NICM, dilated cardiomyopathy, DCM, post-viral cardiomyopathy, which very often it's not, and then idiopathic dilated cardiomyopathy. And one of the themes of the talk this morning is that it's very important to look for the etiology of these. It seems like the majority of patients that we see have not had a careful search for the cause of their cardiomyopathy. They're often told, oh, yeah, it's post-viral. But 40% of them are genetic. And that number is likely to grow as more and more of the causative gene mutations are delineated. Then the other categories, so you can have post-myocarditis, post-viral myocarditis, cardiomyopathy, other inflammatory diseases, particularly from the standpoint of those with frequent arrhythmias, sarcoid is extremely important to consider, autoimmune diseases, and then in South and Central America, predominantly Chagas disease. And then toxins, most common that we encounter is alcohol and post-chemotherapy, notably anthracyclines. And then increasingly recognized are dilated cardiomyopathies that are due to an arrhythmia, either a tachycardia-mediated cardiomyopathy, frequent PBCs, or atrial fibrillation. So these folks may present with heart failure and symptoms of heart failure, but fairly commonly, there'll be an arrhythmia presentation, either with PBCs or a long history of PBCs, atrial arrhythmias. Some of these myopathic processes are associated with heart block, and then monomorphic VT, polymorphic VT, cardiac arrest, or syncope. So when the diagnosis is first entertained, a patient presents with one of these findings, and they have left ventricular dysfunctions, extremely important to rule out coronary artery disease, which is the most common cause of ventricular dysfunction in our population. Also rule out valvular heart disease, and then characterize the severity of left ventricular dysfunction, define the chronicity, and then you wanna address any aggravating factors or treatable causes, and that includes atrial fibrillation, very frequent PBCs or other incessant arrhythmias, alcohol, and left bundle branch block, which is something that we can do something about with resynchronization therapy. Then the patient needs to be on optimal medical therapy, have a careful further delineation of the etiology, and then we're to the arrhythmia risk management piece. Nope, this one. Now we got somebody else who's trying to take control. Let's see, so there's somebody whose last name is R-A-G-E-N-D-R-A-N, is trying to Zoom bomb the meeting. I don't know if you have a way of getting rid of that person. So let's talk a little more about ventricular arrhythmias, if I can advance the slide. There we go. And I may have lost control of the... Sorry, Bill, let me, what was the name again? The last name is R-A-G-E-N-D-R-A-N. There we go. So sustained arrhythmias in non-ischemic dilated cardiomyopathy are not all that common. So now there's another person named Carter. C-A-R-T-E-R. Geez, I'm sorry. If it keeps going, we'll probably have to just shut it down and move to a different... Move to a different site. So this is data from the DEFINITE trial from back in 2006. And so these were people who had non-ischemic dilated cardiomyopathy and had depressed ventricular function and a left ventricular ejection fraction of 35% or less. And now there's a person named G-U-R-R who's requesting control. And they had defibrillators implanted for primary prevention. And the incidence of sustained arrhythmias was about 6% per year. And of the arrhythmias recorded by the defibrillators, about half of them were monomorphic BT and half of them were polymorphic BT. So sustained arrhythmias are not that common in the non-ischemic cardiomyopathy population. And sustained monomorphic BT is not all that common. Now, the underlying electrophysiological substrate for these arrhythmias is complex and a little bit variable. So for the polymorphic BTs in particular, it's likely that it relates to some of the electrophysiologic remodeling of ion currents that can occur in any of the diseases that are characterized by ventricular hypertrophy, which also occurs in this condition. So you get downregulation of repolarizing potassium currents, which prolongs the action potential duration, prolongs the QT interval, and that happens in a heterogeneous manner. So you increase dispersion of refractoriness across the myocardium. There's abnormal calcium handling and intracellular calcium loading, which predisposes to both early and late after depolarizations, which may be a cause of PVCs as well as arrhythmias and triggers for reentrant arrhythmias. And then there's fibrosis that occurs, both interstitial fibrosis and replacement fibrosis. And interstitial fibrosis leads to cellular uncoupling, which then increases or magnifies the potential electrophysiologic effects of these other features that predispose to heterogeneity of recovery across the ventricular wall and predispose to arrhythmias. Now, as we saw from the definite trial data, sustained monomorphic VT, it's only about 3% to 4% per year at that time back in 2006. And the vast majority of these are due to scar-related reentry. So if you look at all the sustained monomorphic VTs that wind up coming to the EP lab in people with non-ischemic dilated cardiomyopathy, only less than 5% to 10% of them are due to bundle branch reentry. And a few of them will be focal automaticity, but 90% or so are related to reentry in regions of scar. So fibrosis is a really important pathophysiologic substrate for arrhythmias in non-ischemic dilated cardiomyopathy. And that message has also been made very clear by studies of MR imaging in this disorder. So if you take people to all comers with non-ischemic dilated cardiomyopathy who are referred for an MR evaluation, you find that about a third of them have substantial areas of late gadolinium enhancement, the marker for fibrosis. And most commonly, it's in this sort of a mid-wall pattern, as you see in this upper left panel. And of the people that have that, they have a much greater risk of sudden death, as you see here, compared to the people that do not have fibrosis. And that holds up even if you try and correct for the severity of ventricular dysfunction. So the people that develop fibrosis with their non-ischemic cardiomyopathy are at increased risk for sudden death. Now, another interesting thing that's happened is that in heart failure in general, as the therapies, as the medical therapies for heart failure have improved, the sudden death risk has fallen. So this is a graph of the sudden death rates in the control arms from various trials, over from 1995 back in the beta blocker and ACE inhibitor era to the present with the PARADIGM trial and the neprilysin. And the risk of sudden death in heart failure in general has fallen pretty dramatically over that time. And all of the medical therapies for heart failure that have shown a mortality benefit pretty much have been shown to reduce sudden death. So that includes mineralocorticoid antagonists like eplerinone and spironolactone, beta blockers, ACEs and ARBs, and then the neprilysin-ARB combination. And this is just the sudden death curves from that trial. So you can see that the sudden death risk here now is in the range of two to 3% per year in people who enter heart failure trials. So then it shouldn't come as too big a surprise that it's hard to show now a survival benefit for therapies that reduce sudden death, that target ventricular arrhythmias in non-ischemic cardiomyopathy. So this is the Danish trial. So people that had non-ischemic dilated cardiomyopathy in New York heart class two or three and a left ventricular ejection fraction of 35% or less, or they could have New York Heart Association functional class four if they were candidates for biventricular pacing. And so they were randomized to a defibrillator or no defibrillator or biventricular pacer, no biventricular pacer. And with a pretty substantial follow-up, you could not demonstrate an improvement in overall mortality for the defibrillator, although sudden deaths were reduced. But the rate of sudden death is about 1% per year. So this is an incredible success story in cardiology, the improvements in medical therapy. And then the defibrillator still does offer protection against sudden death in selected patients. So this prompted a couple of meta-analyses that included the Danish trial along with previous studies. And to just make the point that there is still a survival benefit for defibrillators, although it's now probably relatively small. And then this is the guidelines that were updated in 2017. On the right, the primary prevention indications for a defibrillator in non-ischemic cardiomyopathy. So it's class II-III heart failure, ejection fraction of 35% or less. And then they're an ICD candidate based on comorbidities and expected longevity of a year with reasonable quality of life. And then there's this important caveat, is this new heart failure. Have they had more than three months of medical therapy? And the reason for this is that some of these people will improve. So with a new onset diagnosis of non-ischemic cardiomyopathy, who is likely to improve? And there are a few things we can look at in this regard. So this is a study from Duke in which they took everybody who came through the echo lab who had non-ischemic dilated cardiomyopathy with or coronary disease and an ejection fraction that was newly discovered to be depressed in less than 35%. And then look at what happened to ventricular function at three to six months of follow-up. And this is grouped by their baseline EKG. And the folks who had a narrow QRS at presentation who then were put on medical therapy and followed, 43% of them improved to an ejection fraction above 35% over the subsequent three to six months. In contrast, if you've got a wide QRS and particularly left bundle branch block, the likelihood of improving to an ejection fraction from below 35% up to above 35% is only 23%. So evidence that there is underlying myocardial disease, PIS-Purkinje disease makes it less likely that that person's going to recover. And the ones that have left bundle branch block, the odds are pretty good that you can help them with biventricular pacing. So, and in the others, you may want to, it would be appropriate to wait three to six months of medical therapy before deciding on a defibrillator and see if their ventricular function will improve. Another group are the atrial fibrillation patients. So you are likely aware that if somebody has rapid atrial fibrillation and depressed ventricular function, their ventricular function can improve quite dramatically just with rate control, just the tachycardia cardiomyopathy issue. But there's also some data that even the people who don't have rapid ventricular rates as an explanation for their depressed ventricular function may benefit from restoration of sinus rhythm. At least some of them may. And so this is an interesting, some interesting data from the CAMRA MRI trial. So this was a small number of people who had persistent atrial fibrillation, non ischemic dilated cardiomyopathy, and they had reasonable rate control. And they were randomized to catheter ablation versus just ongoing medical rate control. And of those who had catheter ablation, there was a pretty substantial improvement in ventricular function. And the outcome of ablation was unusually good for a persistent AF population with depressed ventricular function. Their AF burden at follow-up was down to 1.6%. And 75% were free of AF, including those on drug therapy. But a pretty substantial improvement in ventricular function versus no improvement in the rate control group, even though the rate control, the average heart rate was in the 80s. So it wasn't really up in the range where we would generally worry about a tachycardia-induced cardiomyopathy. And so there's been thought, is the irregularity of atrial fibrillation possibly a contributor to adverse hemodynamic effects of atrial fibrillation, putting a bit more workload on the heart and contributing to ventricular dysfunction? And then they have an MRI group who, and the folks that had fibrosis, the areas of late gadolinium enhancement on MR imaging were less likely to improve and overall had a smaller improvement in ventricular function compared to those who did not have evidence of fibrosis in the LB prior to ablation. So somebody with an atrial arrhythmia who does have areas of late gadolinium enhancement, those folks in particular may tend to benefit from attempts to restore sinus rhythm. This is a very small population, but it's also consistent, of course, with the CASEL trial as well. So there may be, I'm sure there'll be more data coming to address this issue, but atrial fibrillation is something to consider. And then PVCs. We know that very frequent PVCs, generally more than 20 to 23% PVC burden can be associated with depressed ventricular function and control of the PVCs can improve ventricular function. And so when you're confronted with somebody who's got a picture of dilated cardiomyopathy and they've got frequent PVCs, there are kind of three possibilities. One is that they've got a cardiomyopathic disease that is causing the PVCs. And if you get rid of their PVCs, they're still gonna have depressed ventricular function. Now, it may be that the PVCs are aggravating the process. And so ventricular function may improve somewhat, but there's still a cardiomyopathic process. Second possibility is that it's all the PVCs. And if you get rid of the PVCs, you'll see gradual recovery of ventricular dysfunction. And then the third possibility is that the PVCs are not really having much of an effect, but every time they get an imaging study, there's so many PVCs, you can't tell if ventricular function is really impaired or not because you can't get a good measure of it. Very often, these are people who don't have much in the way of ventricular dilation and ventricular dysfunction is just modestly depressed. So this is data from Frank Bogan at the University of Michigan that pertains to this issue. So of people who had frequent PVCs who were referred for ablation, this includes people with and without ventricular dysfunction, they did a pre-procedure MR imaging in a large number of them. And of those 321, they saw evidence of structural heart disease in 66 of the patients. And most of these 60 of the 66 were areas of delayed gadolinium enhancement. Now, they also did program ventricular stimulation at the time of the PVC ablation. And of those people who had late gadolinium enhancement or an abnormal MRI, 22% of them had inducible sustained monomorphic ventricular tachycardia. So again, kind of pulls us back to this issue of fibrosis as being part of the myopathic process that may be related to arrhythmia risk. And that arrhythmia risk is in the presence of fibrosis is often potential reentry circuits to support sustained ventricular tachycardia. So program stimulation may have a role in considering who is at high risk who presents with a non-ischemic dilated cardiomyopathy. If they've got areas of fibrosis, they may have reentry that can be exposed with program stimulation. And there was this interesting study a few years ago now of 158 patients non-ischemic dilated cardiomyopathy who presented to this German center for their cardiomyopathy. Of those that agreed to under program stimulation, 28% had inducible sustained VT. About half of those were polymorphic arrhythmias and 13% were sustained monomorphic ventricular tachycardia. So those are some things that one might consider in selecting the patient at initial presentation as to who's likely to improve and who may be at particularly high risk, the person who's got areas of fibrosis already. And then there's another factor and that's the genetic piece. So if of the patients who have a genetic cause of their cardiomyopathy, their mortality is higher than folks who are genotype negative. And the worst is lamin disease. So lamin A-C mutations are associated with marked fibrosis often involving a septum, high risk of heart block, high risk of atrial fibrillation, high risk of ventricular tachycardia. So the patient who has a family history of cardiomyopathy or even who doesn't have a family history, but you don't have another etiology, genotyping is really become an important part of the evaluation of these folks. And you'll find a genetic cause in about 40% of patients. So to review the defibrillator issue, here are the present guideline recommendations in a patient who has non ischemic cardiomyopathy, New York Heart Association, class two and three symptoms, EF 35% or less, despite guideline directed medical therapy, and that should be for probably three months. And ICD is recommended if a meaningful survival of greater than a year is anticipated. In some of the genetic diseases, the one for which there's the most data is probably lamin. And it's recognized that these folks are at high risk. And so a person who's got lamin heart disease who's got an EF of less than 45%, non-sustained VT and non-missense mutation, and males die more quickly than women with this disease. And ICD has a 2A indication. Okay, so let's talk about a case. So here's a 77 year old male, and he's got a 20 year history of frequent PBCs that have been noted on routine examinations. He was a kind of an athletic guy and they were noted back in his early running days. He still is on his Fitbit logging 10,000 steps daily, and he had syncope while working at home. The paramedics were summoned and this was the strip that they recorded. And so you can see this is a wide complex tachycardia and the left bundyloid configuration in V1. You get the sense that there's some AB dissociation. Here's a P wave hanging out in the breeze there that's not there. Maybe here it is there. So it looks like a left bundle, probably inferior axis VT, and they cardioverted this to atrial fibrillation, which then spontaneously reverted to sinus rhythm. He's got no family history of sudden death or heart failure. He had coronary angiography that showed mild non-obstructive disease. His echo shows an EF of 35 to 45%. His left ventricular end diastolic dimension is just slightly enlarged for upper normal. He's got mild LA and he's got mild left atrial enlargement and mitral regurgitation. And this is his 12 lead EKG. And I don't know, I don't think we have the capability of polling. Is that right, Nishant? Yeah, we lost that function when I switched over. So we could look at the question, but I can't send that. Okay. So here's this guy who presented with VT. He's got this long history of PVCs and he's got lots of PVCs just on monitoring in the hospital and on his EKG. And so you can see that his conducted QRSs look pretty normal. And the PVCs, he's got at least two morphologies on this 12 lead EKG. And it looks like, well, we don't get to see a good V1 here, but they're inferior axis PVCs. Oh yeah, here's V1, excuse me. It looks like it's a left ventricular outflow tract sort of perhaps atrial mitral continuity area, PVC. So what would you be worried about? Could this be PVC induced cardiomyopathy? He converted to AFib. Is it possible he's having episodes of AFib more than he recognizes? And that's doing it. Or is this some other myopathic process? Either genetic, sarcoid, or some other myopathic process. So we took him to the EP lab and the first observation was that we could induce sustained VT and we could induce more than one morphology of sustained VT. So whenever you see that, that pretty much excludes idiopathic VT. It's very rare to have multiple morphologies of monomorphic VT for an idiopathic VT. And although it looks like this comes from the outflow tract region with left fundaloid and V1, inferior axis for VT2, but VT1 is isoelectric in three. So an axis of about minus or plus 30 rather degrees. So lower down probably in a kind of perihistian region, almost left perihistian region is where you would put this. So it suggests that he's got scar over underneath the, and around the aortic valve. And this was his voltage map. And you can see that he does have low bipolar voltage extending down the septum. And he's got these PVCs of multiple morphologies, but most of them are early up in the aortic mitral continuity and periaortic region. And the electrograms there are abnormal. You see that here's, this electrogram shows a little atrial deflection and a ventricular deflection that's complex. So that's further evidence that there's likely fibrosis in this region. So this is a basal septal periaortic kind of VT substrate. So on identifying that, he doesn't have areas of low voltage elsewhere. He had ablation targeting those VTs and the PVCs and then had no inducible VT post ablation. And on monitoring now very rare PVCs, but we took this as evidence that this is a myopathic process and an ICD was implanted. We also did a right ventricular biopsy, which showed, which was unrevealing. It didn't show any specific, non-specific findings only. So then the question is, so 77 year old guy with this disease process, would you send a genetic testing in him? He's got no family history. So a few years ago we would have said, no, it's not going to make any difference. But now we recognize that these genetic diseases often can present late. And so this is this typical periaortic basal septal VT substrate. That's one of the common phenotypes in non-ischemic cardiomyopathy. They have VTs that look like they come from the left ventricular and right ventricular outflow tract. The voltage map usually will show some low voltage in that region. The unipolar voltage map is often much more dramatic than the bipolar voltage map. And ablation of VTs from this area is often difficult. They're often intramural. You may not see much on the endocardium and you're very close to the conduction system. So there's a high risk of heart block with ablation of these VTs. And that of course raises the issue of, you need to be prepared to provide biventricular pacing if you're going to extend your ablation lesions close to the region of AV conduction. For VTs in this area, an epicardial approach is usually not helpful. And we rarely even look when we see these VTs because sitting on top of this area is the right ventricular outflow tract. There's no access to the region from the pericardium. And when endocardial ablation then fails, we consider ablation from the right side of the septum, the right ventricular outflow tract. Also look in the aortic sinuses, the great cardiac vein, and then ways to get deep into the septum become a consideration. Simultaneous unipolar ablation from both sides of the septum or bipolar ablation if you have that capability. Transcoronary alcohol of the first septal perforator can be used to target this region. And then other investigational therapies like we've used the needle catheter quite a bit for this type of VT substrate. Here's another example of this phenotype of a periaortic scar, a low voltage area extending from the aorta outflow tract like VTs, fractionated abnormal electrograms up in that region. And occasionally you'll see this phenotype in people that have very mild ventricular dysfunction or elderly and have a history of hypertension. And it could be that even just hypertension can give you enough fibrosis that if it occurs in the right spot, you can get these ventricular tachycardias. So back to our case, as I mentioned, would you do genetic testing? Well, he's got a pathogenic titan mutation that was discovered presenting in his 70s. And now this has relevance for his family for screening. And surveillance in the family members. But as I mentioned, about 40% of non-ischemic cardiomyopathy patients will be found to have a pathogenic mutation. And there are certain ones that have prominent arrhythmia phenotypes. So we've mentioned lamin disease, which by the age of 60 years old, virtually everybody who has a lamin mutation is having some cardiac issues, often atrial arrhythmias, AV block, or ventricular tachycardia. But other diseases, the desmosomal diseases that we commonly associate with arrhythmogenic right ventricular dysplasia, many of those can have left ventricular phenotypes with prominent ventricular arrhythmias as well. And then phospholambin mutations often produce scars in the basolateral left ventricle. And there are a number of others that have been linked to prominent arrhythmia phenotypes. This is the lamin data that I mentioned. So time from first clinical contact, the cumulative event rate, and the event rate for ventricular arrhythmias here in orange, you can see that by the time the patient's had 20 years of known lamin disease, 80% of them are dealing with ventricular arrhythmias. It's really a terrible mutation to have. So genetic screening is important, is increasingly important in these folks. And you also know that if somebody's got lamin disease and they present with VT and you get the VT under control, the odds are very high that it's not gonna be under control for very long and that within a few years you're going to be dealing with it again. Very often these people are heading for transplant. So sustained monomorphic VT in non-ischemic cardiomyopathies is usually related to an area of scar in the disease ventricle. The location and the nature of the scars likely determines the VT risk, and we don't understand a lot about that. As I mentioned, if you just do MRIs in non-ischemic cardiomyopathy, the most common scar patterns are these mid-ventricular wall patterns that are not periannular necessarily. But when we take people to the EP lab who have monomorphic VT, they usually have scar that's along the annulus, either the mitral or aortic valve rings, that is the source of their VT. So you can often make a pretty good guess about where the scar is located based on the QRS morphology of the VT that they present with or inducible VTs in the EP lab. And then we use voltage mapping to identify scar, of course, in the EP lab. So now let me show you another case. So this is a middle-aged man presented with palpitations, and he came in with this tachycardia, and you can see it's left bundle branch block, inferior axis. And again, there's some evidence of AV dissociation. So you're thinking outflow tract tachycardia, and following cardioversion, this is his EKG. So from this morphology, you might think, okay, maybe it's idiopathic outflow tract VT, but then once he's cardioverted, it's very clear that he's got right bundle branch block and a long, very long PR interval. So what diseases are associated with outflow tract VT and AV conduction disease? Well, arrhythmogenic right ventricular cardiomyopathy can certainly be associated with right bundle branch block, but it's very uncommon for it to cause first-degree AV block or evidence of septal involvement. Most people with ARV-C have involvement of the RV-free wall, and evidence of septal involvement is reported, but very uncommon. We mentioned that lamin cardiomyopathies can develop heart block. So could this be lamin, conceivable. But the most common thing with this presentation is somebody with AV conduction disease or heart block and a right ventricular VT is very important to consider sarcoidosis, because this is pretty common with those folks. And sarcoid can mimic ARV-C, and there have been many, many cases of people that were felt to have ARV-C, who once you had the heart out at transplant, you found it was sarcoidosis, and there have been cases diagnosed with sarcoid that wound up really being ARV-C. So the way that one tries to distinguish if they've got a family history of disease, it's more likely to be ARV-C, since sarcoid generally is not familial, whereas if they've got evidence of septal involvement, AV conduction disease, then sarcoid is more likely. And of course, genotyping has an important role here, because over 70% of people with ARV-C now have an identifiable pathogenic mutation. So this is relevant to people that present with VT that have a left bundle branch block configuration tachycardia. Whenever somebody presents with a left bundle branch block VT, you're worried about, is this coming from the right ventricle? And there aren't that many disease processes that produce right ventricular VT. So sarcoid and ARV-C being the big ones. Is it coming from the interventricular septum, in which case it could be scar in the septum? Or it's important to keep in mind that this is also the most common morphology for bundle branch reentry, because the most common circuit there is going up the left bundle retrograde and then coming down the right bundle antegrade, producing a left bundle branch block like QRS configuration. So whenever you have a left bundle branch block configuration tachycardia in a patient with non-ischemic dilated cardiomyopathy, you need to consider, could this be bundle branch reentry? A very quick way of getting a read on that, if you don't have a hiss catheter in position, is to entrain it from the right ventricular apex, because usually the post-pacing interval there will be 30 milliseconds or less greater than the VT cycle length, because you're fairly close to the insertion of the right bundle branch down there. So whenever you encounter that scenario, you need to take a step back and say, could this be bundle branch reentry? In which case, that's easily addressable by ablating the right bundle. As we mentioned, it's less than 10% of monomorphic VTs in patients with non-ischemic dilated cardiomyopathy. So we'll come back to this concept of there are EP laboratory phenotypes for VTs in non-ischemic cardiomyopathy. So we talked a lot about the basal septal periaortic scar phenotype. The next most common is the LV-free wall, the basal LV-free wall along the mitral annulus of VTs coming from scar in that location. And then a couple others that we'll mention are the patients who have very extensive scar that extends from the base all the way to the apex, which is a bad sign, crux VTs that originate from below the septum, often back at the base, but can be down towards the apex. And then there are some patients who have minimal amounts of scar, but still have VT. And then there are some that have prominent RV VTs. And again, the big offender here is usually sarcoidosis. So in the EP lab, we're often using voltage maps to define where the scar is located. And there are too many lines on this slide, but this summarizes pretty much the situation with voltage maps. So you know that a bipolar voltage of less than 1.5 millivolts is pretty specific for endocardial scar, and usually indicates that more than 75% of the wall contains fibrotic tissue. However, it only takes 2 millimeters of surviving endocardial myocardium to produce a voltage of greater than 1.5 millivolts. So you can have substantial fibrosis below an area that has a voltage greater than 1.5 millivolts. And you may not appreciate that there's intramural and epicardial scar based just on the bipolar voltage map. So unipolar voltage maps have been used to try and appreciate the presence of intramyocardial and subepicardial scar. And the 95th percentile of voltages in normal ventricles exceeds 8.3 millivolts. So that was used to define by the Penn Group this threshold. But it's recognized that there's quite a bit of variability to this. And it's important within an individual patient to consider just changing your thresholds to evaluate for the presence of areas that are relatively low voltage for that individual person. And in hypertrophied ventricles, voltage increases. Both the bipolar and the unipolar voltage increase. In dilated ventricles, they tend to decrease the voltage. And fractionated electrograms are an important marker of scar because this is not influenced by just simply wall thickness and the amount of myocardium. So these are some nice MR images from this nice publication that just make that point. Here you see ex vivo MR images. You can see this area of scar with the little surviving rim of myocardium. Here's one where there's a very thick rim of endocardial myocardium with substantial fibrosis that's kind of deep to that, closer to the RB than the LD. And some work from Kutches-Eppenfeld and Leiden that again just makes the point that as the thickness of the viable myocardium that's present underneath your electrode increases, the amplitude of the signal will increase. And that can be unrelated to how much fibrosis you've got underneath that electrode. And again, this is data from the Penn Group that then makes the point that in sarcoid very often you'll see areas where the bipolar voltage is greater than 1.5. So that would be this quadrant to the right. But you've got abnormal fractionated electrograms, which are the blue dots. So areas where the arrhythmias substrate is outside the low voltage area. Okay, so let's look at another case. This is a 58-year-old with non-ischemic cardiomyopathy identified over 20 years ago. He's had this a long time. He's had atrial fibrillation in a prior PVI, and now he's got recurrent VT and VT storm. And he's got these VTs. So here's a VT that is left bundyloid, superior axis, positive in one. So you know he probably has some septal involvement. And here's a VT that's got a rightward axis, so this is a QS in lead one, with a right bundle branch block configuration, and looks somewhat apical in these leads. Well, maybe an RS and V3, V4, so a little hard to know. But this looks like it's coming out of the lateral left ventricular wall. So you know that this guy has extensive scar, quite likely. He's got both septal and lateral wall involvement. And this is his endocardial LV bipolar voltage map, and you can see that he's got low voltage involving the septum, and along the inferior mitral annulus extending apically. But when we went to the site of earliest activation on the endocardium for his VTs, and this is for VT3, you can see that the electrogram is not very abnormal looking. And pacing here does entrain this tachycardia, and the post-pacing interval is in the circuit, but it's with a little bit of fusion. So this is typical of a site that is in an outer loop just outside the exit from the VT, and this was the best thing on the endocardium. So from this, we know then that we're not very close to this circuit. Whether or not we can interrupt it from there, we could try RF and see if it did anything to it, but likely this is more intramural or epicardial. And that morphology that's negative in lead I, which is not very well seen here, also suggests possible epicardial. And this is the unipolar endocardial voltage map, and you can see that there's a very large lateral wall component of low voltage that overlies the greater than 1.5 millivolt signal. And so this issue has been highlighted by the Penn Group in this nice publication from some years ago, showed very clearly you can have patients like ours whose normal, or I should say just greater than 1.5 millivolt endocardial bipolar voltage, low unipolar voltage, and you go to the epicardium and you find an area of low epicardial voltage that coincides with the location of the low unipolar voltage, and that's what this guy had. So here's his epicardial bipolar voltage map, and he's got extensive very low voltage over the lateral wall of the LD. And this is where his VT is, and there were areas like this where the voltage is so low you don't really see hardly any signal. You might think that activation is occurring here, but if you pace this, you can capture and entrain this tachycardia from its distal isthmus. And what we're capturing is probably something in here, so it's a little hard to really measure a post-pacing interval. The Stem2QRS would put it right at this little signal, so maybe that's relevant. So it looks like we need to ablate the epicardium, and this is one where it was tolerated well enough you could do a map. And very often, if you're able to do high-density maps of scar-related VTs, I'm impressed that more and more we are seeing these sorts of figure-eight configurations that Rod Tong has also shown very nicely, many of these. I wonder, I don't really know, is the circuit truly a figure-eight, or is it just if you have a little slow conduction area that forms the isthmus and activation of the rest of the ventricle proceeds from there? Well, it's kind of spread out in both directions, and then we make it look like a figure-eight. Is that really the circuit, or is it really a smaller circuit or a more complex circuit in this region? I think you can't really tell without entraining it from multiple sites, which is usually not possible. But we were convinced that if we could ablate in this area, we would get rid of this tachycardia. And of course, the problem over here is the coronary arteries, so you have to shoot the coronaries and make sure that you're not close to a marginal. And then the phrenic nerve, which in his case was a problem, and we needed to deploy a balloon into the pericardial space to protect the phrenic nerve. But then once we did that, we were able to ablate and terminate tachycardia. So then, well, are we done? And the problem with this substrate is that it can be intramural. So this is the lateral wall type of substrate where you have VTs that have a right bundle branch block, right axis configuration, often a QS in one, which suggests that the exit is epicardial. However, we always start on the endocardium because a fair number of these are ablatable from the endocardium and do have endocardial scar as well as epicardial scar. And the issues with ablating these, the obstacles here on the endocardium, the papillary muscle, the anterolateral muscle is often in the way. In the epicardium, you're worried about coronary arteries, the left phrenic nerve, and epicardial fat. And in our guy, he's got pretty extensive scar. And again, this nice publication from the Penn Group, if you see VTs that have a somewhat apical morphology with big S waves in the mid-pericordial leads, that tells you that the exit is out near the apex. And since in non-ischemic cardiomyopathy, the scar usually starts back at the mitral annulus and then kind of moves out towards the apex. When you see somebody who's got apical VTs, very often they have very extensive scar extending from base to apex. They have worse ventricular function and worse prognosis because of the severity of their ventricular dysfunction. So that was kind of the case in this guy. After we ablated that VT, he had this VT still inducible that looks more apical. And it's exiting out of that lateral wall still. It's right bundle, right axis. And he actually wound up requiring simultaneous ablation from the endocardium and the epicardium in order to try and get at that substrate because we were not able to abolish it just with endocardial or epicardial ablation. So looking at these combined bipolar and unipolar voltage maps can be helpful in some of these patients. This is another example. This is a patient with Lamin-Hart disease. His LV endocardial voltage is all greater than 1.5. His epicardial voltage is all greater than 1.5. But his septal unipolar voltage is quite low. And he had extensive substrate there generating multiple VTs. Here's another EP lab phenotype, which is a bit less common. So this is a patient with recurrent VT and ICD shocks. His VTs are right bundle, superior axis in their configuration, look like they're coming out of the left ventricle, out of the mid to apical left ventricle. His endocardial voltage map doesn't show any areas less than 1.5. His endocardial unipolar voltage map doesn't show any areas less than 8.3. So what does one do with this? It looks like it ought to be a lateral wall VT, but there's nothing interesting on the endocardium. And in this case, in the epicardium, although there was very little low voltage, there were areas of very abnormal electrograms with fractionated late potentials, lava-type potentials that were the source of his VT that could be ablated. So you can't rely too heavily on just the voltage maps in terms of scar. And imaging is very important in this regard. So ischemic dilated cardiomyopathy with ventricular scars, very important, again, to consider genetics increasingly. And we still see so many patients that come to the lab, as I mentioned, where the diagnosis is non-ischemic dilated cardiomyopathy, and that's it. There's no, well, what's it due to kind of question. It's just, well, that's it. And now that's not it. One needs to consider, is this genetic, which has implications for the family and someday may have implications for disease treatment, is it an inflammatory disease? Particularly, sarcoid, extremely important to consider, very easy to miss and very hard to diagnose. And then the scar distributions that you discover often point you towards the underlying etiology. So we mentioned with laminopathies, very often septum, although we've seen very extensive lateral wall involvement in some cases. Cardiac sarcoidosis can be anywhere, but also can include the right ventricle, which most other diseases do not. So that's very, very helpful. With postmyocarditis VT, there's a very nice paper from Paolo De La Bella's group recently making the point that very often the scars involve the basal lateral VT in those folks. Now, outcomes of a catheter ablation in non-ischemic cardiomyopathy are not as good as they are for patients with coronary disease. And it relates to this heterogeneous distribution of scar locations and the arrhythmia substrate that can just be difficult to find, difficult to address. So there are several papers in the literature that make this point, that outcomes achieving abolition of all VTs in non-ischemic cardiomyopathy is harder and the recurrence rates are higher than in patients with ischemic disease. And this is from the VTCC collaborative study group showing you the VT recurrence following ablation for ARVC. We're doing quite well now. Dilated cardiomyopathy in general, recurrences of around 40% or so at two years. Sarcoid, probably one of the most difficult diseases to treat because of its diffuse often diffuse and progressive nature. So to summarize, ventricular fibrosis in patients with non-ischemic cardiomyopathy is associated with the worst prognosis. You can detect fibrosis from MR imaging, which is increasingly important and useful. In the EP lab, we try to detect it with voltage maps. The ECG of the VTs that you induce suggests the likely scar locations. And you can pretty much predict what you're going to need to do based on the morphologies of those VTs very often. The patterns of scar vary with the type of disease, so it's useful in pointing you towards possible diagnosis. And there's a lot of work that remains to be done on trying to figure out why these diseases cause scars in specific locations and why some locations seem to be more arrhythmogenic than others. I'll stop there. Thank you, Bill. That was fantastic. There are a few questions that have come in while you've been talking. I'll kind of try and do them sequentially. But the first one was in terms of workup for when you see these patients, both for trying to determine the etiology and pre-procedural planning. What's your checklist in terms of the studies that you ordered? Does everyone get a PET scan? Does everyone get a cardiac MRI? Yeah. So everyone gets a cardiac MRI if we can, you know, if they have a device that doesn't preclude it. And then the next thing is, we're always asking, is it genetic or could it be sarcoid? So if somebody has septal involvement or right ventricular involvement, then we usually do plan to do a biopsy at the time of the EP study if we think sarcoid is a consideration. And we can consider getting a PET scan. If they don't have that, if they have a family history, then we'll usually send genetics and plan. And if the genetics are negative, then we'll do the PET scan. And the other thing that we consider is that if they've had kind of a rapid course of rapid downhill course, or it seems like things are changing, that's more consistent with an inflammatory process than with a genetic process. So then we also will have a lower threshold to get a PET scan. But pretty much everybody now, we're considering, you know, do they need genetics? Do they need an evaluation for sarcoid? In what order should we do those things? And then in the patients who have active inflammation, for example, a sarcoid patient with an active PET scan, how do you approach that? Do you wait until all the inflammation has gone down before you take them to the lab? Or will you bring them to the lab even if they're actively inflamed? Yeah, I'll tell you what I do. And then if Will is on, he has a huge sarcoid experience, and we should ask him what he does. So if someone has monomorphic VT in sarcoid, that's almost always scar-related, rarely Purkinje-related. And our experience is that usually doesn't get better with immunosuppression. Occasionally, somebody who's having lots of non-sustained VT and PVCs, that may get better with immunosuppression. And if that's triggering VT, then that may settle down. But if somebody's having a lot of defibrillator shocks, and they're already on three antiarrhythmic drugs, I think you're pretty much going to have to take them to the lab and get that settled down. If they're not having frequent VT, and they have active inflammation, and they have a lot of ectopy, you might think about immunosuppression for a while. Because I do worry that we're going to ablate something, and then it's going to change anyway, because they've got active inflammation. Will, what's your approach? You know, I'm in agreement with that. We generally want to use immunosuppression guided by PET scanning. And I agree with you that you can really see the antiarrhythmic potential of immunosuppression with reduction of PVCs. It's almost like patients are having a little mini-EP study, because they're having so much ectopy, and it just induces it. So it appears that you're reducing the amount of monomorphic VT, but maybe you're just reducing the amount of PVCs that initiate it. The only other thing I would mention is that there is some information about surviving fascicular potentials in the sarcoid scar, similar to like an inferior wall myocardial infarction. It's almost like you can have these Purkinje-like potentials in a sarcoid scar, and so they can sometimes be involved. That's maybe a little bit different than the experience you just described, but it is a challenging substrate for arrhythmia, for sure. Thank you. And then, Bill, there's a couple of questions on when you suspect a diagnosis, Lamin or sarcoid, but your testing is negative, you have a negative PET scan, you have a negative genetic testing, do you presumptively make the diagnosis, or are they being enrolled in studies to be followed as we get more mutations? Well, we are, you know, we're saving the blood. So, it could be, when you get negative studies, well, one possibility is that it was sarcoid, but now it's burnt out, and so you're not going to find it. It's done what it's going to do, and you kind of always hope that if it's sarcoid, that's what happened, that it is now quiescent. The patients still need to be followed, but it's done whatever it's going to do in terms of fibrosis. If it's genetic, and we don't know the gene, it may be discovered in the future. So, we do hang on to those folks. But there will still be probably 50% or so of the people that you see, where even going through all of this, you don't find an etiology. But that's many fewer than what it was 10 years ago. And then some questions about mapping. One is, do you use unipolar mapping for all non-ischemics? And then, do you agree with the 0.5 millivolt cutoff? Do you ever use a lower cutoff to try and identify critical areas? So, the voltage thresholds that one uses, I think it's a very important one. I think it's important to recognize that there's some variability there. And the 1.5 millivolt threshold that the Pennsylvania group defined as abnormal, that often people refer to as abnormal, I don't think we should call it. I think when it's above 1.5 millivolt, we shouldn't call that normal. Below 1.5 millivolt is very conservative. That was the 95th percentile of voltage in normal hearts. So, 95% of sites have a voltage greater than 1.5 millivolts. So, if it's less than 1.5 millivolt, that's usually a pretty severe abnormality, unless you're along the aortic valve ring or back along a valve annulus. There you can have low voltage normally because you don't have as much myocardium around you. But in the body of the ventricle, or more than two centimeters from a valve annulus, less than 1.5 millivolt indicates that you've got pretty substantial fibrosis in that area. But you can have a lot of fibrosis in there, and the voltage can be greater than that. And you can see fractionated, late potentials, abnormal signals in areas where the voltage is two and a half or three, and you know you've got fibrosis underneath there. So, I think it's important not to get too focused on a specific number for the voltage criteria. As I mentioned, a rim of two millimeters of myocardium visible on MRI is enough to give you a voltage of more than 1.5 millivolts, even with extensive fibrosis underneath that. So, looking at the relative voltages across the ventricles. So, for example, if you have somebody whose unipolar voltage is all greater than 8.3, but as you adjust your slider up, you find that there are areas where the voltage is, you know, 8.5, and the rest of the ventricle is all 12, you know, that would suggest that you've probably got some regional areas of fibrosis. And I know that Dr. Marsalinski makes this point frequently as well. So, the voltage maps are a good guide. Abnormal signals are more, fractionated signals are a more reliable indicator of fibrosis. And one other caveat about this voltage mapping issue is I do worry a little bit that now that we recognize that there can be intramural fibrosis and that you can potentially recognize that with unipolar voltage maps, and there's this tendency of substrate-guided ablation. I think we don't want to be doing substrate-guided ablation based only on a unipolar voltage map, because you could be taking out large amounts of functioning myocardium that's not necessarily arrhythmogenic. So, a lot of work needs to be done in that area. And I think that the imaging, combining with MR imaging is going to be very helpful. And then a good question just came in here. If you can't map during VT, what do you use as your endpoint for the ablation? Yeah, so what we do is we look at the morphologies of the VT. And we initially target the exits based on pace mapping, which is kind of what you saw in this talk. So, we put the catheter at the region where we think the exit is likely to be. And then hopefully we'll see that there's evidence of some abnormal signals there. And hopefully there'll be low voltage, either unipolar or bipolar there. And if we're a little uncertain, we'll induce the tachycardia and just entrain it once from that site. And that's what you saw in that one case where we were in the outer loop, just outside the exit. We could tell, okay, we're close, there's no abnormal signal, but the circuit's probably just below that. And then we'll restore sinus rhythm and we'll ablate that region, rendering it electrically unexcitable to pacing, and then retest. And it's very rare, I would say that we almost never do that in a region where we don't have some evidence that there's scar underneath it. Most commonly where this comes up is for that periaortic substrate. So, along the aortic valve, in the aortic mitral continuity, the basal septum where you're close to a valve annulus. And the other thing that usually happens there is once you ablate a little bit, now an area that was previously 1.5 millivolts, you see a larger area that's less than 1.5 millivolts because you've removed a surviving rim of myocardium that was contributing to that voltage and it exposes the fact that there's a lot of fibrosis underneath that. When we see that, then we'll usually do a line of lesions along the aortic valve ring, extending over to the septum, particularly when there are multiple VTs coming out of that area. And with most of these cases, there usually are multiple VTs. So, you're trying to find the substrate that supports all of those VTs. Hopefully, it's along a valve annulus where you feel that it's likely that ablation there is probably not going to diminish ventricular function. And then you target that substrate. And that's our approach to those.

non-ischemic cardiomyopathy

ventricular arrhythmias

underlying etiology

left ventricular dysfunction

genetic causes

inflammatory diseases

sarcoidosis

MRI imaging

fibrosis detection

ablation procedures