Randy Martin, MD, joins Marc Miller, MD, and Dimos Pandis, MD, who provide new insight about arrhythmic mitral valve prolapse – which has been identified as a potential cause of sudden cardiac death in some individuals with primary mitral valve regurgitation. Drs. Pandis and Miller have extensive experience in understanding the complexity of this syndrome and highlight which patients could be identified as at risk. They discuss common phenotypes and characteristics, such as: the presence of complex arrhythmias, female gender and other risk factors, will aid in risk stratification. Drs. Miller and Pandis share insights about imaging, including Echo, MRI and PET scanning, as well as EKG characteristics. The heart team at The Mount Sinai Hospital have developed an algorithmic approach on how to handle patients who are thought to be at risk of arrhythmic mitral valve prolapse as well as potential electrophysiologic and surgical approaches. Physicians who evaluate patients with mitral valve prolapse will benefit from learning new insights about how these patients can be identified and properly treated. Hi, I'm Doctor Andy Martin. We're here at Mount Sinai. I'm clinical professor of cardiovascular surgery. I'm thrilled to have two of my colleagues. Demos. Pandas. Demos is as assistant professor of cardiovascular surgery and is also the associate director, clinical research and education. And Doctor Mark Miller, Mark's a cardiologist, but an important cardiologist as most cardiologists are. But he's, he's the, uh, is the head of the cardiac arrhythmia service uh in the Cardiovascular Institute. And one of the things we've talked about is a team approach to problems. And I think what we're gonna talk about here is really, uh a great example of this. So this really comes to the topic that we know of people who have mitral valve pro ops and who e experience sudden cardiac events, sudden cardiac death. And we've learned a lot about that over the, over the period of the year. So, demos, why don't you start us out and give us a little bit of a historical perspective of that? Thank you. It's great to be here and discussing this, very important matter mostly. Uh, because it's, it's gained this crescendo of interest in, in the last about 10 years because it concerns a part of the population that uh are affected in an otherwise benign disease, which is uh uh movar prolapse. As you will said, mo is modular prolapse. You know, being the most common uh valvular heart disease uh uh uh in, in the world currently and also in the United States affecting about about 3% of its population. Now, um we know that the majority of these patients are afflicted but uh uh ventricular ectopy uh which is not always something very significant. But however, uh we've come to realize uh with uh recent data, more cohesive data uh that there is this part of the population even smaller than that exhibits about 2% of this patient with much of our prolapse that can have significant uh ectopy and sudden death. So you're talking. So what you're saying, we've got a lot of people with much regurgitation and mitral valve prolapse. We have some of those or a lot of those might have isolated, isolated PV CS and stuff. But there is a subgroup which makes up, you said 1.8% of those patients who could have, who could be at risk for or have had cardiac arrest. Exactly. And this is what makes it difficult for us to find a way to stratify these patients and to make some kind of a meaningful understanding of whatever reported data has been available to us over the past decade. So we can advise our patients because, you know, we see and I'm sure Mark you may be but where you are now with this level of sophistication, but we've seen for years, patients who come in and say, I my heart's beating irregularly and you've got some isolated PV CS and they might have a little bit of ma regurge the question really is who's at risk and how do we determine that? And, and then how do we treat it? So, once you continue, so that's good. So the risk, it's a small pool, but a very significant pool, of course, we don't want to be in that 0.2 you know, 2% that might end up having a very short life otherwise, because these patients uh under uh uh uh uh early surgery and treatment, they go up to have a uh uh a life expectancy of uh nearly to the healthy population. So, um, we need to prevent this and we need to be able to find a way to isolate these patients and to make sure that they are seeing a specialist early on in their, in their disease process. So was there, there has been a feeling that if you had mitral valve prolapse and you had significant mitral regurgitation in PV CS that you were in that group, but you're going to tell me that that might not be the case. So I think a couple of things, one is, I think that's a very important point earlier about the risk of sudden death is that very often we think of more common substrates for sudden death, like hypertrophic cardiomyopathy that everyone knows about. Everyone recognizes as a risk. But based on the number of patients in the United States that have mitral valve prolapse, more patients are likely dying of sudden death due to mitra valve prolapse than due to hypertrophic cardiomyopathy. It's estimated about 25,000 patients a year in the United States alone. One of the common misconceptions to your point is years ago when you went to a cardiologist, if you had bileaflet prolapse with a little bit of Mr and some PV CS, ultimately, what they'd always say is, don't worry about it. It's a benign condition, just go about your life and get an echo every few years. And we know that's not the case anymore. Besides the actual risk, we know that most sudden deaths actually occur in patients with just mild Mr. Now I'll just show you one slide here. This is from one particular study where they looked at all the patients who actually had MVP related sudden death and more than 80% of them occurred in patients with less than severe Mr if you just look at the mild and it's the majority. Exactly. So it's important not to associate that the risk is only in those patients with significant micro regurgitation. It's actually quite the opposite. And that makes the thing a two pronged approach, which is necessary for us, not only for us to understand it, but also educate the patients that the context of the severity of the disease is not necessarily the driving force that they should be having or building a relationship with a physician. And I'm not sure that the vast majority of cardiologists appreciate that fact. At this point, I think it is the least known fact in MVP related, no doubt, no doubt. So, about 10% of our own population that has been referred to us for surgery. Mind you with significant mitral regurgitation for, for surgery. Uh, their physician had actually associated their concomitant presence of ventricul toy uh with their mi uh prolapse which, you know, says a lot. So, so let me and I know you're gonna talk, you're both gonna talk me through this. But if so if, if I, you, yeah, that's fine. But so if you're telling me that I don't, you know, it's not necessarily the people that have severe Mr is that the people who come in, I'm thinking of patients of mine that I've sent up here. Uh You, you guys have worked on patients who have frequent activity could have couplets, you know, not, not any known history of malignant arrhythmias but have, by way for prolapse with moderate Mr just, just you, you, you started at the outset that just PV CS alone, even in the presence of bi foot prolapse is not necessarily the subst state that's gonna have sudden cardiac death. No. And unfortunately, you know, PV CS are so common as pointed out that, you know, 60 to 70% of patients have PV C. So it's just way too non specific and sensitive to use that as a marker of sudden death in and of itself to your point. Just to show you here is that there's, there's two groups of patients, there's a group of patients with mitral valve prolapse, of which at least two thirds have PV CS. But if you look at just the patients who had sudden death, 100% of them have PV CS. So if you start, if a patient has no ventricular ectopy, then obviously, I think they automatically fall into a low risk category if they have ventricular ectopy. And to me, burden is less important than complexity, which I'll get to in a minute is those obviously are the patients you want at least start to explore a little bit more. There's two, there's a couple of things about ventricular ectopy. One is the complexity. For example, if they have couplets and triplets, to me, that's a higher risk than if someone just has a high burden of single morphology. P BC. If people have two or three different morphologies on the holter, that to me is higher risk than someone who has a single morphology with a high burden. What we also know is that location does matter it's like real estate in the sense that most patients who've had malignant events, usually at least one of their morphologies is coming from the papillary muscle or other areas that we call the Perini system. So if it's purely outflow tract PV CS, it's probably less important, at least the data that we have than for example, patients who have Perini related PV CS. And I think what mark says is uh reflective of how far we've come along since the past 1015 years. Well, we only identified this constellation of characteristics that are identified in this patient with the much of our problem, regardless of the severity of Mr those were those abnormal EKG findings like inverse T waves like infer patterns or inferior leads or conduction delays or uh you know, patients that were those that ended up having those events were, you know, younger patients, predominantly females. But now, as Mark pointed out, uh we've now gone and identified very granularly a lot more of the, the, the morphology of the uh of the and the complexity of, of those activities. And you, I mean, it's, this is fabulous because you're really telling me stuff that I didn't know or I wasn't up to date with, is that basically the, the two facts that you've mentioned is not necessarily, you have to have some significant Mr and two that it's really the complexity of the PV CS as opposed to the burden I opposed to Justin Unit. Yeah. So that's I'll make just one other comment in regards to this is so, you know, this seems complicated to a non electrophysiologist and I totally understand that, but that's why you're here very, very often what we talk about in literature or at least the early literature was just using the term ventricular arrhythmia. And I do think that there are different categories of ventricular arrhythmias and the mechanisms that predispose you to those arrhythmias are actually related to the interplay between the prolapse and the substrate. And so hopefully, in the future, we'll start to clarify the difference between a monomorphic ventricular tachycardia that's due to something like triggered activity, which should resolve with surgery versus monomorphic ventricular tachycardia that's due to scar that already exists that the risk will be there, irrespective of the surgical intervention. And you just mentioned now, one of those characteristics that are usually finding in these patients, and we'd like to use as markers to keep these patients under the radar, like for example, my cardial scar and its distribution. So we, we've also gone far a long way identifying uh not only how important that is but its location and how we can uh how we can use this uh to certify this patient mark, go back one slide because you, you were talking, I was trying to concentrate. So the difference, tell me what, what you're trying to show or tell us and me and the audience what you're trying to show with these two. Sure, I'll give you an example. So the bottom left hand of the screen here is an example of monomorphic ventricular tachycardia and a patient with severe Mr that the mechanism appears related more to what we call triggered activity. So, is irritation of the papillary muscle from the prolapsing leaflet and it just has that characteristic. Now, why is that important? Because this patient with this type of arrhythmia, even though it's monomorphic VT is very low risk for sudden death. And this patient, if you fix the mechanical forces during surgery, it will resolve. That's exactly what happened. In this case, most people would look at that and say, gee no, I think, you know, we need to do something besides surgery correct. And I think that's where one is having, you know, the more patients you see and the more you kind of put them into their correct categories, the easier the outcomes or predicting the outcomes will be. And that's a lot different than the patient here in the right upper hand column here. This was a patient who already had surgery years ago, who had monomorphic VT that was simply related to scar. So similar arrhythmia, completely different mechanisms, the interventions are completely different. So hopefully in the future, rather than in these prospective trials that will be ongoing, they'll start to clarify the types of arrhythmias rather than one broad category and their mechanisms and the context here would be that we, we are lost because we are looking at this retrospectoscope from the back end, we've known the event at the end and we try to figure out what the steps were that initiated all this process. And so far, we just accepted the obvious and the obvious was excess, excess prolapse excess, uh uh uh uh excursion of the leaflet, excess tugging and that means myocardial injury. However, we've also known for many years since our anatomy, uh uh understanding of the anatomy that uh myocyte are built for that, they're built for cyclical contraction and relaxation during. So, uh they have ways to, to counteract the excess of inflammatory response. So there has to be an additional way or additional signaling pathway that ends up not having the same effect to the these types of patients that are exposed to the same risk factor. They're all progressing, but not all of them have ectopy. And as Mark said, not all of them have exactly the same substrate because of their, the, the, the way that they, the, the my car injury, the scar is distributed. Some it's focal and other patients is more diffused and we're still working out what the role is and, and how has this been going about and its relationship to the manifestation of the ventricular sy. So, so I'm still trying to, who's at risk here. Is this gonna, you're gonna help me know the patients that might be at risk. We're talking about substrates, but I wanna know the patients that might be at risk. So I think my personal belief is that it is accumulation of risk factors of every other disease. It's not just one risk factor, it's usually multiple risk factors. So a few years ago, at least based on literature, there's a fair number of studies at that point. Looking at patients with malignant micro epilepsy, meaning those are patients who already had events and we tried to put together what we believe to be some of the risk factors necessary for patients to have cardiac arrest in the future. And so in this particular figure here, what you see in the middle in the triangle are the identified risk factors, how much they're weighted. We don't know yet and on the outside is the environmental factors which contribute to it as well. So to give you an example, we know that female gender is higher risk than male gender, we know younger is higher risk than older. We know that from an individual risk factor, it is worse to have severe Mr than it is to have mild. Mr though on a population level, many more patients mild are having sudden death. Bileaflet prolapse is worse than uni leaflet prolapse complex ventricular ectopy such as multiple morphologies is worse. The next one is forms of mechanical traction. So the pickle hub sign where you see high velocities on the annulus seems to be a risk factor for the development of ventricle. Is that more common with bi proops? Uh I'm not, I'm not sure if it's more common bi props you have the echocardiograph. Yeah, you see it, it's more pronounced in patients would have more redundancy. So whether or not there is bileaflet or not, it's, it's usually the posterior leaflet that will result into this type of uh people and crazy annual disjunction. So that's, that's the one I wanted. So the next one up there is mitra angular dys junction and myocardial fibrosis. So, in electrophysiology, every patient who has sudden death, almost every patient has some form of substrate, meaning whether or not it's inflammation or fibrosis, there has to be something that perpetuates the ventricular arrhythmia. Ok. The one below that Milan junction is probably the most controversial one as you pointed out because early on there were many associations with mitra andros junction and ventricular arrhythmias. The problem is, and I think we're now learning this is that mitra annular disjunction is over diagnosed overemphasized. And so there was a nice UK bio bank study recently which took all these healthy patients who got cardiac MRI S about 2000 patients. And if they just use traditional criteria for mian junction, 75% of the patients of healthy patients would have micro an junction. Importantly, the only one that was associated with prolapse was inferolateral adjacent to the P two. So the reality is, is that it's probably very location specific and it's related to the distance. So two millimeters is probably irrelevant. 10 millimeters adjacent to P two is probably a risk. But so, so you, and, and this is really good. I mean, you're, so you're painting a picture that, that we need, you know, needs that people need to know about. I mean, you've gone through other, other things, we've delved a lot deeper than just a picture. We, I think we we've identified very specific imaging uh and echocardio uh electrocardiographic markers. So, yeah. No, and I'm sorry, I don't mean to cut you off, but you've got fibrosis in there. So you're looking at scar cardiac MRI with scar. OK. And then what, now you're gonna wonder what's on, right? So the outside is, you know, this is the idea that for why does a ventricular, why does sudden death happen on a Tuesday versus a Friday in a given patient? And so a couple of things have to happen. One is you have to have a trigger. So something to initiate the event classically A PV C A short coupled PV C as an example, then you have to have something that perpetuates it such as the myocardial scar. But why it happens on a Tuesday versus a Thursday probably has a lot to do with your adrenergic tone. For example, what we call a transient modulator, there's good data that an overwhelming majority of sudden deaths in MVP occur in patients. For example, during an argument, uh one of my patients was waiting for her first job interview, she had sudden death in the lobby. Other patients are nervous about uh a speech they're about to give, you know, cat, this cat surge is probably what contributes to it. Why there is, is exercise related in a lot of these patients. It almost never happens as far as I know during sleep, any of those stressors that will uh increase your catecholamine levels can instigate in the presence of the of the. The the question is uh we've understood and we've accepted that connection that you need to have that spark like you said, but you can have the sub and I think the substrate you can't, certainly can't keep people from having. Yeah. Well, there, there is so the scar is a definitive end point of a process which is, is is irreversible and having uh having uh arrived at a moment to understand this. Uh I think it's now time that we started to appreciate the importance of what happens before this endpoint. And the, you know, from these patients that have much of our prolapse and uh progressive severity of them are from the beginning of their lives because this is one of the most common heritable diseases we know that this is volume loading from for decades. And the wonder of the myocardium is that it feels every, every change from sheer stress from any kind of forces and it starts this inflammatory process way before it can be perceived by the patient or identified by any kind of uh uh diagnostic tests. And by the time we see this, it's way too late. So perhaps one of the aspects that we we should be looking at is not what happens to the patient that actually have established scar, but patients that had a myocardial injury and development because of the inflammation for reasons that might be contributory uh from the prolapse. So how do I work this patient out? Right. So I think it would be, it would be a good example. Now, like we'll take an example of where I think all of this was put together into a patient actually by a different group of cardiologists. OK? We saw this patient as a second opinion, but it's nice to see that in 2023 this patient is being treated differently than they would have. In, for example, 2018, we learned a lot in that discussion about arhythmic mitral valve prolapse. In part two, we're gonna look at a case and tie it all together. I hope you'll join us.