I'll call to the podium Dr. Giovanni Pareto from the arrhythmia and myocarditis unit at San Raffaele. Thank you. Thank you very much, Alessio. You've got 10 minutes and we'll be, you know, on the clock. Precise. Okay. So it's quite a complex topic to be managing 10 minutes, but I have chosen the key question. So first of all, I'm Giovanni Pareto from Sarafella Hospital, Milan. And basically, I work at a referral center for ventricular tachycardia ablation. And at the same time, we have a referral center for the multidisciplinary management of arrhythmic myocarditis. To date, we have more than 600 patients with biopsy-proven myocarditis in regular follow-up at our center undergoing multidisciplinary workup. A little bit of background. Myocarditis is an inflammatory disease of the myocardium, which is diagnosed by established histological, immunological, and immunohistochemical criteria. We have a number of pathophysiological clues, which may differ according to the kind of arrhythmia. For example, we have mechanisms dedicated for supraventricular arrhythmias. Frequently, the pericardium is involved. We have a separate mechanism for bradyarrhythmias, for example, in cardiac sarcoidosis, giant cell myocarditis, or Lyme carditis. And we have, of course, mechanisms responsible for ventricular arrhythmias, which is the key topic of today. So I've chosen three questions, which are clinically relevant in my view. The first question is, how to detect myocardial inflammation? That means, how to diagnose myocarditis? You probably know that we have at least two gold standard diagnostic techniques. One is endomyocardial biopsy. It is invasive. It may be limited by the so-called sampling error, but it is the only technique allowing to get the true diagnosis of myocarditis. On the other hand, we have MRI. MRI is a multi-planar, is multi-parametric, and of course, provides evaluation of the whole heart. However, in patients with arrhythmias, it may lack sensitivity and specificity. Based on the American College of Cardiology Consensus 2024, we define different kinds of myocarditis. Stage B is the asymptomatic myocarditis. Stage C is symptomatic myocarditis. And here are the indication recommendations. We would perform biopsy for those patients with left ventricular systolic dysfunction, so severe heart failure presentation, and patients with arrhythmias, high degree AV blocks, but also frequent multifocal PVCs or VT or VF. And of course, a number of additional clues. For cases with stable clinical presentation, in particular normal ejection fraction, absent or minimal late enhancement, and hemodynamic and electrical stability, MRI is fine as a single diagnostic technique, except for the immune checkpoint-related myocarditis, which is more severe and require biopsies in most cases. What if MRI is unsuitable? In our experience, we use the FTG PET, which, as you know, is a way to indirectly measure inflammation. Actually, FTG measures the metabolic status of the heart, and it is an approved diagnostic technique for cardiac sarcoidosis, which is just one of the most aggressive inflammatory presentation of inflammatory heart disease. But even in lymphocytic myocarditis, we observe the fine accuracy for FTG PET, in particular for patients with true acute myocarditis, so with a standard and not only the updated Lake-Lewis criteria on MRI. The second question is when to consider ICD implant in patients with myocarditis. Here a little bit of pathophysiology of the disease. Whatever the cause, infectious or non-infection, and whatever the histotype, classic form, lymphocytic, special forms, the granulomatous one, giant cell, or sarcoidosis, we have two possibilities. One is complete healing, and even if we have complete healing, in most cases we observe that non-ischemic scar is present on MRI. So it is not full restitution of the integrum. We have replacement fibrosis. The other scenario is that we have evolution toward chronic active myocarditis, and in the end, inflammatory dilated cardiomyopathy. It is pretty clear that the risk of heart failure increases in proportion to the degree of left ventricular dilation and dysfunction, but it is relevant to observe that even in the presence of normal or near-normal rejection fraction and non-dilated left ventricle, the risk of arrhythmias is significant as far as we have a scar. And in this multicenter study, it has been shown that there are at least two predictors of major ventricular arrhythmias during follow-up in patients with arrhythmic myocarditis. First is presentation with sustained ventricular tachycardia. Second is, I have two factors together, presence of late enhancement involving at least two consecutive segments in the absence of positivity at T2 stair sequences, indicating the presence of a so-called dry scar, so without active inflammation detectable by MRI. Consistently, in Europe, we have a significant change in guidelines because the former one, 2015, indicated that ICD was not a good first option for patients with arrhythmic myocarditis, but a watchful waiting strategy was recommended until recovery from myocardial inflammation and injury. Nowadays, the indication has changed, and in patients with hemodynamically non-tolerated sustained ventricular tachycardia, or VF, during acute myocarditis, ICD implant is recommended as early as before discharge. And in this setting, the role of ventricular tachycardia ablation in replacement of ICD implant is questionable. Last question for today, how to target ventricular tachycardias in myocarditis? First of all, we have to consider that the source of ventricular tachycardia is the non-ischemic scar, as you see from both MRI, usually inferolateral wall, basal mid-segments with epicardial or mid-wall distribution, and the same low-voltage areas detectable on epicardial electronatomical map. Consistently, the dominant morphology of ventricular echotopia and ventricular tachycardia is right bundle branch block with a superior axis. We observed in the clinical setting that the features of ventricular arrhythmias vary according to the degree of myocardial inflammation. In patients with active phase myocarditis, including both acute and chronically active, we have prevalence of either irregular or polymorphic ventricular arrhythmias, indicating the presence of a dynamic substrate. On the other hand, patients with chronic myocarditis with no more active inflammation, so post-inflammatory scar, we have prevalence of regular and monomorphic tachycardia, indicating the scar-related phenomenon. And here comes a very recently published experience from our hospital, 276 patients with multimodal diagnostic workup, biopsy, MRI, and sometimes FTG PET, divided into three groups, truly acute myocarditis, hot phase, chronic myocarditis with persistent activity, chronically active disease, and prior myocarditis, so non-ischemic scar with no more evidence of myocardial inflammation. The first message is that treatment strategies and success of treatment strategies are sensitive to the stage of a disease. Patients with acute myocarditis benefit most from immunosuppressive treatment alone. Patients with non-active disease benefit from ventricular tachycardia ablation alone, whereas patients with chronically active disease benefit from combination strategy in most cases. And the second result, very important, is that the so-called cool-down-then-ablate strategy, so immunosuppression first, ventricular tachycardia ablation after, is better in terms of freedom from ventricular tachycardia recurrences as compared to the opposite strategy. Here just an example of a patient with regular, sustained monomorphic tachycardia, right mandible branch block superior axis morphology, with electron-atomical map epicardial showing the entire re-entry circuit involving the inferolateral subsurface of the basal segment of the left ventricle. Here, ventricular tachycardia ablation is fantastic because it is possible to interrupt this tachycardia with no further recurrences if our ablation strategy is successful. What to do in patients with acute or active myocarditis. Immunosuppression is an alternative strategy. You can see we use combination strategy in most cases, not only steroids, but steroid-sparing agents as a thioprene first, but also mycophenolate, methotrexate, depending also on the comorbidities of the patient. And again, the use of immunosuppression is associated with the freedom from ventricular tachycardia recurrences late after treatment termination, on average 12 months in our experience. So the conclusion of my talk today is that arrhythmic myocarditis is for sure a complex and a multifactorial disease, that both imaging and histology are relevant for diagnostic purposes, but in the presence of arrhythmic presentation, histology has today a very relevant role and should be favored over MRI. A multidisciplinary approach is required for optimal clinical management of this patient, and the correct staging of the disease, identify if myocarditis is active or healed, is the cornerstone to decide the best treatment strategies, which may be immunosuppression and or VT ablation. Thank you very much for your attention. Thank you. Thank you for the introduction and the opportunity to talk to you today about sarcoidosis, inflammation and arrhythmias. So sarcoidosis is a systemic inflammatory disease highlighted by non-necrotizing granulomas which leads to chronic inflammation which then leads to fibrosis and permanent organ tissue dysfunction. It's appreciated that impaired regular T cell function may lead to unchecked inflammation but the entire etiology for sarcoidosis is still a little bit unclear. It's been known for some time that the main manifestations of cardiac involvement in sarcoidosis includes heart block, heart failure and tachyarrhythmias to include both atrial and ventricular arrhythmias. This is data from the Danish National Patient Registry of 12,000 patients with sarcoidosis who are matched to 47,000 controls and we see here that patients with sarcoidosis are seven times more likely to have ventricular arrhythmias or sudden cardiac arrest, two times more likely to have heart block and three times more likely to have atrial fibrillation or atrial flutter. And the main driver for all of this is both inflammation and fibrosis. So in the top left we have a PET image of a patient with sarcoidosis. Here we see things lighting up in the basal septum as well as the inferior lateral wall. This is an MRI of a different patient that has involvement of late gallon enhancement in the apex as well as the lateral wall, which correlated with their autopsy and histology where we see fibrosis and non-necrotizing granuloma. So as we heard from the previous speaker, MRIs and PET scans are really sort of the main imaging modalities, not only for making a diagnosis, but we actually get a lot of information in terms of the phenotype, how patients present and potential future risk for ventricular and atrial arrhythmias. So in the top row is a patient who has an MRI where there's no LGE, but there's active inflammation here in the basal septum. And so this is a typical presentation, somebody comes in with heart block. This is actually a sign of kind of an early phase of the disease itself. There's data supporting that if you treat with immunosuppressants at this phase that you actually sometimes reverse the heart block, but it's still recommended that you put in a permanent device because it is a little bit unpredictable in terms of their future course. Here in the second row is a patient who has LGE involving multiple segments here in the base, here in the infralateral wall, as well as a little bit here in the RV, and they also have inflammation on their PET scan. And so these patients present with heart block, ventricular arrhythmias, and LV dysfunction. And finally here is kind of a more chronic phase of sarcoidosis where you have LGE involving multiple segments here in the left ventricle, but there's no active inflammation. So if they don't have active, you know, conduction system disease at this point in time, it's unlikely they'll develop it, but usually they will have ventricular arrhythmias and LV dysfunction. And not to be forgotten, you know, atrial fibrillation is, you know, obviously the most common chronic arrhythmia there is in the world, but it's also common in patients who have sarcoidosis. And we actually get information from their PET scan about what their future risk for having atrial fibrillation is. So this is a study we did where we looked at our cohort of individuals who underwent PET imaging with a diagnosis of sarcoidosis. And you can see, you can actually see FEG uptake in the atrium. And this correlated pretty well with your future risk for developing atrial fibrillation. So if you do see this on PET imaging and you're kind of attuned to it, maybe it'll be an individual you want to screen a little bit closely for development of atrial fibrillation. Well how would these imaging tools in terms of predicting future risk for ventricular arrhythmias and mortality? This is a study of 118 patients, all who went to cardiac PET imaging, and they all had a diagnosis of sarcoidosis. There was a fourfold increased risk for death and ventricular arrhythmias if there was an abnormality on your PET imaging. Here in the top green are patients who had a normal perfusion and normal FEG PET, so they did the best. Those who had abnormal perfusion and FEG uptake, so signs of both scarring and inflammation, they did the worst. Cardiac MRI I think is probably the better tool in terms of risk stratification for sudden cardiac death and ventricular arrhythmias. This was a study of over 600 patients, all of them with a diagnosis of sarcoidosis, all of them who went to cardiac MRI imaging. And what we see is that patients who had positive LG, so they had evidence of scarring in MRI, their mortality rates were higher, and they were the only group that actually went on to have ventricular arrhythmias, meaning that if you get an MRI in a patient with sarcoidosis and there's no scarring, this individual is probably not going to develop ventricular arrhythmias at that point in time. Certainly things could change if they develop inflammation down the road, and so you always want to be vigilant for that. But if there's no LG on your MRI, then your risk for ventricular arrhythmias is exceedingly low. This is a study from the University of Minnesota of over 600 patients, all of them, once again, who had sarcoidosis. And what they were trying to do is looking at different sort of phenotypes on MRI that may predict risk for ventricular arrhythmias and sudden cardiac arrest. And so here we have the top group where there's a normal ejection fraction and there's no LG. You can make the argument that, you know, once again, these are patients with sarcoidosis and then all of them have cardiac involvement. And so somebody with this MRI, you want to diagnose them with cardiac sarcoidosis, and so these patients did very well. If you had an abnormal EF, so even if your EF was low, but if your ejection fraction – sorry, if there's no scarring on your MRI, your risk of having ventricular arrhythmias is also extremely low. So pretty much similar to the group that had a more preserved EF. And in this cohort of individuals, the average EF in this population was 31 percent, once again highlighting the fact that it's scarring your MRI, it's really sort of driving the substrate for ventricular arrhythmias. I'll jump over here to the pathology rare LGE. And so you have LGE, that's a little bit more subcutaneous cardio, limited to sort of one segment of the LV. These patients also did very well in terms of their risk for ventricular arrhythmias. So it's only these individuals who had this pathology, the term pathology frequent LGE. So if you had subcutaneous cardio involvement, involved multiple different segments, and in particular, if you see bipentricular LGE, that's really the highest risk group of individuals for sudden cardiac arrest and ventricular arrhythmias. So is one better than the other in terms of risk prediction? So we try to look at this by looking at our cohort of individuals who had both MRI images imaging, as well as cardiac PET at the same time, and we broke them into three different groups. Those who had LGE on their MRI, and those who were FDG PET positive. Those who did not have any LGE, but were PET positive. And those who were LGE positive, but had no inflammation on their PET scan. And what we found is that it was really the LGE on your MRI that drove your risk. So the cohort of individuals who had inflammation on their PET scan, but no scarring on their MRI, none of those individuals went on to have ventricular arrhythmias. And so, once again, highlighting the fact that it's your scar burden that's really sort of the driving factor. And in the last couple slides, I'm just going to touch base on just how we treat ventricular arrhythmias. You know, certainly, antirethric drugs are a mainstay of therapy. As electrophysiologists, we certainly get referred to a lot of individuals for consideration of VT ablation. And, you know, historically, we kind of felt that VT ablation is not very good in terms of the outcomes in this population. This is sort of an earlier study of 21 individuals, all who underwent catheter ablation with the diagnosis of cardiac sarcoidosis. And you can see after one VT ablation, the recurrence rate was pretty high, you know, 86%. Certainly, with more ablation procedures, you're able to reduce the burden of VT. But you know, really, the overall recurrence rate was extremely high even after multiple ablations. And so, similar to kind of other non-ischemic studies, you know, you certainly may reduce the burden of VT overall, but it's really hard to kind of tell somebody that you're going to make them VT-free with a VT ablation alone. But I don't think that tells the whole story. And you know, as we heard from the last talk, you know, I think there's certain patterns and certain characteristics, especially on the pet skin, that may show that, you know, you actually have a pretty excellent outcome with VT ablation. So this VT map looks exactly like the one you saw before. I promise you it's not the same patient, but this is a very typical kind of scar pattern you see. This is the epicardium of the LV, and we're looking at the lateral wall. And this is a patient who had sarcoidosis, but usually when I get these sort of individuals, I get a PET scan to see if there's active inflammation. And we have study data to kind of support this. This is from the Cardiac Sarcoidosis Consortium of 99 patients who underwent VT ablation, and they stratified their outcomes based on whether there was inflammation in their pet skin or not. And actually, those who had no inflammation, they actually did, you know, pretty well for VT ablation compared to those who had inflammation on their PET scan. And so before considering an invasive approach for these individuals, I think it's critical to get a PET scan to make sure inflammation's not a driving factor. And I do think that when you have this sort of epicardial, you know, lateral wall VT circuits, you actually do very well in terms of the catheter ablation for these individuals. So in conclusion, inflammation and scar are the primary drivers for the rhythmic manifestations of cardiac sarcoidosis. Surely you should have a high in excess suspicion when patients present with unexplained heart block, VT, or heart failure. Compared to other clinical and imaging tools, I think CMR is more sensitive in predicting future risk of ventricular arrhythmias, with the highest risk amongst those with biventricular involvement. And, you know, before you think about VT ablation, you really want to treat inflammation, which I think is critical to improve outcomes. Thank you. Fantastic presentation. Jonathan, thank you. Next speaker, Dr. Sini James from our home program, John Sopkins, talking about a topic very close to my heart, desmoplasticity. All right, well, thank you, Alessio, and really thank you to the conference organizers for this opportunity to speak with you today about what I consider to be an entirely fascinating inherited form of arrhythmogenic cardiomyopathy. For those of you who I don't know, I am a PhD geneticist and genetic counselor. I've spent my career in cardiovascular genetics, specifically in the Johns Hopkins ARVC program, which was founded and led by Hugh Calkins. So I look at this challenge from that perspective. What I'll do in the next nine and a half minutes or so is briefly touch on risk of ventricular arrhythmias in desmoplacan cardiomyopathy and what we're learning about risk stratification for sudden death, touch on characteristic myocarditis-like myocardial injury episodes in this condition and their implications for long-term disease course, and then put the first two points together and discuss a little bit about what we're learning about potential gene-specific therapeutic approaches for this condition. All right, so desmoplacan cardiomyopathy caused by pathogenic or likely pathogenic variants in DSP, which is the gene that encodes desmoplacan, which is part of the cardiac desmosome. However, DSP cardiomyopathy looks different than other desmosomal forms of cardiomyopathy, which you think of most classically as right-sided ARVC. Desmoplacan cardiomyopathy is disproportionately left-sided. Late gadolinium enhancement on CMR is common, primarily subepicardial. Rates of stained ventricular arrhythmia are high. There are these funny acute myocardial injury-like episodes. And where we're going first, arrhythmic risk stratification is difficult because strategies you usually use for dilated cardiomyopathy or strategies you might use for ARVC neither work particularly well in this cohort. So with this very nice paper by our colleagues at the University of Michigan, as well as similar observations by our group and others, we realized there was a lot more work that needed to be done on desmoplacan cardiomyopathy. Led by my colleague Alessio here during his time as a fellow with us, we were fortunate to join with really the entire arrhythmogenic cardiomyopathy community to put together the Desperados Network, which in this very first stage involved 815 patients with a DSP variant from 26 centers in North America, Europe, and Australia. And initially our goals were really to focus on risk stratification. Did the ARVC risk calculator, which we had developed, work for risk stratification? What were really the rates of outcomes in univariate and multivariate predictors of ventricular arrhythmias in desmoplacan cardiomyopathy? And was it possible or advisable to develop a DSP-specific algorithm for risk stratification? I'm pleased to report we've accomplished all three of those goals. First of all, the ARVC risk calculator does not work in DSP cardiomyopathy. Even when you apply it to patients who technically are eligible, they meet 2010 ARVC task force criteria and they haven't had a sustained ventricular arrhythmia at baseline, the performance isn't very good. The C-statistic is .6, and as you can see with the red arrow, fundamentally you do not want your calibration plot to look like an M. That is bad news. So moving on, we then took a look at all of our 800 patients in the registry with a single pathogenic or likely pathogenic desmoplacan variant, and we observed really a high risk of sustained ventricular arrhythmias at 3.9% per year, which may not sound so bad except for when you consider the fact that half of the individuals in our registry were family members, many of whom met no criteria formally for a diagnosis other than having a pathogenic variant. Also in this initial exploration, we observed that indeed LVEF appeared to be really important to risk stratification along with risk predictors common in arrhythmogenic cardiomyopathy such as frequent PVCs and SVT. Using this information, led by our colleague Rick Carrick, who is now a faculty member at Johns Hopkins, we developed a DSP risk score for incident sustained ventricular arrhythmia risk prediction with a derivation cohort and a holdout validation cohort that really performed nicely. Key points here are indeed risk factors for desmoplacan cardiomyopathy are different than for either DCM or ARVC. In particular, female sex is a risk of sustained ventricular arrhythmias in this disease. LVEF is important, and because I imagine in this setting I'll get asked that, we did look at LGE and it fell out of the model. All right, so pulling that all together, I would end this section of the talk by arguing that desmoplacan cardiomyopathy is an arrhythmogenic cardiomyopathy for which a genotype-specific approach to risk stratification for sudden cardiac death is warranted. All right, on to the next topic. These myocardial injury episodes in this initial cohort, we saw that the prevalence was about 8.7 percent, although we're pretty sure that's an underestimate given some centers sent us a rate of zero, so we think they were being under-ascertained. We were worried about these episodes because in a single-center study we had previously done on a group of 91 Johns Hopkins patients with desmoplacan cardiomyopathy, we had observed that these myocardial injury episodes were associated with worse risk of heart failure and a higher prevalence of sustained ventricular arrhythmias afterwards, and the Desperados cohort was really the opportunity to definitively answer this question. So using a definition of myocardial injury, myocarditis-like episodes is a symptomatic event associated with the presence of increased levels of serum cardiac troponin over the 99th percentile and the exclusion of coronary artery disease and histologic and or CMR criteria consistent with acute myocarditis, we found that individuals who'd had a myocardial injury episode in the red had a two-and-a-half-fold risk of sustained ventricular arrhythmias afterward and a five-fold risk of heart failure afterward. So these symptomatic myocardial injury episodes are not benign in desmoplacan cardiomyopathy, which begs the question, if they are unpleasant in the moment and have bad implications for long-term trajectory, should we treat them, and if so, how? This is a retrospective exploratory study, again, leveraging the Desperados cohort. It's still under review. Now we have a little over 1,000 patients from 31 centers, 11-and-a-half percent of patients had experienced myocardial injury. The take-home message here is that patients whose first myocardial injury episode was treated with immunosuppression, so that's the red line in the Kaplan-Meier curves, had better survival free from sustained ventricular arrhythmias and from combined endpoints than individuals who were either not treated in the blue or treated with NSAIDs or colchicine, which is the yellow line. Unfortunately, treatment did not seem to reduce the likelihood of a recurrent myocardial injury episode, which is panel B. And finally, trying to stay under my 10 minutes, the other thing we have learned in our center is that these myocardial injury episodes in desmoplacan cardiomyopathy may be promoted by participation in high-intensity exercise in people who have a pathogenic or likely pathogenic desmoplacan variant. In our program, we do a lot of work on the impact of exercise and outcomes in arrhythmogenic cardiomyopathy, and here you can see in this study of just 100 patients from our center, while we didn't see a big difference in VA free survival over the course of a lifetime or heart failure free survival over the course of a lifetime in athletes in the blue versus non-athletes in the yellow, you can see athletes developed earlier and more frequent myocardial injury episodes. So I hope I've convinced you that desmoplacan cardiomyopathy is a condition in which gene-specific approaches to management are warranted. I think there's gene-specific opportunities for diagnosis. We talked about risk stratification, lifestyle guidance, and therapeutic management. A lot of the work I shared today is being put together along with data from other ACM genotypes into an international expert consensus document on the diagnosis and management of genetic variant-based arrhythmogenic cardiomyopathies, which is being led by Hugh Calkins and Firat Duru, and we look forward to sharing that with the community. And I'll end just by saying thank you. Thank you to Alessio for all the work you've done in this area. Thank you to my colleagues at Johns Hopkins, and really thank you to the entire Desperados network. You can't make progress in rare disease research without this sort of collaboration. So I'm grateful, and I look forward to your questions. Next speaker, a friend and a mentor, it's my pleasure to introduce Dr. Santangeli from Cleveland Clinic to enlighten us with some insights on VT ablation in those patients. Thank you so much, Dr. Gasparetti. Refreshing to be in a session with no PFA in the talks, which is great. All right, so thanks everyone for being here. So I was assigned the task of talking about VT ablation in inflammatory cardiomyopathy. When I went back and looked at the definition of inflammatory cardiomyopathy, I realized it's quite heterogeneous as a group, really. So here, for whatever reason this is not displaying, it was displaying on my... What this slide was supposed to show you is that inflammatory cardiomyopathy is a heterogeneous group which include genetic conditions, acquired conditions, myocardial infectious conditions, like Chagas cardiomyopathy, for example. Some of this, of course, we do have, like the DSP mutation we talked about already, is genetically driven, of course, and there are multiple insults with inflammation and replacement fibrosis, and we talk about that. There is also a large group of patients with unexplained non-ischemic cardiomyopathy, undefined, I would say, and some of these also underwent genetic testing. Most of them were negative. These were data from Rotang way back when it was a UCLA, 103 patients. There was a 49% incidence of positive PET findings at baseline for patients that presented with VT. We don't really know what this means, nor how to treat this, but the group of patients that we probably more understand in terms of what to do in terms of VT management, in terms of the inflammation and VT, is cardiac sarcoidosis, and of course, I think the very first step of, before you take them into the lab, is try to understand what the substrate will look like in the individual patient, because sarcoidosis is a condition where you have coexistence of inflammation and scar in the same patient, how this translates to what you will find at the time of the ablation. So here, we'll look at the correlation between imaging findings of positive PET and MRI here and abnormal electrograms, which were defined as anything that was not normal, and normal definition was three or fewer sharp deflections with a duration of less than 70 milliseconds and a ratio between amplitude and duration more than 0.046 here, and you see there was a good correlation between scar transmurality, an LGE on MRI, and abnormal electrograms. There was a trend towards a correlation, statistical correlation actually was significant here, but if you look, there is a lot of overlap here between positive PET findings, so inflammation, and abnormal electrograms. So sometimes you may have normal electrograms in presence of inflammation or can be also abnormal, but typically when you have late announcement, the electrograms will look like fragmented, low amplitude, and multi-component. Now we look at voltage mapping, because we've been working with voltage mapping for defining the substrate, here we realize that there were essentially three types of groups here. The one that present just with inflammation and no scar tends to have a low unipolar voltage, less than 8.3 millivolts really, with no abnormality in the bipolar electrogram in terms of voltage. The one that present with more scar and less inflammation tends to have the classical presentation of low fragmented, late potentials, low bipolar voltage, and of course also low unipolar voltage. So now there is a group of patients with non-ischemic cardiomyopathy with no late announcement, and particularly the one that present also with positive PET, we try to define whether MRI with T1 mapping may help to define where the substrate may be located. This is a group of patients with only septal substrate found at the time of the procedure, and negative LGE on the MRI. We found that decreasing value of T1 mapping here was associated with a larger area of septal scar, and this again is only done with septal substrates. I think we need to study T1 mapping in other areas of the left ventricle, but I think it's quite promising in this group of non-ischemic cardiomyopathy. Now a bit busy here, but here we reviewed 14,000 electrograms from patients, or 31 patients with cardiac sarcoidosis. Each one of these dot is one electrogram, and in green you will see normal electrograms, and in blue the abnormal electrograms. Abnormal electrograms are target for potential substrate base ablation. What I'm going to show you here on the y-axis here, there is a unipolar amplitude less than 8.3, which is standard for us to call it your low unipolar, and here on the x-axis less than 1.5 millivolts will be the area of scar defined by voltage criteria. You can appreciate that although this is quite specific for the blue type of electrograms that are abnormal, there's a lot of abnormal electrograms that fall beyond the 1.5 cutoff millivolts for voltage for bipolar, and even above 8.3 millivolts. So again, whatever is the best cutoff value to identify abnormality in cardiac sarcoidosis is not defined yet, but it's definitely the standard criteria do not apply perfectly to this group of patients. 40% of abnormal electrograms were outside the areas of low unipolar and low bipolar voltage, something to keep in mind when you're dealing with these patients. Now, Jonathan has shown some of this data here. This was our outcomes when I was back at University of Pennsylvania for a patient with sarcoidosis, 31 patients and 44 procedures. And here's a timeline of events for the patient. But what I want to show you here, this is the group of patients that does the worst in terms of the BT ablation outcomes. It's 55% BT-free survival after multiple procedures, and it was a 17% rate of death and transplant, and really a relatively short-term follow-up, actually, between one and two years. There was a reduction of the BT burden, but again, if you look at BT rate in terms of success here, it's definitely at best palliation. And when we looked at the predictors of outcomes, the strongest predictor was a presence of active inflammation, a baseline that was indexed by a positive baseline PET. Or whenever you start immunosuppression, you have a failure of improving the PET scan over follow-up here. And of course, the more inflammation you have and the more scar you have, which is something that has been also shown in other subgroup of non-ischemic atomyopathy, the more likely you will have to fail. So more than five segments with LG and MRI was another important predictor. Now, we always say we like to start with immunosuppression. One thing we don't really talk about much is that some patients are metabolic non-responders. In some ways, despite escalation of immunosuppressive therapy, there was a group of 20 patients with more than three serial PET after sarcoidosis with prednisone and methotrexate and escalation of doses, 55% metabolically were non-responders. The PET continued to be positive, and they continued to have BT. So in some patients, you are almost compelled to take them to the EP lab despite immunosuppression because immunosuppression fails to provide a negative PET. And of course, in the US, we don't have a high prevalence of other form of granulomatous cardiomyopathy like tuberculosis. But whenever we see this type of pattern, we always screen for other causes because, of course, the PET scan doesn't become negative after immunosuppression. You have to think about some other conditions. So far, we haven't found a single case of that. But of course, it's more prevalent in other places in the world. So DSP cardiomyopathy, these are the data from Alessio, 24 patients, median follow-up of 2.9 years here. You can see that there is a fair good follow-up. This is, I believe, and correct me if I'm wrong, after a single procedure, index procedure, which is actually quite good. And the patients that did the best were the ones with free wall substrate, which is most typical for these patients. And most of the times, you require an endopic ideal approach. Now, this was already shown way back when by Frank Marszuliski, actually, where there was no genetic testing there. But I realized in the very first paper from, I believe, 2004 here, exactly, there were a subgroup of patients with arrhythmogenic cardiomyopathy that had biventricular involvement and presented to red bundle VTs. I bet that this patient had some form of DSP mutation. This is not the typical presentation in terms of the map and the VTs that we see for PKP2, RV-dominant cardiomyopathy. Now, another important group of patients that is not very prevalent in the US, but has been studied extensively, particularly in Brazil, that also falls into the category of inflammatory cardiomyopathy, is Chagas cardiomyopathy. In these patients, we do know that most of the times, the substrate is located in the epicardium, and that's how epicardial ablation was actually born to deal with this problem, was essentially started in Brazil because of this. And here you can see, there was a randomized trial by a group of Mauricio Scannavacca in Sao Paulo and the randomized patient with Chagas cardiomyopathy and VT, which is a form of inflammatory cardiomyopathy, to an endoepicardial approach versus endocardial only, with significant benefit with epicardial. So the bottom line is, most inflammatory cardiomyopathies with free wall involvement require epicardial approach. So I'll conclude here saying that inflammatory cardiomyopathy are a heterogeneous group of disease characterized by different degrees of acute inflammation and fibrosis. In the presence of acute inflammation, catheter ablation seems less effective, particularly in the case of cardiac sarcoidosis. 40% of normal electrograms will be located outside the bipolar scar, so be aware of that. Just don't use voltage mapping alone to define the target. Increased uptake of PET significantly less specific than LG on MRI to predict and localize abnormal electrograms. And abnormal electrograms tend to be located more in areas with increased scar transmurality on MRI compared to positive PET. Catheter ablation with a frequent epicardial approach that is needed is associated with worse outcomes in cardiac sarcoidosis patients compared to other forms of inflammatory cardiomyopathy. I'm gonna stop here. Thank you for your attention. Thank you. Thank you so much. That was fantastic. So the last of this all-star cast is Rachel Lampert from Yale University who will be talking about sport in the setting of inflammatory cardiomyopathies. Ten minutes. Pressure's on. As we've just heard from Dr. Cindy James, DSP cardiomyopathy is an inflammatory, arrhythmogenic cardiomyopathy marked by fibrosis in 40% and periods of active inflammation described in 9%. As Cindy has shown, exercise promotes myocardial injury and a greater likelihood of injury episodes in those doing the most vigorous exercise, although they did not find a worsening of heart failure or ventricular arrhythmias. Cindy and her team have also shown that exercise increases both penetrance and arrhythmic risk in ARVC variant carriers, which in this group was mostly PKP2. Those who reported the greatest lifetime density of endurance exercise developed disease and heart failure sooner and were more likely to have arrhythmias at younger ages. Moving forward, those who stopped exercising did better. In addition to these long-term effects, our ICD sports registry, which included 55 athletes with ARVC, just defined sort of broadly as common at that time, among the 440 athletes enrolled, the ARVC athletes were among the most likely to have appropriate shocks as well as storms of appropriate shocks during sports. Based on these data, the 2015 eligibility guidelines for competitive athletes recommended that athletes with a definite diagnosis, a borderline diagnosis, or even a possible diagnosis of ARVC, again defined broadly, should refrain from sports. By 2019, understanding of genetic cardiomyopathies was advancing, and the Heart Rhythm Society expert consensus statement on ACMs at that time notes that data on exercise in non-PKP2 cardiomyopathies was sorely lacking. One of our top take-home messages in last year's Heart Rhythm Society consensus statement on arrhythmias in the athlete was that not all genetic cardiomyopathies are the same when it comes to exercise. This table, put together mainly by Cindy, summarizes both the direction of the data and the extent and validity of the data on the impact of exercise on likelihood of arrhythmia, on progression of underlying disease, and on penetrance for each of these genetic entities. Recognizing this heterogeneity, our document describes that for athletes with a lower risk genotype, sports may be considered, while for those with a higher risk, sports may be harmful. For these athletes, shared decision-making with frank discussion of both the data and the lack of data and uncertainties where that's the case is critical. Further data in this population may come from the ongoing ORCA study, Outcomes Registry for Cardiac Conditions in Athletes, and if anyone in the audience has any ACM patients, either DSP or other types of ACMs, doing sports, please let your patients know about that study as they can self-enroll on the website and help us all gain more data in this population. Now, so what is the mechanism of these deleterious effects of exercise in DSP? So it's well-known that exercise almost doubles wall stress in the right ventricle with just a 23% increase in LV. In a mouse model here of placoglobin-deficient mice, different than DSP, mice who were made to run and swim developed fibrosis and heart failure. Of course, there were limitations to this study, lacking a bicycle component, but these are the data. So how do we put this together for DSP? Does the hemodynamic effect promote the underlying inflammatory pathway, or could a direct inflammatory effect of exercise be what sets this off, particularly as DSP is a predominantly left ventricular entity, and the mechanisms for all the ARVCs and exercise may not be the same. So the concept that exercise may create an inflammatory condition has been around for a while. In this hypothesis, local acute inflammation creates local chronic inflammation, which then leads to chronic systemic inflammation, which most of the data on this has come from atrial fibrillation, another area in which inflammation is important, and probably this is because there's a lot more athletes who have AFib than have cardiomyopathies. So in this mouse study, looking at atrial fibrillation, mice who were exercised had increased inducibility of atrial fibrillation, although not ventricular arrhythmias, and fibrosis seen histologically with blockade of TNF-alpha, either pharmacologically or through use of genetic modification, exercise no longer had these effects, suggesting a role of exercise-induced inflammation in this arrhythmogenic process. So this hypothesis has been a lot harder to show, however, in humans. In this meta-analysis of multiple studies looking at CRP, CRP was actually lower in the trained athletes. There's just one study that I was able to find that was from last year of circulating proteome analysis in athletes before, during, and after exercise, which found that acute high-intensity exercise modulated immunologic response pathways, but there really isn't much data on this in humans. All right, so switching gears to myocarditis, sports eligibility guidelines from 1985 to the present day recommend that athletes with myocarditis should not be participating in sports while active inflammation is present. So this recommendation is based first on concern for arrhythmias. Arrhythmias are common in myocarditis, as we've heard, occurring at up to 19%, and in the recently updated series of sudden cardiac death in NCAA athletes, myocarditis also is one of the causes of sudden cardiac death in athletes, attributing about 7%. Next is concern for increased likelihood of development of long-term cardiomyopathy. For decades, this concept was based on a single murine study, which showed that mice infected by Coxsackie B virus in ways that cause myocarditis had larger hearts at sacrifice when they were forced to swim during the myocarditis period. After a long time, there was actually a confirmatory study of this by Heidbuechel et al., who confirmed this finding in a more rigorous and detailed experiment. In a single model of Coxsackie myocarditis, the mice who were exercised prior to infection did better, as one might expect of a physically conditioned animal, but those who were randomized to continue exercise after the infection had more inflammation and more fibrosis. What has evolved, though, in our thinking about myocarditis in athletes is when we can let them return to play. Earlier recommendations gave a wait time of three to six months prior to reevaluation for resolution of inflammation and arrhythmias, and this was really just based on not much data, but COVID-19 has greatly expanded our understanding of viral myocarditis. Myocarditis was probably not more common in COVID-19 than in other viruses, but as everyone got it at the same time, we could learn a lot more from this as sort of a natural experiment. In this observational study of 20,000 athletes at 42 colleges who were tested for COVID-19 at the time of returning to college, as was going on in the early days of the pandemic, there were about 3,000 who tested positive and underwent cardiac evaluation, which again was routine at the beginning of the pandemic. So the majority underwent a triad testing, as it was called, of EKG, troponin, and echo first, and overall, about 2% of these had an abnormality and went on to CMR, which showed 13% abnormalities on CMR. There was another group who went straight to CMR, and of these, the yield was much lower, and based on these data, there was really, even at the beginning, the recommendation was not to perform CMR, and given this low yield, we don't perform this triad testing either unless patients either have a very severe case of COVID or athletes or young people, or they develop symptoms concerning for myocarditis or cardiac abnormalities. Now, the Big Ten did do cardiac MR first, and they followed up those who had abnormal findings. Now, these data showed us just not a very high likelihood of abnormalities based on this type of screening, and they further do not support the use of routine screening for myocarditis in athletes who have COVID-19, but again, we were able to sort of leverage the fact that people were doing this to get a better sense of the natural history of COVID-19 in athletes, and what this study found was that prior to that sort of common pulled-out-of-the-air number three to six months, in fact, many of those who did actually have inflammation had resolved by one month or many within that three-month period, so based on this, this has changed, and we now recommend that an athlete who develops myocarditis, whether due to COVID or anything else, can start to be evaluated at one month. Is there some chance that things will have resolved, and if not, they can be, again, evaluated at three and six months before they go back to play, so I'll stop here. Thank you. Well, certainly you try to, sometimes you're just not able to. And so, usually during an acute inflammatory phase, you know, they get started on immunosuppressants, put them on antiarrhythmics, typically amiodarone, and hopefully that's for a long-term course, but at least until things do subside. And if you're lucky, then the amio kind of helps quite a bit. the concerns for ablating during an active inflammation phase? Yeah, very interesting question. I don't have a unique answer to your question, but I can say that in our experience, patients undergoing recurrence after ablation frequently had VTs of different morphology and or a cycle length if detectable by cardiac devices. So in a way, it was not the index clinical VT ablated during the procedure. When you undergo VT ablation, you usually focus on that particular ventricular tachycardia. If you don't care of a substrate, you may fail in achieving the control of a whole disease. That's the concept. All the panelists, how will FDG. I'm not sure about FDG, but certainly. the presenters, specifically. Yeah, that's a very interesting question. Many patients with systemic rheumatologic diseases have cardiac involvement, and it is inflammatory in most cases, and in the late stage, we have fibrosis, basically. And in our experience, we didn't observe flares of arrhythmias during, at the time of diagnosis of the systemic autoimmune disease, or carditis. But in general, we think that 24-hour, 48-hour alter ECG, even repeated twice a year, is not sufficient in many cases, especially if symptomatic. We make large use of implantable cardiac monitors in patient with dissociation between findings on alter and evidence of a pro-arrhythmic substrate or symptoms in different moments. Hi. Quick question for Dr. James. Very beautiful presentation. We know that in PKP2, we do have alteration in calcium stasis, you know, around the receptor 2, calc-segue strain triadine and so on. And so we have this increased frequency in calcium sparks and CPVT-like. So any data on DSP and calcium aminostasis? So it's a great question, and I should know this off the top of my head, but I do not. I'm looking at the gentleman behind you, Jeff, and wondering if you know the answer to that question mechanistically? Yeah. I honestly don't know. Leslie, do you know the answer? Not to my knowledge. I don't think that has been reported. So we're talking about two different phenomena here. So we know that, just take a normal person, exercise does increase pressure on the right ventricle but also does improve diastolic function of the left ventricle. So they're very, they're different phenomena and both occur. So I think there are certain, for entities in which diastolic dysfunction is important such as hypertrophic cardiomyopathy, I think there are many potential benefits of exercise. For this population, I think it's going to turn out to be either neutral. particularly considering the limitation of PET versus LGMRI in identifying abnormal substrates? Yeah, great question. We basically have abandoned voltage mapping for these patients. Actually, for all non-ischemic patients in particular, it's very not sensitive. It tends to be specific, but very low sensitivity. So we just look at the electrogen morphology, and we do annotate them. When you have multi-components, of course, if you have late potentials, you can work in activation mapping. That's way more sensitive to annotate all these areas. Now, most of the times, you end up with several areas of interest, and then you really need to prioritize where to start ablating. And of course, induction of VT is important in these cases. Going back to the inflammation question, what we found in the initial study, reason why positive PET was associated with recurrence is because we found multiple morphologies not always re-entry. Some of these patients presented with a lot of focal activity type of VTs, changing morphologies as well. So it's very difficult to locate the different sites and to be successful with those. So we try not to touch them unless we're necessary to do it. When they fail. Let's do it by condition, we'll start. Giovanni, what do you think in myocarditis? And then we'll ask Jonathan for a summary. Follow-up MRI in myocarditis is recommended by six to 12 months according to guidelines. However, today we have a great sensitivity of the mapping criteria as compared to the prior likelihood criteria. Now we have the T1 and T2, especially in chronic stage myocarditis, are really, really sensitive. And in our experience, even 12-month MRI may show residuals of T2 and T1, ACV abnormalities, especially in patients with systemic rheumatologic diseases. So the idea is that first MRI, six to 12 months, and then personalize based on your findings. Can I ask a question about this, which sometimes we see these patients. The question is, how do you change your management based on these results on the repeat MRIs? So let's say it gets better, so nothing changes. But what if it doesn't change at all, or it's slightly worse? Do you, because with myocarditis, it's so difficult to have a therapy that actually works. So how do you interpret the findings? Very challenging question. We changed our mind and basically set our treatment goals based on clinically relevant endpoints. I mean, low ejection fraction, symptomatic troponin birth, or ventricular arrhythmias. If you have everything OK and just persisting T1, T2 abnormality, or persisting troponin release, we don't care, actually. We have no bad outcomes even at five years in many patients. So it would be almost better not to do it, just to connect to it. Yeah, sometimes you have also to be wise and not exceed in your treatment options, because no benefits, basically. Yeah, so for the sarcoidoscope population, typically you don't. No, it's not a tissue contact issue, it's more of a resolution issue. So in other words, you can see more near field electrograms with a higher clarity with multipolar because the electrodes are smaller and the inter-electrode distance is narrower. But I don't think there is a huge difference in terms of the outcomes of ablation if you use one. There is some data that using multipolar catheter for mapping, it comes from Bordeaux, it associated with better outcomes for ablation. We haven't really reproduced that. So it's just like a matter of having a good map that is fast with a larger footprint. But I don't think it changes really the outcomes in the big picture. Thank you all for coming. I appreciate the panel, I appreciate my co-chair, I appreciate the audience. We'll close the session. Thank you.

arrhythmogenic cardiomyopathies

ventricular arrhythmias

diagnostic imaging

myocarditis

sarcoidosis

MRI

PET scans

endomyocardial biopsy

immunosuppression

DSP cardiomyopathy