hypertrophy, just people missed it for whatever reasons. And then when she did present with advanced heart failure, the LV was dilated out and we found this prodigy to G and then we showed you those E C G s and the daughter, two daughters and the son the son and one daughter were normal. One daughter had pre excitation prodigy to cardiomyopathy is really important to know because it's not soccer merits a glycogen storage disease. And you'll remember inborn errors of metabolism tend to present at neonatal very early and pediatric, not this one. This one is adult onset, the usual ages, 40 years. So you can see how chunky that ventricle actually is. Thank you very much, Billy. Okay. Um And then here, look at the late gadolinium enhancement here, an incredible amount there. So the questions are, you know, do you put an I C D in which calculated you use, how do you manage obstruction and so prodigy to this is what we actually did write the sudden death calculator shouldn't be used for this um prodigy two sequencing. There's just not much you can actually do about it, but we ended up putting in an I C D, um ended up putting in a sub Q I C D. Here's a reference for you. I was going to talk a little bit about HCM, but I know we're short on time, but the big thing I wanted to really share with you. Hopefully, these are now playing the HCM comes in different types, have shown you A G L A case of fabrics have shown your prodigy two. And the variation in the data that variable expressivity that we talked about at the beginning is all of this with the sigmoid sector reverse contour, mid cavity obstruction and a pickle variant HCM. Okay. These are the copies that we have to exclude what I want you to take away is if you use imaging and use genetics, you can exclude these things because the management is different. Okay. The sudden death calculator doesn't include package E two. So actually you're on your own. It's a judgment call. Okay. It also doesn't apply to fabricate. How do we manage obstruction? I want to make you aware of this drug. The cardiac myosin inhibitor Navy Captain, which is now FDA approved. It's the first in class drug that actually affects hypertrophic cardiomyopathy. It does that by actually affecting the subcommittee. A it's negatively in a tropic and it targets a mechanism of hyper contracting witty and it improves myocardial energetic. So it's now approved to be able to do this for patients. There's some trial data there. I'm just gonna whisk through, but essentially the FDA has approved it for anybody who would be a candidate for septal reduction therapy that you can now consider them for this drug. But the big worry everyone has it's so powerful, it drops the EF patients don't develop heart failure. So there's this REMS based system that really helps us do that. And the question is, how is this going to change management in 2023? We now have a precision drug. Do we have to go through the usual management of HCM Vita box? Will disappear. Um I'd or will we just be going to mice and inhibitor? And if that fails, send them from my ectomy, okay. There was some research I wanted to share with you, but I know we're short of time. I leave the slides in there. But just to say that population screening or precision health, this, this, this paper that we published last year in circulation. The nice thing is that what we showed is that actually healthy individuals, you do find these variants, but the penetrates is very low. So if we're trying to make a case for offering population based genetic screening, it's very difficult to do that. But this slide, I really want you to take away if we looked at what kills you. So it doesn't matter what the cause of death is, it could be heart failure, it could be a sudden death any cause you're going to die. If you carry these genes, I don't know what that means. Does that mean? You've just got a predilection for a problem with a genetically unhealthy myocardial that's now more susceptible. I don't know. But for the first time we showed this signal, now other groups are starting to show these signals. So the future of precision, I think we're gonna be combining all of these approaches, as I mentioned to you earlier, jean first screening, this just came out. This was a simulation basically said we can save lives, but it's gonna cost a lot of money. All right. So I'm gonna conclude here, genetic testing is just going to grow. That's all I want you to remember from this slide is going to get increasingly utilized. You can't avoid it. It's going to turn up in your clinic. Takes a multidisciplinary team. It takes people like genetic counselors. It means that we talk to imaging ep intervention, our cardiac surgeons, our physiologist to get together and say we need to figure out what's going on with these cases. I put genomics England there because their model now which I think we're going to adopt in the U S is to devolve genetic services instead of everything going to clinical genetics is actually say you have your own expert, neurologist is a neuromuscular disease genetics person who deals with that and anything weird and wonderful syndrome. You can't figure it out. The diagnostic Odysseys, send them to clinical genetics because basically we're massively understaffed, same in the US as well. Okay. Um I think what we're going to see and I'm excited about this with my scientist hat owners, we're gonna go bedside bench back to bed side, back to bench. So quickly the 15 to 20 years to get a drug is going to change, we're going to discover things far, far faster than we ever did before and this is the future. Now, data harmonization, taking the hr using their wearable technologies, collecting all their own mix and piecing it together to say, you know, how do we figure out what this stuff is? So I'm going to conclude there with some take home messages, hopefully bang on the dot um So genomic precision is here okay. It's just set to grow the model of having a cardiologist with expertise in GPM. Genomic precision and inherited is a key through cases. We've shown the power of genetics to read defined clinical diagnosis, guide our management and prognosticate family screening is crucial. For example, we've just shown you that prodigy to case where we're going to save her daughter's life rather than just leaving her going by a symptom based approach. You know, the guy guidelines for genetic testing of change. We now actually include A F genetics of long Q T makes a big difference to management. As we showed in that one case, their rhythm of genic mitral valve prolapse. I'm putting this out there. I'm not saying we have the evidence but is genetics part of that perfect storm that leads to sudden death. Females do get Fabregas. It's lionization and it can mimic cardiac conduction disease all the way through to overt hypertrophic cardiomyopathy. The G two is one of the important glycogen storage diseases that presents in adulthood. So, don't think, oh, it's out, it's just pediatric. That's not true. Maverick Canton is the first FDA approved drug for treating psychometric HCM would have helped us in the prodigy to a colleague of mine phoned me and asked me. I said no, because the mechanism is different. So their genetics is important again to try to figure out why they have HCM. First screening strategies show a lot of promise, haven't delved into the data. But I'm tempering this to say we have to have return, we can't bankrupt health systems or countries by doing genetic testing where there's no actual yield. And if you have things like low penetrates, there's a lot of unnecessary testing for the rest of their life. And we have to be cautious about that. I have a review, a state of the art review that will be coming out on that Soon, that will discuss that. So there are lots of knowledge gaps and they will only get worse unless we address training. And I'm not being for change that we actually, you know, have training there. This slide from Eugene Braunwald on the left and Michelle has a on the right or from their latest grand round and keynote speaker sessions. The cardiologists of 2032 applies genetic information and ai and prevention, diagnosis and treatment. And here you see, genotype imaging E P has to all come together. So the leaders in the field are telling us that's what's going to happen. There's a course coming out, it should have come out last year, but the H A had to go through due process is definitely coming out by April this year. Okay, look forward to that. It was a, it was a pleasure to work with my colleague, Andrew Lance Strong to do it. If you want to cheat sheet to print on the wall. This is an infographic I made for the A C C. There's a link print it, put it up on the wall. It's a reminder to all of you about the genes that summarizes this talk in one side. Okay. I want to thank our team. Well, Span, I want to thank all our research collaborators and we'll stop there. Thank you. Yeah. Okay. And you heard things that frankly some of us had touched on in our lives, but they're so complicated and, and explained so well. And what does it mean to us today? So I do think we have some time for questions. I know those of you that have to go, should go. Um But um you know what I was like fascinated by is, you know, you talked about, you know, these diseases that we don't at least recognize that often. I braise, you know, the arithmetic genic mitral regurgitation case. I mean, now you as clinicians, how often do we see mitral regurgitation? How often do we see cardiomyopathy is, you know, they come through our eco labs, they come to the Cath labs. You're like, oh, you've got a non ischemic cardiomyopathy or coronary is our normal go home on your triple therapy or for therapies, right? So I guess my question to you is, you know, when precision medicine and cardiovascular space comes to full fruition as it, as we go through this journey, what percentage of sort of the common diseases? We see a tre fibrillation, non ischemic cardiomyopathy, congestive heart failure will have an underlying genetic sort of signature that will alter our therapy. Are we thinking about 1% 2% or do you think as you suggested that it might be a larger portion of our patients? I think if we take all Mandolin disease, right. The way to think about it is Mandelli in disease and multifactorial e inherited or apologetic is the other term use. Things like coronary artery disease as you know, and you'll feel premature CAD F H. Right. And I've been hearing that since I was at medical school, Alistair Hall who has F H and advertises that has been drilling it into people to check for it. People don't check for it. Okay. We were told it was one in 500 then one in 2 50. Well, guess what the latest is? It's one in 1 75. So we know they get premature cad. So if you see a young patient with CAD, it should automatically triggered that evaluation and then put into place cascade screening. Okay. So you only its cascade family screenings. Yes. So they should have invited all first degree blood relatives, parents if they're alive, siblings, Children. Okay. That's what should happen. And now you suddenly have five or six, half of whom should probably have the disease by probably agreed. So, all you're going to find is it's even more prevalent than you realize. Let's take hypertrophic cardiomyopathy, sack America. It's one in 500. Let's take DCM, it's one in 3 50. And if you include ischemic in that mix, disproportionate ischemic, etcetera gets to one in 2 50. Right. Um And then the rhythm again, it's about one in 5000 restrictive. We don't really know the true population prevalence. What about things like amyloid that causes infiltrated disease, African Americans. About 4% carry that variant that was identified in this young man who is otherwise okay, a little bit overweight but had a fib and what's going to happen with him? He's going to present you with advanced heart failure. So actually, I think we don't know is the answer because all these population prevalence estimates are based on epidemiological data on phenotype. And it's usually more aggressive bits on that clinical iceberg that you see. So what about all this subclinical disease, which is where we end up in prevention. Precision health versus precision medicine. Precision health is, is really the screening bit before you have disease, primary prevention. Can we get in there? And that's the big challenge that by necessary, by the, by the way, screening works, it has to be sensitive, which means you're gonna catch a lot of things that are unnecessary. That's what worries people. But what do we know as the true overall prevalence and the incidents? We don't, we only have things like framing Rochester epidemiology project to tell us that. I think what we're going to find as we combine it all, it's going to challenge what we understand as disease. And that's what I meant by redefining mixology because we're saying, what do you mean by non ischemic? What does that mean? That's 100 and 50 different heart muscle causes, right? You know, that's where I think it's going to change it. So I think we're gonna see more disease and we're going to redefine the disease. We are going to see increasingly a genetic component. The Mandolin disease, yes, will be easy. The multifactorial inherited disease, which is most of it, the diabetes hypertension and there's a lot of lifestyle becomes harder, but we're going to see things like apologetic risk scores come in that are going to say, right? If you're a smoker, it doesn't matter what your apologetic risk or is, that's the biggest risk factor, you've got to stop it. Lipids fix that, then palla genic scores, et cetera will be adjunct to that. So I think then they will help us in this area too. Figure it out. Someone like yourself who probably could get apologetic scoring done is well informed. Well read, looks at your diet, looks at your lifestyle that apologetic risk or does it improve outcomes is the big question and that hasn't been consistently demonstrated in the CAD area and not yet in a fit. But the mandolin stuff is the one that we want to pick up because they're going to get the titan cardiomyopathy, they're going to get amyloid. So right there is just unbelievably um unbelievable insights. Um and we as clinicians, Jamie, thank you and thank you for an excellent presentation. Very enlightening. So at our lipid clinic, we routinely do genetic testing for patients with severe hypercholesterolemia and severe hypertrophy academia, both for familial hypercholesterolemia and Callum MacRae anemia syndrome. So about 20% of the time we get back this the US, how do you cancel those patients? So I gave you a couple of examples where we get the U S is the big problem with the U S is, is that essentially why are you getting to repeat what it means? Yeah. So, so what the question there is a variant of uncertain or unknown significance. Remember I said the genetic tests will come back saying either this is negative, you have the wild type, regular version most healthy humans have or there's a change and the change is going to be classified into benign or likely benign pathogenic, likely pathogenic or variant of uncertain significance. The difference between what is variant of uncertain significance from likely benign to likely pathogenic is 5-95%. That's a huge variation. So the question is why do we keep getting the us? Is because we haven't yet figured out what is normal genetic variation, right? That makes us taller, shorter around etc. It's generally not considered a disease from what is actually causing the disease to get that signal from. The noise is the difficult bit when we counsel them, which is why I strongly advocate genetic counseling should be done pretest and then post test and it should be done by whoever is qualified to do it. The law doesn't require a genetic counselor in most states. I don't know that, I don't know what Georgia's rules are, but I would say, you know, there's things you should do and things that actually are best or optimal care and best practice, I would say get a genetic counselor because that's what they've spent their time doing. And the pretest counseling will say, hey, this is what it's going to come back as the V US. We're not sure what it means. And over time that will either get classified into benign or likely pathogenic as we get more and more data. What can you do to try to reclassify in your clinic? You're going to clinically screen the family members anyway. And lipids, at least you can get lipid profile, which is something quantifiable, that's measurable as well as you're looking for the other clues of the Fredericks and classification of, you know, different, you know, dis lipid e means that you see, you could then offer this resolution, for example. So you could draw a pedigree and say phenotype positive, negative and then say who carries this for us? Who does not? If somebody shows the phenotype and doesn't carry the V U S, the U S is out, instantly thrown out as it can't be this. Then okay if the view s tracks with the disease, so it co segregates in the family, it's giving you evidence that this is likely to be the cause. So for us with CPV, T, just to take that example, are Y are two to the most common gene that causes CPV T. Most variants, especially if their germline, meaning you don't see them in parents are miss sent single point mutation and come back as the U S. And if they have the phenotype is actually usually the cause and we get it reclassified. So the V US reclassification depends on the disease is what I'm trying to say that. Hope that answers your question. Thank you. Thank you. Do we have any more questions before we depart? Today, we have one question back here and then this will need to be the last question we take today. Thanks for enlightening discussion there. So I'll kind of go back to comment and be made about a non ischemic. So for the heart feeling program, we do have a standardized protocols. All these patients do get genetic testing so they don't get treated and sent out. And we found, I think about 20% of these patients actually have TTN mutation, which I think is consistent with a national database. Uh So, so much so that we have identified a pretty large cord. And now they're looking at clinical trials that specifically target TTN pathway as a dedicated treatment. So we'll be able to enroll some of those nations in those clinical trials. Um As, as we've done a lot of genetic testing here, but I think I've discussed this with you at the last conference. We're seeing more and more patients that actually have multiple hit mutations, right? So, uh do you have a gentleman who's maybe 24 25 he's got TTN mutation and also has a new mutation. Um What are you again, as we're looking, we're finding more and more interesting combinations. What is your approach uh to patients who have uh to for example, to genetic mutations who potentially may have different presentations or expressivity, but it coexists in the same patients. And how do you tease those two out? Thanks for that. Absolute. Super question. So what we're saying they're just rephrase it for the audience is that sometimes you do a panel of genes and it comes back with a one gene hit. Great. But increasingly there are people actually have two genes that are affected. So about 5-10% of these Mandelli in diseases or actually either compound hetero cigarettes. So in other words, they're two alleles are both disease causing. OK. So that's a double hit or their die genic. So for example, with dilated cardiomyopathy, titan is the number one gene that's usually seen in dilated cardiomyopathy. So you have a hit in titan, but you also have a hit in one of these other genes that can cause DCM or restrictive cardiomyopathy and hypertrophic cardiomyopathy. The example you gave there was noonan's which are open these. So what what happens in those situations where we know when you have a double hit, you tend to have earlier onset of disease, you tend to have more severe disease and it's actually more likely to be penetrated. So actually they're higher risk. So for long duties, certainly for the risk calculators there, we actually say, do you have a double hit? Because if you do, well, you remember Java Lang Nielsen and Romano Ward, right? Romano Ward syndrome is the dominant needs single and double. Lange Nielsen is a recessive version. So you can be recessive because both bad copies are the same or compound hetero, both are bad copies but different. They're born with hearing problems, right? So they get more severe disease and death have low fetal heart rate. So these ion channel diseases when you're double hits cause earlier onset disease, more severe disease. Um and and disease that actually can have expression throughout the body. So not just the heart. And I absolutely agree with you. There's no solid guideline, high evidence based recommendation on what to do it's a judgment call and I treat them more aggressively is the answer. Well, um that, that was amazing. Thank you very much for coming. Um It sounds like Dr has a few more minutes. I heard from Billy that we have some time before we go record in the recording studio. So if there are any additional questions, maybe you can take it offline, but on Mark, thank you so much for coming and enlightening us.
