So, just a set-the-table talk for an electrophysiologist. What do we know about the variations in the normal mitral valve and specifically about disjunction? So, nothing specific to this talk that I'll be, that I have a conflict with. So really, it all started a long time ago when we had to deal with a small number of patients with a common disease dying suddenly. And early descriptions of why some patients had this and others didn't started focusing on something about the morphology of the mitral valve. Barlow himself was like focused on how floppy myxomatous it was. And then as the studies started coming in, in the echo era, it was started about thickness, thickness about the valve. But over time, it started looking more and more like a cardiomyopathy that happened to have some issues with the mitral valve. So with the advent of MRI, focus became little less on actual morphology of the valve, how it was seated, but more about the ventricle, just under the valve, papillary muscle and sometimes very disparate sites that had fibrosis. Maybe one of the early descriptions to give some kind of phenotype of a malignant mitral valve prolapse syndrome was looking retrospectively about what the valve looked like in people who had experienced sudden death. And then checking both echocardiographically and ECG, and it seemed to involve as one common factor by leaflet mitral valve prolapse, in addition to some of the previously described morphology. And then a very important added phenotype that's still an evolving factor is mitral annular disjunction. So seating point of the mitral valve leaflets exactly on the annulus or somewhere a little different. And I'll try to review this in the context of variation in mitral valve anatomy. So a few points of difference between the tricuspid valve and the mitral valve. So two kind of commissural sites in the mitral valve. We have three in the tricuspid valve. It's a slanted valve. It's almost parallel to this main axis of this tricuspid valve. And the leaflets themselves are fibrous, and they have a fibrous landing zone. This landing zone is different at different points, and I'll try to point out some of those differences. So while you look circumferentially, you can see that there is fibrous elements, and then we start seeing myocardium. We start seeing ventricular myocardium at the time, at the location or point of attachment of the leaflets. It's very different along the circumference, because more posteriorly and laterally, you have muscle, ventricular myocardium, and part of the outlet of the LV, inlet of the LV, outlet of the LV being separated by this anterior leaflet. So what this means is the mitral normal junction with the annulus is variable across its course. Note that anteriorly and medially, it forms the aortic mitral continuity, which is a more cranial structure than the mitral annulus. And as a result, you have this slant. It's a little more towards the feet as you go to a myocardial attachment to the ventricle, and the aortic mitral continuity being more cephalad. So this is fairly fixed. This point of attachment can vary. And this variation at one extreme becomes mitral annular disjunction. So you could see this difference along the sites. You start seeing myocardium versus seeing this curtain or aortic mitral curtain. Another normal variation that when we look at this mitral valve is when we look posteriorly, we're below the plane, posterior to the plane of the aortic valve. But because of the membranous septum, as it comes down to becoming the crest of the interventricular septum, it's a higher point of attachment septally. So you can see this kind of gap between the ventricular myocardium, and then you go up to one of these struts close to the interatrial septum compared to out laterally where you actually join onto ventricular myocardium. Should also be noted that a normal variant of mitral valve anatomy is for the leaflets to get pasted not on the annulus, but on the ventricular myocardium itself. So you have this kind of little peak or summit of left ventricular myocardium, valve gets attached there. This can be very important in ablation of some VTs or for accessory pathways where to get close to the ventricular attachment, you actually have to be underneath the mitral valve. Finally, a difference between tricuspid and the mitral valve. Notice our normal anatomy, the tricuspid valve, septal leaflet is very much on muscle, whereas the mitral annulus goes up close to the interatrial septum. And this is a normal variant, this is exaggerated in Epstein anomaly. But when we look at the other end here, if this instead of being on muscle, the attachment is actually towards the atrium, more cranial, more superior than the coronary vessels, then we have mitral annular disjunction. Should also point out another difference between the anterior and posterior leaflets, they have a natural offset. So it's not one brush stroke circle. Notice the anterior leaflet, then you have this little dip or this offset before you get to this site. This is also normal and this can be pretty prominent or exaggerated in some patients. Now why do we as electrophysiologists care about this entity? So what's happening is if we get that leaflet, instead of being stuck smack in the middle of the annulus or towards the ventricular myocardium, if it's actually towards the atrium, then we have one fundamental difference, we have tissue that's ventricular kind of hemodynamics, but no ventricular myocardium. So it's like an inverse of Epstein anomaly in this location, and one difference here is what it does to the atrial tissue and what it does to the ventricular tissue. Now underneath the valve is where we're going to meet the coronary vessels. Very important point when you try to ablate patients who have abnormal subvalvular substrate in mitral annular disjunction. We're closer to the arteries, we run along and parallel to the veins. The opposite happens in the atrium. Because we're attaching closer and up further into the atrium, our isthmus or vestibule of the mitral valve is shortened, so we're closer to the valve leaflet and to the pulmonary veins, and sometimes these diverticula, pseudodiverticula that are in the plane of the appendage may now be found underneath the mitral valve. So it affects how we are maneuvering catheters and finishing lines in the atrium. It also affects how we are appreciating ventricular substrate when we are trying to ablate right up onto this crest. In a sense, annular disjunction gives us better access to the ventricular myocardial mass and less access to the mitral annulus vestibular tissue of the atrium. Now for unclear reasons and even though it's been studied for a while, this malpositioning, this change in the position of attachment of the mitral valve is affecting ventricular tissue. Now several reasons for this. One is an abnormality in repolarization, and this has been part of the phenotype of malignant mitral valve prolapse. Normally the latest areas in the heart to repolarize are the mitral annular tissue. You essentially have an extension of this tissue further towards the atrium, so abnormalities in repolarization probably underlie some of this myopathy or electrical pathology that you see near the mitral valve. We also have different strain on the papillary muscles as well as the ventricular myocardium. Valve leaflets itself are higher in position, so the chordae, the papillary muscles are put under more tension, and this tension may be also responsible for some of the fibrosis or some of the problems that we see with MRI. Another point of difference is the conduction system. The conduction system normally reaches the left ventricular free wall through some structures that traverse across the cavity. When we have mitral annular disjunction, this point at which it attaches is relatively lower to the myocardial mass that's most atrial. So there is conduction, takes longer to get to that location, and may explain some of the abnormalities, for instance, in signal averaged ECG in patients who have mitral annular disjunction. VT ablation in this syndrome, long recognized, very abnormal signals that you'll see in that region. They are ventricular myocardial strands. You can get PVCs from this location. You can pace and capture the ventricle from this location. But the weariness has to be the extreme proximity to the coronary vessels. Other pathology can affect mitral annular disjunction. If we have large atria and we have small ventricles, like restrictive cardiomyopathy, then that stretch point for the disjunction is even longer and presumably even more abnormal in terms of pathology. Now these are contact lesions, endocardial friction lesions, as a result of movement of the valve up and down. These friction lesions are more whenever you have more of a myxomatous valve and you have more stretch and abnormalities in the tendons. And this may be the reason why you get ectopy, partly because of the fibrosis that occurs, partly because of mechanical, mechanically actually hitting on that site. And a very important part of the phenotype is complex ventricular ectopy that you see in mitral valve prolapse, bileaflet prolapse syndromes, and mitral annular disjunction. Last point that I'll make is age-related changes, how it affects the normal valve and disjunction. Notice the angulation of the anterior leaflet changes because of the septal bulge that develops over age, even in normal tensive individuals. It also creates stress posteriorly and laterally. So mitral annular disjunction, the amount, the extent, the stress, what's underneath the valve, it's a dynamic variable over time that's affected with the shape of the heart, atrial enlargement, and age. Other diseases, like fibrosis, when it affects the mitral valve, tends to be at the point of attachment, the free margins of the mitral valve. But renal disease, for instance, where we can get calcification around the valve, is at the point of attachment of the mitral leaflet. So where you see mitral annular calcification, frame shifts when you have mitral annular disjunction. These are some things to just keep in mind for the electrophysiologist. Atrial ablation, ventricular ablation, definition of disjunction, and to appreciate it's something that changes over time and affects hemodynamics, stretch, contact lesions, and what's happening to the ventricular myocardium. Thank you very much for your attention. Thank you, Sam. Great presentation. And do we have time for one short question? I would hope so. So just one short question from my side. So what differentiates those patients who have arrhythmias compared to those who do not have arrhythmias but have the same phenotype? So it's very difficult to know if that's actually a true statement because that phenotype is so variable to get exactly the same phenotype. But it's like any ventricular arrhythmia. The assumption is it's the perfect storm. The phenotype is one aspect. Autonomics is another aspect. Cardiomyopathy is another aspect. If you think about the development of the mitral valve and the annular fibrosis, it's very closely linked process with three other processes. The ventricular mass compaction, the nodal compaction, all the node-like cells that's on our annulus that compact towards the septum, and also this distinction of the true annulus, this insulation. So that process, if it's disordered, we're just seeing one effect. The mitral valve leaflet is further up or floppier. But you can expect some disorder on the type of myocardium that's there, the likelihood of having some node-like remnants in that region, heterogeneity of the tissue in that region. That's probably a spectrum. When you add in autonomics into that, then some people get the perfect storm sometimes. A very similar question can be asked. You know, everybody has hypertrophic cardiomyopathy and we have phenotypes. But why is it that some people get malignant death? So we have a scoring system. But for a given score, why on a particular time or why on a particular day? You know, we have, I think, a similar question in this phenotype. Thank you very much. Thank you. Our next speaker is Dr. Pavri from Thomas Jefferson University Hospital. Diagnosis and imaging modalities for MAD. Thank you very much, Chairpersons. Ladies and gentlemen, it's my pleasure and honor to be here. But I have the unenviable position of speaking after Sam. And that's always an impossibly difficult act to follow. My task today is to talk about the diagnosis and imaging modalities of MAD. And Sam has already pretty much covered what I have to say. So I could just sit down, but I'll go over what I have. So I'd like to go over how we approach the diagnosis of this condition. The initial suspicion can come from symptoms, exam findings, ECG and Holder clues. We'll talk about the role of trans thoracic echocardiography, trans esophageal echocardiography, cardiac CT scanning, the cardiac, sorry, MRI, magnetic resonance imaging is probably the gold standard and also provides important information about scar burden and EP imaging and some take home messages. So let's get started. Initial presentation can be quite nonspecific. Symptoms of palpitations, dyspnea, fatigue, presyncope, syncope, completely nonspecific findings. On examination, one clue might be the presence of a mid systolic click, which may clue you into the presence of mitral valve prolapse, which often accompanies mitral annular disjunction. You can hear the murmur of mitral regurgitation if present and a displaced apical point of maximal impulse and an S3 gallop depending on the severity of the mitral regurg. ECGs, Sam has already alluded to some of the findings. There is QRST discordance specifically in lead III is very common. The QRS is upright and the T wave is inverted. That is a common finding in patients with MVP and MAD. Biphasic or inverted T waves in the inferior leads can be seen in other inferior leads as well and in fact it turns out that the number of leads with T wave inversions is sort of weakly associated with the amount of fibrosis seen by MRI. PVCs arising from the papillary muscles of the mitral annulus can be noted as well and if you have interatrial conduction delay pattern that would suggest that you have more mitral regurgitation and left atrial enlargement. In fact, as a historical footnote, this combination of a systolic murmur and inferior T wave inversion was initially labeled by Humphreys as the auscultatory electrocardiographic syndrome back in the 1960s. Holter can be done. That usually is extended Holter for up to two weeks to assess PVC burden and morphology. Often there will be one predominant morphology of PVC that will be recorded and it will often be consistent pap muscle origin or mitral annular origin. The PVC burden tracks very often the sinus rate so it suggests an adrenergic trigger and there can be different patterns of bigeminy, trigeminy, non-sustained VT, et cetera that can be picked up on the Holter. Arrhythmia screening can be undertaken by ILR. A loop recorder has been deemed to be appropriate for high risk patients. This is a study that was done where they looked at 60 MAD patients, 40 got a loop recorder and 20 were thought to be so high risk that they actually got an ICD and they were followed for three years and severe ventricular arrhythmias were recorded in 12% of the loop recorder patients. The incidence was 4% per year and in 20% of ICD patients, 8% per year and the ILR group, non-sustained VT burden was greater in patients with post-remedial pap muscle fibrosis, bileaflet prolapse, moderate to severe MR, frequent PVCs, larger left ventricular end diastolic dimension and greater post-relateral MAD distance and they concluded that the annual incidence of ventricular arrhythmias was high in MAD patients, at least the high risk patients that were included in this study as detected by loop recorder and the incidence was even higher in patients who were thought to be high enough for risk to get a secondary prevention ICD and these were the characteristics that were associated with increased risk of severe arrhythmic event. That brings us to the role of transthoracic echocardiography. It is the most common initial test done as a screen when you suspect this condition. The parasternal long axis view shows it the best. It shows the presence and extent of MAD, the degree of MVP, the degree of associated mitral regurge. You can diagnose pseudo-MAD where the leaflet prolapses against the atrial wall and it looks like the point of attachment is higher up but it's actually not, so you have to view it in systole and diastole. Annular expansion during systole, I'll talk to you more about that. That's a very characteristic finding. And the pickle harp sign, that's a tissue Doppler signal from the mitral annulus where it suggests hypermobility of the annulus as already explained by Sam. It's thought to represent the shape of a German helmet called the pickle harp and some fanciful person thought that this signal looked very much like the helmet, so it's called the pickle harp sign. And you can of course assess the ejection fraction. Strain imaging in MAD shows that there's lower basal strain compared to MVP without MAD indicating regional left ventricular dysfunction. And so here's an example of a patient with clear cut MAD and floppy thickened mitral valve, MVP plus MAD, and now you can clearly measure the annular disjunction and the degree of prolapse in systole. This brings us to the role of transesophageal echo. It is primarily as a pre-surgical evaluation, especially in patients who have severe enough MR that requires surgical correction. TEE provides detailed visualization of the mitral valve apparatus, including the extent and location of the MAD that is crucial for surgical planning and decision making. It has a higher sensitivity and specificity for identifying MAD, and it shows good agreement with cardiac MRI. TEE has an important role intraoperatively to guide the surgeon about how well the repair is going. This study was a wonderful study. It showed the decoupling of the annulus and the left ventricular orifice, as alluded to by Dr. Asavatham already. They looked at 156 patients. 101 had mitral valve prolapse, but no MAD. 30 were normals, and 25 patients with functional MR because of dilation and heart failure. And MAD was identified in 42 of the 101 MVP patients, and the mean disjunction was about nine millimeters. It circumferentially spanned 87 degrees or about one-fourth of the annulus. In normals, the annulus contracts with systole, and its saddle shape actually increases with systole. In heart failure patients with functional MR, the annulus basically stayed dilated and was very immobile. It was linked to the low ejection fraction. But in patients with MAD, the annulus displayed this paradoxical systolic expansion and flattening despite normal left ventricular strain. And here's the reason behind it. Because of this detachment, it's not correctly connected to the top of the ventricular mass. In diastole, the mitral valve looks like this in its position, but in systole, the ventricular muscle moves inward, but the points of attachment of the mitral valve move outward, they bulge outward. So the mitral valve actually expands and becomes flatter in systole compared to normal hearts. And this decoupling is very well illustrated by TEE. MAD is common in MVP, and TEE can show this functional decoupling from the left ventricle. And here's a patient of mine. You can see the point of attachment of the atrium to the ventricle. And you can see the point of attachment of the mitral valve posteriorly. You're sitting in the region of the aortic valve looking back, and when you run the TEE, you can see that in 3D imaging, the floppy nature of the valve, and how there is a severe extent of disjunction that is going on. That brings us to cardiac CT scanning. CT scanning in MRI is especially useful when the disjunction is adjacent to a prolapsed or flayed leaflet that may not allow full visualization with TEE. It allows recognition of up to two millimeters of MAD, better resolution than CMR in some studies. CT in a study of 90 patients with mitral regurge showed that MAD was found in 20% of patients with MVP. And these were the findings that were associated with greater MAD distance. Age-related changes, as Sam alluded to, is an important concept because it's clear that MAD is more common and extensive the older we get. So it probably starts out as a smaller proportion of disjunction, but with the millions of heartbeats over decades of life, that disjunction extent probably increases over time. So this gives us some insight into the progression of this disease with aging. And the majority of patients actually have a very small amount of MAD, and a small proportion have larger than four or five millimeters. So that raises the question, what is the cutoff for normal? We really don't know that. Maybe two, three, four millimeters of MAD may be a variant of normal. Maybe those small amounts of MAD don't increase with aging, but certainly MAD above four millimeters is thought to be, four or five millimeters is thought to be abnormal. And that brings us to the MRI, cardiac MR, which is probably the most powerful test for MAD. It provides very precise measurements, up to two millimeters. It allows evaluation of the entire circumference of the mitral annulus, not just posteriorly. It recognizes increased extracellular volume by T1 imaging, a marker of strain in the base of the left ventricle, and increase in left ventricle end diastolic dimension. And you can see in this study that the patients with normal patients, MR patients, have very little T1 imaging, but patients with MAD and MVP show a lot of extracellular fluid. And as the left ventricular, as the degree of MAD increases, the LVN diastolic dimension also increases. So clearly this affects the dynamics of the left ventricle over years of contraction as Sam described. And it identifies the presence and extent of fibrosis in addition and helps in risk stratification, which will be the next talk. Pap muscle LGE is more common in MAD as compared to MVP alone. Here's an example from a paper we published where we looked at the amount of MAD by MRI, and you can clearly see, you can quantify exactly the amount of MAD and the degree of prolapse that is seen. You can quantify the LGE that occurs at the base of the mitral valve, and so on. Here's a cine angiogram provided by my colleague, Dr. Sundaram. You can see beautifully here how the mitral annulus expands in systole. Look at it in systole when the MAD shows up, the mitral valve bulges outward, and that expansion is thought to be pathognomonic of MAD. This study was done to compare these imaging modalities. How well does TEE, transthoracic echo, and CMR compare? And they looked at 131 patients who had both modalities, and TEE was available in 106, and the results are as follows. Clearly, assuming CMR is the gold standard, you can pick up a lot more MAD in patients with MVP with CMR compared to TEE and even less with transthoracic. But once you identify any degree of MAD on a TEE or a TTE, it's very specific. So it's very sensitive when it's seen. Sorry, it's very specific when it's seen, but it misses a fair amount of smaller amounts of disjunction, so you can see the sensitivity for TEE is quite low, especially for small amounts of MAD. You'll miss that on a TEE. You'll pick it up slightly better on a TEE, and MRI is the gold standard. And as expected, you can pick up smaller amounts of MAD on MR, and the amount of MAD has to be larger to be picked up by transthoracic echo. So the agreement is moderate between TEE and CMR, but it's stronger between TEE and CMR. And the conclusion was that an integrated imaging approach is necessary for assessment of MVP patients, and echocardiography is essential for hemodynamic assessment, whereas CMR is better for small-length MAD and myocardial fibrosis. That brings us to EP imaging. As Sam alluded, EP studies may have a role. MAD is associated with increased risk of ventricular arrhythmias and rarely sudden death. EP studies are useful to map and ablate frequent ventricular ectopy. Infrequent PVCs cause symptoms. They contribute to worsening LV dysfunction, increasing diameters, increasing MR, decreasing EF, or if the patient has had arrhythmic-sounding syncope. Voltage mapping often shows co-localization of low-voltage LGE and T1 imaging. In a study of 40 patients with MAD, frequent PVCs, 25% had low-voltage signals adjacent to the mitral annular disjunctional area, but 20% had abnormal voltages in other areas of left ventricle as well. This alludes to the fact that this could be a more diffuse cardiomyopathy, as Sam alluded to, and 90% had successful ablation. So here's a case report that we published, a 60-year-old man with longstanding MR bileaflet prolapse, multimodality imaging was required, he had frequent PVCs, MRI showed MAD extent, enhanced T1 imaging, LGE, and EP study showed co-localization of the basal LV showing fractionated signals. So take-home messages, ladies and gentlemen, MAD is increasingly recognized now that we know about this entity. As Dr. John Burley said, the eyes cannot see what the mind does not know. Now that we know about it, we are beginning to see it a lot more, and we yet have to define accurately how much MAD can be considered to be a variant of normal and how much displacement is required for it to become pathologic. As Sam said, it's probably a multivariable issue in terms of the risk of sudden death, the perfect storm. MAD assessment always requires multimodality imaging. Usual assessment starts with clinical ECG suspicion, getting a TE and then an MRI, that's the usual sequence. In the future, we may have more information for genetic screening. Currently, only the DCHS1 and the SMAD3 genes have been associated with what is called longitudinally extensive MAD, where much of the circumference of the annulus is involved. And finally, the results of imaging then lead to risk assessment, which is going to be discussed next by Dr. Chakrabarty. So I thank you so much for your attention. Thank you. Some of the data you presented showed MAD was greater in extent in women, and there's other data that shows that women actually more frequently have MAD, and in all of the sudden death reports, most of the patients are young women. I just wanted to ask you if you know why we see these observations in women. So as far as I know, the risk of sudden death is actually greater in men than in women with bileaflet prolapse, but women are more likely to show MAD, but they don't have a higher risk of sudden death. Why it is that women have more risk of MAD is not clear to me. It may have something to do with the hormonal changes that occur in pregnancy. This has yet to be worked out. So for example, in pregnancy, you know that ligaments become loose to allow the pelvic bones to allow parturition. Women are more prone to that kind of displacement, so it's possible that pregnancy may have a role to play in the worsening of this condition. Pure conjecture, I have no knowledge. This is all yet to be worked out. One more question. In asymptomatic patients who have incidental detection of MAD, how do you follow these patients in the clinic? So if I pick up asymptomatic MAD, I get the holter, and if I see complex ventricular ectopy, I consider a loop recorder. If they're asymptomatic and they have no significant ectopy, I simply repeat an echo maybe annually every two years, get an MRI to look for the burden of LG at baseline. If there's no MRI, I wait five, six years to get another MRI. I am always hesitant to get very frequent MRIs because gadolinium is a heavy metal. It is not excreted by the human body. It deposits in the cerebellum, and there are some rare case reports about ataxia after repeated exposure to gadolinium. So I am cautious about how often I recommend MRI scanning. I don't want gadolinium in my brain if I don't have to have it. And so that's the way I approach asymptomatic patients. I don't know if the panel has any other thoughts. No, thank you very much. Thank you. Yeah, I think we have to move on time-wise. And the next presentation will be on risk stratification, which is a tough topic, and we have a, in the European Hybrid Association, have written a consensus manuscript discussing all these things, and we know quite a little of that. So we're looking forward to your presentation. You're from University of Michigan in Ann Arbor? Correct. Well, thank you for the opportunity to speak on this challenging topic, as you mentioned, on risk stratification for patients with mitral annular disjunction. Great. So I'd like to start with a case. This is a 42-year-old female I saw about five years ago now with palpitations. She had on a monitor rapid, non-sustained VT that was monomorphic and with rates exceeding 200 beats a minute. She had an echo and followed by an MRI, as Dr. Pavri mentioned, and that showed bileaflet mitral valve prolapse, mitral annular disjunction, as well as papillary muscle LV fibrosis. She was first seen locally in Detroit, and there they just recommended simple monitoring, no advanced testing. She had came down the road to Ann Arbor, where we saw the same data, but we actually recommended an EP study with possible ICD versus loop recorder. Now this young woman is facing two different opinions, so she gets a third opinion. She ends up in Cleveland, and surprisingly, they give a totally different opinion with just a loop recorder. I think we've all seen, when we're facing three different opinions for the same case, that means we're operating at the edge of current knowledge. This is the Hunt-Lennox globe that was made in 1510, and it showed the unexplored new world. And here they wrote, Hic suit Draconis. Here be dragons. Oh, I apologize. And that's where we were for many years. We were with the unknown in the dragons, trying to navigate this unexplored territory. Thankfully, in the last five years, we have an explosion of retrospective studies, as well as a new set of guidelines that I'll outline, and hopefully, by going over that, we can banish some of those dragons today. I want to briefly touch on the connection. We've already discussed this briefly, how mitral valve pathology is related to arrhythmias first. As we've heard, different forms of MAD may not all be pathologic. Infralateral MAD near P2 is the most pathologic and least common. A very well-done UK biobank study looked at MRIs of 2,500 healthy patients. And while P1, P3 might be present in 80, 90% of patients, P2, infralateral MAD, is quite rare in 5% of patients. There have been a couple of uncontrolled case series looking at MAD specifically, and those have been associated with increased ventricular arrhythmia risk, with MVP, as you can see in the bottom left, but also pure MAD has been associated with arrhythmias independent of MVP. Of course, we know more about MVP. That's present in about 2% to 3% of patients in that same study. It's associated with a 0.1% to 0.5% annual risk of sudden cardiac death. And that's less than HCM, but when you factor in that MVP is five to 10 times more common, that's a significant public health concern. Unfortunately, the combination is even worse. These are two retrospective cohort studies showing arrhythmia-free survival. On the top in the red lines, we see MVP patients, and when you add in MAD, they have substantially worse arrhythmia-free survival. The last anatomic abnormality that's been associated with arrhythmias is infralateral curling. It's present in about 2% of patients, and it's when the basal ventricle and the mitral annulus move abnormally and systally. And that's been directly associated with arrhythmias independent of MAD or fibrosis. In reality view, these three abnormalities are not independent. They occur concurrently. And our goal is to identify that tiny fraction of patients that is going to go on to have serious arrhythmias. So let's talk about the best ways we can do that. This is a simplified approach to how we need to think about an MAD patient. And the first step is actually to confirm the diagnosis. As Dr. Pavley mentioned, oftentimes imaging reports will totally miss the MAD, or they'll mistake pseudo-MAD for true MAD, or they may not report the other relevant details, bileaflet prolapse, curling, any of those. So at this time, I strongly recommend if you're seeing these patients, you need to manually review the images. Then we'll do a detailed risk factor assessment and gather all the data to help re-stratify them. So I apologize for the busy slide, but there are a lot of known risk factors. I'm not going to go over every single risk factor that's present in the guidelines and many review articles. But my point is to say what modalities of evaluation are necessary when we see the patient, and what are the highest risk factors that I want us to remember? First, a detailed history is important. And syncope is an incredibly important point of history to elicit. When it's present in an MAD patient, it probably increases the chance of severe arrhythmias by two to threefold. Despite that, when we look at cardiac arrest patients, it's only present in about 40 to 50% of patients who've had a known cardiac arrest or severe ventricular arrhythmia. As Dr. Pavri mentioned, ECGs have long shown infralateral T-wave inversions, but there's an increasing amount of evidence that the more diffuse the T-wave inversions, the higher the arrhythmic risk. And the largest case series on sudden cardiac death patients has recently shown anterolateral T-wave inversions may be associated with risk. As mentioned, I think all of these patients deserve an extended cardiac monitor. The European guidelines would say some of the lower risk patients get a shorter monitor. Regardless, there are some different arrhythmias that we'll talk about. I'll talk about that more at the end. When we look at the valve itself, we've already mentioned that bileaflet prolapse is riskier than single leaflet. And I've mentioned that I think it's important to identify where the MAD is. The infralateral P2 junction is the pathologic area of MAD. The distance is also somewhat controversial. It depends on the study. 8.5 is definitively risky. And somewhere between 5 to 8.5 millimeters should raise some eyebrows. Severe mitral regurgitation is actually quite uncommon. A lot of people think it's common, but most patients with cardiac arrest will not have severe MR. That being said, when you see it, it is a high-risk finding. And last, we've already mentioned the pickle-up sign. There's a wide variety of research in speckle tracking, echo, strain, as well as tissue Doppler that shows these abnormalities. We've already talked about infralateral curling, but I want to mention the ejection fraction, too. Most of these patients are going to have a normal EF, but when we see that low EF, we need to be concerned about that. The next one is one I think that's really important. Exercise ECG is probably underutilized. We heard from Dr. Pabry that there's data that the sinus adrenergic tone is probably related to arrhythmic risk. And this prospective study by Oslo, by Five, and Hogwan colleagues, they looked at 19 patients, no prior arrhythmias, prospectively did exercise ECG. And those who had a non-sustained VT on that had over a 20-fold increase of severe ventricular arrhythmias in the next four to five years. And the European guidelines agree with this, and I would recommend an exercise ECG in most of these patients. Now, who needs a cardiac MRI? Not everybody, but I think those who have abnormalities on echo, monitor, or ECG deserve a cardiac MRI. And one of the most important things, as we've heard, is fibrosis. So myocardial replacement fibrosis, as manifested by late gadolinium enhancement, is associated with worse arrhythmias. And when you look at patients with cardiac arrest, it's present in about 50% of patients. And I know this is obvious, but I just want to emphasize this, because 50% of patients therefore will not have any LGE. And the reason I emphasize this is if you're seeing a patient who has multiple other risk factors, and then you get an MRI and it shows no LGE, you should not just put them in a low-risk category, because a substantial portion of patients will not have any LGE. As we've heard, the papillary muscle and infralateral left ventricle are the most common areas, and the burden is low. Even in high-risk patients, the burden might be 2% to 5%. Compare that to HCM, where the guidelines have found greater than 15% is associated with arrhythmias. So don't be misled by a low burden of LGE. Lastly, as we've heard, true MAD is actually associated with perianular fibrosis, which is different than most MVP patients. And as we've heard, arrhythmias can actually originate from that area and be successfully ablated. A different type of fibrosis is also important. This is diffuse interstitial fibrosis. This has been identified histologically in autopsy studies, and it can occur with or without LGE. Noninvasively, as we heard from Dr. Povery, it's assessed with T1 mapping, and it can be quantitated in different ways. One of the most common ones, as he mentioned, was extracellular volume percentage. And the cutoffs vary, but somewhere between 31% to 35% is associated with risk. Luckily, most centers are now doing T1 mapping with their MRIs. Before we jump into the final risk stratification, I want to talk about a couple of select important populations. First, in Marfan and Lois Deet syndrome, MAD is not only associated with mitral valve events as well as severe arrhythmias, but it's actually associated with aortic events, especially when the distance is greater than 10 millimeters. And this is a really important topic. It's been very controversial for years. How well do these patients do after surgery? There have been many uncontrolled case theories going back decades that suggest, oh, maybe the MVP patients do better after surgery. This study was actually published two weeks ago, and they looked at MVP versus MAD patients. And in the blue curve, you can see patients with no MAD actually have relatively few arrhythmias after surgery. But those with MAD go on to have higher burden of arrhythmias after surgery, even though all of these patients had the area looked at, and MAD was corrected by surgery in all. So I think this is a very important finding. We should not blow these patients off after surgery. Lastly, as alluded to, unfortunately, cardiac arrest and severe arrhythmias often affects young women of childbearing age. We knew that, but we didn't have any data to look at that population until last year. This was a European study. They looked at arrhythmic MVP, 18 patients who had a severe event in the past. 62% of them had MAD, and the incidence of arrhythmias during pregnancy or the six months that followed after was 2.7-fold higher. This is obviously one small study, but it's all the data we have, and I think this can be helpful when we're counseling patients. So now that we have all this data, how do we stratify them? As we just heard about, the European Heart Rhythm Association in 2022 published this seminal workflow on how to approach these patients. Admittedly, there was a lot of expert consensus because we just didn't have a lot of data, and a lot of it was retrospective. I'm going to show you a modified version of this that is most focused on MAD, but all of my recommendations closely align with these guidelines. So this is my proposed workflow. I know it's a really, really busy slide, but I'm going to talk to you about it section by section. So first, confirm the diagnosis. Get all the data. I'm showing you the risk factors there. You don't have to have them memorized, but that's obviously the first step. Then let's talk about the high-risk patients. Obviously, if they qualify for primary prevention ICD or secondary prevention ICD, they should get it. That's a no-brainer. That's standard guidelines for all patients. We've talked about severe mitral regurgitation is a major risk factor. And if those patients qualify for mitral valve surgery, they should get it. There's an increasing amount of data that I'm sure Dr. Jalal will talk about, about should we be doing this surgery for arrhythmia indications independent of MR. So I won't touch base on that. But I do wanna emphasize based on that recent study, don't ignore these patients after surgery and continue to surveil them for arrhythmias and symptoms that might warrant an ICD. On the flip side, if they're asymptomatic, that's pretty easy. Just get periodic echoes and monitors. We don't know the long-term natural history. And some of these patients who are benign at first might develop echo or electrical abnormalities over time. The middle is often the most complex as we've all experienced. So syncope patients are high risk. According to the European guidelines, if they have NSVT or multiple risk factors and true arrhythmic syncope, they should go to a primary prevention ICD. I don't see that a lot in the US. Many of these patients in the US might get an EP study, but there's published data and we have unpublished data that the negative predictive value of an EP study is not good. And many of these are polymorphic, VF, like nonspecific. So I don't know what the right answer here is, but I'm not sure ICD as they recommend for all of those patients is best. If they don't have a risk factor, they get a loop recorder. In terms of when you get these monitors, what should you be worried about and not worried about? Retrospective data says rapid non-sustained VT greater than 180 beats per minute and so-called polymorphic NSVT are the highest risk findings. Those patients, according to the European guidelines, if they have multiple risk factors, should get an ICD or an EP study. And if they don't have it, to get a loop recorder. Lower risk patients, those with slow NSVT, PVCs, or maybe just a lot of abnormalities on MRI, I think the vast majority of those patients will be doing fine with just periodic monitoring. But if they do have LGE or have high levels of concern, I think a loop recorder, especially in LGE patients, is reasonable. So in summary, MAD is associated with severe arrhythmias rarely, but it's a significant public health concern. Risk stratification is really still in its infancy. This is all retrospective data. There's been a handful of prospective data, but there's a growing amount of multicenter and prospective studies that are underway right now. It requires us to manually review the ECG and imaging, as we've talked about. And I think it's very important that no single finding is pathognomonic. Even in cardiac arrest patients, LGE, syncope, those will be absent in half of patients. And so don't get fooled by any single one variable that you can hang your hat on. This is a bit tongue-in-cheek, but when Supreme Court Justice Potter Stewart was asked to define what obscenity was in the 1960s, he couldn't, but he said, I'll know it when I see it. I think for now, a lot of risk stratification falls into those heuristics and holistic evaluation until we get more nuanced algorithms. Here are my references, and I'm happy to take any questions if there are any. Thank you. Thank you very much, great presentation and clear messages, I think it's really a tough topic. Before we have one short question, how often should we re-evaluate? That's completely unknown. Our general practice, like many conditions, is to get closer, follow up at first, and then as findings become stable, to space it out, but that's purely conjecture and expert opinion. We don't have any data to support a specific algorithm. Can I just ask, because one aspect that's been alluded to here is, you can have a cardiomyopathic picture in these patients, which would be a high risk, can you comment on the actual structure of the papillary muscles and morphological abnormalities in the ventricle, and what your impression of that is in relation to the risk? Yeah, I mean there's a lot of morphologic changes that happen. There's some unpublished data, especially by ice and ablation patients, which is a selective population that the papillary muscle anatomy may be more complicated. MAD specifically, due to the altered mechanics that Dr. Pavri alluded to, is associated with actually basal lateral hypertrophy, which may change, kind of, you know, vicious cycle and worsen the MAD distance. The connection between those progressive morphologic changes and arrhythmias, I'm not sure is fully understood. Quick question, any recommendations on cascade screening for family members? I mean, the genetics, as Dr. Pavri alluded to, is unclear. As far as I know, there is no official recommendations for cascade screening. Personally, if they've had a sudden cardiac arrest or sustained arrhythmias, I, you know, must, like, bicuspid aortic valve, I do recommend first degree screening, but that's personal opinion. I'm not aware of any data for that. Thank you very much. Thank you. Thank you. Our final speaker is Dr. Garg from Loma Linda University, Management and Treatment Options for Patients with MAD. Good morning, everyone. Thank you, Program Chairs, for the invitation. Okay. No relevant disclosures with the talk, so let's begin with the case. This is a 42-year-old lady, recently came into the hospital without hospital cardiac arrest at a ski resort. She was at a ski lift when this happened. Five minutes of CPR. Ross can achieve it in five minutes. This is an EKG on presentation in the hospital. As you can see here, normal sinus rhythm, nonspecific STT wave changes in the inferior leads and the lateral leads. She did have intermittent PVCs a few minutes later, and this is the EKG of the PVCs. As you can see here, QR complex in V1 and AVR, similar appearing morphology, right bundle in nature, some notching in the QRS, superior axis, or I would say leftward axis, suggestive of post-traumatic papillary muscle PVCs in nature. Three years ago, she had a similar event. She had a syncopal event, was evaluated in San Diego. This was the EKG that time. Sinus rhythm, extensive T wave inversions in the inferior leads and the entire pericardium. So in present admission, she gets an EEG, which was normal. Coronary angiogram, again, normal course. No vasospasm, no myocardial bridging. She undergoes an echocardiogram. As you can see here, normal LV function, mitral valve prolapse, severe MAD, and mild MR. Following the MAD finding, she undergoes a CMR. Patient also had a piccolops sign with tissue lateral decline velocity of 19 centimeters per second. She gets a CMR. This is a CMR finding. Mitral valve prolapse, which was mild, severe MAD of 17 millimeters. There was no LGE at this point in time. So I'll go over the management plan towards the end of the presentation. Let's begin with case number two. 66-year-old guy was admitted here at this time for diarrhea. In 2009, patient had a polymorphic VT, got an ICD that time. ECHO back in 2009 did demonstrate normal LV function, post-trobasal valve hypokinesis, mitral valve prolapse, and trace MR. This was the EKG back in 2009. As you can see here, normal sinus rhythm, some T wave inversions in lead 3 and AVF. Otherwise, essentially, T wave flattening all across. Of course, in 2016, doing well, repeat ECHO shows moderate MR, mitral valve prolapse now, which was more evident. December of 2018 has a mitral valve repair for flail P2 segment. In February 2020, which is this time, admitted here for diarrhea and dehydration. Was noted to have AKI, labs and presentation, potassium of 3.7. Device check was totally clean since the index implant, and ERI less than three months. This was the EKG at 2 a.m. at night. Patient goes into VF and gets an ICD shock. This is the ECHO right before the patient had an event. Essentially, normal LV function, normally functioning mitral valve prosthesis. There was no piccolops sign on the ECHO. MRI could not be performed because device was not compatible. So the question that becomes is, did the mitral valve surgery reduce this patient's risk of having an ICD shock? So MAD, as we all know, evolution of MAD over a period of time remains highly unknown. I mean, we'll go over the studies later, but at the most, we only know about 10 years. Nothing beyond 10 years. And therefore, the clinical decision-making in these patients is often challenging and largely empirical-based. And if you go over the treatment modalities for MAD patients, there is no dedicated MAD, antiarrhythmic therapy for MAD patients. Anecdotally speaking, beta blockers are commonly used because they reduce the hypercontractile force on the papillary muscle and the caudate, thereby reducing the stretch on the sub-mitral valvular apparatus. In this small study of seven patients who have had MAD, their refractory PVC is a non-sustained VT on a beta blocker started on flecainide. What's more interesting is there was significant reduction in the PVC, but show us the episodes of non-sustained VT. But again, these are all high-risk patients. They all were mostly females, had mitral valve prolapse, low ejection fraction, had LGE on the cardiac MR. And we also know flecainide reduces the myocardial conduction velocity. And hence, that also puts these patients at a higher risk of having more arrhythmias from flecainide. And hence, these patients need more close monitoring, maybe a loop recorder or maybe a long-term holter monitor. The question now becomes, would catheter ablation in these patient populations, especially MAD or maybe MVP, alter the risk of sudden cardiac death? So in this patient, a 50-year-old woman evaluated for palpitations. PVC burden is 34%, runs of non-sustained VT. The resting EKG, as you can see here, normal sinus rhythm, QR complex in AVR and V1, which are often looking similar. Launching of the QRS, again, superior axis, suggestive of post-tumor middle papillary muscle, probably coming somewhere mid-body. This was the runs of non-sustained VT during the clinic visit. So the work that this patient had was a code that demonstrated moderate LV dysfunction, moderate size MAD, there was no MVP at this point in time. Coronary angiogram, normal coronaries, no coronary vasospasm. Cardiac MR did show evidence of focal scar on the papillary muscle in absence of mitral valve prolapse, moderate LV dysfunction, and obviously the LV function improved after the catheter ablation. So the question that becomes is, would catheter ablation for idiopathic VF or PVC triggers for VF make any difference? Well, in this study, all comers who had PVC-related VF, there was significant reduction in the VT episodes or VF episodes at the end of one-year follow-up. What's more interesting is eight of 30 patients did have PVCs coming from the papillary muscles. Five of these patients had a Purkinje fibers, which are the terminal conduction fibers, as we all know, resting on the papillary muscles in sinus rhythm. And three of these patients did have recurrent VT, VF episodes post-ablation. Again, in a separate study, six patients, structurally normal heart, one with non-ischemic cardiomyopathy, all with PVC triggers for VF. Post-ablation, there was no recurrent episodes. So the data is essentially mixed. If you look at this study, 14 patients, six with cardiac arrest, eight with non-cardiac arrest, all these patients had MAD. In the patients who had no cardiac arrest patients, targeting the PVC triggers did reduce the episodes of ICD shock, but there was no reduction in PVC burden in the non-cardiac arrest group. In the non-cardiac arrest group, there was significant suppression of the PVC burden. What's more interesting is six patients did undergo redo ablation, three in each arm. And what's more interesting is, as you can see here, there was recurrent episodes of more PVCs coming in, suggesting a progressive development of a substrate over the period of time in this patient population. So the question becomes, should we chase the target, or should we chase the trigger, or should we chase the substrate? In this small study of 40 patients who had MAD with ventricular arrhythmias, who were undergoing catheter ablation, there were two arms, one with a substrate-based approach and a non-substrate-based approach, which is a trigger-based approach. While P-value was not statistically significant, the interesting finding is the group which underwent a substrate-based approach, there was a reduction in the recurrent ventricular arrhythmia episodes, ICD shocks, and so was the need for sympathectomy, as compared to the trigger-based approach. So back to our patient. So our patient underwent a PVC ablation. I found the trigger near the mid-body of the post-traumatic papillary muscle, and PVC disappeared, LV function normalized. However, this procedure is technically challenging, A, because of catheter instability, deep intramural substrate, and again, as shown here, need to ablate the papillary muscles. And therefore, the risk of scar remains, and so is the risk of another event in future. So would ICD make any difference in this case or not? LV, the data on secondary prevention ICD is pretty easy, that patient with aborted cardiac arrest needs an ICD for secondary prevention, but the data on role of primary prevention ICD remains unknown, especially in this patient like this, and hence needs close monitoring. Would surgery make any difference? So there are two kinds of approaches for mitral valve surgery, a respect approach and a resect approach. Resect, as the name suggests, you resect the entire annulus, put a new prosthesis, you're all done. In the respect approach, you essentially preserve the mitral valve annulus. The distinction is different in a MAD patient, because in MAD patients, surgeons actually cinch down the entire MAD distance so that the distance is reduced or is totally minimized, with the hope that you are eliminating the entire trigger because of tethering forces on the papillary muscles and the chordae. So the data on the reduction of ventricular arrhythmia but in post-mitral valve surgery essentially remains sparse. Limited to a few studies, and while this does not reduce the PVC burden, there's a reduction in appropriate ICD shocks in this patient population. As we learned all this morning, that MAD does not essentially impact the survival, and this is what I was talking about. The 10-year survival rate between MAD patients and no MAD patients essentially remains the same. But we do know that MAD does increase the risk of arrhythmic endpoints after adjusting for mitral valve characteristics, AF, and left ventricle ejection fraction. And if we add beta blockers on the top, significant reduction in arrhythmia burden, and narrowly missing the statistical significance after the mitral valve surgery. So clearly there is something else we are missing. And if you look at this small study, this is all patients who underwent mitral valve prolapse and had a mitral valve surgery. In a small study of 40 patients, there was no reduction in the arrhythmia burden. But if you subgroup the study actually, the patients who had 10% PVC reduction were all young. Essentially suggesting the mechanical trauma, either stretch or affliction, is not the only cause. There has to be underlying substrate which develops over the period of time in elderly patients that put these patients at the higher risk of having ventricular arrhythmias. And to answer this particular question, 58 patients who had complex ventricular arrhythmias underwent mitral valve surgery, and they were subgrouped into two groups, 26 with simple ventricular arrhythmias, that is isolated PVCs, and 32 patients with complex arrhythmias, that is either couplets, triplets, non-sustained VT, or episodes of VT. And following the mitral valve surgery, the risk of the group which had recurrent episodes are the same group of patients who had complex arrhythmias to start with. Suggested that the benefit of surgery may be limited in this patient population because the substrate has already been developed. There's already a replacement fibrosis at the basal lateral annulus, which is triggering these episodes. However, the surgery still remains a treatment modality when a patient has MAD and severe MR. But since these patients have a complex arrhythmias to start with, these patients need long-term monitoring. And in addition, survival benefit and risk reduction of sudden cardiac death remains unknown in this patient population. What's the role of MitraClip in this situation? Well, we all know MitraClip might improve survival in patients with MVP and severe MR. Its role in MAD patients is unknown because it does not correct the annular myocardial separation. And therefore, surgical repair still remains a gold standard in this patient population. What's the role of surgical cryo-ablation? In this small study of three patients who had MVP, not MAD, had MVP and underwent elective mitral valve repair for severe MR, there was significant reduction in the PVC burden and the short-term follow-up. But again, long-term data remains unknown. And as I said, they all were MVP patients, not MAD patients. Again, the evolution of MAD over time remains largely unknown. There's a progressive development of ventricular arrhythmias over the period of time, as you can see here. And once these arrhythmias develop, there's increases for mortality. So patients die from ventricular arrhythmias, not from MAD per se. And therefore, frequent rhythm monitoring is essential in this patient population, especially with a high-risk phenotype, which is being women, presence of LGE, presence of mitral valve prolapse, or bilipral prolapse. And MAD patients with complex arrhythmias, catheter ablation might be a considerable option to reduce the ventricular arrhythmia burden. So let's go back to case one. So again, the risk factor, while she remains a female, has mitral valve prolapse, T-wave changes in the inferior leads, presence of ventricular arrhythmias on the EKG, has echo evidence of mechanical traction, piccolopsine, severe MAD on MR. Now she has aborted cardiac arrest. She underwent a secondary prevention ICD. She was also started on a beta blocker. I saw her in a clinic last week, and she was complaining of tiredness, so beta blockers has to be stopped. Back to case two. Borderline potassium, ventricular arrhythmias requiring ICD shock, echo evidence of normal mitral valve function or mitral valve repair, unclear if MAD was present because there was no prior MRR studies for the patient, patient declined any antiarrhythmic drugs or sympathectomy, so beta blockers were started and the patient is doing well now. Thank you so much. And this is a flowchart of how I manage MAD in my clinical practice. The only thing which I would like experts to comment on is the role of induction of polymorphic VF with one or two extra stimuli remains unknown. We all know VF induction is not a positive EP study. It's a negative EP study. But what I've been seeing is easily inducible VF with one extra stimuli, I think is a positive predictor value for implanting an ICD as a secondary prevention in this patient population. Any comments from the experts as you pose the question? The role of the single extra stimulus VF risk stratification. I think in the right clinical context, I think that's reasonable, but I think more prospective data is obviously necessary. It's a completely open question. It's a bit like a Degarda dilemma, isn't it? With substrate, single extra inducing VF may be predictive up to two extras, but it's just not data. A couple of questions because I know we've overrun. Mark Miller from Mount Sinai. What are your thoughts on the idea that percutaneous mitral valve interventions for prolapse with complex ectopy may actually make the problem worse, and there's good modeling data to suggest that, by basically putting more forces or traction on the prolapsing leaflets? Are we getting ourselves into trouble if we start referring patients for percutaneous mitral valve interventions? I think so. Just to all know, he's my mentor, actually. Mark, I think it should make the problem worse than to make the problems better because I think the traction still remains. I think what we are only fixing is the MR, but the traction forces would still remain. I think it might make it worse just because the atrial part of the tissue is compliant now, and that causes more traction, more pulling forces into the atrium rather than it was before. So I think it will make the problem worse, in my opinion. Just one more quick question that was touched on in the earlier talk was the idea of LV dysfunction, which I agree with, which is that if you have prolapse with, let's say, an injection fraction of 48%, those patients seem to be extraordinarily high risk. I guess the real question is why do those patients have an EF of 48%? Very often they have a very low amount of ventricular ectopy, and should all of those patients be worked up for something like lamin mutations, like a second-hit phenomenon? I think what I have also noticed is it's probably because of the apical dispersion of the pap muscle. If you look at the old echoes, which I haven't seen on these patients, there's an apical displacement for these papillary muscles. I think that is what is accounting for LV remodeling and reduction in LV function. I think you're right. I think now a group of these patients do have Mondelein genetic cardiomyopathy in addition to the substrate relief to the MDP, because MDP is common, MAD is common, and then you've got a background cardiomyopathic process that's going to compound the issue. Yeah, they almost act like the Marfan's patients, which again are ultra-high risk patients for unclear reasons. I think you're right to be thinking in that direction, with the Mondelein-possible cardiomyopathy in a subgroup. Thank you. Last question. Good morning. Great session. This question is for the panel and maybe more for Dr. Asirvatham. In your experience, most of these PVCs are coming from papillary muscle or from that abnormal tissue just at the valve that displaced. Please touch on those syndromes that we see, mitral valve prolapse or abnormal, and at the same time on the tricuspid valve, we see the PVC coming from tricuspid annulus and from the RV base of the right ventricle. Okay, so maybe very quickly, PVCs you can get kind of three types in mitral valve prolapse syndromes observed for decades. One of them is probably related to stretch and mitral valve contact with a very myxomatous valve on the papillary muscles. The second one is provocable PVCs, so the couplet. The second and the couplet are during EP study, and those tend to be on the annulus. So substrate is there, some trigger, presumably a reentry beat that comes on. But very important. Third is also mechanical PVCs. This is very important because it's very hard to plate mechanical PVCs. These are just hitting. You can see it on the echo. At the time of contact, you'll generate the PVC. So there may be some substrate there, but this you have to do something about the mitral valve. Clinical clue to the syndrome is whenever patient's dehydrated LV size is smaller, they tend to get more of these PVCs. If they're hypotensive and you tank them up with fluid during the EP study, you'll actually see less of those PVCs. Send them back to the room, it will start coming up again. You can actually check for this with your catheter. When you curl the catheter under the mitral valve and you suddenly see the PVC stop, you should think of that. I'm not aware of tricuspid annular PVCs being a second PVC in mitral valve prolapse syndromes, but there are some annular syndromes, some that were mentioned, that affect the aortic valve, mitral valve, and this tricuspid valve. Problems with genesis, incontinentia pigmenti, some types of dysplasias in the cartilaginous tissue. You can get mitral valve, tricuspid valve, and aortic. Maybe that's what you meant over there. Thank you very much indeed. Thank you to the speakers for excellent presentations. Next year we'll have to ask HRS to extend the session for 19 more minutes.

risk stratification

mitral annular disjunction

mitral valve prolapse

imaging techniques

ventricular arrhythmias

echocardiography

MRI

beta-blockers

catheter ablation

percutaneous interventions