Dr. Ajay Srivastava reviews classifications of cardiomyopathies and the role of genetics when determining appropriate screening for patients.
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All right. Good morning, everyone. Thank you for joining us for our third annual cardio myopathy and cardio oncology symposium. We wish, of course, that we could all be together in a hotel ballroom. You know, sitting, sitting in person together, learning about this stuff and interacting with each other. But of course, given the circumstances, this is kind of what we're forced to do. Having attended a couple of these type of symposiums online. Um, surprisingly, actually, you know, the formatting could be quite helpful. You know, get to do it in the convenience of your own home, which is kind of nice. Um, eso thank you all for for coming out this morning. We're very excited for our lineup of talks. Uh, today sort of an abbreviated version of what we normally would plan for a sort of in person conference. Uh, but we are excited to have Dr Ron with Palace from Stanford. He is currently the program director for the internal medicine residency program, but additionally, is one of the world's leading experts in the field of cardiac amyloidosis and cardio oncology. He directs their cardiac amyloidosis program as well as their sarcoidosis program. Eso. We're very fortunate to have him be one of our guest speakers here today. Additionally, we have Dr Juan Lopez anti from India. Answer. Andy Anderson, Cancer Center Cancer center in Texas. Um, there he's an associate professor of cardiology and diagnostic imaging on co directs the cardiac Radiology service. Very well renowned expert in the field of cardiac imaging specifically as it relates to cancer care. So we're excited to have him here. A swell Dr. Shrivastava is the director of our sarcoidosis program here and co directs the HCM program on DSO. We're very excited, of course. Thio here his talk to start things off with that we've got a couple of sort of housekeeping type announcements for the course itself. S O. I hope by now everybody has downloaded the script CMI app, the conference agenda and course materials can be found on the APP itself. Um, a lot access Thio recorded version of this program will be available about a month from now for best performance in terms of live streaming. We do recommend that you closed down other APS and Web pages that you may have open on your device that you're using the stream right now a Z may slow down your Internet connection. You can submit questions using the asked a question button on the live feed on goes questions will be shared with us with the faculty. If the live video freezes tried just refreshing your browser and hit play again to resume the video, be sure to visit the sort of virtual exhibit hall during the break time. Those breaks will come up after here. We have our case discussion this morning. Um and you could also use a chat feed on the side to kind of network with other colleagues. Let us know where you're from. Onda, Uh, that would be interested in hearing your thoughts on how things were going. Um, see any certificates in order. Thio, receive those. You have to complete the online course evaluation after the course. Then you'll be able to claim your CMI certificates. So once again, thank you very much for coming out. We look forward to our talk today and I'll turn it over to abduct us. Huh? Yeah. Change. Hey, Good morning, everyone. Welcome to the Cardio Myopathy Cardio Oncology Symposium. Thanks for taking the time the Saturday morning to join us Yes, of course, it feels a little. Not a little a lot different. Doing this virtually as opposed to sort of be a symposium. But I think we've all attended enough board review courses and or WAAS would review videos that I think there's some what used to this format, uh, intentionally or unintentionally. I do hope everyone gets something out of this. I talks are focused and politically based, and about 30 minutes each 30 40 minutes each. So with a couple of sessions on purely just cases without lectures, where we have sort of a panel discussion on different approaches thio some of these conditions. So that's why disclosure slide. Okay, so what I hope to cover in the next 30 minutes or so is talked about cardiomyopathy more from a standpoint off. When do you suspect cardiomyopathy? Um, you know, patient comes in with some vague complaints of fatigue or shortness of bread, or you have to get an e k G. And you know there's a BBC. They're usually that's a referral from a primary care physician as well. Eyes. There's something underlying going on here. So what exactly is cutting myopathy? How do we screen for these patients and what techniques we employ. We don't wanna do 10 tests for every patient. But how do we triage? And Taylor? Who needs what? Testing to be done. Um, how do we apply? We're all hearing and learning more about sort of genetic testing becoming more mainstream. And with the availability off, you know, whole genome sequencing. Next. Gen sequencing. We are using it more than we've ever done. But how do we use that in a sort of busy clinical practice? Give you a couple love patient examples that illustrate some of these points and then maybe one disease condition that I spent a little bit more time would be hypertrophic cardiomyopathy, Given the recent developments, as well as the prevalence in the community compared to some of the other cardiomyopathy, these so the film cutting myopathy itself and sort of use very, you know interchangeably in that, you know, patients are either too, you know, CHF heart failure, non ischemic cardiomyopathy, dilated cardiomyopathy. Maybe you have amyloid, so sometimes the term can be confusing for patients as well. So when I see a patient for a sort of a concert reference from a general, cardiologists Oftentimes they're confused and initially just start with sort off setting the ground right in terms of he, uh, the reason your effort is not because you have something that terminal, but it more has to do with There is a suspicion off heart muscle condition, and we're going to try to figure out what it is if there is on also during that time explaining to them. You know, while the storm heart failure exists, it doesn't mean it's the end of life. It's more a condition in the you know what the heart from keep up with blood flow and fluid levels and things like that, and it's sort of a term that's just stuck with us on bits. There may be the advanced heart failure patients. It fits more appropriate, but not for the vast majority of patients. So sometimes the first five minutes of the visited is purely spent just explaining to them. Here's where we are, um, and here's another reason why you know, this term is sort off. Still not clear cut as opposed to a myocardial infarction or coronary artery disease. The term itself has evolved over time. It was first not that long ago, only the 19 eighties where you know John Goodwin and the group clearly came up with the term cardiomyopathy, dilated cardiomyopathy restaurant, active hypertrophic cardiomyopathy. That was sort of the first foray into him. We need you coin a separate term for this group of disorders that started, and then it sort of got a little bit more complicated with the W H O classification. But more recently now about in 2006, with the American Heart Association coming up with sort of their classifications, it's a little bit more mainstream and lays out clearly. You know how to differentiate cutting off these and how to explain it to patients as well. So what is the American Heart Association definition? So basically cutting myopathy is defined as sort of a condition associated with mechanical meaning. The contract ality, or relaxation properties off the heart muscle and usually associated with some sort of an electrical dysfunction. But not always, and oftentimes patients will have every remodeling so other hypertrophy or a dilated cavity, but not all the time, so meaning there could be a patient who had some with me, a completely normal looking echocardiogram that does not rule out the president off playing myopathy frequently. Genetic more often than not, these airman. A genetic disorders meeting associated with a single gene. Uh, but there are many conditions where there's more than one G in plate, and often times they can be an aggregate risk involved when there are multiple genes involved, not one off, which comes out as being pathogenic. So there is it genetic component as one of the familiar components, thereby oftentimes and involves the heart. But not always. I mean, these conditions can involve other organ systems as well. So getting a thorough history becomes crucial and sort off narrowing down. What for the testing to order or what even the differential diagnosis it's. Every conference should have one slide that is so busy and there's a lot going on. So here is my one slide, Um, but this is from the American Heart Association and sort of the classifications used for cardiomyopathy. The only reason I show this is not that we need to know this classifications, but it's sort of good to have this approach a tow back of your mind. When you see one of these patients, um, we often time start with the patient is referred to us, you know usually starts with They've had an echocardiogram. Okay, there at least function normal or what does it look like? The atria enlarged in there will be wall thick. So that's sort of the morphology and the more full functional phenotype. How does it look when we just look at whatever image ing is at hand? It could be a memory. Could be a CT. They had some other reason. Could be a memory that they've had early on in their evaluation. But that's sort of the first step. How does this eventually even look, the second step is a history. Okay, Does this patient have primarily cardiac related symptoms, or is it more than that? You know what I mean? Is there, uh is there on the labs? Is the kidney function off? Is there any skin or rash cough, other system involvement, so that follows next and then getting a good family history is crucial at the onset. Or the big picture could just be like, Is there any history of sudden cardiac death in your family at the first broad question and family doesn't stop with siblings and parents, but first degree relative, grand parents. Do you know anything? And did anyone die at a young age? Is there any history of heart disease? So that's a familiar competent. And then, based on what you think is going on, you can then get into okay, this somebody I need to do a test on or is this somebody I should basically work up for amyloid as my first go to? Or could this be hemochromatosis so that close and based on the visual appearance on the echo or image ing the organ system, involvement the family history and then then deciding what the next step iss ah, stage of heart failure purely refers Thio. When you see them, what stage are they? And are they sort of plateau exchange there? Or is this someone who is progressing and likely is going to need advanced have faded therapies, just cardiac transplantation in any other future. So what happens in a sort of BT clinical practice way? All go with pattern recognition. It's how we craned. It's how our human mind is sort of crane to function way. See someone? Okay, I've seen 10 patients in a similar sort of history or similar E k g or echo. Here's my differential. That's how we start with. And we then decided what diagnostic imaging modality to get. Of course, echo is go to bread and butter. Almost always, it's echo. But after that, is there someone who needs a cardiac city? Is that someone who needs a cardiac emery eyes? There's somebody who needs a scan for amyloid. Or is this Somebody needs an FTC text can looking for Starr coy. And I think Dr Juan Lopez will be talking about this. You know, even cardiac memory. What I've learned, Um, in the recent few years, it's not as simple as ordering a cardiac Emory, but having some differential to clue the radiologist or the image ing physician that, Hey, here's what I'm suspecting. So given the number of sequences that can be done with an emery, they decide. Okay, how do we package this emery and look for the 56 conditions, Um, as opposed to just a generate m r I. Then who gets sort of genetic testing, who needs an arrhythmia monitor and who should be referred to a cardiomyopathy heart failure specialist. These are questions that comes up in one's mind when you see a patient like this and it's crucial to remember, you know, heart failure, specialist. It's not just that Oh, you need a transplant on dure that safe. But often times it's like, Hey, you know I don't have the band with Can you just I know there's something going on here, but can you help Sort of figure out what's going on? And sometimes it's having access. Do all the stuff that you just alluded to, whether it's Z, um, or permanent or long term sort of very clear monitor that's implanted. That's not done in a physicians practice or getting easy access to getting genetic testing, genetic counseling or one of thes imaging techniques as well. So that's usually where we function as cutting up. You have specialists, the self quarterbacking this piece off it, getting to the diagnosis and then laying out a road map. Okay, here's your diagnosis, and here's where we go from. Here s Oh, that's a lot of what we do and a small percentage of these patients we'll need either heart transplantation or specialized treatment for employees or cardiac sarcoidosis like conditions. So this is what when I say pattern recognition when we get the echocardiogram, when we just look at it visually, even without looking at dimensions or strain imaging, we get some visual clues. Okay, this looks like non compaction. This looks like HCM, and it gives us something to work with. Not uncommon, many a time the echocardiogram could completely normal, as on the top left with the L B and atrial sizes looking okay. And that's usually when, um, either the patient roughly to me or there's a discussion at least. Hey, I think you know this patient probably should get some imaging technique and see you as well. Eso this graph here, which was published in Jack a few years back, Sort of give us some clues how to go about this. So we have a pitch in with either heart failure or a symptoms suggestive of cardiomyopathy. We get an echocardiogram. One way to go about this is okay. What is the L b wall thickness look like? Is it increased hypertrophy or is the wall thickness normal? And if the wall thicknesses increased usually what we're trying to figure out just just hypertension. Uh, could this be hypertrophic cut him out pretty or something infiltrated, such as Emma Lloyd uses, um, on and in some cases, fabric disease, which is a mimic off hypertrophic cardiomyopathy. Look, it was a lot like a C M ACOG's, um, young men. Um, but it has renal involvement, unlike hypertrophic cardio ma graffiti. But these are the clues we get with an echocardiogram showing increased wall thickness. And then we go on thio, the other group. You have an echocardiogram. The function is preserved on the wall. Thickness is normal. Now, in these cases, you're thinking about not so much conditions like HCM. What could this be? I've seen a couple of cases actually wanted very, very and high tire oId Hypo Thyroid President. This way on bond more commonly is sort of this restrictive cutting myopathy picture where patients could have one of these different conditions get into it a little bit, that where the echocardiogram is normal, But you have clues where the a tree are enlarged. You see echo cartographic evidence of high filling pressures. You tissue Doppler velocities. Several velocities are decrease. Those clue us in. OK, well, there's something going on over here, and construction usually has to deal with a history? A. The patient's construction is not the easiest diagnosis to make make right away. And you know some of it is suspicion. If the fact cardiac surgery, it's more easy to think about it. But otherwise you see these cases where people have construction, idiopathic unclear reasons on day, then it sort of takes a few visits to figure out why they have. Or could they have construction? Oh, so So this is an example of an echocardiogram restriction where the atrial really dilated and usually by atrial dilation, almost at times equal to the side off the ventricles. And when it gets to that stage, this patient is profoundly limited, symptomatic fatigue with minimal exertion, and usually they're gonna end up needing. And that's how figure therapies or depend on the age group. It might be alleviation because it's very difficult to treat patients once they get to that stage. So ideally, we want to catch these patients and intervene before they get to this, uh, stage restrictive picture. So when I suspect restrictive cardiomyopathy on the echocardiogram where the wall thickness is normal for this profound diastolic dysfunction or relaxation of normality is the heart muscle is stiff. First question, I asked myself in my head, Is this a young patient or an older patient? And when I have that, it helps me sort of come up with a differential diagnosis. And then I get into what are their primary symptoms? Arrhythmia, Um, diastolic dysfunction, volume symptoms, fatigue, low cardiac output because of the stroke volume, Um, and then decided what imaging technique to use to get to the diagnosis. You're gonna have a copy of these sites, but it sort of lays out that pathway off how you start with an echocardiogram, whether it's a symptomatic patient, normal wall thickness looks like restriction on How do you proceed with a differential and getting to a diagnosis? Yeah. Other specific entities that are not clear. But, you know, I mean, a lot of it has to do with history that clue us in. You know, if if women still with the baby and 456 months later, they she now has symptoms of heart failure, Could this be very bottom cardiomyopathy? Um, diagnosed hypertension. Sarcoidosis is probably one of the most challenging diagnosis personally for me to make because of its multi system involvement. And there is not one test that is absolutely tell you yes or no For SAARC oId it's not someone you know. You can trust your biopsies because of the granular deposits. So it requires more than one visit requires perhaps more than one test and sort of really getting to know the patient, their history and putting it together to get to a diagnosis off circle doses and more importantly for this topic cardiac sarcoidosis, chemo induced Kareem operative we're gonna hear about from Dr Hotels and how that has really changed with all the different chemotherapeutic agents. So a swell as cancer treatments out there and more into pattern recognition. So the images one piece off it, and then it's combining the image ing with the history. You know, if we see somebody will be dysfunction, that promise we're going to think about, you know, this year's no Filic if this law floss versus will be dysfunction with heart block but just heart block and some PVC, don't think about cardiac sarcoidosis. So there are these patterns that over time, you know when you see a couple of patients we all get tuned into, and usually when we see a patient with this, okay? We're going to think about this. Differential needs to be, um this diagnosis needs to be at the top of my differential. So this is both the disease pattern recognition beyond the imaging techniques, what do you see? Most commonly in clinical practice, so usually tend to be patient has palpitations to get an e, k g or a holder and arrhythmia suspected and or they have evidence of arrhythmia, which could be atrial or ventricular. That usually at least in my practice, is sort of the most common pathway of reference for some of these patients. Hey, there's some arrhythmia. The echo and the function is normal. Can you take a look and see? Is there some underlying cardiomyopathy, especially in a younger patient? You know, their fifties early sixties forties? Um, there is more off the suspicion this left ventricular hypertrophy in clinical practice. Most commonly, what I've seen is amyloidosis. Hypertrophic cardiomyopathy will be non compaction. Sarcoidosis is interesting, and some patients will have some lb thickness or hypertrophy. But most times can have a completely normal echocardiogram. Same thing goes with restrictive cutting myopathy where you could have left ventricular hypertrophy and develop a restrictive filling pattern different from restrictive cardiomyopathy, which is a different entity on then air B D. C. Some off those concepts from our GP colleagues. Um, so he secured some conditions that, you know again associate with clinical practice and usually cut it come up with these hypertrophic dilated. Restrictive is what we're trying to figure out. We're seeing more and more of non conviction, some off. This has to do with sort of our imaging techniques getting better on DNA, having higher resolution to look at compacted with his non compacted myocardial eso. There's a lot of still debate and talk on what is the clinical relevance. Was his incidental finding off non compaction on emerging? Um, arrhythmias? CPV T tends to be fairly common. Um, a fib, of course. Is there usually when there was just a fib? We don't start out in practice. Most times they cut him up. If you work up usually tends to be other risk factors obesity, sleep apnea, hypertension, uh, and rarely may be in a younger patient with a faith, we tend to look for other conditions. We're going to hear more about emerging in terms of image ing and cardiac. Emery is a screening test in the right patient. How it gives us clues beyond just, uh, if this car is the Galilean enhancement or not, how do we get beyond that from an m R I and get more information on? We'll hear more about that in the next talk. So coming to genetic screening or screening in general. So that why is it we know all the imaging tests available? We know all the tools available, But why is it so challenging on? It's frustrating for patients as well that they have to see sometimes two or three cardiologists before they get to a diagnosis and why it takes X number of tests. A lot of things has to deal with. You know, the variation in the clinical expression off disease. I mean, yes, you can have a gene associated with the condition, but this tremendous variation that goes beyond even if two family members have the same gene, how they express the disease, which makes getting to the diagnosis uh, challenging, uh, ended. Go. So there is both that in terms off. Okay, well, you could have something like HCM and with genes involved. Are there more than one genes involved? And then even within a given gene with the mutation czar and these can play a role, and then you're factoring other environmental factors that epigenetic factors that play a role. And all of this can really very the clinical expression, making the diagnosis a bit challenging. So it is sort of a bit of a complex issue in terms off. Okay, who do I get? A generated test, and then to it is How do I interpret the test is not binary as yes. You have a positive test? No. You have a negative test. Uh, it's a little bit more like this. Okay, you have a pathogenic mutation. Most often you see something like a variant off unknown or uncertain significance. And then every now and then you get Okay. This is a benign test we've checked for 27 genes are 52 on the panel, didn't reveal anything. And how do you take that in the context for a given patient and discuss the findings off this chest? Take. So this is where again, you know, having a cut him up with your heart failure specialist helps and seeing these patients, because once you get a text back and there is a certain given mutation, it is likely benign or variant of uncertain significance. Explaining that to the family. And how does that plan in terms off their roadmap? And who should get screened then in their family, these air, certain questions that come up that we can help with when we take care of so patients. And here are some of the common reasons when you think about screening and genetic testing and practice one. You know, we think we have a diagnosis. This looks like HCM, and now I want to get a genetic test. I wanna correlated with the clinical phenotype and can clinch the diagnosis and be sure this is it. Oftentimes patients want more clarity, and you could tell them, Hey, I think this is what you have based on your history, your image ing on. Do they want to know? Is this something that runs in my family? I'm gonna have kids or I have kids should they be worried? So there's that that comes in beyond just the patient itself, and sometimes it actually adds to more confusion because you get one of these benign or likely benign variant that shows up and you think you've had the diagnosis perfect and patients happy, and then you get this back, and then it can create more confusion. So sorting that out with the patient and then offering counseling once you get a test back, what does this mean? Um, sometimes mostly for the patients, but uncommon. But happens every now and then. You get a chest back and then have to come to my partner calling physician. Don't worry about it. This is not anything that Z two worrisome in the clinical context. The workflow in practice these days, it's gotten so seamless. You know, you could get a saliva test. You could get a blood draw test. I usually get it, then done right then and there just to facilitate. So I'll have my nose, you know, get a sample, get a sample and then you send the paperwork out. And usually I find out based on insurance and Kobe, what is the patient? Convey that to the patient, either zero co pay or based on insurance, 5100 bucks. Make sure they're okay with it before running the test. It used to be in the past, and this was a few years ago away. Unknowingly, they would get a bill for a few $100 and that was not very pleasant, both for me, of the patient. But that seems to have streamlined. We figured out a work flew for that don't give you a few patient examples showing how some of this has come together bringing in screening testing in patients referred for one of these about symptoms. So here's a 60 year old patient with arrhythmia. Heart failure of the functions have been on the reduced side. Patients diagnosed having SPT and VT. So this is a patient transferred from outside, actually insistent arrhythmia on deck. Aquatic graduate might be reduced function. There's arrhythmia. Get a memory that shows a lateral scar. And now I'm trying to put all this to get I mean, it's not a 40 year old, but it's not a 19 year old, you know, sixties this age, where he could easily have familiar conditions on Based on the mutation, it might not be picked up until much later eso so this patient gets a genetic testing done, which then reveals homeless, I guess. But a pathogenic variant in a sudden gene. And then this is a gene associated with muscular dystrophy and dilated cardiomyopathy. And this station actually has known sort of muscular dystrophy and had that as a kid is fully functional, can walk and do stuff has proximal muscle weakness. But this is very nicely tightened the diagnosis and added clarity for the patient explaining why what is going on? So in that case, I think it helped, Um, so I have five minutes to go. I'll go through a few other cases. Here's another patient, a 27 year old male with acute heart failure and colonization shop reference to me. You know, I get a biopsy was not particularly revealing. Emery was done and showed Carolinian enhancement. And then you get a genetic testing. We showed a couple of different mutations, and here is a clear example where you know you don't have a pathogenic mutation in one gene, but there is aggregate risk when you have multiple mutations at some of these mutations that clearly be implicated in arrhythmia on underlying cut him off. So this is a patient, you know, if you're on the fence if they need a different later. Uh, this is not made in the guidelines yet, but when taken into clinical context with some arrhythmia mutations that clearly increase the risk for for the events this patient did end up getting a different later. And actually, just a couple of weeks back came in with a full blown VT that had I c d had shocked him out off. So So So it it has these, uh, rules out in full force here. The 50 year old highly functional mail, No symptoms at rest. And then with exercise, he has PVCs. Um, and he had an extensive work up, Brian revealing echocardiogram, un revealing. But it was so profound. When you look at his e k g, you know that there's something going on this wasn't like, Are we also attract or anything? So here we get a new agenda test done, and it revealed clearly the president's off mutations that put him at a higher risk for arrhythmias. Aan de. So this helps sort of exercise prescription and more for him and his case in terms of screening, how it goes about managing. So let's skip this one and quickly. Last two slides on just hypertrophic Karima. Given the prevalence off this disease, I think where this audience is quite familiar with hypertrophic cardiomyopathy, we rule out other conditions, like hypertension and low doses extrano sis. Other reasons for hypertrophy. And then you're left with now the steak heart muscle, which is not just accept them, but you can involve any other morphology. At least five or six have been described. Um, it isn't always Oh, no dominant trait and it can be incomplete penetrates at a young age. And hence you might see patients who didn't have anything in the twenties or thirties but can be symptomatic in their fifties or sixties. Presentations can vary from yes, you have the mutation. Yes, you have the condition and no implication from a sudden cardiac death viewpoint. Was this your highly susceptible for an event? Arrhythmias or heart failure? Needing transplantation? Um, multiple genes have been implicated the miles and binding protein, as well as the mice in heavy chains that one's implicated in 50% off this condition, and usually the patients get diagnosed or at a younger age, tend to beam or symptomatic. Sometimes you can find these patients later in life who have get diagnosed. They have the mutation, but these are populations. Are patients self selected themselves for a better outcome on? We've seen this in certain sort of ancestries that if they have it and you diagnose it at 70 75 they may or may not need for their interventions. Especially, they don't have high risk features that is passing out or arrhythmia. Uh, and here's an echocardiogram just showing you know what example of how they can have em are and how they can present, um, And but the drug treatment usually helps a lot on how these patients do Early on, it's a very dynamic, pre load dependent condition, so so these patients will do quite well. Uh, just the reason I should. HTM is one is extremely prevalent in the population. One in 500 patients, the far as we know habit. But to just like Malloy doses, we're making tremendous progress in 80 emboldened diagnosis and management. Just wanna throw one slide on map camped in a new drug. Think off this and a super relaxer off the heart muscle inhibited correct miles and a TPS slows down contract ability and thereby the hypothesis help patients feel better because one of the problems this is the hyper contracted city. This was a multi center trial just published a few weeks back in the Lancet. Um, done in 13 countries, 68 centers. Looking at this population, the blue line is a drug. Red line is the placebo. And every outcome that was looked at thes patients did better when they looked at biomarkers like NT BNP looked at radiance looked at proponents. Looked at N Y j functional class across the boat. These patients did better on the captain with no was side effects than placebo. This described here on the left is the study. Drugs have a captain on the right of placebo, and it shows you between baseline and we 30. How there were more patients, uh, lower function class. Lavender is n yj function. Class one s so you can see on receiving the drug for a few months. How? Patients did a lot better with the study drug. Yeah, um, let's skip this s o. My taking points don't under Smith, pattern recognition is actually really useful to come up with a difference to the start. with genetic testing can play, play a vital role and have a low threshold for everything. We are monitoring using more than one image in technique and getting the input of a cardiomyopathy specialist for helping clinch the diagnosis or laying out a road map for a given patient. I'm gonna stop there and thank you so much everyone for taking the time and we'll get back. I'll be back again for cases. Thank you.