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EP Fellows Curriculum: Brugada Syndrome
EP Fellows Curriculum: Brugada Syndrome
EP Fellows Curriculum: Brugada Syndrome
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Great. Thanks, Nishant. So I just want to say thank you to Nishant also for organizing this lecture series, which certainly for my fellows has been a godsend during the pandemic. But I think on top of that, as you and I were discussing, this is going to be a resource for fellows for, I think, years to come. So I'm really proud to be a part of this, and I want to thank him for the effort in organizing this. So we'll get started here. Sorry, it's the, OK. So I'm having some trouble with the, OK, here we go. So I've got nothing to disclose, and I'm going to have a case here. I have a few people logged in so far. So this is a real case, a little bit seen through the retrospective scope. And what we have here is a 50-year-old man who has a pre-op EKG done prior to knee surgery. Totally healthy guy, no history of syncopear palpitations, but he does have an uncle who died suddenly at age 42. And you see he's got this EKG here. And actually, when this was done, this was simply a retrospective scope EKG that I was able to find. But let's say this guy comes and is referred to your electrophysiology clinic for this finding in this EKG, which, of course, if you look in V2, is a little bit abnormal. We'll talk about that in a minute. And I want to know in a poll here what people would do. So OK, good. Here's the poll. Perfect. So number one, take a thorough history, explain the EKG finding, advise the patient to treat high fevers aggressively with acetaminophen and avoid certain drugs, and provide some reassurance. Number two, discuss the risks, schedule the patient for an EP study to assess if he has inducible VT, and then implant a defibrillator if ventricular arrhythmias are reduced with a triple stem. C, schedule a patient for ICD implant after you discuss the risks of Brigotta syndrome. And four, send off genetic testing, make a decision for care once the results are available. So we're going to get back to this a little bit later. I'd love for those of you who are here to have a vote. This is great. We've got some disparate opinions, which is fantastic. So we've got a couple of votes for number one, a couple of votes for number two. I'm just going to move this out of my screen here. And I just kind of want to leave this here for later. We're going to see this later. So we've got the poll results here. We've got, looks like, almost even split between number one, conservative management. Number two, think about an EP study, which is great, because I think those are the two potential answers that you could use. There's not really a right answer here. And number one and number A and number B are the best, probably, options for management that I think are at the center of the controversy around Brigotta syndrome. So I'm just going to drop this down to the side here. I'm going to share the results here. So you can see 60% think conservative management. 40% would like to do an EP study. OK. So I'm going to close that. OK. So Brigotta syndrome. And this was first reported, actually, not through a known diagnosis, but retrospectively looking at the literature, there was a case report of three healthy males, C.F. Beth Israel and Boston, where I trained. 39-year-old male admitted with evaluation of vague chest pain in normal labs. And his EKG looked as follows. So you can see the EKG findings in V1 and V2, both on the left over here, as well as quite abnormal EKG findings, particularly over here in V2 on the EKG for another one of these patients. One feature that I think is interesting is if you look at V1 and V2, there's some variability over time of different electrocardiograms for each of these patients. And I think that that's important because that's one of the hallmarks of Brigotta syndrome is that the EKG is not always the same. So the first actual identification of this as a syndrome is, of course, made by Pedro and Joseph Brigotta starting in the 80s when they were referred a three-year-old boy with recurrent syncope. And this boy's sister had repeated episodes of sudden cardiac death. And they looked at the electrocardiograms of these two kids. And you can see that in V1, there's this characteristic sort of pseudo right bundle pattern with an ST elevation, a down-sloping ST segment, and a T-wave inversion. And the Brigotta brothers got an interest in this and gathered a large number of cases. And have actually identified this as a syndrome, of course, that we all now know as Brigotta syndrome. So this is a classic figure that is shown looking at the electrocardiograms in Brigotta syndrome. And there's really now used to be type 1, type 2, and type 3. Now there's really just type 1 and type 2. Type 1 is the Brigotta EKG. Type 2 is not diagnostic, but is suggested that the patient may have a propensity for developing a type 1 electrocardiogram. And to be very specific, in V1 or V2, there needs to be at least a 2-millimeter ST elevation with a down-sloping ST segment and then a T-wave inversion. So all three of those components have to be present to diagnose the type 1 electrocardiogram. Now type 2 can have several morphologies. One can be the classic saddleback, where there is a 2-millimeter ST elevation in V1 or V2. And then kind of the saddleback without the T-wave inversion. Or you can have almost the T-wave inversion at less than a 2-millimeter elevation. And that used to be called type 3. So these are not diagnostic of Brigotta, but they may spark your interest and may make you think about a drug challenge in the appropriate patient. So a few notes on diagnosing these EKG findings. Number one, moving these V1 and V2 up from the fourth inner space to the second or third inner space can increase the sensitivity in the diagnosis of Brigotta syndrome electrocardiograms. Interestingly, it's been shown in cardiac MRI studies that the most sensitive V1 and V2 locations are directly over the right ventricular alveolar tract. So some people's heart sits a little lower, that's where it's best diagnosed, a little higher, that's where it's best diagnosed. So that's probably why there's some variation in the ideal location for V1 and V2. There's also significant fluctuation in the appearance of a Brigotta EKG. So there's a longitudinal study of 43 patients with a known type 1 electrocardiogram. And at some point, every one but one of those patients had a non-diagnostic, meaning type 2 or otherwise electrocardiogram follow-up. So just because they don't have a Brigotta EKG that day doesn't necessarily mean they don't have a Brigotta syndrome EKG. Also know that there are mimics of the Brigotta EKG. ARVD can cause very similar EKG findings to Brigotta because, of course, a lot of the pathology in ARVD is in a similar area in the anterior RV. Acute myocarditis or acute cardiomyopathy can create a very similar electrocardiogram. And RV trauma, direct trauma to the sternum can cause localized trauma to the anterior RV epicardium, mimicking Brigotta syndrome. So it's actually the same EKG again because it's such a nice example. You can see the 2-millimeter ester elevations in V2, the down-sloping ST and T-ray inversions. Now, note, you only need to have the diagnostic finding in either V1 or V2. Do not need to have it in both. V3 no longer counts. It's just V1 and V2. Those are right over the RVOT. But, of course, you can also have it in both in some patients. So what are the diagnostic criteria for this as a syndrome? So what we've been talking about in the last few slides is the Brigotta EKG. The Brigotta syndrome, to be clear, is a little bit different. So the Brigotta syndrome encompasses having that electrocardiogram finding either spontaneously or in the presence of a sodium channel blocker, and either some sort of symptom that can be related to this diagnosis. That can be anything from documented ventricular arrhythmias, a family history of sudden cardiac death, other family members with similar EKG findings, inducibility of BT on EP study, syncope or nocturnal agonal respiration, which is thought to be a variation on syncope. So let's just go back and talk about the cellular mechanisms of the action potential, and then we'll talk about how this relates to the Brigotta EKG. So as I hope all of you are aware, we've got phase zero of the action potential, followed by the transient phase one, in which we have transient outflow of potassium, the ITO channel. Okay, this is very important in Brigotta syndrome to remember that there's a little bit of potassium that goes out after the sodium channel fires. You then have maintenance of the plateau of the action potential, with both calcium and sodium, slow sodium channels, particularly the SCM5A, as we know. And then of course, in phase three and phase four, you have a return to baseline with rapid potassium outflow, and then in phase four, the funny channel. So what we're gonna focus on is this area here in phase one. So this is a classic figure from Manzelowicz, who, along with Brigotta, did a lot of the basic early research in Brigotta syndrome. So in the RV, we've got, as you know, the epicardial, the M cells, and endocardial cells, and these depolarize and repolarize in a fairly similar fashion in normal hearts. Now in Brigotta hearts, the abnormality tends to be more pronounced in epicardial RV, particularly RVOT, but generally anterior RV cells. And so you get a gradient between endocardial cells, which tend to have a little bit more normal action potentials, and the epicardial cells, which tend to have loss of function of the sodium channels that maintain the plateau. And you've got, basically, you have an overactive ITO. So that potassium outflow causes a diminishment of the peak of the action potential because it's unopposed by sodium channels. And that can cause a gradient over the anterior RV, causing this ST elevation during the beginning of repolarization. And then conversely, T wave inversion because of flow the other direction after early repolarization at the end of the action potential. Now, you can get more extreme forms of this with diminishment more quickly and actually return to baseline immediately from the ITO, causing a much bigger potential gradient between the epicardium and endocardium. And that large gradient, and actually once these channels then return to excitability in the epicardium, you can get phase two re-entry. So you can get flow from the endo to the epi, causing a second action potential in the epicardium. And then, of course, you're in trouble because you've got disjointed activation of the epicardium and the endocardium, and you can lead to runs of polymorphic PT and ventricular fibrillation. So this is the repolarization hypothesis which is really the basis of why we think patients with Brigotta syndrome have triggered re-entry polymorphic PT and VF. Now, there's also structural abnormalities in Brigotta syndrome. And this is the depolarization hypothesis as opposed to the repolarization hypothesis. And of course, like anything in medicine, probably both have truth and both contribute to the abnormalities in patients. But we do know that we get myocardial fibrosis seen in RVOT in patients with Brigotta. And also we know from mapping, which I'll talk about later, that we get low voltage fracturing electrograms using the RVOT epicardium. So most likely what we're seeing is that there is a interplay between the loss of the channelopathy, basically, and development of fibrosis and abnormal mechanical function in that same region. We know that there's increased collagen in the RVOT, decreased connection 43. And this just creates, when there's ventricular ectopy from phase two re-entry, of course, then if you have local scar infractionation, you're more likely to have ventricular arrhythmias. And we know that there's conduction delay and that actually homogenizing this substrate with ablation can actually eliminate the type one pattern by basically probably just eliminating that gradient between the epicardium and endocardium by simply ablating the whole area. And you can actually eliminate inducible arrhythmias. And we'll talk about that near the end of this talk. Now, but then why does the EKG finding come and go in patients? Why is it so relatively sensitive to drugs and fever? That does not really explain the depolarization hypothesis. So that's why really the channelopathy and the action potential differences in the epicardium and endocardium still are an essential part of the Brugada pathology. And that this is likely somewhat secondary, but still important to the pathology of the disease. And probably some of the reason why most patients don't present until their 30s or 40s, because you have to have these fibrosis develop and some structural agonize develop later in life to have the setup for persistent sustained arrhythmia, such as polymorphic VT or VF from the phase two reentrance. You probably need both. It's probably a two hit hypothesis here. This is a figure from Dr. Nadamami's work who's been very important in the characterization of the substrate and ablation of Brugada. And this just highlights the findings that reduce gap junction expression and fibrosis and increased fibroblasts and collagen in patients with Brugada syndrome resulting in local electrograms, which are fractionated, low voltage and long. So an interesting recent study out of Dr. Paponi in Italy actually correlated RV mechanical changes with electrical substrate. And remarkably, so sodium channel blockers accentuate the action potential differences in Brugada syndrome, because they allow unopposed ITO and accentuate the sodium channel abnormalities, which are predominant in most patients with Brugada. And he demonstrated in a recent paper that when you give adrenaline, which is an IV sodium channel blocker, that there actually was a decline in the RV ejection fraction in patients with Brugada, primarily in the free wall of the RV. And that this correlated with areas of mechanical, of abnormal EGM substrate, which actually got larger in the setting of sodium channel blockers. So this was a nice correlation between the electrical findings and mechanical findings in Brugada syndrome. And this effect, once you eliminate it with the substrate through ablation, the delta in RV function went away and that it showed that there was this link between electrical substrate and RV mechanical abnormalities. So a little bit about the epidemiology of Brugada syndrome. It's quite variable depending on the population studied. In Japan, it's approximately 0.1 to 0.15% of all EKGs show the type one pattern. There was a fair incidence of type two EKGs in Finland, but very few type ones. In the U.S. at a large teaching hospital, they found a 0.4% incidence, definitely more common in men than women, and average age of diagnosis is 41 years. Again, as I said earlier, likely because those mechanical changes lag behind electrical changes that are probably present from birth, but that extra probably strain on the epicardium leads to fibrosis later in life and some of the symptoms of Brugada syndrome, thus making a diagnosis of middle age. Interestingly, and this is not quite clear why, doesn't really apply to the RV, but there's probably some abnormalities in the atria due to these channel abnormalities. And there's a 20% prevalence of atrial fibrillation in patients with Brugada syndrome. One of the reasons why everyone should be diligent about checking an electrocardiogram fairly soon after starting any patient on a 1C antiarrhythmic agent, because of course a 1C agent in a patient with Brugada syndrome can be fatal. And if let's say they've got a type two or type three electrocardiogram, you start them on flecainide for their atrial fibrillation, they may develop a rip-boring type one Brugada EKG and will certainly be at increased risk of ventricular arrhythmias on that medication. So some of the genetics of Brugada, so it is autosomal dominant inheritance pattern that was identified quite early. And the first gene and still the most prevalent gene is an SCN5A mutation. And this is that plateau of the action potential and loss of function is the mutation that's found. And this is in about 20 to 30% of cases have an SCN5A mutation. There's many mutations that have been discovered in this gene. Interestingly, gain of function of this gene can cause long QT3 by extending that plateau of the action potential. And people with this mutation in Brugada also have a higher incidence of sick sinus syndrome and early onset heart fall. SCN10A is a mutation that has been discovered about seven or eight years ago to account for another 20% of cases of Brugada syndrome. And there's some rare calcium genes have been identified and some sodium channel mutations. So overall is about 12 Brugada syndrome susceptibility genes that can be tested when you send a Brugada pen. But you're only gonna get at most a 50% yield and many studies which are older of smaller panels suggest only a 30% yield of positive gene mutations in patients with Brugada syndrome. So this is not how you make the diagnosis of Brugada. The use of genetic testing in patients with Brugada is generally for management of family trees and figuring out who in the family may be susceptible and having genetic counseling with those family members. I think it's very important to counsel your patients when you do genetic testing about the potential risks and benefits of genetic testing. We don't, it does not appear that having a known genetic mutation, particularly SCN5A is neither a malignant or benign mutation. So it does not appear to increase the risk of sudden death whether or not you have a mutation identified. So there really is no prognostic utility of genetic testing in Brugada syndrome. That it really only should be used for family tracking, figuring out family members at risk and cascade testing of families for a discovered gene. And also because the yield is relatively low, most patients with Brugada, still the majority will have negative genetic testing. So it has really only limited utility, but I do think there's still good utility in a patient with extended family tree or children or brothers and sisters of testing them. And if they are positive, then focused genetic testing in a cascade manner can be done on family members. So one interesting thing, there's this sudden unexpected death syndrome in Southeast Asia called Lai Tai. And this is agonal breathing and sudden death at night. It appears that this is actually simply Brugada syndrome, one in the same. And in fact, Brugada syndrome has the highest incidence in the population from Southeast Asia. So Southeast Asian males in particular are particularly high risk for Brugada syndrome. Brugada, a very important thing in counseling patients who have either Brugada EKG or Brugada syndrome is that there are several known provoking factors that both bring out the type one EKG and also increase risk for ventricular arrhythmias. Number one, fever. So patients with Brugada syndrome should be counseled that they need to treat fevers aggressively. They need to take round the clock acetaminophen or ibuprofen and that it needs to be taken quite seriously. Cocaine is essentially a class one sodium channel blocker. So it can precipitate ventricular arrhythmias both due to bringing out the abnormalities of Brugada and of course, propensity for ventricular arrhythmias with cocaine use. Anyways, tricyclic overdose. One thing that comes up a lot, inhalational anesthetics. So in the operating room, inhalational anesthetics can bring out the type one Brugada EKG and even precipitate ventricular arrhythmias in patients with Brugada. So patients with Brugada need to be very carefully managed around in the operating room. And of course, class one antiarrhythmic drugs are contraindicated sodium channel blockers. In terms of drugs, there are some other drugs which have been associated with Brugada arrhythmias. There's a wonderful website, www.brugadadrugs.org which I use as a reference and give to patients with this diagnosis. I write it down and give it to them, make sure that any new drug that they are prescribed that they check it against this database. So now we're gonna get to sort of the more controversial portion of this talk, which is risk stratification in patients with Brugada syndrome. So I think we all agree that symptomatic patients with the type one EKG are at the highest risk of recurrent arrhythmias. And patients with aborted sudden death at a 62% recurrence rate and a higher rate of recurrent syncope as well. And patients with syncope have a higher recurrence rate of syncope or sudden death as well. So symptomatic patients, meaning aborted sudden death or syncope also in which they have a sort of suspicious EKG or as part of your syncope workup, you do a sudden channel block of challenge are also at high risk. And certainly I will go through the second criteria for ICD implantation. So these patients, I think in all guidelines and consensus statements that are written, people agree that they are at high risk for recurrent arrhythmias and should receive a defibrillator. So the current, there's the most recent statement from HRS specifically on Brugada stated that people with a type one EKG and should undergo risk stratification. And if they have syncope, fragmented QRS is actually a finding on the electrocardiogram, particularly in the pericardial leads and the right pericardial leads that has been shown to be associated with sudden death. Some other sort of individual risk factors can be a short ERP, a VERP less than 200 milliseconds on EP testing, male gender, and also patients with atrial fibrillation at higher risk. The 2013 consensus stated unequivocally that asymptomatic patients do not qualify for a defibrillator and also identify the role of quinity which I'll address a little bit later for patients with shocks or an ICD. So the algorithm that was proposed by this consensus statement was that in patients who have had an arrest or sustained BT and type one EKG certainly get a defibrillator. If they have syncope that seems not basal vagal but more malignant, then an ICD is certainly it's a class two recommendation but most people would agree that this is a pretty clear indication for defibrillator. Now what gets a little bit or a lot more controversial and I'm gonna talk about this in great depth in a second is the role of EP study. So in a patient with no syncope, no prior cardiac arrest so they've induced a little BF for applying more BT and EP study it was a 2B recommendation for ICD implantation. And in patients who are asymptomatic and they for some reason have a drug induced type one EKG and or a family history of sudden cardiac death ICD is not indicated. So family history has been pretty much clearly shown not to be a, unlike certain HCM mutations, not to be a risk factor for sudden death in any individual patient. I'm sorry for the quality of this, but so what about electrophysiology study? And this has been studied pretty extensively. The first report of this was from the Brugada brothers in 550 patients with either spontaneous or evoked EKGs, some of whom had syncope. And they all underwent electrophysiology study in two-year follow-up. And you can see that, kind of circle down here, that in people with a spontaneous EKG and no syncope, if they're not inducible, the rate of sudden death or syncope was, or excuse me, of an event that included STD shocks, which is important, was about 2%. And if they're inducible, it's 14%. So clearly this study argued for EP study. Now, one of the criticisms of this study from the Brugada brothers is that this was published in 2003 based on their experience in the 90s when they had just diagnosed Brugada syndrome. And so there was a lot of referral bias, and this is well documented that when a new diagnosis or disease is identified, the first people who are identified who have that disease or condition tend to be higher risk groups and does not necessarily make that generalizable to patients who we may see in everyday practice. And so it's very important to take that into context, this incredibly high rate of asymptomatic patients with positive EP studies having subsequent arrhythmias and follow-up. So there've been 12 subsequent studies trying to test this hypothesis that the Brugada brothers proposed. And these studies are generally of lower risk patients, more than drug-induced, and probably were more real-world than the Brugada brothers' experience. And none of these studies showed any prognostic utility of EP study. And there's a recent meta-analysis of some of these studies which I'm going to talk about in a second, but the consensus statements haven't really been revised. So EP study still sits as a 2B recommendation for an asymptomatic patient with a type 1 EKG. Some fields signal average EKG, may have some utility in risk stratification for places that still do these tests. I know certainly our signal average EKG machine broke a long time ago, and we don't use it as a regular part of our risk stratification. So a couple of the biggest studies of EP testing in Brugada, this is really often ends up being the most relevant question that comes up in managing these patients. So up to 1,000 patients in this registry, 64% asymptomatic, and many of them were studied with EP testing. In the end, 26% of people who were asymptomatic ended up getting a defibrillator, including most of whom were those with positive EP studies. And there was a 5% event rate over 32 months in this registry of patients with Brugada. And many of those were aborted sudden death. So if you had aborted sudden death, your rate was about 8% of having an event. Syncope 2%, if you're asymptomatic, the event rate was extremely low at 0.5%. And remember, some of these asymptomatic, many of these asymptomatic events were in patients who got a defibrillator and then got a shot. So it doesn't mean they necessarily would have died if they didn't have a defibrillator. And this is a point we have to keep coming back to. And they looked at predictors of outcome, they looked at symptoms. Spontaneous type 1 EKG were two predictors of outcome. And EP study outcome did not predict long-term outcomes with either ICD shock or death. Also having mutation or not having mutation or having a family history of sudden death. So importantly, this is the largest study of patients with BRUGADA and EP study. EP study testing was not predictive of outcome. The pre-lib registry was a little bit smaller. I include this one because there's a very interesting point. So 300 patients had a type 1 EKG, no history of sudden death, and everyone had an EP, had EP testing with up to triple VES from two sites. Okay, so pretty aggressive protocol. And they followed them for six months. So 40% of patients had inducible VT on EP study. Okay, now they tested afterwards. Okay, so 10 minutes after they induced VF, they tested them again. And 66% of those who were inducible were then non-inducible on EP testing. And notably, I don't include that here, but about 35% who were not inducible were then inducible on EP testing. So the point I'm trying to make here is that it was kind of a crapshoot whether or not you were inducible with up to triple stimulation on an EP study. And you might get a negative result, and the next time get a positive result, and vice versa. And so a test like that, that seems almost like a random result, it's hard to put a lot of faith in making a decision on whether you can put a defibrillator in somebody based on that. So in inducible patients, there was a follow-up and follow-up. There was a 4% incidence of arrhythmia events, either IC shocks or sudden death. And there was a 5% incidence in non-inducible patients. So EP testing had no predictability, either in predicting future inducibility on EP testing or outcomes. So this was a pretty strong argument against EP study as using it as a predictive test in patients with Pagana. Things that were predictive, syncope, spontaneous type 1 EKG, having a very short reverb. So the action will be very short, actually short and particularly from the RV, obviously, because that's where you're testing during EP study. And QRS fragmentation in the right pericordial leads were only pictures of subsequent sudden death. So a pooled analysis of eight studies, actually not including the Bregada Brothers studies, including the finger registry, was published a few years ago. And they followed, and this was a per patient meta-analysis, pooled analysis. So they got per patient data. And in this study, there was some association between EP study and advanced gene follow-up. It has a ratio of two and a half. And one of the things that they picked up on, because they were able to analyze patient level data in this meta-analysis, in this pooled analysis, which is a really nice paper, was that with single or double extra stimuli, there was greater risk in follow-up if you were inducible with doubles or singles. When you added triples, it didn't increase the risk of arrhythmias in follow-up, but you lost some specificity. So it became a less specific test. So one of the criticisms of earlier studies is may have been that triple VES isn't terribly predictive and doubles may be, being positive doubles may be a little bit more predictive. Now, again, one of the problems with this study that I see is that the primary outcome that drove this hazard ratio, there were 65 primary outcomes in these 1300 patients. And 60 of these were ICD shots, only five were sudden death. So, you know, you only got a defibrillator in most of these patients, not everyone, most of the patients only got a defibrillator if they had a positive EP study. And you only get an ICD shock as your outcome if you have an ICD. So the bias here is to make EP tests look better than it probably is, because as we all know, ICD shocks don't equal sudden death. ICD shocks equal, could be non-sustained arrhythmias, could be arrhythmias that you would have converted out of and probably more for PT. So I think it's really important to remember ICD shocks don't equal sudden death. Most of the outcomes in these studies that argue for EP testing are ICD shocks. And one of the reasons you get an ICD is to have a positive EP study. So it's not a randomized study, it's retrospective. And there's a lot of lack of generalizability and bias because of that. But there was a nice gradient that was demonstrated by this study. So in patients with no syncope and a drug-induced EKG, very low risk in three-year follow-up of arrhythmic events, whether or not your EP study was positive. So these patients are very low risk. A little bit higher risk, people with spontaneous EKG, but no syncope. So in this study, there was a 1.7% risk of arrhythmic events in patients with positive EP study versus 0.78%. But again, remember, most of the events are ICD shocks. And finally, the highest risk, as we know, is patients with syncope and a spontaneous EKG, which actually many people would agree these people should probably have defibrillators implanted anyways. And you can see here, negative EP study was less risk than positive EP study, but a 2.5% risk of sudden death or arrhythmic events is probably not something, a risk that we're willing to take for our patients. This is just some data from that study. They parsed it down to the gradient risk, and it just doubles VES. And look here, asymptomatic patients with spontaneous ECG. There was a bit of a separation of those curves for a few years, but the curves are small, but as the years go on, those curves are pretty close. So there is risk in these patients, but I think that the risk is not terribly well differentiated by EP testing. Though there are certain situations certainly where maybe a questionable syncope, where a patient, you might feel that they're higher risk, even though family history is not predictive, family history colors a lot of patients' feelings about their disease. And a patient who's had a family member die of sudden death is obviously gonna be much more concerned about this. And EP testing may have some intermediate risk stratification abilities, although in my opinion, this is still very much not terribly well proven at this point. So we'll talk a little bit about pharmacologic management, which of patients with RUGADA, we know that, I should say at the beginning that patients who have ventricular arrhythmias, I mean, beta blockers are still the cornerstone management, not specifically for RUGADA, but for any ventricular arrhythmias, obviously you often need additional therapies. We know that Clinity actually blocks the ITO channel that is often the culprit here in patients with RUGADA and presents phase two re-entry both in vitro and renders the majority of patients who are inducible on EP study non-inducible. Of course, again, as we talked about before, sometimes inducibility doesn't predict subsequent inducibility, so I'm not sure the value of that. And it can be used in VT storm as well as isopryl. So 600 to 900 milligrams a day is tolerated. You divide that at least VID or TID if the patient can do it. Isopryl infusion can be used for VT storm acutely. So if a patient with RUGADA is getting multiple ICD shocks and they're admitted to the hospital or RUGADA and multiple ventricular defibrillation events, isopryl can be used in the ICU in acute management patients with RUGADA. And quinidine, main utilities in people who either don't wanna have a defibrillator or have been shocked by their defibrillator. So who gets an ICD? As we talked about earlier, people who have that syncope or sudden death and have a spontaneous type one EKG or an induced type one EKG. And this is one of the reasons why the workup of patients with sudden death, well, sudden death, people probably need a defibrillator anyway, but with concerning syncope or high-risk syncope, sodium channel blocker challenge, generally 10 milligrams per kilogram of procainamide is what we use given over 10 minutes as the sodium channel blocker challenge. You can also do 400 milligrams of flaconide, but that requires the patient to be monitored for longer afterwards, it takes longer to take effect. Of course, in the US we don't have ajmaline, but in Europe that's the best choice as it's very short-acting. Most recent ACCHA guidelines for device therapy support the use of ICD implant in patients with, meet this criteria with sudden arrest, syncope or BT, and a type one EKG, either spontaneous or induced. EP testing is still a two B, both in that consensus guidelines and in the AHA, ACC guidelines. The specific language is what may be considered, and they specifically recommend only a double extra stimuli due to the study I just quoted earlier. And that family history is not really a reliable risk factor for determining whether or not someone should have a defibrillator. And defibrillators aren't all wine and roses in patients with brugada. Patients with brugada tend to be younger, tend to be more active and have less heart disease. And of course that means they have more complications for their defibrillator. You can get up to 8% with appropriate shocks over three years, but that same group of patients had a 28% complication rate over three years, most of which were inappropriate shocks, but also lead failures were higher in patients with brugada due to their age. And a recent meta-analysis published to 1,500 patients show that the average patient with brugada and a defibrillator had three appropriate shocks per 100 patient years, but they also had three inappropriate shocks and three device complications. So it's not a decision to be made lightly. I find that I've had, I believe, two patients with brugada screen positively for a sub-QICD implant, meaning that they were candidates and we've implanted subcutaneous ICDs. I think it's a great choice for patients with this disease or diagnosis, but you just have to make sure you're not gonna get T-wave over-sensing. Again, as I said, I haven't found it to be a problem, but there are certainly reasons to think it could be in some patients. You have to make sure they're very carefully screened, supine, upright, perhaps with some activity before implanting a subcutaneous ICD, but in many of these patients, it is an excellent option. Most of them don't, even though some have sick science, most don't need pacing and they do tend to be young and active. So the most recent thing in brugada syndrome is mapping and then ablating the substrate. So Dr. Natamani has been the pioneer in this field and he first described about 10 years ago mapping ablation of an epicardial substrate in patients with brugada. And a more recent review looked at epicardial ablation in 180 patients. And this was incredibly effective. Most of these patients were ablated because they had BT or ICD shocks and it prevented recurrent BT in 97%. Inducibility, which again may or may not be predictive, was quite reduced in patients after ablation. And in most all patients, the type one brugada pattern resolved. And that was actually predictive. In fact, the few patients in the type one brugada pattern that did not resolve, they're the ones who had subsequent BT for the most part. Substrates defined as voltage less than 1.5 millivolts, late potentials and fragmented potentials. And a recent paper from Dr. Popone showed that action syndrome channel blocker increases the area of substrate seen on mapping. So what are we looking for? We're looking for, we go in epicardial mapping of the anterior RV and RV of T. And the map on the left that Dr. Mani published here and Dr. Popone has published similar maps, look at, it's a cardinal map of course, and it looks at action potential duration is the scale there. So purple is long electrograms over 150 milliseconds. You can see there's a cluster of those in the anterior RV. You see one of the measurements on the right there. Here's a bipolar map of the same area. Bipolar map, of course, what you're looking for there is a voltage. And you can see this area, the same area there's a long action potentials is also low voltage action potentials, which are quite fractionated. A great example there right in the middle. And there's just basic carpet bombing ablation. So you just ablate the entire area of late and fractionate potentials. Here's some more examples of EGMs we're looking at, bipolar particularly. You can see they're very long. There's one of 255 milliseconds and low amplitude. So this is the paper from Dr. Popone recently showing on the left here, the late potential, they did long duration action potentials. This is another A1, A2 map. You can see the area of long potentials gets larger as you lean and you can see it augments the electrocardiogram. So if you look at B1 and B2, you can see a little bit of a regatta pattern and of course after azimutally, it's more prominent. This is after ablation. You can see those long EGMs are gone and everything's nice and short. And there is an injury current. If you look in B1 and B2, both before and after azimutally on the side of EKGs, there you can see an injury current from the ablation of course, but there's no longer that down sloping with the T wave inversion and just being an example of successful epicardial ablation. So to wrap up here, some conclusions about regatta syndrome is that it's an important cause of sudden death in patients with structurally normal hearts. Can be difficult to diagnose because someone's EKG can come and go. So you need to, if you have a high suspicion for a channelopathy or a malignant arrhythmia, you need to give a sodium channel blocker challenge. Again, 10 milligrams per kilogram of canamide over 10 minutes, 400 flecainide or ethylene. And the EKG can come and go. So a longitudinal follow-up is a good idea. We can see regatta syndrome with SCN5A mutations, but that's only about 30% of patients and most are sporadic and not familial. Symptomatic patients are at the highest risk and generally need an ICD implanted. EP testing, I think, is still very controversial. I'm not saying that I've never done it, but I think you have to be very individualized per patient to understand that there's an unknown sensitivity and specificity of this testing. And you may end up implanting it in a fibrillating patient who may or may not need it. However, ICD implantation is currently the only reliable treatment modality that does have a high complication rate. Quinidine can be used generally in patients with ICD shocks. And epicardial ablation is promising and I think it's coming to the forefront of treatment of patients who have ICD therapies or say VT storm and who have a regatta diagnosis. I think epicardial ablation really shouldn't at this point be considered almost standard care for patients with recurrent ventricular arrhythmias and regatta syndrome. So before we wrap up, I just want to go back to the case and give you guys some follow-up. So we had our poll here and we had a pretty even split between A and B. And I'd like you guys after listening to this talk, and we've got a few more, actually I think some people have left. If anyone would like to answer this poll again and change their answer, I'll give you a little follow-up on this patient. If you guys want to vote again, I'm just going to put this over to the side, Nishant, and go to the next slide. So basically, I think the options here are to be either conservative to help the patient treat fevers, provide reassurance, avoid certain drugs and regattadrugs.org. And I think that would be a very reasonable recommendation for this patient personally. And I've certainly made that recommendation for many patients. Now, patient's uncle died suddenly. They may be very worried about this diagnosis. EP study would not be unreasonable to do in this case. And if you induce VT with doubles, not triples, so B is kind of a trick question, but if you induce VT with doubles and plan to get a tripleter, would be where you'd end up doing. But I think that the majority of VPs that I know would really kind of go with A and a completely asymptomatic patient who's getting the TKG for no other reason than a pre-operative knee surgery and maybe they didn't even probably need that EKG. Now, so I think most people look at EP conservative man, which I think is great. I think really it's appropriate. However, I wanna give you guys follow up. So this is a patient of mine. I didn't meet the patient until four years later when he had a cardiac arrest in his son's basketball game. True story. Passed out cold, coming out of the game, had bystander CPR, shocked by an AED at the gym, was in fact awake and talking to everyone by the time he got to the emergency room. Of course, he had a cath, no CAD, normal EF. And this was his EKG on arrival in the emergency room in our hospital. You can see, no, he had been shocked. It could be a little bit of stunning, but you can see, especially in V2 here, you've got two millimeter rest elevation arguably that classic T-wave inversion. Interestingly, the next day, he really had reverted to a type two EKG. Of course, after sudden death, he gets a defibrillator, does great for a few years, never has any more arrhythmias. We put a little bit of beta blocker. Amazingly, three years later, he's in the same gym. He's at his son's basketball game. His son's now a senior in high school, goes into VF, gets an ICD shock. So he'd done well for three years, had intermittent Brugada EKGs. I now see his whole family, none of them have had, interestingly, his brother. So he was genetic tested. He's a brother with a CN5A mutation, but normal electrocardiogram. So that brother we've treated conservatively. His son is actually negative for the gene. His brother's son, also positive for the gene, normally EKG. So what did we do for him? I started him on quinidine. He tolerated fine, did well, but a year later, a recurrent VF with another ICD shock. Therefore, had a new epicardial mapping and ablation of extensive area of anterior fractionation from the RBI blood tract. I'm sorry, I don't have the EGMs from this. And he actually still has a continued type, intermittent type one Brugada pattern. We thought initially it was just injury from the ablation, but he still has that pattern. But he's been off quinidine and arrhythmia-free for the last two years. So, you know, I'm not sure if he, and actually, interestingly, he was not inducible on his EP study. So, you know, make of that what you will. Because we tried, you know, we're going to do inducibility and then ablation and non-inducibility, but he's not inducible at the end. So that's the talk. And I don't know, Sean, if we've got time for questions. Yes. That was great. Thank you for coming. A little picture of Boston here, back in the good old days, when we actually had baseball. So there are a couple of questions. Yeah, great. One was regarding why it primarily affects the RVOT. You know, what would be the benefit of ablating that area? Or why do we get preferential involvement of the RVOT as opposed to other areas of the myocardium? So that's a little, it's not totally known, but we do know that the epicardium of the RVOT has a higher concentration of ITO channels. So that's probably why. It's that there's not, we don't have uniform distribution of different sodium and potassium channels in our parts. And for whatever reason, the RVOT epicardium, there's a higher concentration of ITO channels. And that's probably the reason. And, you know, that's true in Brugada patients. And I'm not actually sure, to be honest, if that's true in everybody. But that does seem to be true in Brugada patients. So the other reason may be that it's the thinnest area of the ventricle. And so it may be more susceptible to variations. But I do know that there's a higher concentration of ITO channels in that region of the heart. And then has there been any looks at the functional effect of extensive epicardial ablation of the RV? Does it impair RV function over time? Yeah, I mean, you know, this is still, you know, a really small series. You know, 180 patients was, you know, like 15 trials put together. None have been reported. In fact, Dr. Pappone's recent paper in Heart Rhythm looked at strain. I didn't show those slides, but it looked at strain in the RVOT. And there was a significant strain pattern that got worse with adrenaline. And actually that went away after ablation. So actually he was arguing that the RVOT function got a little better, not worse, which, you know, interesting, very interesting. Okay, if anyone else has any questions, you can unmute yourself and go ahead and ask. Otherwise, that was a great lecture. I mean, covered a lot of important topics, especially for boards and things. Yep. And that case at the end, unfortunately highlighted. Yeah. I mean, it's, you know, the guy was not inducible on his EP study. So, you know, I think that, you know, we pulled that EKG up and we found it from his pre-op testing from like, you know, four years before. In fact, he pulled it up. If you can believe it, he pulled it up on his phone in the ICU after his cardiac arrest. Like he was able to access it, you know, in the portal, he was in a different hospital system. He was able to access the portal and he pulls it up on his phone and there it is. Like who got an EKG from four years ago when he had it, you know, prepping for his knee surgery. And that was like this Eureka moment. But yeah, I, you know, these patients are at risk and you can't put defibrillators in everybody, especially because of the complication rate. But some people are at high risk. And I don't, you know, I wish we had a better test. I, you know, I don't love EP testing because I think the data isn't great, but I think that people at high risk. And so often we resort to EP testing because we feel like we need to do something, that to, you know, justify a decision for or against the defibrillator. Yeah. Great. Well, I think it's a great topic. Thank you guys all for listening. And Nishan, again, thank you for organizing.
Video Summary
The lecture discussed Brugada syndrome, a genetic condition that affects the electrical system of the heart and can lead to sudden death. The syndrome is characterized by specific changes in the electrocardiogram (EKG) known as the Brugada pattern. The lecturer discussed the diagnostic criteria for Brugada syndrome, which includes the presence of the Brugada pattern on the EKG and symptoms such as syncope or sudden cardiac arrest. The lecture also covered the genetics of Brugada syndrome, with mutations in the SCN5A gene being the most common cause. The lecturer discussed the management of Brugada syndrome, which includes risk stratification using EP studies, the use of medications such as quinidine to prevent arrhythmias, and the implantation of defibrillators in high-risk patients. The lecturer also discussed recent advances in the field, including the use of epicardial ablation to treat patients with recurrent arrhythmias. Overall, the lecture highlighted the importance of identifying and managing Brugada syndrome to prevent sudden death in affected individuals.
Keywords
Brugada syndrome
genetic condition
sudden death
Brugada pattern
diagnostic criteria
SCN5A gene
arrhythmias
defibrillators
epicardial ablation
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