Thank you, Nishant. Welcome, everybody. I hope everybody's doing well and staying safe. This is actually a very, very important topic, not just for the boards, but actually in your clinical practice as well. The areas I want to cover today, first, I want to talk about the approach to acute management and inherited arrhythmias. Again, a lot of the board questions will be focused on acute management or VT or VF. I think it is important that you understand some of the mechanisms of the arrhythmias and how they can be treated pharmacologically or otherwise. Then most of the talk will be focused on, obviously, the inherited arrhythmia syndromes like long QT syndrome, short QT, regarder syndrome, and the gene wave syndromes. That's an area which I suspect isn't covered very well, but it's certainly a prime for the boards in terms of questions, gene wave syndromes. Then a few words about ARVC, particularly ventricular arrhythmias in ARVC, CPVT, and then finally an area which I have a lot of experiences, which is familial atrial fibrillation. Again, you'd be surprised about the advances in familial atrial fibrillation that have occurred over the last two decades. This is actually a great review from Andrew Cron's group in terms of the approach to assessment and management of ventricular arrhythmias. Again, I would advise all of you to really read this, especially before you take your boards, because it really does summarize your approach to the acute management of inherited arrhythmia syndromes. Obviously, the first aspect of this is to rule out ischemia and structural heart disease. Once you've done that, then you can assess the QT interval, what's the mode of onset, what's the T wave morphology, and then you divide it up into two categories. Essentially, one is, is it TOSAD1 related to QT interval, or do they have a normal QTC? Then in which case, what's the differential diagnosis of somebody with polymorphic PT in the setting of a normal QTC right in here? The important thing is to look at all the coupling intervals in terms of the initiating PVC. Is it a short-coupled PVC or a long-coupled PVC? Then you go down that tree, and as you can see, a short-coupled PVC triggered ventricular arrhythmia. You could treat the acute arrhythmia with isopropanol. Long-term, you can treat with quinidine. A long-coupled, you treat with beta blockers. Then longer term, you could certainly treat with amiodarone, lidocaine, or cocaineamide. I think, again, I certainly would advise you to sort of review this summary by Andrew Krohn and his group that was published just last year. It really is a very, very good summary of the assessment of acute management of interdivergenous syndromes. Now, I'm sure you've seen this headline many, many times before, and this reflects the sort of different phases of inherited arrhythmia syndrome. This is a teen who collapses and dies at a basketball. You may think, well, perhaps the patient has hypertrophic cardiomyopathy, but in fact, that was not the case, right? This is the tree. This is the program who passed away, unfortunately, on the basketball floor. This is the nine-year-old sibling's ECG. I don't need to point out to you that the QTC is markedly prolonged. Remember, we always look at the corrected QTC, and here we use the Bazette formula. The corrected QTC in this case was 551. Now, going back to the pedigree, this was the proband or the index case, we call it, and this is the sister whose ECG I just showed you. Then, having two siblings, one which we suspect died of the long QT syndrome and the other one who has evidence of prolonged QTC, we then did an ECG on the mother. The mother's ECG at baseline QTC was normal. Important to remember that 30% of patients with the congenital long QT syndrome have normal baseline QTCs. One of the first screening tests that we do, particularly for long QT1, is to do an exercise test. This is the mother's ECG post-exercise. What I want you to really focus on is the QT interval post-exercise, immediately post-exercise. What you can see here is that it's greater than 50% of the RR interval, meaning that it does not shorten appropriately with exercise. Again, this is almost diagnostic of the congenital long QT syndrome, which is, in fact, what this family had, the long QT syndrome 1. As I showed you, as I told you, 30% of patients who carry a mutation in one of the long QT genes have a normal QTC. This is reflected by the grandfather. He had a QTC of 402. This is what we call incomplete penetrance. This is a second case. This was actually a case at UIC. A 49-year-old Latina woman presents with recurrent syncopal episodes. Most recently, while she was praying at church. She was on hydroxyapatite for hypertension. On admission, potassium was 3.2. She did give a strong family history of sudden death at a young age with fainting. This is presenting ECG. Again, I don't need to stress that the QTC is markedly prolonged. The absolute QTC QT was over 600. This lady actually comes from a tiny town in the middle of Mexico, where the population consists of 339 men and 396 women. Look at her pedigree. This is a pedigree that we got from her as well. Look at the number of aunts and uncles that died. Sudden death with fainting. Sudden death with fainting at the age of 40. Somebody fainted whilst they were swimming and passed away. Another one whilst they were working as well. Then her mother died at the age of 30 during her sleep. This is a fairly dramatic pedigree of a family with long QT syndrome. We corrected her hyperkalemia. We actually started on a beta blocker, which is what's recommended. This is after correction of the hyperkalemia. Her QTC was 535. While she was in hospital with a potassium of 4.6, she had this episode as well. The first question I'm going to ask you, which I hope is very, very straightforward, is what is the most likely diagnosis? Is it CPVT? Is it congenital long QT syndrome? Is it QT interval prolongation related to hyperkalemia? Or the patient needs genetic testing to make a definitive diagnosis? I'll give you just a second or two. I think 90% of you got it right, which is the congenital long QT syndrome. The question is, how did we make that diagnosis? On what basis? Well, these are recommendations, expert consensus opinion in 2013. Those say that if the long QT risk score is greater than or equal to 3.5 in the absence of a secondary cause of the prolongation of QT, or you have unequivocal pathogenic mutation in one of the long QT syndrome genes, or the QTC is greater than 500 in the absence of a secondary cause, then you can make a diagnosis of long QT syndrome. These are the famous Schwartz criteria. If we apply them to our patient, her score was definitely greater than 3.5. That's how we made the diagnosis of congenital long QT syndrome in this patient. This is a summary. I will focus on the first three long QT syndromes, long QT1, which is related to a loss of function mutation in a gene called KCNQ1. Okay. That's responsible for 30 to 35% of all long QT cases. KCNH2 causes long QT2. That's also a loss of function mutation in the IKR current. That's responsible for about 25 to 30% of cases. Then long QT3 is related to a gain of function mutation in the cardiac sodium channel called SCN5A. That's responsible for about 5 to 10%. It is possible they could ask you a question about some of the rarer forms of long QT. The particular ones I might think about are the Anderson-Tavill syndrome, where not only do you have QTC prolongation, but you also have some neuromuscular manifestations. Then the Timothy syndrome consists of mental retardation and syndactyly. The other one is highly unlikely they would ask you about, but certainly remember Anderson-Tavill syndrome related to a mutation in KCNJ2 of the calcium channel. Then Timothy syndrome associated with syndactyly and mental retardation. Now, this is a very, very rare ECG that you're likely to see maybe once in your lifetime. This was a 26-year-old woman with congenital deafness with a lifelong seizure disorder who presented to our emergency room with recurrent syncope one week after the birth of a third child. I actually saw this patient when I was at Vanderbilt, and I call these T waves, Himalayan T waves, and look at the QTs. QT is over 900 milliseconds. I didn't put a question up, but I'm asking you now, what syndrome does this patient have? Just give you a second or two. I didn't ask a question, I should have done, but just think what syndrome does this patient have? She's 26. She's got congenital deafness, a lifelong seizure disorder in inverted commas, and presented with recurrent syncope after the birth of a third child. For those of you that thought about it, it's the Jevelle Lange-Nielsen syndrome. This is an autosomal recessive syndrome where the patient carries two abnormal potassium channel genes. Remember, one question they could definitely ask you is, what is the risk of the offspring of somebody with Jevelle Lange-Nielsen syndrome having the long QT syndrome? Because it's an autosomal recessive, every single offspring of the patient will have long QT syndrome. In fact, this patient, all her kids did have long QT syndrome. Two of them actually landed up having to have an ICD, implanted by Frank Fish at Vanderbilt Medical Center. Okay, getting back to our family, I just show you this in preparation for the next question. Next question is, which subtype of long QT syndrome do you think a Latino woman has? Okay, just take a look at ECG. Long QT1, long QT2, long QT3, difficult to determine. Let's give people a second. 44% got the right answer, but I want to explain why long QT2 is the right answer. Okay, so let's go back to the pedigree. Again, look at the pedigree, look at how some of the family members died. You may think that because the family member died in their sleep. Remember, long QT3, the patients died in their sleep. So you might think, well, maybe it's long QT3 because her mother died in her sleep. However, what about this patient who died while swimming? Maybe that's long QT1. Swimming is strongly associated with long QT1. And then working, that could be either. So I think based on the pedigree, I think it's very hard to tell. Now, does the ECG give us some more clues? I think it does. Look at V2, look at this notching. I brought it up here just so that you could see it. So this is the reason why it's long QT2. And we actually made this diagnosis before some other tests that we did as well. Now, this is a very, very important slide because it tells you the triggers for each of the long QT syndromes. As I mentioned, long QT1 is swimming. Swimming is a major trigger for long QT1. On the ECG, as I showed you in the first case, the QT does not shorten with exercise. So if somebody's ECG, when they exercise, it doesn't shorten with exercise. And a family member died during swimming, almost certainly it's long QT1. Long QT1 is a mutation that encodes for the IKS current. Long QT2 is the alarm bell, the sudden noise, like the alarm going off in the morning. So long QT2 is a sudden noise trigger. And then long QT3 is sleep and rest. Sleep is by far the strongest trigger for long QT3, and that's a mutation in the cardiac sodium channel, cholesterol and lipase. And these are the percentage of mutation carriers with events age less than 40. So 25% have long QT1, 50% and 50% long QT3. This is actually a very, very important slide because again, they can ask you a lot of questions about the triggers for TOSAD in long QT syndrome. Coming to the next question, besides beta blockers, which we started this patient on, what else would you advise at this time? She's still an inpatient, no additional therapy, perform genetic testing for risk stratification, single chamber ICD because patient is at high risk for cardiac events. Okay. 62% got the, well, should change, you know, about half got the right answer. The right answer is actually single chamber ICD and I'll explain why. So how do you risk stratify patients with long QT syndrome? Well, there's three things you need to look at. One is gender, two is the QTC and three is the actual disease gene. This is a review that Sylvia Peore published almost two decades ago now. What it emphasizes is anybody with QTC over 500 milliseconds in the absence of a secondary cause for the QT prolongation is at high risk, over 50% risk of a cardiac event. Long QT1 is also high risk, long QT2, male sex and long QT3 as well. Okay. So our patient had long QT2 and she also had a QTC in the absence of a secondary cause that was greater than 500 milliseconds. So she was at high risk. So that's why we implanted a single chamber ICD in addition to the beta blockers that we had started almost immediately when she was in hospital. This is the management of long QT. And again, the high risk groups of people who have children who have long QT and particularly syncope are at high risk. Other high risk groups are the Chevelle-Lang-Nielsen syndrome, anybody with QTC greater than 500, males with long QT3. One important thing to remember, which is that long QT1 is not the same as long QT2, in contrast to the other inherited erudite syndromes, a family history of sudden cardiac death is not a marker of high risk. So they could ask you that, whether a family history of sudden cardiac death is a marker of high risk. And if you notice for this Latina woman, I did not put that as a risk factor. So sudden cardiac death in a family member is not a risk for long QT syndrome. Next question, when ICD is implanted and the patient returns three months later, what do you recommend now? No additional testing. There's no role for genetic testing. Genetic testing to identify a pathogenic mutation in a long QT syndrome gene so that family members can be screened or a left stellate ganglionectomy. Okay. That's good. A hundred percent said genetic testing. And you're absolutely right. The reason why genetic testing is important, not to make the diagnosis in this case, but for cascade screening in family members. And again, this is the role of genetic testing in long QT syndrome where the diagnosis is equivocal. It's also useful to help personalize treatment options and management, particularly for long QT3. Remember long QT3 is a mutation in the cardiac sodium channel, a gain of function mutation. And there you can use sodium channel blockers like maxillotine potentially to treat the patient. So that's why knowing the genotype, knowing which type of long QT syndrome they have may affect your management. And then finally to confirm or exclude the presence of a pathogenic mutation in a pre-symptomatic family member or what we call cascade genetic testing. So this patient did actually undergo genetic testing and this is the result we got back. A variant of unknown significance identified in KCNH2. Remember KCNH2 is long QT2, which is what we suspected. Now what? And this is often, we often get this result. What do you do now? So the next question, what is the quickest way to determine if the VUS is pathogenic or disease causing? Functionally characterizing heterologous model systems. It is not possible to determine if the VUS is pathogenic. Genotype affected first degree relatives looking for co-segregation of the VUS with long QT syndrome or perform olexome sequencing. Very good. 76%, almost 75% got the correct answer. It is actually genotype affected first degree relatives. And why do we want to do that? Well, if you can show that another affected family member who's affected carries that variant, that same VUS, then it co-segregates with the phenotype. And that's exactly what we did. Unbeknownst to us, she has an arm of the family that underwent genetic testing by the Brugada brothers, would you believe, in Europe. Look at this, right? Her cousin has the disease, and so do all her sons. They've all tested positive for the same variant that the program carried. So again, this emphasizes the importance of expanding the family and finding other family members who carry the variant, and then you can determine that that variant is actually not a VUS, but it is actually a disease-causing variant or mutation. Very good. Clinical assessment of probands and families with long QT, as I mentioned, prolonged QTc after syncope episode is diagnostic in the absence of acquired cortis. So if you see an ECG in somebody after a syncope episode and their QTc is prolonged, as long as they don't have hypokalemia or some secondary cause for the QT prolongation, you don't have to do any other additional testing that's diagnosed for the congenital long QT syndrome. Unexplained sudden death in a young individual should trigger a similar evaluation. So again, I often get referred patients where a family member has died unexpectedly and again, one of the things I almost always do is do an exercise test to look for a primary long QT1. Also need to get a detailed family history is critical, important to obviously exclude secondary causes of QT prolongation. Assessment of probands with long QT2. Here, swimming, like I said, is not a major trigger, but sudden noises are. You can also then obviously use the Schwartz criteria, as I mentioned, as I mentioned earlier, QTc less than 430 milliseconds distinguishes carriers from non-carriers. That's actually quite an important number to remember, right? The other thing to remember is that QTc is dynamic. If you do a 24-hour hold on these patients, that QTc can vary quite a bit. The other ways to look for, to screen for long QT2 is to do a heart monitor standard exercise test. An epinephrine test, we rarely do it nowadays. It is a very, very sensitive. It's very specific and highly sensitive. But again, we rarely use epinephrine test to look for congenital long QT syndrome. Moving on to different syndromes. I'll just give you a second to look at this asymptomatic 10-year-old recorded after 11-year-old brother dies of cardiac arrest. What's the diagnosis? Again, I didn't put a question up, but just sort of think out loud what you think the diagnosis is. I would draw your attention particularly to the T waves here. It's actually a short QT syndrome. How do you define short QT syndrome? Is QT less than 360 or a QTc less than 370 should raise strong suspicion. It's autosomal dominant. Very short atrial and ventricular refractory periods predisposed to not only VF, but also atrial fibrillation. Many of these patients also have atrial fibrillation as well as ventricular fibrillation. Mutations, gain, and loss of function mutations in cardiac potassium and calcium channels have been linked to the short QT syndrome. The big problem with patients with short QT syndrome is the double counting when they have an ICD. Really, ICD is probably the best form of therapy to prevent the VF. But when you implant an ICD, the peak T waves cause double counting and they have a lot of inappropriate shocks. One way to reduce the inappropriate shock is actually to use quinidine. That can actually normalize the QT. Remember, quinidine prolongs the QT, but it can actually be used for the treatment of the short QT syndrome and actually prevents the double counting that's seen with ICDs in these patients. Next one, 18-month-old has a witness cardiac arrest. Post-resuscitation ECG is unremarkable. Parent's ECG is normal, but the four-year-old brother shows this. Again, I don't think I put a question up, but I would hope it's fairly obvious. You see the marked T-wave coving and the J-point elevation in these V1, V2. This is obviously the Brugada syndrome. How can we unmask the Brugada syndrome? Well, one way to do it is actually to infuse prokinamide. The first ECG shows a baseline that is maybe small amount of J-point elevation, maybe a saddleback appearance, maybe, but after you've given 500 milligrams, the J-point elevates, and then you begin to see this coved appearance. After 1,000 milligrams, you do see the autonomic coved appearance. Remember, you have to have two leads. One lead is insufficient. What is a Brugada? Oh, one other thing I should mention, and this might give you a clue as to what gene is causing the Brugada syndrome. If you see PR interval prolongation on the ECG, that's a strong suggestion that they have a mutation in the cardiac sorting channel, which is the main gene. SCN5A is the main gene that causes Brugada syndrome, but if you see PR interval prolongation like we did in this patient, likely chances are they've got a mutation in the cardiac sorting channel that's giving rise to Brugada syndrome. It causes sudden death due to ventricular fibrillation, especially initially identified in Southeast Asian men who often die at night. Typically, ECG findings are not always present, exacerbated by sodium channel blockade, syncope, and sudden cardiac death. This is something that is very testable, is fever. They may show you an ECG at baseline and then tell you that this patient has a fever and this is the ECG. What's the diagnosis? Fever is a trigger for VF episodes in patients with Brugada syndrome. It's autosomal dominant, a major gene, and it's a loss of function mutation in the cardiac sodium channel gene, SCN5A, but it's only been identified in about 20% of affected subjects. There are rare mutations in other genes like the L-type calcium channel gene, but they are very, very rare. The major gene is SCN5A for the Brugada syndrome, and really the only form of therapy is the ICD. Quinidine is very useful for ICD storms in patients with Brugada syndrome. How do you risk certify patients? High risk for patients who have syncope, a spontaneous type 1 Brugada ECG pattern, and then low risk are asymptomatic, intermittent, or drug-induced ECG, type 1 ECG pattern. This was a sort of incidental finding that we found a number of years ago. We got consulted on a patient in the psychiatric unit. It had been started on lithium, and this was presenting ECG. As you can see, the T-rate coving and the T-point elevation is classical for type 1 Brugada ECG pattern. When we stopped the lithium, it actually went away. Again, lithium is a sodium channel blocker, and the cause of Brugada syndrome is a mutation in the cardiac sodium channel. Giving a sodium channel blocker is going to unmask the ECG pattern, and that's what happened with this patient. The other thing that they will certainly ask you about is about lead placement for the Brugada syndrome. Moving the V1 and V2 up by two intercostal spaces can also unmask that type 1 Brugada ECG pattern. Here is a normal ECG with a normal lead placement, and this B is where the leads were moved two intercostal spaces up above, and it certainly unmasked the type 1 Brugada ECG pattern. Certainly, they will ask you about the importance of lead placement in the Brugada syndrome. Coming on to the J-wave syndromes, like I mentioned, these are rarely covered, but I think they are important. What are the J-wave syndromes? Well, Brugada syndrome is one form of J-wave syndrome. First, before I talk about them, how do you define J-wave? It's a positive deflection immediately following the QRS, either in the form of a notch, like here, or a C-segment elevation, as shown here. That's how you define, and this is the notch, and this is the J-wave elevation, as you can see here. It is important to know the definition of the J-wave as well. It's a post-persistent ST-segment or J-point elevation. It's suspicious for inheriting Ehrlich-Meyer syndromes, and it's due to transmural differences in the action potential notch or early recolorization. Again, it's possible they could ask you about the mechanism of Ehrlich-Meyer in J-wave syndromes, and again, it's related to transmural differences in the action potential notch. What are the J-wave syndromes? Congenital ones include the early recolorization syndrome and Brugada syndrome, including those of the B2. But remember, you can also have acquired J-wave syndromes, and those are caused by transmural ischemia, hypothermia, because they also cause similar changes in the J-wave as the congenital J-wave syndromes do as well. Importance of the J-wave syndromes, especially the early recolorization syndrome, Brugada syndrome, is in terms of the short-coupled BF electrical storm, and again, I'll come to that towards the end of the talk. Actually, it's the next slide, right? I mentioned earlier that the acute management of inherited arrhythmias, you divide the ventricular arrhythmias either into foci, which is related obviously to long QD syndrome, or to polymorphic ventricular tachycardia. Here, it's important to know whether it's a short-coupled PBC or a long-coupled PBC, because then the diagnosis is quite different. For short-coupled PBC, it could be Brugada syndrome, it could be early recolorization syndrome, or the short QT syndrome, or short-coupled BF as well. That's the differential diagnosis. For late-coupled PBC, it's CPVT, which I'll come to in a second, and then late-coupled BF, or late in cardiomyopathy as well. Actually, it's a good way to distinguish between the different types of polymorphic ventricular tachycardia, whether it's short-coupled or long-coupled, and again, depending on which one it is, the management will also differ between the two as well. How do we define short-coupled PBC? RI interval is less than four milliseconds between the preceding QRS and the subsequent PBC. That's how we define short-coupled PBC. Coming on to the next one. 38-year-old Latina woman presented palpitations during a 5K run. She's had two single episodes and no family history of cardiac disease. I'll give you a second to take a look at the ECG. Let's think about what the diagnosis is, what the rhythm is, and then potentially what the diagnosis is. That was the presenting ECG, and this is the ECG after she converted back to sinus rhythm. Just give me a second to take a look at that. Does she have ARVC? I hope you did think of ARVC as a differential diagnosis, but we actually went ahead and did cardiac MRI because we had a strong suspicion it was ARVC. What we found was that the ARV function, ARV ejection fraction was 35% in a lady who's a long-distance runner. Otherwise, her left ventricular function size was normal. She had no evidence of any infiltrative diseases, no evidence of fibrofatigue replacement. This differential diagnosis is important because ARVC can mimic many diseases, including myocarditis, sarcoidosis, dilated cardiomyopathy, athlete's heart, Brugada syndrome. I've seen cases of ARVC that are very similar to Brugada syndrome. Certainly, their presentation can be very similar. Then some sort of rarer causes as well like Epstein's anomaly. Just have these at the back of your mind when you're thinking of ARVC as well. What are the criteria? These are the revised task force criteria. Major criteria in our patient was regional RVA kinesia or dyskinesia with a right ventricular ejection fraction less than 40%. A left bundle branch block, BT, with a superior axis is a major criteria. Then in her case, the ECG during sinus rhythm showed T wave inversion in B1 and B2. As you can see, there's T wave inversion in B1 and B2, but that's a minor criteria. I don't want to belabor this point, but the major criteria for making a diagnosis of ARVC is the cardiac MRI. Majority of the criteria are very much based on the cardiac MRI. Certainly, it's the gold standard for making the diagnosis of ARVC, but there are other criteria, ECG criteria, the type of ventricular arrhythmia the patient has. Then also, family history is also a major criteria for making a diagnosis of ARVC. There's also a role for genetic testing. Again, this is a consensus opinion suggesting that comprehensive or targeted screening of ARVC genes can be useful for patients satisfying the taskforce criteria for ARVC. Again, in ARVC, I think we use genetic testing more for the diagnosis where the diagnosis is more equivocal, but also we use it for cascade screening of family members as well. This patient did go on to have genetic testing done. Even though she met the criteria, we did do genetic testing. Again, this is a very common finding, a variant of unknown significance, but in a gene that has previously been linked with ARVC. The reason we think why this was a BUS is because she was of Hispanic origin and very few cases of ARVC have been documented in patients of Hispanic descent. I think it's just that this variant has just not been identified previously, but we strongly suspected that this variant was actually disease-causing in this particular patient. Actually, we went on to expand the family, and there were a couple of other family siblings that also carried it and had some minor criteria for ARVC, so we were fairly sure that mutation did cause the disease. What is ARVC? Again, suspecting anybody with BF or PT with a normal heart. Diagnostic epsilon waves are unusual. They only occur maybe in about 20% of cases. A major criteria is T-wave inversion in B1 to B3. Remember, B1 to B2 is only minor, but you get T-wave inversion in B1 to B3. Somebody who is over the age of 18 thinks strongly about ARVC. I mean, that's a very... Because you don't see T-wave inversion in B1 to B3 in anybody over the age of 18. MRI is the gold standard. Mutations in heart junctions have been identified. Many mutations, glycophyllin is probably one of the most common genes that's linked with ARVC. It's also known as a brain system in terms of establishing diagnosis. Coming on to syndrome number five, this is an interesting case. A six-year-old presents with syncope. This is a baseline ECG. I'll tell you that the QTC is not prolonged. Because the QTC was not prolonged and there's no family history of sudden death, we actually did an exercise test in the six-year-old, and this is what we saw after two minutes of exercise. You can see PBCs, salvos of PBCs, and this was after only four minutes of exercise. I'll let you postulate what the diagnosis is, but I hope most of you realize that this is CPVT, a disease, an autosomal dominant disease, where there are mutations in the cardiac release channel, RYR2, and it causes sort of a calcium leak in the sarcoplasmic reticulum. The distinguishing part about this inherited arrhythmia syndrome is that it's exercise induced, but so is long QT. That's why I mentioned before that at baseline, the QTC was not prolonged. That's your differential diagnosis with somebody with exercise-induced syncope and ventricular fibrillation. It's long QT1, which is exercise induced, or CPVT. That should be the differential you should be thinking about. Obviously, you can rule out long QT. The baseline ECG is not prolonged, especially if it's not over 500, then most likely it's going to be CPVT. There is an autosomal recessive form where these mutations and calcium sequestration, calcium buffering protein, but that's very, very rare. Then finally, in the last five minutes, familial atrial fibrillation, or actually we prefer to call it early-onset atrial fibrillation. The definitions have changed in the last couple of years. How do I define early-onset atrial fibrillation is typically atrial fibrillation in somebody who is less than 16 years of age, irrespective of whether they have hypertension, diabetes, or other risk factors for atrial fibrillation. That's how we currently define early-onset atrial fibrillation, because we know from genetic studies that carrying a common genetic variant for atrial fibrillation is just one risk factor, or carrying a mutation in a gene linked with atrial fibrillation is just one risk factor. The more risk factors you have, the more likely you're going to have manifest atrial fibrillation. That's why the classification of early-onset atrial fibrillation is essentially anybody below the age of 60 who develops atrial fibrillation is defined as having early-onset atrial fibrillation. This question, they will ask you, what was the first gene that was linked with familial atrial fibrillation? It was KCNQ1. This was in a large Chinese family where they had familial atrial fibrillation, and it was a gain-of-function mutation in a cardiac potassium channel gene, KCNQ1. The physiologic effect of that mutation was it shortened the atrial action potential duration, and noticeably, and again, they could certainly ask you, would you actually prolong the QT interval? These patients on the ECG actually had prolonged QT, and that was a clue that they may actually carry a mutation, a gain-of-function mutation, in this particular ion channel. They may, again, they may ask you, what's the first gene that was linked with familial atrial fibrillation? It was KCNQ1. The other genes that have been identified have mostly been ion channels, and then the first non-ion channel gene that was identified is a gene that encodes for atrial natriuretic peptide. The gene is called NVPA, natriuretic peptide precursor A. It's also inherited autosomal dominant. It's a gain-of-function mutation, but in this case, it actually shortens the APD, and the associated phenotype with this particular form of familial atrial fibrillation is that they actually develop an atrial myopathy, and it's actually quite funny, the family that we discovered this particular gene in, an electrophysiologist in Boston actually did a EP study on a family member, and he could not pace the atrium because they had developed this severe atrial myopathy associated with this mutation in this particular gene. The patient also had atrial fibrillation as well, right? It was actually very striking that these patients also develop a severe form of atrial myopathy, but we think that's probably the mechanism by which they develop atrial fibrillation. But again, this is the first non-ion channel gene that has been linked with familial atrial fibrillation. And then more recently, and this is actually important, and it's important for a number of reasons, is for a long time, we've known the association between heart failure and cardiomyopathy and atrial fibrillation, but we really don't understand the mechanism by why is it that patients with heart failure develop atrial fibrillation. Yes, we can postulate ion channel remodeling and structural remodeling, but recently mutations in myocardial structural proteins, like Titan, have now been also linked with atrial fibrillation. Last year, mutations in Titan were associated with early onset atrial fibrillation, and that's the first... I mean, remember, Titan is an incredibly important gene. It's the most common cause of inherited dilated cardiomyopathy. 20 to 30% of patients who have dilated cardiomyopathy carry a mutation in Titan. So as you can imagine, these patients also have a very high risk of developing atrial fibrillation as well. But in this particular study, all these patients actually develop their atrial fibrillation before they develop their cardiomyopathy, and that's how we associated a mutation in Titan with early onset atrial fibrillation. And we think it's a loss of function mutation, but really nobody understands the mechanism, how a mutation in a myocardial structural protein can give rise to an arrhythmia, like atrial fibrillation. Okay, and then final slide, last few minutes. Take-home messages, both genetic and phenotypic variability of inherited arrhythmia syndromes is very, very common. Patients with greater than one mutation tend to have a worse phenotype, like the Jovell-Lang-Nielsen syndrome. They have a very severe phenotype. If you carry more than one mutation, then the phenotype is often lethal and very, very severe. Detailed clinical assessment of the index cases begins with personal and family history, and then you can do provocative testing, like prokaryotic challenges, or you can do an exercise test for CPVT, or you can do an exercise test for Long QT syndrome. Evaluating families is critical for inherited arrhythmia syndromes, and genetic testing is increasingly being used, particularly for cascade screening of family members. And again, they will ask you almost certainly a question on cascade screening of family members. And then finally, assessment of the QT interval, the mode of onset, and the T-wave morphology of recurrent ventricular arrhythmias may provide important clues as to the underlying inherited arrhythmia syndromes. And I'll stop there, and I'll be happy to take any questions. Thanks. That was fantastic. There are a few questions that have come through the chat function. Yeah. Some kind of beta blocker questions on Long QT. Are beta blockers equally effective in all versions? Do you use them in all Long QT patients? And which beta blockers are preferred? Yeah, that's a very good question. Yes, beta blockers in all Long QT patients. That's the recommendation. I think it's a level one recommendation, beta blockers. And again, the beta blocker that I use most commonly is NADOLOL. In children, NADOLOL is weight-based. In adults, usually you just sort of increase the dose to what they tolerate. And again, there's a lot of data on the use of NADOLOL particularly. So that's the treatment of choice. It's very well tolerated by children as well as young adults. And then there were some questions on autonomic modulation. So is there any role for sympathetic denervation for drug-resistant Long QT 2 and 3, or sympathetic ganglion ablation as performed by the anesthesia folks? There is. There is. And if you look at the guidelines, it does recommend it for drug refractory and recurrent VF storms. That's when it's most highly recommended. Again, I would be very careful about referring somebody to... I would refer to a center that has experience in doing that. And again, there's very few centers that actually do it that have enough experience to do that. But it is recommended. And again, as you mentioned, it's typically for drug refractory VF, recurrent VF storms in patients with Long QT syndrome. And I guess this is a follow-up clarification. So not just for Long QT 1, but would you also recommend for 2 and 3? Yes. Yeah. And then there was a question here. If someone had Long QT and a cardiac arrest, is there any situation where you would not give them an ICD, like if they were not on a beta blocker? Again, it would depend a lot on the other high-risk factors. It would depend strongly. It would depend strongly. Having a cardiac arrest, again, the recommendation is that beta blockers really before you think about an ICD. But if they have other high-risk factors, like a QTC greater than 500, I think most arrhythmia physicians would be very reluctant not to put an ICD in that patient. Yeah, I would agree. I think they probably would end up with an ICD. And then one of our fellows, Anna, had a question. How does a gain-of-function mutation in KCNQ1 cause Long QT? Okay. That's a challenging question. I think what is related to Anna is that it's related to differential expression of the beta subunits of KCNQ1. And I think the reason why you get QT prolongation in KCNQ1 mutation in atrial fibrillation is because the beta subunits are differentially expressed in the ventricle versus the atrium. And I think in the ventricle, there, they actually do prolong the atrium potential duration. That's how we think it is. Again, it's a very good question. Nobody really understands why a patient with a familial atrial fibrillation with a mutation in KCNQ1 will end up having a QT prolongation. But I think it's related to the differential expression of the beta subunits that are associated with the protein.

inherited arrhythmias

management

genetic implications

long QT syndrome

Brugada syndrome

genetic testing

beta blockers

treatment

atrial fibrillation