Okay, welcome everyone to the oral abstract session here. I'd like to introduce James Salazar, who will be presenting on weight status and incidents and causes of sudden death by autopsy. Thank you. Hello, everyone. My name is James Salazar. I'm a first-year EP fellow at UCSF. It's an honor to present our project, Weight Status and Incidents and Causes of Sudden Death by Autopsy, on behalf of our team. I'd like to give special recognition to my co-lead on this project, Matthew Yee, a UCSF medical student who submitted this abstract but unfortunately could not attend. So, abnormal weight status has been associated with increased risk of sudden cardiac death. This figure from a meta-analysis demonstrates a J-shaped association between BMI and sudden cardiac death, ranging from mildly increased in the underweight to two- to three-fold increased risk in those with obesity. As such, weight status is an important target for sudden death prevention, and with anti-obesity therapies may be increasingly modifiable. Much has been invested in understanding this increased risk. As this figure from a Jack Review article shows, though, proposed mechanisms make the critical presumption that these deaths are due to arrhythmia. However, in our post-STD study, a prospective autopsy study of all presumed sudden cardiac deaths in San Francisco, we showed nearly half of traditionally defined sudden cardiac deaths are not due to arrhythmia. These deaths shown in green included a cold overdose and sudden neurologic death, which are clearly distinct from those in red, such as coronary artery disease and cardiomyopathy, which are arrhythmic deaths, potentially rescuable with a defibrillator. To emphasize the distinction between presumed sudden cardiac death and autopsy-defined sudden cardiac death, as it's central to this work, here's a figure from the recent Lancet Commission on Sudden Cardiac Death. Presumed sudden cardiac death is the definition traditionally employed in observational research, and it presumes cardiac cause based on the circumstance of death. This is compared to autopsy-defined sudden cardiac death, which employs autopsy and toxicology to exclude the considerable burden of sudden non-cardiac deaths, which have underappreciated burden and deserve their own focused efforts for prevention. Moreover, work based on presumed sudden cardiac death may lead to flawed associations, as we showed in the study of QT-prolonging medications, which surprisingly showed the association between QT-prolonging medications and sudden cardiac death may be driven by the non-cardiac sudden deaths, so confound it. Therefore, in order to mitigate the increased risk of sudden cardiac death associated with abnormal weight status, improved understanding of the causes of death are needed. Here we leverage post-SED to determine rates and autopsy-defined causes of presumed sudden cardiac death by weight status. Our population comprised of adult presumed sudden cardiac deaths in San Francisco County from 2011 to 2024, via collaboration with the San Francisco Medical Examiner. During the original study period, we collected every incident case that ran from 2011 to 2014. Since then, we've continued to collect cases about every third day, which is tied up with our Medical Examiner call schedule, and in total we have had 1,115 cases. Each case undergoes a comprehensive post-mortem evaluation, with evaluation of all pre-mortem medical records and EMS run sheets, but couples that with detailed post-mortem evaluation, including gross and histologic autopsy, toxicology, and vitreous chemical analyses and genetic studies when appropriate. And a cause of presumed sudden cardiac death is then adjudicated by a multidisciplinary expert panel, including cardiologists, neurologists, and pathologists, with causes of death defined as arrhythmic, non-arrhythmic, non-arrhythmic cardiac, including causes such as tamponade, and non-cardiac, which I previously described. We define weight status according to World Health Organization criteria, as shown here, and calculated incident rate ratios and rates for the original cohort, where every incident case was captured, and used contemporaneous population survey data from the Census and the California Health Interview Survey to determine at-risk population sizes. The median age for our cohort was about 59 years, the majority were male, and the race and ethnicity distribution was reflective of the diverse population of San Francisco. The autopsy-defined causes of death from the entire cohort were nearly identical to the original cohort, where every case was collected, and as you can see, almost nearly half were non-arrhythmic deaths. Here's the weight status distribution for our overall post-SED cohort, and we see that the majority of our presumed sudden cardiac deaths are overweight and obese. Putting this in the context of the weight status distribution of San Francisco County, we see that cases with obesity, and that's shown in this hatched orange, we see that obese cases were overrepresented, and to a lesser extent, overweight and underweight cases as well. To highlight a few key population characteristics, here I have the total cohort and the weight statuses to the right. We see the median BMI for our overall cohort was 27. Some population characteristics within each of those categories that I would like to highlight, within our obese cases, they tended to be younger, and there were more females in our underweight cases. Looking at the race and ethnicity distribution, we saw relatively more black cases among the obese, and fewer Asian cases in the same group. The remainder distributions were largely the same. And looking at their past medical history, as could be expected, we see increasing burden of cardiovascular risk factors and cardiovascular disease as we go to the overweight and obese groups, and this was despite having similar tobacco use. Looking at the actual incidence by weight status, here we see for presumed sudden cardiac death, it was about 30 per 100,000 person years, and now we see these incidents and how they change per weight status. We see incident rate ratios on the right compared to normal weight, and we see that overweight and obese had about five times fold increase from the normal weight presumed sudden cardiac death incidence. Evaluating how this changes by autopsy-defined cause, I show here in these dashed blue bars autopsy-defined arrhythmic deaths. Going from left to right, we see less, actually that non-cardiac causes predominated in the underweight, and there was increasing arrhythmic causes as we went to overweight and obese. Now it's important to consider how the incident rate ratios change. This presumed sudden cardiac death, again, is a traditional definition of observational data, and we see that obese, the risk of true sudden arrhythmic death is underestimated by that definition. It jumps out to 6.2, while in underweight, it's potentially overestimated. Applying those same data out in a different illustrative format, here's incident rate ratio by BMI, and this is for presumed sudden cardiac death. The same curve that would have been mapped out in this meta-analysis, we see more of a U-shaped curve. In showing how this changes, just as I previously described, plotting out the sudden arrhythmic deaths, and you can see how the rate ratios may be underestimated for the obese and overestimated for the underweight. We were limited in our ability to do adjusted analyses, just because of lack of granularity in the survey data, but we were able to adjust it by race and sex for the arrhythmic deaths, and we see that the relationship largely holds, but when adjusting for age, it did mitigate the increased risk associated with underweight, suggesting age may be confounding this finding. Looking at the causes of presumed sudden cardiac death across the weight spectrum, you see again, these are statistically significant differences, more non-cardiac and underweight, where it's predominating in terms of the causes, and more arrhythmic in the obese group. Looking at the exact causes within the arrhythmic deaths, which included CAD, both acute and chronic, hypertrophy, and primary electric disease, we see largely a similar profile regardless of the weight status. These are different people, and they might have different pathology. Those are outstanding initiatives that we're working to look into, but they're largely dying of the same thing, so I think obese patients are dying more frequently of similar causes. But when we look at the causes of non-cardiac death, we do see some differences in the underlying profile, including the underweight, which died more frequently of infection, and the obese, which died more frequently of pulmonary embolism. So, in conclusion, abnormal weight status was associated with increased incidence of sudden death, with the caveat that the association with underweight may be confounded by age. Overweight individuals are more likely to die suddenly of an arrhythmic cause, and underweight individuals are more likely to die suddenly of non-cardiac cause. And therefore, distinct strategies are required to mitigate sudden death risk at each end of the weight spectrum. I'd like to thank Sudden Death Victims and their surviving family members for contributing to this study and this work, my mentors, Ian Tseng, and all my team members that contributed to this project. I thank you for your attention. Any questions for Dr. Salazar? I don't know if there's a mic for him. I think that's what he's asking. Oh, right. So, ours are mic'd up. I think I have this mic. This is the only mic, so everything else is just hearing, right? Come on up here. Why don't you just speak into the microphone. Yeah, thanks for this presentation. So, from the genetic basis, did you explore at all the different genetics, especially in the patients who suffered from sudden cardiac death? Did you explore a specific gene that was more associated with sudden cardiac death, more than other genes? Genes like DSP, FLNC, stuff related to cardiomyopathies, or did you explore genetics or not? Yeah, I actually was co-first author on a paper looking at the genetics in our cohort. And genetics were a very uncommon cause of sudden death in our cohort. So, I think when you look at the population, the general community sudden deaths, having a genetic cause is uncommon. Okay. Definitely when you check that with autopsy and verify, because sometimes these genetic tests could be positive, but they don't actually have pathology that maps to it. Okay. So, you mentioned that age and sex could be confounders. Did you do an adjusted and multivariable analysis for age and sex? Right. So, to combine, we did separate. For the race and sex, the relationship was preserved. And for the age, separating that out, that did diminish the relationship. But we lacked our ability to, because of lack of granularity in the survey data for the at-risk populations, we weren't able to do much more adjusting within the same analysis. But we're ongoing efforts to do so. And is there any information that's linked to the electronic health records here about known CAD or known heart failure in any of these people? Yeah. I had that brief slide where certainly obese patients did have more past medical history that was known, but there is certainly more occult disease that was not known. So, we're going to do analysis to see how much of that past medical history mediated some of these findings. But my suspicion is that these obese patients have a lot of undetected disease as well, until they die, unfortunately. Yeah, that's an interesting causal analysis. And there's this whole field called mediation analysis, where, as you know, you can assess a confounder and just see if there's a direct relationship, how direct the relationship is obesity, or maybe how some percentage of it is mediated by these other things. So, very interesting presentation, and certainly thought-provoking. And it sounds like you have some more questions to answer, right? Yes. Thank you. Okay, thanks everyone for joining. Just to follow my colleagues here, James, I'm proud to present our work, Fragmented QRS, Arrhythmic Causes, and Myocardial Fibrosis Burden by Autopsy Among County-Wise Sudden Deaths. I have nothing to disclose. So all of the audience here listening to this session are convinced and believe that sudden cardiac death is a global major issue and is one of the leading causes of death worldwide. Fragmented QRS has been shown to be associated with increased risk of sudden cardiac death and myocardial fibrosis burden. However, previous studies on this association use the conventional definition of sudden cardiac death without autopsy, and with the most recent Lancet Commission on Sudden Cardiac Death, that should be defined as presumed sudden cardiac death until autopsy proven otherwise. Additionally, association of Fragmented QRS and myocardial fibrosis burden primarily derive from emerging studies, which is indirect assessment of myocardial fibrosis. In summary, evidence on this association on autopsy data is limited. Briefly, James has already introduced us to the post-ACD study, but it is an ongoing prospective study since 2011. We use autopsy and clinical records to adjudicate single cause of death among presumed sudden cardiac death in San Francisco County. So every sudden death in the San Francisco County that met the definition of sudden cardiac death by WHO and ACCHA-HRS guideline will undergo autopsy. We have regular adjudication meeting with panel comprised of experts from multiple specialties using all available pre-mortem, post-mortem clinical data from every healthcare system in San Francisco, and we adjudicate a single cause of death as either arrhythmic or non-arrhythmic. And we consider it to be arrhythmic if the cause of death were potentially rescuable by ICD, and non-arrhythmic if it won't be able to rescue with ICD, and that includes cardiac non-arrhythmic as well, such as tamponade or wall rupture. I'm showing you here the original publication from the post-ACD cohort. It was back in 2018. Out of 525 cases that would have met and be called sudden cardiac death in any other studies, only 60% were actually from cardiac causes, whereas 40% were from non-cardiac causes. So that emphasized importance of autopsy to really define what is the cause of death. So in this sub-study of post-ACD cohort, we sought to evaluate whether fragmented QRS was associated with autopsy-defined arrhythmic cause of a sudden death and histology-defined replacement and interstitial myocardial fibrosis burden. The replacement fibrosis can be detected on MRI using the, we all know, the LG technique, but interstitial fibrosis is more diffuse, is more subtle, and is not reliably detected by LG on MRI. Both types of fibrosis can serve as a trigger and substrate for ventricular arrhythmia and sudden cardiac death. We used the most recent EKG that we have, so we have the closest time to death. The EKG will be independently interpreted by two cardiologists using pre-specified criteria. Readers were blind to autopsy results. We exclude EKG with perimodem rhythm, SVT, VT, and V-PACE, as obviously we cannot interpret the fragmentation of the QRS. We used a standard definition of fragmented QRS. For narrow QRS, we need the presence of S-prime notching the R or the S-wave. For wide QRS, we need additional notch or S-prime, so we need at least three notches. There is growing evidence that possibly the presence of fragmented QRS on just one lead or non-contiguous lead can be associated with fibrosis and worse outcomes. And with that, we decided to include the fragmented QRS in only one lead or non-contiguous lead in our study, in contrast to we need it in two contiguous lead per standard definition. We take tissues from four areas of the heart, stained with H&E and mass and trichrome, and the slide will be independently reviewed by two pathologists. We calculated the burden of fibrosis using a pixel counting program. For example, I presented you here a slide from our, one of the slides from our study. We have replacement fibrosis here, and we have interstitial fibrosis here. The program will count a total pixels of the fibrosis divided by pixels of all myocardium. We did analysis separately for replacement and interstitial, and together we get a total fibrosis burden. The average burden of all four walls, four segments will be used as a final fibrosis burden for that respective cases. From 2011 to 2023, we have a total of 943 cases, presumed sudden cardiac death cases that underwent autopsy. And out of that, 300 cases has complete histology data, and around 400 cases have pre-mortem 12-lead EKGs. And together we have 104 cases undergo analysis. Apology, we excluded six because of these reasons, so 98 12-lead EKGs with histology data were included in the analysis. The median EKG to death time was around one year. So out of 98 EKGs, 38 had fragmented QRS on at least one lead, and out of 38 EKGs, 26 had fragmented QRS on just one lead or non-contiguous leads, whereas 12 EKGs had fragmented QRS on two contiguous leads. Looking at wall segment, the inferior wall was the most common, followed by lateral walls, septum, and anterior. So that added up to 71 fragmented QRS leads in 38 EKGs. Example of the EKGs from our cohort, example of non-contiguous leads here. So we found that the presence of fragmented QRS on at least just one lead was associated with a 2.6-fold increase in the odds of arrhythmic cause of sudden death. Fragmented QRS on only one lead or non-contiguous lead, meaning we exclude fragmented QRS on at least two contiguous leads, that show a strong trend as well. And no other EKG markers was associated with the odds of arrhythmic causes of sudden death. Looking at fibrosis burn, we found that the presence of fragmented QRS on at least one lead was associated with a 5.2 absolute percentage increase in fibrosis burn. And looking at replacement or interstitial fibrosis separately, those associations were significant as well. And that translated into a 1.6 relative increase in the fibrosis burn. Fragmented QRS on just one lead or non-contiguous lead also associated with an increased fibrosis burn. Among other EKG markers, only pathologic Q wave was associated with increased fibrosis burn. So in summary, fragmented QRS on at least one lead was associated with a 2.6-fold increase in odds of autopsy-defined arrhythmic cause of sudden death. And that is the only type of sudden death rescuable by ICD. It's also associated with increase in microfibrosis burn. Fragmented QRS on only one lead or non-contiguous leads demonstrated increased fibrosis burn and a trend on association with arrhythmic cause of sudden death. And no other EKG markers was associated with odds of arrhythmic causes. Our analysis was limited by analysis that restricted to the cases with premortem and histology data. And long EKG-to-death time may miss new development of EKG markers, but our median EKG-to-death time was one year, which is rare for a new substrate to develop unless we had a major chronic event such as SMI. So in conclusion, fragmented QRS was associated with a higher odds of arrhythmic cause of sudden death on autopsy and higher burden of both replacement and interstitial fibrosis. Even in one lead or non-contiguous lead, that may be clinically relevant. And our findings support the use of this marker as a risk marker for myocardial fibrosis and arrhythmic cause of sudden death. With that, I want to thank Ziyan, who is back in the back, for mentoring and giving me this opportunity. Thank you, Kosuke, who's going to come back and present his work as well as a major part of this. And most of all, thank you, the victim of sudden death, who made this ultimate sacrifice for us to have the opportunity to push the boundary and try to prevent and predict future tragedies. Thank you. Thanks for the great presentation. So a couple questions for you. One is, did you find that fibrosis in any particular segment was more strongly associated with the fragmented QRS? And you might think that since VF often comes from the Hisperkinje system, that maybe something on the septum might be more important. Yeah, that's a very interesting question. I got asked this question a lot when I showed this work. But I'll show you this here, actually have a slide. So we first, it's hard to establish the strength when we don't know if the fragmented QRS on each lead was associated with the fibrosis or not, meaning we don't have a clear cut point, cut off value. For example, you have fibrosis burden of 1%. Is that a cut point or cut off value that it would show on the EKGs? So we look at that and we found that if you have a fragmented QRS on, let's say for example, inferior leads, the chance of you having fibrosis burden there is very high, 87%, 100% in the lateral and 80% on the anterior wall, et cetera. But when we look closer, we found that the chance of having an even higher fibrosis on other walls is even higher. So in other words, for example, if you have fragmented QRS on the inferior leads, the chance of you having fibrosis on that area is 87%. But only 30% of the time that you're going to have highest fibrosis in the inferior wall, whereas 70% of the time you have more fibrosis in other areas. So to answer your questions, yes, we may have fragmented QRS on the inferior leads, but you have fibrosis otherwhere as well. And that's why it's kind of hard to establish the strength, whether this lead, this wall territory was associated with a more highly likely cause of sudden death or not. I'm sorry, that's a long answer to your question. I think we need to move on to the next presentation, but thanks for a great talk. Mateo? Yeah. Okay. So... All right, so I'd like to introduce Mateo Castricchini, who will be talking about prognostic significance of exercise stress testing in desmosomal arrhythmogenic cardiomyopathy. All right, thank you so much. I'm a little bit scared, Jacqueline, a strong presentation, and I think you can't hear me, but my inferior leads, they don't look great. It's kind of fragmented, so now I'm afraid, so... But yeah, so welcome everybody. Thank you for the opportunity to speak here today. And yes, I'm very happy to share with you our findings on prognostic significance of exercise stress testing in desmosomal arrhythmogenic cardiomyopathy. So arrhythmogenic cardiomyopathy is a genetic heart disease, right? It's a structural heart muscle disease, and it's characterized by fibrous or fibrofactory replacement of the myocardium, leading to ventricular arrhythmia, sudden death, early aphib, ventricular dysfunction. As you know, this term is really an umbrella term because it can encompass different phenotypes from a left-dominant phenotype, right-dominant, biventricular. In the classical ARVC, a big role is played by desmosomal gene mutation, such as PKP2, the most frequent. We have DSP, which actually can cause mostly left-dominant or biventricular phenotypes, and then we have GSG2, C2, JUP, and those are desmosome, right? So disruption of those proteins can really cause electrical instability, but we also know that PKP2 mutations can impair the calcium homeostasis, and they do that through several mechanisms, such as reducing the expression of certain genes like RNA-D-receptor 2, triadine, calciguestrin, leading to increased frequency of calcium sparks, and then calcium overload, which was seen in mutant mice models, especially during training, and can kind of offer a mechanistic explanation on why exercise stress test has such a detrimental effect in the natural history of the disease, and from an arrhythmic standpoint, it really can explain why we might observe trigger activity, such as the late-after depolarization phenomena, which is a well-known mechanism in CPVT, and in fact, CPVT and PKP2, there was a study a few years ago showing how PKP2 patient in a pre-structural electrical phase can actually mimic CPVD patients, and here we have the exercise stress testing tracings of a patient with CPVT on the left, PKP2 on the right, and despite similarities, we can also see some differences, especially in timing of ectopies, and so we asked ourselves, are there any genotype-specific exercise-induced ventricular arrhythmia patterns in desmosomal arrhythmogenic cardiomyopathy, and so we did our retrospective study. We took our cohort of 904 patients at that time with genotype-positive arrhythmogenic cardiomyopathy, evaluated at Mayo, we included all the patients with disease-causative variants in desmosomal genes, and we excluded all the patients without exercise stress testing data, and so we collected our clinical variables, we defined our clinical outcomes, so a composite of sudden death, sustained VT, appropriate ICD shock after exercise stress test, so measure ventricular outcomes, and so here are our stress tests. We have our baseline, our peak, and our recovery phase, so we analyze each test by phase, and for each phase, we analyze the arrhythmic burden in terms of PVC per minute, presence of PVC, couplets, bigeminy, non-sustained VT, VTBF, and so what we found is that in the overall cohort and in PKP2 patients, there was a significant increase in PVC per minute, complex ectopy, and non-sustained VT during the recovery phase of the stress test compared to both baseline and exercise peak, and this was not seen in DSP, DSG2, and DSC2, and so PKP2 patient had an increased arrhythmic burden during the recovery phase when we compared directly to DSP, and the increased ventricular arrhythmia burden was positively associated with measured ventricular arrhythmia outcomes in both the overall desmosomal cohort and in PKP2 patients over a median follow-up of 35 months, and so this is our cohort, so 904 patients, for a total of 147 desmosomal arrhythmogenic cardiomyopathy patients with exercise stress test, so 60% PKP2, 31% DSP, 9% DSG2, DSC2, for a total of 326 exercise stress tests, so also here almost two-thirds PKP2, and so when we analyzed the differences between PKP2 versus non-PKP2, there weren't really many differences, there weren't many differences in age, sex, race, family history for sudden death, measured events, ICD, beta blockers, but of course there were differences in phenotype since as expected, start working maybe, as expected, the ARVC phenotype was most common, was more common in PKP2 patients and left dominant in non-PKP2, and so here we start our stress test analysis, this is the overall core, so 326, you can see here in the upper panel the PVC per minute, and so we have a baseline, the peak of the exercise, the recovery phase, and so the patient is starting to run, and then there is a peak, and then we go on the recovery phase, and you can see here the PVC per minute, they tend to go down at the peak of the exercise and then up at the recovery phase, and this was seen also for the presence of PVC, bigeminy, couplets, non-sustained VT, and in fact, when we compare the recovery phase versus non-recovery phase, we saw a significant difference in PVC per minute, bigeminy, couplets, non-sustained VT, and so we wanted to compare PKP2 and DSP patients, and here they are sitting, this is the baseline, you can see a couple of PVCs in the PKP2 patients on the left side, and then they start to run, and the arrhythmic burden is starting to increase in the PKP2 patient, to then kind of clear up at the peak of the exercise, but really getting worse at the recovery phase, and this pattern was not seen in the desmosomal in the DSP patient, and so here, in fact, we can see when we compare the recovery phase versus non-recovery phase, there was a significant difference in PVC, bigeminy, couplets, non-sustained VT, that was not seen in the desmoplugging patients, and overall, if we take the PVC per minute, the two curves look so different, with the PKP2 patients really having an increased PVC per minute during the recovery phase, while we didn't see that in desmoplugging patients, and so we wanted to compare now the presence of this arrhythmic burden during the recovery phase across the genotypes in patients with another structural phenotype, and when we consider the overall PVCs and all non-sustained VT, we can see a clear difference in PKP2 versus DSP, can't say really anything when we compare to DSG2 and DSC2, since we didn't have many patients, and we saw the same pattern, even when we compare, you know, and we analyze the more complex PVC, so only when we focus on the bigeminy, couplets, and non-sustained VT, so a clear difference between PKP2 and desmoplugging, and then we said, okay, so the presence of this, is it correlating with outcomes, and so this is our couple of major curves, and so we can see here the overall desmosomal core, and you can see that the presence of this pattern is associated with measured ventricular arrhythmias at follow-up, and this was true also for the PKP2 patients, so probably this was driven by the PKP2 patients, was not seen in the desmoplugging patient, and so in conclusion, PKP2 patients showed a really unique pattern of increased ventricular arrhythmia during the recovery phase of the exercise stress test, and this recovery phase ventricular arrhythmia burden was positively associated with measured ventricular arrhythmia events in the overall core, and in particular in PKP2 patients, suggesting a potential prognostic role, and these findings may really represent a unique genotype-phenotype correlation, really helping distinguish PKP2 from other desmosomal genotypes, and why not, from CPVT, especially in the pre-structural or electrical phase of the disease, and so this study may suggest that routine inclusion of exercise stress test in the evaluation of arrhythmogenic cardiomyopathy patients should be considered, particularly for patients with PKP2 variants, because this may really help in the risk stratification for sudden death ventricular arrhythmia in this population, and of course, after external validation, we probably, I like to think that it might be considered in future guidelines, and why not, incorporated in ERVC risk calculator. Thanks. Thank you. Thanks for that. A couple questions for you. So, if it happened more in recovery, presumably, then the heart rate is decreasing in recovery. Did you notice, you know, unlike CPVT, where you get above a certain heart rate, and then you tend to get more PVCs, so it seems like the opposite here with PKP2, did you notice that there was a characteristic heart rate where, you know, the PVCs would increase? Was there a commonality there? Yeah, so there was not a specific heart rate. What I can think, you know, that's a question that I ask myself multiple time, like, I mean, if the mechanism is the calcium overload, if the mechanism is the increasing calcium sparks and leaks in the reactive receptor too, might be similar to the one that we see in the CPVT, when this case is happening more in the recovery phase, and, you know, early after the peak. We don't know, I think probably the vagal rebound may kind of create dispersion of the repolarization, increasing, so, arrhythmic events, but I'm not sure if there was a specific heart rate. Okay, question, would you like to come up to the microphone? We can only hear you if you come up to the microphone. My question was, how much of your patient who had a complex arrhythmia during stress test have a beta blocker when they have left? I'm sorry, can you repeat, please? Yeah, you described 70% of patient who had complex ventricular arrhythmia. How much of them have a beta blocker when they have left? Okay, all right, so. To explain why they had some bad outcome. Yeah, that's a good question. So, the truth is that at Mayo, we don't stop the beta blocker before the stress test in this cohort of patients. So, practically all of them, they were on the normal therapy so, if this can respond to your question. Oh, on the beta blockers, yes. Oh, considering only the one with the complex arrhythmia or overall population? Yeah, so, that's a good question. He was asking how many patients were on beta blockers. So, if we look at our cohort, we can see that in the overall cohort, 41% of patients were on beta blocker. But there were not really differences between PKP2 versus other genotypes. And, yeah, we can probably go and look at the patients with more complex arrhythmia to see if maybe there was a signal there of absence or presence of beta blockers, but I don't have this data right now, but it's for sure an analysis that I can do and I can reach out to you. Was there a characteristic PBC morphology that you saw for the? Yeah, that's a good question. So, of course, I mean, in patients with a more ARVC phenotype, we really saw a left bundle branch morphology. There were a minority of patients, though, that, I mean, we saw multiple morphology and that might be maybe because of the trigger activity, right, that is not only related to. And so, that was interesting and fascinating and for sure that would be something that we can focus for further analysis, yeah. All right, I think we have to move on to the next speaker, but thank you very much. Great, great presentation. Um. Is it, uh, is that, Compagnucci, Compagnucci, Compagnucci? Okay, so I have Paolo Compagnucci presenting here a long-term arrhythmic risk in athletes with complex ventricular arrhythmias. It will come up in a second. Mr. Chairman, dear colleagues, thank you very much for the introduction. So in the next few minutes, we're going to dive into the complex world of athlete's heart, where distinction between physiological exercise induced cardiac remodeling and structural heart disease and cardiomyopathies may sometimes be hard. As you all know, endurance exercise can induce profound structural and electrophysiological changes. Ventricular arrhythmias are not rarely encountered in athletes. It depends on how careful you look for them. For example, if you do a 12-liter kg for pre-participation screening among young athletes, 0.2% of athletes have at least one PVC. And if you do an ultramonitoring with a training session, you will find higher, higher figures. The problem here is that we need to be very careful in the assessment of these athletes, especially when they present with the PVC, because it can be the only sign of an underlying cardiomyopathy that may expose the athlete to an increased risk of sudden cardiac death. Some substrates can be more subtle, more difficult to ascertain, because they cannot be associated with changes at echocardiography. But a PVC can be an important sign of an underlying left ventricular scar, for example, especially when we have polymorphic or atypical right bundle branch block morphology PVCs. So the purpose of our analysis was to assess the prognostic implications of comprehensive diagnostic workup among athletes who were referred because of complex ventricular arrhythmias. This was a multi-center observational study that we conducted at three centers in Italy. Patients were referred after finding frequent PVCs, defined as at least 500 PVCs per day, or non-sustained VT, or of course, a minority of patients who had sustained VT or cardiac arrest at presentation. For inclusion, patients needed to have 12 lead EKG documentation of the arrhythmia to assess morphology, and athletes were categorized into two groups according to morphology. The common morphology group that included patients with fascicular or infundibular morphologies, monomorphic arrhythmias of course, and the uncommon morphology group that included polymorphic arrhythmias, atypical right bundle, or left bundle branch block with intermediate or superior axis. Each patient underwent a baseline evaluation that included the whole term monitoring with training session, maximal exercise stress test, most of patients also underwent CMR, and the majority of patients also underwent invasive electrophysiology tests with the programmed electrical stimulation and electronatomical mapping and lead potentials mapping of the chamber of interest. The follow-up was made to assess the occurrence of primary endpoints that were aborted cardiac arrest, sudden death, or sustained arrhythmias during follow-up. As you can see, we were able to include 215 athletes, 110 with common morphologies that were mainly infundibular morphology, 93% of times, and 105 uncommon ventricular arrhythmias patients that had mainly polymorphic or atypical right bundle branch block morphologies. As you see, most athletes were competitive athletes. We also had an 11% prevalence of occupational level athletes, so elite professional athletes. Half of patients were asymptomatic and referred after pre-participation screening. As you may know, in Italy we got a very strict pre-participation screening protocol that includes 12 VDKG plus maximal exercise stress testing. Looking at non-invasive tests, as you can see, findings from EKG were more commonly where there was a higher prevalence of abnormal findings in the uncommon morphology arrhythmias. And also, these are true also for echocardiography, while exercise stress tests showed PVC suppression at peak exercise in a higher proportion of common morphology arrhythmias, infundibular PVCs mainly. Looking at CMR, LG was approximately three to fourfold more common in the uncommon morphology group, and most patients had a stria left ventricular pattern. Looking at electronatomical mapping, the prevalence of unipolar or bipolar scar in the chamber of interest and the prevalence of late potentials in sinus rhythm at late potential mapping was higher in the uncommon morphology group. On the other hand, ablation was more commonly performed in patients with common morphologies mainly, as I already said, infundibular morphologies. Underlying diagnoses were clearly different. Patients who had common morphology arrhythmias had mainly idiopathic VT, although some of them also had arrhythmogenic cardiomyopathy, a minority of them, while the most common diagnosis underlying uncommon arrhythmias was arrhythmogenic cardiomyopathy, and also some patients with myocarditis. So the primary outcome of sudden death or sustained VT during follow-up occurred more frequently in patients with uncommon morphologies. The clinical follow-up lasted more than six years, 6.2 years, and this held true even after excluding patients who already had a sustained VT at baseline. This was a minority of patients, only 25 patients out of 215 had sustained arrhythmias at baseline. Looking at factors associated with primary outcome events during follow-up, besides traditional clinical factors such as hysterosyncope, sustained VT already at baseline, and abnormal 12-lead aging in sinus, absence of arrhythmia suppression by a stress test, and LGE, also invasive electrophysiological findings were associated with a higher chance of having a primary outcome event during follow-up, including inducibility by programmed electrical stimulation, presence of electronatomical scar, and presence of late potentials in sinus rhythm. And this was also similar after excluding patients with sustained VT, so the analysis was repeated also by only including patients with PVCs and non-sustained VT at baseline. We did some sensitivity analysis, such as propensity score weaving, that confirmed the association between late potentials and inducibility by electrophysiological study in primary endpoints, and also we found that by log-likelihood ratio test, the incorporation of findings from invasive evaluation improved the prediction of, slightly improved the prediction of primary endpoints. We tried to put all of this together, although numbers were small, you know, we only had 16 primary endpoints, but you know, this was a quite healthy population with young athletes. The survival training analysis categorized athletes according to the occurrence of events during follow-up, so there are several nodes. The first node is the type of arrhythmia at baseline, so if the patient does have a sustained VT at baseline, he is definitely at high risk, 9 events out of 25 patients. If not, we look at the morphology, that's the second most important node. If the patient has a common, so infalimbular or fascicular morphology, no events during follow-up. And then we can go on and evaluate further with LG-ECMR and electron-atomical mapping to refine risk stratification. So return to play, after three months, most patients returned to play, but long-term only a minority continued. Younger age, absence of LG, and professional sports practice were predictors of long-term continuation of sports. According to the discussion, our studies suggest that athletes who only have PVCs of common morphology, infalimbular or fascicular morphology, have low risk of arrhythmic events during follow-up. Other factors, including factors from invasive electrophysiology tests, may be used for risk stratification, but we need to be very careful with simple, simple clinical elements such as arrhythmia morphology and arrhythmia type. There are some limitations. The main one is related to the low number of events, but again, this was a healthy cohort of young athletes. So I want to close my presentation sharing with you with this EKG. You see several, you know, risk markers that cannot be overlooked. Low voltage QRS in peripheral leads, fragmented QRS in D2, inverted T waves in inferior leads and lateral leads, and a typical right bundle branch block morphology PVC. The sad story here is that the cardiologist who initially evaluated the patient gave this EKG as normal, and the patient was later found to have an arrhythmogenic, left dominant arrhythmogenic cardiomyopathy. So, going to the conclusion. The prognostic assessment of athletes presenting with complex ventricular arrhythmias should always start from the evaluation of the type of arrhythmia and the arrhythmia morphology. It's important to also go on and perform second and third level assessments, including CMR and also electrophysiology assessments, when there is a suspicion there are clinical markers, especially PVC morphology, that may suggest an underlying arrhythmogenic substrate and that may inform a safe return to play. Thank you for your attention. Let me take one sec to thank my mentor, Professor Della Russo, and my colleagues from Ancona, Giovanni Volpata and Laura Cipolletta, who have supported and who have made this all possible. Thank you. Yeah, thanks, Paolo, for that very interesting presentation. So who needs a CMR? Want to tell us? Thank you. So we need to do a comprehensive evaluation. We need to take everything from the clinical evaluation into account, of course. Patients who have isolated PVCs of an infundibular morphology have a normal tolidic A.G. The PVC is suppressed during exercise testing and the echocardiography is normal. I would not suggest to perform a CMR. There were, in this court, most of them, however, underwent CMR. There were 15 athletes who had LGE, however, none of them developed clinical events. So the main message here is that if everything from the first level evaluation is normal, maybe it's not good to go on with the CMR. If there are other signs that may suggest that there may be an abnormal left ventricular substrate, then it may be useful to go on and perform the CMR. Yeah, I think this is an important point, is we're moving towards an ECG-first strategy then followed by CMR as needed in different conditions. This is important data. I noticed that the age range was quite wide. You had some people under 20 and some people over 40. Do you want to comment on that? Yeah, thank you. So, of course, most of the patients were young. You know, the average age was 28, but there were also some master athletes. In those athletes, usually it's also important when they pass the age of 35 to rule out the coronary substrate, so it's important to perform a coronary CT or other things, especially if the arrhythmia burden increases during exercise by exercise testing. All right. Thank you. All right. Thank you. Is it Kasuki? Yes. Kasuki, okay. So I'd like to introduce Kasuki Nakasuka. Good? Okay. Presenting on myocardial infarction. Let's go to the next slide here. It's presenting on myocardial infarction with non-obstructive coronary arteries and fibrosis burden among community-wide sudden cardiac deaths by autopsy. Thank you for introduction, and good afternoon, everyone. I'm Kosuke Nakasuka from UCSF EP, and it's a great honor to present our abstract myocardial infarction with non-obstructive coronary arteries and fibrosis burden among community-wide sudden cardiac deaths by autopsy. As you all know, myocardial infarction with non-obstructive coronary arteries, MINOCA, is a subset of acute myocardial infarction, recently gaining recognition by the medical communities. In 2019, AHA scientific statement defined MINOCA as acute myocardial infarction in the absence of coronary artery disease without any other identifier or diagnosis of acute MI. In the clinical setting, the MINOCA accounts for 5% of all acute MI cases who underwent coronary angiography. Regarding the MINOCA in the out-of-hospital setting, it is reported that MINOCA accounts for 4% of the resuscitated out-of-hospital cardiac arrest cases. However, these cases are the resuscitated cases, so they didn't die out of hospital. Another data from the UK Pathology Centre shows that among 5,000 sudden cardiac death cases referred for autopsy from all over the UK for 22 years, the MINOCA was defined as 0.7% of those. However, their autopsy rate was less than 1% considering all of the sudden deaths over 22 years in the UK. So, what is the true burden of MINOCA on the committed sudden cardiac death? So, back into our post-HC study. In our post-HC study, we took all of the sudden death cases meeting the traditional sudden cardiac death criteria and defined that 6% of the sudden death cases were cardiac death and 40% were non-cardiac death by the high autopsy rate of 97% which can address the autopsy bio-tissue. We also defined that among all the sudden death cases, the 55% were arrhythmic death, meaning that only half of the traditional defined sudden cardiac death cases will be saved by ICDs. Now, using our post-HC cohort, we investigate the sudden cardiac burden attributable to MINOCA among country-wide autopsy-defined sudden cardiac death. Our study was a prospective autopsy-based cohort study in San Francisco County over 12 years. The study subject was autopsy-defined sudden cardiac death cases. We comprehensively reviewed both pre-mortem information and post-mortem findings, and on autopsy, the coronary artery was sectioned every 5 mm to observe the coronary artery lesions. The LV transmural myocardial tissues were sectioned for histological assessment, and then we quantified the LV myocardial fibrosis burden, including perivascular, interstitial, or replacement fibrosis by a digital pixel count algorithm. We detected myocardial infarction, including acute MI and acute MI by histopathology, and then we defined sudden cardiac death due to MI as sudden cardiac death attributable to acute or acute MI. The obstructive coronary artery disease, CAD, was defined as the 50% or more coronary artery stenosis or the prior coronary intervention, such as PCI and the CIVG, or the presence of acute coronary lesions, such as plaque rupture or the coronary thrombus. So let's move on to the later section. So of all the presumed sudden cardiac deaths who underwent premodern investigation, including autopsy, 583 cases were autopsy-defined sudden cardiac death, accounting for 60%. Of those, 41% were due to myocardial infarction, and 20% were due to acute MI. Of these acute MI cases, one-fifth were minokas, accounting for 4% of autopsy-defined sudden cardiac deaths. This prevalence is higher than the minoka cases of the resuscitated cases reported from the UK Pathology Centre. This table shows the clinical characteristics of these study populations. Compared to the acute MI with CAD cases, minoka were 20 older and 20 more female. This age was 10 years older than the minoka cases reported from the clinical studies, meaning that the sudden cardiac deaths due to minoka cases were older-sized compared to the clinical minoka. So again, let me remind you that we can separate that cardiac deaths were separated into arrhythmic deaths and non-arrhythmic deaths. The arrhythmic deaths would have been saved by ICD, whereas the non-arrhythmic deaths were not. The example of the non-arrhythmic deaths included tamponade or the pump failure with pulmonary edema. So, among sudden cardiac deaths due to acute MI, the proportion of non-arrhythmic deaths in minoka was significantly larger compared to that in acute MI with CAD cases, more than double. 109 cases had fibrosis data for analysis, and you might expect that the MI with CAD cases had more fibrosis because they had already acquired the significant coronary artery disease. However, there is no difference in the fibrosis burden between minoka and acute MI with CAD cases. Notably, this fibrosis burden was derived from primarily the interstitial or perivascular fibrosis, rather than the replacement fibrosis, which is recognized as an MI score in the clinical setting. So there are some limitations of this study. During the hyperacute phase of acute MI, the histopathological signs of acute MI might not be represented, so such cases might be classified as non-MI cases. Second, this study is based on the diverse San Francisco population, which can lead to the generalizability issues. However, because of this diversity of San Francisco, we can have the result from the various populations. So in conclusion, ladies and gentlemen, among community-wide sudden cardiac deaths defined by autopsy, around 41% was due to MI, and 20% were due to acute MI. Of these acute MIs, one-fifth were minokas. Such community-wide sudden cardiac deaths due to minokas were older than previously reported clinical minokas, and had non-arrhythmic deaths more than twice as common as the acute MI with CAD cases. And they had a similar fibrosis burden to acute MI with CAD cases. So from these findings, the early detection of the minoka and the recognition of non-arrhythmic causes beyond focusing on the coronary arteries are required to fully address the sudden cardiac risk attributable to myocardial infarction. Lastly, I'd like to express my heartfelt thanks to all sudden death victims and their family members, and all of the collaborators and contributors of this study, especially my mentor, Dr. Jian Sen. Thank you very much for your attention. Thanks for the great talk. So I noticed that the interstitial fibrosis was higher in all three groups, right, compared to replacement. Is that what you were expecting to see? No. No. To be honest, I expect that the fibrosis burden, especially interstitial fibrosis, is more in MI with CAD cases. So yeah, it is surprising findings for me, actually. Do you think the UK, the lower estimate in the UK, is just an underestimate of the true prevalence? Or do you think the people you were looking at in San Francisco and the UK actually have some different characteristics? Yeah, thank you for a very good question. So our post-ACD study is focusing on the out-of-hospital cardiac arrest comprehensively, prospectively, in the cohort in San Francisco County. But the UK post-hospitality center study is from the autopsy cases or referral cases, only referral cases. And so, yeah, a lot of selection bias there, I think. Yeah. Even there, corrected from all over the UK. Well, thank you for the wonderful presentation. It's 5 o'clock, so we'll close the session. But feel free to approach the presenters if you'd like to speak to them personally. Thank you.

sudden cardiac death

weight status

genetics

autopsy data

obesity

arrhythmic causes

fragmented QRS

arrhythmogenic cardiomyopathy

ventricular arrhythmias

MINOCA