Good afternoon, ladies and gentlemen. So we would like to start the LAHRS and the APHRS joint session entitled Risk Stratification and Therapy for Inherited Endemic Arrhythmias. My name is Wataru Shimizu from Tokyo, Japan. I'm a current president of APHRS and I will chair this session together with Professor Edward Saad from Brazil. So we will invite the four distinguished speakers from Asia and from the United States and from Canada and Brazil. Okay, so Spain. So let me start the first speaker, Dr. Georgia Sarukera-Burugada. She is talking about congenital long QT syndrome, the risk stratification therapy. So please. Okay, thank you so much. Thank you to the audience and the organization. It's an absolute pleasure to be to be part of this joint session and also to to be to be part of sharing those difficult cases that we all go dealing with. We were just talking with one of our colleagues, Dr. Quezada, about how complex and how difficult are certain certain patients, especially young patients, really small ones, how difficult this is. And so it's the time to share all those all those ugly things. Okay, so my deal here, my goal here is to talk a little bit about diagnostic. That's not the point of the talk, but risk stratification and the therapies that can go with long QT syndrome. Concerning diagnostic, and I know it was not the title of my talk, but concerning diagnostic there is something very important. Sometimes it's not so easy, but sometimes it comes very early. This is the case of fetal bradycardia from a fetus, a 22-week gestation fetus in bradycardia. Fetus by this age, gestational age, should be around 120-150. This fetus was 60 beats per minute, which was coping with this ectopy, some runs of atrial ectopy, and some runs of 2-to-1 block. And that we can see here, we can see here the atrium, and this is the ventricle, so a 2-to-1 block in that patient. So when this patient is born, we can see that there is a prolonged QT interval, so we start suspecting a long QT syndrome with an intermittent 2-to-1 phenomenon. Intrauterous. When we do, wow that's huge, when we do the genetics, we get a type one long QT syndrome, so KCNQ1, and of course this is very important in terms of not only the child, but also the mother, who's also a carrier of this mutation, and she was not aware of that. So this is very important, but the same bradycardia and 2-to-1 block can be present in other patients like this other. We had in our case, this is a 2-to-1 block, this is a newborn, and we can see P wave, QRS, P wave, T wave from the previous QRS, and once again. So 2-to-1 block, very bradycardic, very prolonged QT, with this spontaneous continuously during the first days of life. So what we got here was a type 3 long QT, so same presentation in prenatal period, but very different genetics. So other forms of diagnostic is sometimes we have to force the diagnostic, and of course what we call B-skin test, the QT is stunning when we put the patients from laying position to a stand-up position. So this is what we call the B-skin test, after Dr. B-skin's description, we make them rest for five minutes. In pediatrics, we know making rest five minutes a child, it's impossible. So if we get 10 second resting, it's enough. Then we make them stand, everything with continuous ECG, and what we get is the correction of that QT. That will help us identify very quickly if there is a QT stunning, a false prolongation, or an abnormal reduction of the QT interval after the tachycardia that we got when the patient stands up. This is very important because sometimes we don't have the opportunity to do exercise test on our patients. So this is a very quick, fast, and reliable test that we can do in consultation for those patients. So epinephrine test, another way to diagnose and to help us with diagnosis and risk stratification. To be honest, we don't perform it at all. It does not help me at all to identify patients because we all know that isoproteranol, or epinephrine, or any types of those drugs, they normally they prolong QT interval, and we have a lot of false positive patients. So we stopped performing epinephrine isoproteranol test when we suspect a long QT. And of course we have to explore our patients, and that will help us with not only the diagnostic, but also the risk stratification. If we have a retrognathia, if we have this kind of small lips, and this type of hands, this is clearly under sentinel going with prolonged QU interval. So that will help us to know which are the therapies that are better for this patient, and second of all, which is the risk that this patient has, and how much do we have to worry. Finally, of course, genetics. Genetics is marvelous if we can have it, and for long QT is even better. Genetics can give us the answer for more than 70% of our patients. So we have 75% of our patients will be either type 1, 2, or 3, KCN Q1, KCN H2, SCN 5A, that counts up to 25%. There is an extra 5% which is going to be explained by all these other genes, but there is a remaining 20-25% that we still don't know. But the benefit of having a genetic test in our long QT patients is very optimal, because therapy is going to be different in each type of those QTs, which are the electro mechanisms, and that's why it's so important to know the genetics, and it's going to be so important in order to decide which are the drugs we are going to give that patient. So we know that this is action potential, when there is a loss of function in sodium channel, there is a prolongation of the QT related to this loss of function of potassium channels. If we have a gain of function of sodium channels, and we will have sodium channel entrance all along the action potential, so we will have a prolongation of the QT interval. That's very important, because then we know which drug is better for those patients. So for risk stratification, we know that gender is important, and actually this is in fact the pyramid, this funny shape of pyramid that goes in such a big screen, but that's a pyramid. We know that men are at higher risk if they have type 1. Females are at higher risk if they are type 2. Age, we know that infants with long QT type 3 present a more severe phenotype, and type 1 and type 2 present later in life, let's say 5-10 years of age. If QTC is longer than 500 milliseconds, that's higher risk as well, and of course circumstances, water in type 1, emotions in type 2 or sounds, and sleep in type 3. And of course, we can have a sudden death in a type 2 while jumping in the water. This is not exclusive for each type, but we know there are certain things that will help us identify which patients might be of higher risk, and which is the chronic management. So for those patients, magnesium is so important. You have a patient with long QT who's having something no matter what, give magnesium, okay? Extra, you have a child who has gone through whatever surgery of non-cardiac surgery, and it's in the post-operative period, and they have extra beads. That can be very dangerous, so make sure you are giving loads of magnesium so you will have everything more stable. Then hydration, one of the main causes of sudden death in patients with long QT which are well treated, well beta-blocked, are dehydration. So it's very important that part of the treatment you are going to prescribe to your patient is make sure you drink lots of water in whatever circumstances. Of course, all those spores or situations that might be at risk should be reduced at least, but remember this is a but, not but you have to negotiate. We are dealing with children, and that's important, and it's a chronic disease, and they will have that disease all along their life. So important, so important that you negotiate, they understand their disease, they understand why you're saying that, and they participate in decisions we are going to do. Otherwise, they are going to oppose, get an opposition to whatever we say, and that's going to be really dangerous. Nalolol. Nalolol is the best drug we can give to our patients, especially type 1 and 2, and of course, Nalolol is going to protect and reduce the risk of arrhythmias. Nalolol is the best beta-blocker, but unfortunately, in many countries, we don't have that drug. In Spain, we need to import it from other countries, and the alternative to that is propranolol, which is also as good as Nalolol, but all the rest are not as good. There is clearly a reduced protection with bisoprolol and atenolol, and so on. So if you can make sure we, as societies, and now we have representation of many societies, rhythm societies in the world, it's clearly very important that we fight for Nalolol everywhere. Nalolol is a very cheap drug, but we need it for our patients. So I really encourage the society, and I want to take the benefit of being here, standing with very important people next to me, just to say that help us to have Nalolol everywhere. Finally, for certain groups, especially type 3, maxillitin and flecainid, will help us control this gain of function of sodium channel. Those are sodium blockers, sodium channel blockers, so we need that combination, which will help us reduce also the arrhythmic burden. And finally, not finally, second to the last, left cardiac sympathetic denervation, this very ancient intervention that helps us reduce also the arrhythmic burden on our patients. Sometimes also right has to be done. In our case, this is one of our cases, this is one of the risks or the complications for left cardiac sympathetic denervation. Actually, I love when this happens the day after the surgery, meaning that the surgeon has gone high enough to make sure that the the stellate ganglion, the lower part of the stellate ganglion, is out. This lasts 24-48 hours and then it becomes too normal. And that's a very good sign that the surgery has been done really beautifully. And finally, for our patients, we tend to implant, especially for those difficult cases, we tend to implant subcutaneous folder. Why? Because it's a way to either control if they have asymptomatic arrhythmias. Second of all, to give an explanation for those funny symptoms that we never know if they are arrhythmic. and third, because we can titrate the dose of medication we are giving to our patients by looking if they are doing well. So for us it's very useful, we receive patients from all over the world, so having them with home monitoring is very convenient because they don't need to come as often to the hospital as they should. So finally, we have the ICD, sometimes we need to get into the ICD, but only if everything fails, and that's very important. A patient who has had a syncope and did not know that had a long QT, this is not a reason to implant an ICD. You implant an ICD when, under good treatment, everything fails and you still have arrhythmias. But remember that ICD, it's not free of secondary effects, and we have to be very cautious when indicating an ICD in long QT patients. Thank you very much. Thank you very much, Dr. Burgadar, for a very nice, comprehensive presentation. So at this moment, are there any comments or questions from the floor? We would accept one or two questions from this. Everything clear or everything very unclear, right? Yeah, okay. Hi, it was a great talk, congratulations. Thank you. Why is it so important, the NADALOL, what is the mechanism that actually makes it more beneficial than propranolol or any other beta blocker? Well, I'm not a pharmacist and I'm very bad at these things, but in terms of practicity, propranolol you need to give three or sometimes four times per day. Can you imagine an adolescence having three pills per day if we have nightmares to make them have once per day? This is the good thing of NADALOL. You just give it in the morning and you are protected 24 hours. For me, it's the most important thing. If you want the child to go to school and you need to give the teachers a pill that have to be given to the child every single day at lunchtime, the child is going to be an ill child. He will have this kind of identification of, oh, it's your time for medication. This is going to be very disappointing for the child and for the well-being of this situation, which is once again a chronic situation and it's going to be for a lifetime. That's the main point, I think. Both propranolol and NADALOL are non-selective beta blockers. In general, in long QT, non-selective beta blocker is more effective and recommended. Yeah. Yeah. Thank you. Thank you so much. Thank you. Our next speaker is my co-chair, Dr. Shimizu from Nippon Medical School in Tokyo, Japan. He's going to be talking for us about Brugada syndrome. Okay. Thank you, Chairman. Good afternoon, ladies and gentlemen. My name is Wataru Shimizu from Tokyo, Japan. Today I will talk about the risk stratification and therapy for Brugada syndrome. This is my disclosure. This slide illustrates cause of sudden cardiac death and late and age of sudden cardiac death onset. Coronary heart disease is a leading cause of sudden cardiac death in both Western countries and in Asian countries, including Japan. On the other hand, some inherited arrhythmia syndromes, such as congenital long QT syndrome and Brugada syndrome, account for 1% or 2% of sudden cardiac death in Western countries and even more, 5% to 10% of sudden cardiac death in Asian countries, including Japan. Age of sudden cardiac death in Brugada syndrome usually occur in middle-aged, around 40 to 50 years old. So Brugada syndrome is characterized by coved type HD segment elevation, so-called type 1 ECG in the right precordial reed, and ventricular fibrillation episode, VF, usually at rest or during sleep. So I will show you only six precordial reed in the three different cases of Brugada syndromes in whom spontaneous VF episodes were documented. In the first case, panel A, typical type 1 ECG is recruited under the baseline condition. In the second case, panel B, only type 2, Saddleback type HD segment elevation, was observed under the baseline condition. However, in this case, sodium channel broker, in this case, pyrrhic anhydride, and masked, typical type 1 ECG, coved type HD segment elevation in reed 2. In the third case, no Brugada ECG was recorded in the standard fourth intercostal space V1, V2 reed. However, type 2 ECG was recorded in the third intercostal space V2 reed and finally, typical type 1 ECG was unmasked in the second intercostal space V2 reed, V2 and V1 reed. So these are all type 1 ECG. So the current clinical diagnosis of Brugada syndrome is based on the 2013 expert consensus statement on the diagnosis and the management of inherited arrhythmias endorsed by the three intercontinental heart rhythm society, European Heart Rhythm Association and Asia Pacific Heart Rhythm Society. And I presented the diagnosis and the management of Brugada syndrome. So the Brugada syndrome is diagnosed in patient with HD segment elevation with type 1 morphology of greater than equal to 2 millimeter in at least one electrical reed, V1, V2 reed, positioned in the second, third, fourth intercostal space spontaneously or after sodium channel provocative testing. And no need of VF episode or syncope to diagnose Brugada syndrome clinically. So we previously conducted a Japanese Brugada registry and investigated the long-term prognosis of Japanese Brugada patients. So this is the Kaplan-Meier curve of survival. And the annual cardiac event rate in patient with Brugada associated with VF episode or aborted cardiac arrest was 10.7%. And it was 0.7% in patient with Brugada syndrome associated with syncope episode. And it is only 0.4% in asymptomatic Brugada patients. From the literature, the annual cardiac event rate in patient with Brugada syndrome associated with VF or aborted cardiac arrest was high, 7.7 to 10.6%. So it was only 0.6 to 1.9% in patient with syncope episode and only 0.3 to 0.5% in asymptomatic patients. So this is the predictor of lethal cardiac events in Brugada syndrome. A history of aborted cardiac arrest or VF episode is the strongest predictor for subsequent cardiac events, actually the 10% recurrence of VF. A history of syncope, spontaneous type 1 ECG, and male gender were reported to be a significant predictor for subsequent cardiac events. On the other hand, induction of VF during EP study, family history of sudden cardiac deaths and SCN5A mutations have long been controversial for the risk stratification of Brugada syndrome. So we previously reported a critical impact of the number of extra stimuli during EP study for the risk stratification of Brugada syndrome. And the Brugada patients in whom VF was induced by a single or W extra stimulation was associated with a higher cardiac event rate compared with those with triple extra stimulation. Thereafter, a European group conducted meta-analysis and reported induction of VF during EP study by single or double extra stimulation was associated with a higher cardiac event rate, confirming the usefulness of EP study for the risk stratification of Brugada syndrome. So the authors kindly mentioned in their text their observations are consistent with our single center data. This is the same Kaplan-Meier survival curve which I previously showed. The annual cardiac event rate in patients with Brugada syndrome with syncope alone and asymptomatic patients associated with spontaneous type 1 ECG and family history of sudden cardiac deaths was approximately 3%, indicating that the family history of sudden cardiac deaths may be a predictor for subsequent cardiac events. So more recently, Asian group conducted system tech review and meta-analysis and reported our history of sudden cardiac deaths among family members younger than 40 years was associated with a higher risk of malignant arrhythmic events. So this is the forest plot, demonstrating the association of family history of sudden cardiac deaths less than 40 years old and the major arrhythmic events in Brugada syndrome. So in 1998, the first mutation linked to Brugada syndrome was identified in the sodium channel gene, SCN5A. The SCN5A mutations was reported to be identified in 15% to 30% of Brugada syndrome in Western countries, but less in Asian countries, 50% to 20%. So thereafter, more than 20 genotypes have been reported to be responsible for Brugada syndrome. However, recently, only SCN5A gene are believed to be a pathogenic gene. So this is the structure of the sodium SCN5A gene. SCN5A gene consists of four domains, and each domain include six transmembrane regions, including the S5 to S6 polar region. So this is the structure of sodium channel. And S5 to S6 polar regions are very important as a pathway of the sodium current. So we conducted the Japanese Medical Center, another Japanese Medical Center registry, including the data of SCN5A mutations. The study population included 415 Brugada only probands, mainly male and average age 46 years old. The SCN5A mutations was identified in 60 patients, 40% called SCN5A positive group, but not identified in the remaining 355 patients, 86 patients. So, this is the Kaplan-Meier curve of overall survival among all 415 probands. During the mean follow-up, 72 months, and the annual cardiac event rate was 2.5%. And the Brugada probands with the SCN5A mutations had a higher cardiac event rate than those without SCN5A mutations. And moreover, the Brugada probands with SCN5A mutations in the poor regions showed the highest cardiac event rate than the others. So this is the Kaplan-Meier survival curve among only 88 Brugada probands associated with previous aborted cardiac arrest. The annual event rate, recurrence rate of VF was 8.0%. And once again, the Brugada probands with SCN5A mutations showed higher cardiac event rate than those without SCN5A mutations. So this is the Kaplan-Meier survival curve among the residual 327 Brugada probands without aborted cardiac arrest. That means only Brugada probands with syncope and asymptomatic Brugada patients. Although there were no significant difference between the SCN5A positive and negative group, the Brugada probands with SCN5A mutations in the poor regions had the worst outcome than the other SCN5A negative group and the SCN5A positive, but in non-poor regions. It is noteworthy that no cardiac event occurred in patients with non-poor SCN5A positive group. Multiple rate analysis showed primary history of aborted cardiac arrest and SCN5A mutations remained significant association of subsequent cardiac events with hazard ratio of 6.5 and 2.0. So Brugada probands with SCN5A mutations exhibited higher risk of future cardiac event, and the Brugada probands with no history of aborted cardiac arrest seems to be at higher risk only if the SCN5A mutation is located in the poor region. So a tracing Japanese population genetic screening may be useful in Brugada syndrome. We recently conducted functional validated SCN5A variants, allowing interpretation of pathogeneity and prediction of result events in Brugada syndrome. Among the 415 Brugada cohorts I previously showed, we conducted a patch cramp study in 22 VUS, variants of unknown significance, in 24 patients, and divided them into two groups. 40 loss of function mutation in 45 patients and 15 non-loss of function variant in 15 patients. The left one illustrates the Kaplan-Meier curve of risk of arrhythmic event-free survival. So panel shows the Kaplan-Meier curve I previously showed between the SCN5A positive and negative. Comparing to the difference of survival between the SCN5A positive and negative, the survival curve between the loss of function mutations and non-loss of function variant were more prominent. The right panel illustrates the functional classification panel A and location of SCN5A mutations. The loss of function mutations shown in the red circle are more frequently located in the S5 to S6 polar regions. That's why the Brugada programs with SCN5A mutations in the S5 to S6 polar regions had a higher cardiac event rate in the previous hour registry. So this is the revised predictors for risk of cardiac events in Brugada syndrome. In addition to VEF episode, history of VEF, aborted cardiac arrest, syncope, spontaneous type 1 ECG, male gender, now the induction of VEF is up to two ventricular extra stimulus, single or double extra stimulation. And the family history of sudden cardiac death and the SCN5A mutations became updated to be a significant predictor for subsequent cardiac events. So this is my conclusions. The diagnosis of Brugada syndrome is an electrocardiographic diagnosis. The annual event rate of recurrence of VEF in Brugada patients with a history of VEF or aborted cardiac arrest is approximately 10%, strongly suggesting the indication of class 1 indication of ICD for secondary prevention. The indication of ICD for primary prevention in Brugada patients with a history of syncope or asymptomatic Brugada patients is determined in consideration of clinical findings such as history of syncope, family history of sudden cardiac death, induction of VEF, and the SCN5A mutations, and the electrocardiographic findings such as QRS spike or early reproduction pattern, et cetera. This is my international and national collaborator. Thank you for your attention. Thank you, Dr. Shimizu. It was a great presentation. If anyone is willing to make a question for him at this point in time, please come up to the microphone. I will start off just asking you two things. On your practice today, so based on that data that two extra stimuli increase the risk, do you take all your asymptomatic patients with Brugada to EP study as number one? And number two, is there a role for ablation in those patients where you induce trying to avoid ICD implantation? Thank you very much for your excellent question. So for the first question regarding the EP study, especially in asymptomatic patients, we don't do the EP study only in asymptomatic patient with no family history of sudden cardiac death. Yeah. If the patient has a family history of sudden cardiac death or syncope, so we will try to EPS. And with regard to the ablation, so actually the EPICARD ablation are very effective to suppress the BUEF episodes. But the indication, so far the indication of ICD, so far indication of EPICARD ablation is only for Brugada patients with recurrent BUEF episode or electrical stoma BUEF. Please, Georgia. Thank you. Excellent talk. I would like to know, in case of a pediatric patient with a very bad family history, carrying a sodium channel pathogenic mutation, and with a spontaneous type 1 ECG, with no symptoms, how far you go for that? Yeah, actually the many cases were referred to be in such a case. For example, the 15 boy with a family history, both father and grandfather died suddenly around 40 age. So that is a very tough cases. So usually the BUEF episode occur more than 30 years old. So we usually take care for, so very carefully follow up. Even though there is cell fibrillation mutations was documented, we do not do the study for young patients. Would you consider prophylactic quinidine in those? Yeah. Very, you know, very risky, but you have nothing because otherwise if the patient has had syncope or aborted sudden death, you have no doubt that's the easy case. But for those having family history, pathogenic mutation, spontaneous type 1, would you consider without symptoms giving quinidine? Yeah, quinidine will be effective. So we may consider to prescribe quinidine. But there are, you know, quinidine has many side effects for diarrhea or something like that. So it is a little difficult to prescribe for young patients. Well, my experience in those children, few children that I had to give quinidine, I think they tolerate quinidine much better than adults do. Yeah. I think children really are very adaptable to everything. But it's always challenging, right? Yes, I agree. Thank you very much. Thank you, Professor. Thank you very much for a great presentation. Okay, so our next speaker is Dr. Carlos Murillo. I don't see him around. Do you have in the back there any presentations for Dr. Murillo? I'm virtual. Oh, I couldn't see you because you were on my back, Carlos. But you know what, I need the guys over there to allow me to share the screen. So I'm sorry, I wasn't able to be there for some funny reasons. But anyways, can you let me share the screen there? It says that this is disabled by the host. Okay, can you see my screen? Yes, I can see that. It's beautiful. Okay, well, thank you very much, Eduardo and Mr. Chairman. I apologize for not being there in Mexico City. I would love to have been there, joining you all guys and all my friends from Latin America. I've been given the task, it's a complete switch of gears from the topics that we already heard. This has nothing to do with genetic cardiomyopathies or channelopathies, but it's more of an endemic disease of our body. So I'm going to give you a little bit of a heads-up. But it's more of an endemic disease of our region. But we see it now all around the world, and it's Chagas disease. So I'm going to talk about risk stratification in Chagas disease. And what I'm hoping to do is to, these are my conflicts of interest, talk a little bit about the one slide about the disease progression. How can we risk stratify? And what are the predictors that we can derive from the ECG, the Holter and the EP study? Some interesting stuff going on, on different imaging modalities. What are the risk scores in a brief conclusion on that? Now, most people here are familiar with Chagas disease, but those that are not familiar with Chagas disease, we know that there's this bug, that tratuminae that infects patients. And usually there's an asymptomatic stage, and 70% of people stay in that stage for good. There's an acute myocarditis that by and large is mostly asymptomatic, but there's about a 1% death and mortality in that group of patients. Now, a lot of patients continue to be in this indeterminate chronic phase that have a positive serology, but apparently have a normal heart, both an ECG and chest x-ray. And mild changes apparently do not have a lot of prognostic value, but we'll discuss that later. We don't know why 70% to 80% maintain this chronic stage, but about 20% to 30% will progress within 20 to 30 years. This is a very progressive form of dilated cardiomyopathy with the different stages. And you can see there on the slide, A, B1, B2, and C and D, up to refractory heart failure with arrhythmias and sudden cardiac death. But the hallmark of this disease is sudden cardiac death. Although it happens in the later stages, it is very frequent in the earlier stages and even in the indeterminate stage. So that's why it's important to try to identify these patients and try to do something early on. So this table basically summarizes for you the different stages and the abnormalities that you can find in the ECG and the echocardiogram, as well as LV function and whether there is or not heart failure and if this is reversible or not. Now, this is the typical Meyerberg graphic, but adapted to Chagas disease. And you can see that there is a significant amount of sudden cardiac death, but at the bottom of the pyramid, this is the patients that we rarely see or try to prevent. And there's obviously a gradient here in the amount of patients that we see that have recovered from cardiac arrest, which are the minority with the majority down here. So this is a very interesting disease that has a lot of non-sustained and sustained ventricular tachycardia with or without reduction in the ejection fraction that leads to sudden cardiac death. Now, what's the mode of death in Chagas heart disease? And this is a sub-analysis of a prospective trial, REMAD-HEAD trial, done in Brazil. Basically, what this showed is that, you know, all-cause mortality is significantly higher in the earlier stages of patients with Chagas compared with non-suggestive cardiomyopathy, similarly with heart failure mortality, as well as sudden cardiac death after almost five years or so. So this is a disease that progresses quite rapidly. We don't have a lot of clinical trials that tell us what is the best clinical management for heart failure. We are doing the PARACHUTE heart failure trial in five countries in Latin America. As a matter of fact, we already finished recruitment of a thousand patients, randomized trial, tacubitril, valsartan versus enalapril in patients exclusively with Chagas heart failure. At any rate, there's a significant proportion of patients that at different stages have sudden cardiac death, as you can see here in the slide. Now, the main mechanism, as you know, is a severe dilated cardiomyopathy with aneurysms, with a lot of infiltration, and actually persistence and low persistence of the parasite that leads to this substrate of little scars and isthmuses that will trigger both VT and VF. And a very interesting hallmark is a significant proportion of these are more epicardial than endocardial, and we'll get to that a little bit later. Now, this is a typical ventricular tachycardia that is usually associated with syncope, and these patients have significant symptoms associated with heart failure. As you can see here on this slide, there are some other significant hallmarks that include these aneurysms that are usually apical and infrabasal, but interestingly, not necessarily the VT comes from where these aneurysms are, but there's a high rate of thrombi, and a stroke, as well as atrial fibrillation may be the initial manifestations of chronic shagassic cardiomyopathy. Now, are there any good ways of assessing risk in these patients? And there's this ECG score that correlates quite well with myocardial fibrosis assessed by magnetic resonance studies. This is a study that was done by a group in Brazil, published almost over a decade, and they looked at what they call the curious score with a high sensitivity and specificity. This was looking more or less at the, mostly at the duration of the curious system of fragmentation at the end of the curious, and associated it with VT, and with fibrosis greater than six or greater than 20%, with a relatively good sensitivity and specificity. Now, other studies also from my good friend, Tom Ribeiro, in Brazil also, has looked at T-wave alternans. And again, very briefly, I'm gonna summarize that, that they're apparently non-negative, it has a pretty good specificity and predictive value in those patients. Now, we've known for quite some time that non-sustained ventricular tachycardia is a significant hallmark of a marker of risk in patients with Chagas cardiomyopathy. As you can see on the left from Dr. Anis Rassi, has done a very much of the seminal work in Chagas disease all around the world, has shown that non-sustained ventricular tachycardia is a very significant marker of mortality in sudden cardiac death. And that's from another group in Brazil, also showing significant findings. These are the predictors of mortality in patients with Chagas cardiomyopathy and ventricular tachycardia that were not treated with cardioverters and with ICDs. And you can see that there's a little bit of overlap in this population on the right side of the slide, showing in the triangles, non-sustained VT and on the circles, sustained ventricular tachycardia with or without sudden cardiac death or heart failure. So there's significant overlap in this population. So this may be a little difficult to tease out, which is really the marker. And this from one of my former fellows, Dr. Luciana Armandani-Jan, that's at the Dante Pazzanese in Sao Paulo, Brazil, trained when I was back at McMaster University. And we did some look at 115 patients with non-inducible or inducible VT, VF, and different characteristics that included monomorphic VT, non-sustained VT, and saw some of these that were actually interesting. And the most interesting part was that there was, despite the fact that a lot of these patients had aneurysms and the posterior inferior wall, these were not really the origin or the place where most of the VTs were being originated. Most of the VTs came from the infraceptal wall, almost 20% in that case in this series. And again, further data documenting that non-sustained ventricular tachycardia, when it's inducible, has some significant effect on mortality and heart failure in this population. Now, of course, everything today has to be tested with AI and machine learning. And this is an interesting study also from a group in Brazil that looked at some different markers, including the clinical data treatment, including basnitazole, which is the medication that is used to treat the parasite, other heart tests, and other findings. And they did this machine learning algorithm, and they found that actually it had a very high predictive value to detect sustained ventricular tachycardia in patients with a very low, very high sensitivity and specificity. So this is still a work in progress. Now, strain echocardiography is something simpler and maybe cheaper than cardiac resonance. And this study also from Brazil has shown that there's an association of strain echocardiography and what is called dispersion, that can be mechanical dispersion, has a very high sensitivity and basically an 11% risk of detecting ventricular arrhythmias, usually VT and VF, in a population of patients with Chagas cardiomyopathy. From the benefits study, that was a study that we conducted in five countries in Latin America. This is the largest trial ever conducted in Chagas disease. Almost 3,000 patients were randomized to this drug basnitazole or placebo. And we did an echocardiographic sub-study looking at this wild motion score index. And you can see on the left, the primary outcome that was a composite of sudden cardiac death, heart failure, hospitalizations, overall mortality, et cetera. In green, you can see that by seven years, 60% had one of those events. And on the right, the mortality, when you had this score of only one, you see a greater than 1.5, sorry, on green, almost 50% are dead by seven years. And death in this case was 80% of the times due to sudden cardiac death and the rest progression of heart failure. So there's no doubt that this wild motion score index is quite powerful, almost a two to threefold increase in detection of death that is primarily due to sudden cardiac death. As you may or may not know, Chagas is an excellent model of cardioneuropathy. And these studies done from the group of Dr. Marie Neto in Brazil have shown that there is also some changes in the distribution of epic and endocardial sympathetic innervation that can be predictive of this. Now let's move to left ventricular scar endoprenosis and Chagas cardiomyopathy using a cardiac MRI. And this study of about 140 patients looked at the presence of or not of fibrosis detected by LGE. And you can detect several different patterns as shown here. And these were more or less equally distributed among the population studied in this trial. And they're able to identify that patients that had LGE was related with cardiovascular death or sustained ventricular tachycardia, as well as myocardial fibrosis by LGE was related with this composite of cardiovascular death, sustained VT or admission to hospital due to cardiovascular reasons, which in the case of Chagas disease is primarily due to heart failure. Another study that further validates this and looked at more of the, whether it was positive or negative, but also looking at volume like this study, looking at extracellular volume, because it's also a marker of inflammation. And again, maybe primarily triggered by this persistence of low parasitemia. And you can see that depending on the type of preserved mid-ref or half-ref, there is a different distribution of the number of events. And of course, with progression of the disease, there's a higher incidence of ICD implantation. And again, death that is usually due to sudden cardiac death. This is a meta-analysis that the group that I collaborated with in Columbia, that's led by Dr. Echavarria in Bucaramanga, where I used to be a long time ago. This is a meta-analysis of all the studies looking at cardiac magnetic resonance. This is right now under revision in one of the journals. And we're able to detect that those patients, even in the indeterminate stage, there's evidence of fibrosis almost in 20% of these patients with fibrosis extension with a percentage of LV mass also shown in this population. Then when you look at this diagram on the right, was related also with some alterations in the proportion of segments that were affected by LGE. And this is summarized very nicely in this graphic, was related with increase in VT, increase in other risk outcomes that included sudden cardiac death and a significant increase in mortality. So if we tune this up, we'll be able to actually predict even patients in the determinate stage that would probably benefit from prophylactically getting an ICD. And again, inflammation, fibrosis, and not anomic dysfunction, all of these interact and lead to sudden cardiac death. And today we have the technology to identify all of these. We still don't know if treating the parasite or even treating inflammation would have any effect on reducing the events in this population, but we're conducting a few studies to try to look at that. This is the RASI score published more than a decade ago by Dr. RASI and his collaborators in the New England Journal that looked at New York heart class, cardiomegaly, segmental or global wall motion abnormality is what we also validated in the benefit trial, non-sustained VT and low QRS. And we have a high score. These are the points here. The intermediate score, you had a total mortality of five years of 18 and 10 years of 44%. And by 10 to 20 years, almost everybody is dead and mostly due to sudden cardiac death and heart failure. Now there's other risk scores that have been done by different groups. And there's another group in Brazil that's looked at this and looked at the number of PVCs, prior syncope and QT dispersion in addition with severe LV dysfunction. And these were quite significant and had a significant, almost a one to three fold increase in mortality. And you can see the Kaplan-Meier curves here when patients have a high risk, a high score, basically a 51% risk of sudden cardiac death at five years. This translates to about 10% per year. So basically using these scores, we could be able to identify the population that is high risk. This is the benefit trial that we published almost a decade ago in the New England Journal and simply to show you that death was quite frequent. And mostly this was due to sudden cardiac death and progression of heart failure. Now we've developed a benefit score that's also under review in some journals that show that if you have a high risk score by six years, almost a 50% mortality risk in that population to eventually able to identify those patients. There's been a lot of discussion on whether ICDs are beneficial as primary or even secondary prevention in patients with Chagas cardiomyopathy. The meta-analysis that we did with my friends also in Brazil that showed that there was probably not enough benefit derived from an ICD in this population. Now the group from Dr. Martino Martinelli in Brazil is conducting the Chagasic trial, which is a randomized trial that is randomizing patients with non-sustained BT on a Holter and a RAS score greater than 10 to a Miodurone or an ICD. This study already completed enrollment as per my last conversations with Dr. Martino and hopefully will be reported next year in one of the large meetings. And this will be a very important trial to get the information on. Now, there's been some discussion on whether we need to do endocardial or epicardial or a combination. And this is the first randomized trial published a couple of years ago, also from a group in Sao Paulo in Brazil that randomized patients to endocardial only mapping or epicardial and endocardial mapping in a population with Chagas cardiomyopathy. It's a very nicely done trial. It's a small trial, but a very elegant trial. It randomized these patients here. And this is the summary of what happened with the patients. And again, I don't have the time to dwell with the details, but the fact is that in the end, the trial showed that the patients that were randomized to the combined approach of endo-epi, these are the Kaplan-Meier curves, recurrence of VT, probe shocks, were way less and significantly less than the patients that were randomized to the endocardial approach alone. So it seems quite clear that in patients with Chagas cardiomyopathy, this combined approach is important. So advanced therapies for patients that have ventricular arrhythmias are described here. I already told you about the endo-epicardial approach. Cardiac denervation is quite useful in this population that have a very high incidence of VT, VF storms, and even renal denervation has been reported. And some nice, fancy imaging can be done when you integrate our mapping systems with CMR or CT. Now, if patients with chronic Chagas cardiomyopathy have refractory to ventricular tachycardia, then the endo-epi mapping is recommended. If there's recurrence, then these patients derive a significant benefit, either of thoracoscopic sympathetic cardiac denervation, and this has been reported by several groups as well as renal sympathetic denervation. And these are the trials that have shown this. This is Dr. Pisani that showed a combined endo-epicardial randomized trial, Dr. Saenz in Colombia, and Dr. Tejas also in Colombia with cervical thoracic sympathectomy, and this group of patients with Chagas. And again, my former fellow, now established electrophysiologist in Brazil, Dr. Armaganitan, the first case series of renal denervation in Chagas with significant reduction in VT and ATP shocks in that population. This is from the Saenz trial showing before and after sympathetic denervation, the marked reduction in shocks, as you can see here in this graph, in these patients with VT storms and Chagas cardiomyopathy. There's an interesting pilot randomized control trial of renal denervation, and heart failure secondary to Chagas disease. It's a small trial, but it seems to show that there was a trend to reduction in the outcomes with renal denervation. This is not significant, but again, it's a very small trial, so this is food for thought. So what should we do with a patient with positive serological testing? You get an ECG, and if it's abnormal, then determine what's the functional class according to New York Heart. And depending on that, looking at different tests, you can determine where to go with either a normal LV function or an echo-imperial LV function. But today we have a better way of looking at the mechanical dispersion or regional wall motion abnormalities as I showed you with echocardiogram, and maybe early on identify even those patients in the indeterminate stage that are at high risk of having events, particularly VT, VF and sudden cardiac death. And the same with cardiac MRI and LG that can identify which of these patients should receive maybe a prophylactic ICD. Of course, the future probably lands with artificial intelligence and machine learning of these ECGs and halters and imaging that could probably give us this composite score to identify these patients. So in summary, Chagas disease and sudden cardiac death is very frequent and it's observed even in patients with preserved LV function. Screening with multi-imaging modalities may be the future with AI machine learning combined to try to identify these patients. Different scores, including the benefit score, may identify subjects that are high risk of sudden cardiac death or heart failure progression. And there's a randomized control trials comparing imuterone versus ICD, like the Chagasic trial that will hopefully be reported early next year. And again, we're working hard on finding biomarkers to determine the risk of progression and sudden cardiac death. And hopefully we can get some more data in the near future. Again, thank you very much for your invitation. And hopefully there are some questions from the audience. Thank you very much, Dr. Morino, for your excellent presentation. The time is behind, so we will move to the final presentation. The final presentation, Arrhythmogenic Right Ventricular Cardiomyopathy, will be made by Dr. Seiko Ono from Japan National Cardiovascular Center. But she's not in Mexico City, so she sent a video presentation. So please. Thank you very much for inviting me to the FAHRS 2003. Unfortunately, I can't attend the meeting on site, but I want to tell you the risk and therapy of Arrhythmogenic Right Ventricular Cardiomyopathy. So first, I want to explain what is ARV-C. ARV-C is characterized by right ventricular enlargement and failure, shown here, and ventricular arrhythmia originated from a right ventricle, shown here. You can see the ventricular tachycardia like this, and the fibrofacting displacement of cardiovascular cells. And this disease was thought as an autosomal dominant inherited disease caused by desmodromal gene variants. The prevalence of this disease is around 1 per 5,000, but it depends on the countries, because there are a lot of patients in Mediterranean area. And the disease is very dominant, and the mean age of onset is 30s to 40s. So today, I'm going to talk about the risk stratification of ARV-C, and then therapy for ARV-C. These pictures show the accidents in the soccer field. Both players collapsed suddenly in the soccer field, and lately, they were diagnosed with ARV-C. Then why did these soccer players collapse suddenly in the soccer field? Because competitive sport is one of the risk factors in ARV-C. As you know, ARV-C is an inherited disease, shown here. But in addition to the genetic background, ARV-C needs another cause. We call it the second hit for the onset of the carrier, ARV-C. And why stress exercise worsens the ARV-C? One of the reasons is the ARV stretch. ARV stretch causes desmodromal alterations and causes ARV-C. And one of the reasons is the increase of the adrenaline. This increase of adrenaline affects several factors. Now, there is the risk prediction model for ventricular arrhythmias. This study was performed in 520 ARV-C patients with definite criteria from North America and European countries. They had no history of ventricular arrhythmias nor sudden cardiac arrest at diagnosis. And in follow-up, in 5 years follow-up, 74% patients of ventricular arrhythmia are free, shown here. And in this study, they found that male sex, recent cardiac screen copy, clear non-stability, 24-hour PBC count in Holter recordings, lead with T-wave interrupt, inversion in angina and fibrillation, and LVEF is the fractures of the ventricular arrhythmias. And in the managed variant analysis, they use these factors for the risk model. Then, they finally make a model for the risk stratification of the ventricular arrhythmias, including these factors. And they could clearly separate the risk of the ventricular arrhythmias in the ARV-C patients, shown here. Then next, same group tried to make a risk model for the sudden cardiac arrest. And in this study, they included 864 ARV-C patients with definite criteria from North America and European countries. And in this study, they included patients with ventricular arrhythmias. Then, they analyzed the occurrence of the life-threatening ventricular arrhythmias. Depends on the previous event, no previous event, or prior life-threatening ventricular arrhythmias or instability, or stability. But these life-threatening ventricular arrhythmias were not related with the previous ventricular arrhythmias history. But any sustained ventricular arrhythmias was associated with any sustained ventricular arrhythmias, shown in these graphs. Then finally, they found risk factors for cardiac arrest. The factors are male sex. Male sex is the worst prognosis. And the younger age of the onset is one of the risk factors. And 24-PVC count. And these we see with inversion and erode impairment. And these other factors related with ventricular arrhythmias are not related with cardiac arrest. And finally, they found that these four factors, younger age of onset, male sex, and number of risks with inverted T waves and the PVC burden. These factors for the sudden cardiac death in ARV-C. And in previous study, they reported that the previous syncope, arrhythmia-related syncope, this reduced LVE, prior sustained VE, and non-sustained ventricular arrhythmias related with the sustained ventricular arrhythmias. And now we can calculate five-year risk of life-threatening ventricular arrhythmias like this. But in this model, no genetic information is included. Because the genotype and phenotype are different between Asians and Europeans. This left graph shows the causative gene in European province. Three-fourth of the European province carries the PKP variance. But in Japan, half of the ARV-C patients carry the variance in decimal N2. And also in China, the number of the PKP variance and the decimal variance is almost the same. Interestingly, there are phenotype difference. So, in this graph, they show the occurrence of the ventricular arrhythmias in red line, in variant carriers. And you know that most of the European patients carry the PKP variant. The onset of the ventricular arrhythmias at 40 years old is around 60%. In contrast, in Japan, the PKP variant carriers, the occurrence of ventricular arrhythmias is almost the same with European country patients. But in decimal N2 variant carriers showing blue line, the onset of ventricular arrhythmias is older compared to PKP variant carriers. So, we need further verification of the risk calculator for Asians. Then move to the therapy for ARV-C. One of the important therapy is lifestyle modification. As I show in the first slide, the strong exercise is one of the risk for the onset of the ARV-C. So, restriction of moderate and or high-intensity exercise, including competitive sports, is very important for the ARV-C patient. And there are two therapies for the ARV-C. One is the therapy for heart failure. For the heart failure, we use medications, including angiotensin-combating enzyme inhibitors, angiotensin receptor-neutralizing inhibitors, and beta-blockers, and mineralococcal receptor antagonists, and sodium glucose co-transporter-2 inhibitors. These medications are also with other cardiomyopathies. But in very severe cases, we sometimes need heart transplantation. Then in the therapy for ventricular arrhythmias, we can use several medications, including beta-blockers, amiodarone, sodalo, and flaccidin. And sometimes we need ICD implantation. As I've shown in the previous slide, there are several risk calculators for the ventricular arrhythmias of the sternocardiac. If we use these calculators, we can decide which patients need ICD implantation. And now, ablation therapy is very useful for the prevention of the ventricular arrhythmias. So in patients with ARVC, if the patient has a history of cardiac arrest or syncopal VT, the patient has an indication of the ICD implantation. And the non-syncopal cyst endoscopy, the carrier, the ICD indication is class IIa. And also, if the patient is high-risk features, the class indication is IIa. Then, here I show the effect treatments of flecainide for ARVC ventricular arrhythmias. In this study, they included 151 patients suspected to have ARVC and to be treated by flecainide. And finally, they included 100 patients. First, they compared the PVC burden in 24-hour quarters ECG. At baseline, the mean PVC numbers are 2,370. But after flecainide therapy, the number of the PVCs greatly decreased to 415. And this graph B shows the positive date of the programmed ventricular stimulation that occurs of the ventricular arrhythmias, the induction of the provocation. And you can see that 94% of the patients were induced ventricular arrhythmias, but the number decreased to 40% after flecainide. So flecainide reduced the PVC burden in ARVC patients. Then, move to the ablation therapy for ARVC. In this study, they included 645 ARVC patients, and they are well-treated monomorphic VT, and the ejection fraction of the ARV is almost the same, and no zinc B nor X-ray stop. And they performed VT ablation without backup ICTs. And in this study, only 29% of the patients received epicaldehyde ablations, and other patients performed epi and endocardial ablations, and the complete procedure process was 72%. And the median follow-up of the 52 months is no sudden cardiac arrest or aborted cardiac arrest occurred, and VT recurrence occurred in 19 patients, but these patients received only endocardial ablation, shown here. And in these VT recurrence patients, they performed ICD implantation, followed up with ARVC, or anti-arrhythmia modifications, and no sudden cardiac arrest or ICD here occurred. So this is the survival curve with the occurrence of ventricular tachycardia. But this graph is very impressive. Only the endocardial ablation patients suffered ventricular tachycardia, but patients with epicaldehyde ablation suffered no ventricular tachycardia events. And the complete procedure success, patients suffered low rate of the ventricular smears, shown here. So from now on, ablation therapy, especially from the epicaldehyde, including the epicaldehyde ablation, is important for the prevention of the ventricular tachycardia in ARVC. So this slide shows the summary of my presentation. The risk of these ARVC smears can be predicted by four factors, young onset, male sex, number of leads with inverted T waves, and the PPC burden. However, it is unknown the risk calculator is applicable for ARVC patients in Asian countries with different gender backgrounds. Then, antiarismic therapies are important to prevent sudden correctness, including epicaldehyde ablation therapy. Thank you for your attention. Thank you very much. I think this concludes the session. We have a little bit of our time, but I thank you very much for the audience and for the speakers for a great session from my co-chair, Dr. Kim. Thank you very much.

Arrhythmo-Gynic Right Ventricular Cardiomyopathy

ARVC

risk stratification

therapy

genetic basis

second-hit factors

lifestyle modifications

medications

ventricular arrhythmia

ablation therapy

risk calculators