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Session I: Basic Science and Fundamentals of Elect ...
Inherited Ion Channelopathies
Inherited Ion Channelopathies
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Hello, I'm Dr. Barry London, I'm the Director of the Division of Cardiovascular Medicine and Director of the Abood Cardiovascular Research Center at the University of Iowa Carver College of Medicine in Iowa City. My talk today is inherited ion channelopathies. I have nothing to disclose aside from NIH research grants. So the objective of today's talk is to review the monogenic causes of inherited arrhythmias syndromes including syncope, ventricular tachycardia, ventricular fibrillation, and sudden death. This divides into purely or relatively purely electrical conditions such as long QT syndrome, Brugada syndrome, short QT, catecholaminertic polymorphic ventricular tachycardia, early repolarization syndrome, and syndromes that have large mechanical and structural components but also have arrhythmias such as arrhythmogenic right ventricular cardiomyopathy, hypertrophic and dilated cardiomyopathy. We're going to focus on the electrical syndromes today. In addition, we'll review the clinical approach to diagnosing and treating patients with suspected inherited forms of sudden death and the role of genetic testing. And finally, we'll briefly touch on the approach to polygenic diseases and complex traits. So we'll start with a case. So this is a 51-year-old man who had a cardiac arrest at Walmart. He is one of 11 children and four of his siblings died in their 40s and 50s of what was referred to as a heart attack. His brother drowned at age 13. He had a cardiac catheterization following his arrest which was normal and an echocardiogram was normal. His EKG is shown here. Which is the most likely diagnosis? A, CPVT, B, long QT type 2, C, long QT type 1, D, Brugada syndrome, E, arrhythmogenic right ventricular cardiomyopathy. And the best answer here is long QT type 1 or LQT1. So his EKG at baseline is basically normal. His QT interval is 450 milliseconds which is very mildly prolonged at a slow heart rate of less than 60 beats per minute giving him a corrected QTC of 433 milliseconds which is in the normal range. This is his EKG during a stress test. So just standing him up for the stress test increased his heart rate and you can see that now his QT interval is more than half of his RR interval. During exercise, his QT interval continues to be long as his heart rate increases. So in fact his QT interval didn't shorten appropriately with exercise, most notable at peak exercise where his QT interval is way over half of his RR interval. And then during early recovery his heart rate slows down but his QT interval remains significantly prolonged. And this is consistent with long QT type 1 and these are mutations in the KCNQ1 gene which encodes for the KVLQT1 potassium channel and he had a known pathologic mutation in KCNQ1. KCNQ1 is the potassium channel that shortens the action potential and thus the QT interval when people exercise so at high heart rates or in the setting of adrenergic stimulation. Question 2, what other diagnosis is associated with sudden death while swimming and or drowning? A, catecholaminergic polymorphic ventricular tachycardia, B, long QT type 2, C, long QT type 1, D, Brugada syndrome, E, arrhythmogenic right ventricular cardiomyopathy. And the answer is catecholaminergic polymorphic ventricular tachycardia, a syndrome where adrenergic activity and exercise bring out arrhythmias in somebody who otherwise has a normal cardiogram at baseline. Okay so we're going to go over some vocabulary, this is not the most exciting part of the talk but it is necessary. So phenotype is the clinical presentation of a condition. Do you have long QT syndrome or not? Phenotype is your specific DNA type or the specific DNA sequences. Do you have a mutation or not? When we talk about DNA sequence variants we usually divide them into mutations and polymorphisms. So mutations are major functional changes that cause disease, polymorphisms are variants that either have no functional significance or a much more mild phenotype. Variants can either be exonic which means they're in the coding region of the DNA or intronic which means they're in introns. Exonic variants are more likely to be mutations. The most common type of variant is a single nucleotide polymorphism or a SNP which is a single change in a base pair. Synonymous SNPs change the DNA but don't change the amino acid sequence because more than one codon instead of three base pair nucleotides code for the same amino acid. Missense variants change the amino acid sequence so they change the base code and the amino acid sequence. Synonymous mutations insert a premature stop codon. In addition to changing a nucleotide you can either insert one or more base pairs or delete one or more base pairs. If you insert or delete any number of base pairs that are not in a multiple of three this will lead to a frame shift in the amino acid sequence and insertions and deletions are called indels. You can also have copy number variants which is the insertion or deletion of a whole gene or a big piece of a gene. We talk about alleles and so we all have two copies of each chromosomes which means that we can have two copies of the DNA sequence that are either the same or different and different versions of the same gene, one inherited from the mother and one from the father are called alleles. You're homozygous if you have two identical alleles at a position and heterozygous if the alleles are different. A monogenic disorder is a disorder where a mutation in a single gene can cause the disease phenotype things like long QT syndrome, cystic fibrosis, Duchenne's muscular dystrophy. A polygenic disease are diseases where variants in many genes may contribute to the phenotype but a single variant does not cause the disease. Things like high blood pressure, atherosclerosis, many types of cancer are polygenic conditions. There is genetic heterogeneity in diseases and what that means is that mutations in different genes can cause the same or similar phenotype, the same or similar disease. So many different mutations of different genes cause long QT syndrome as one example. Penetrance is the extent to which individuals with the same genotype display the same phenotype and we often and most commonly see incomplete penetrance which means that you can carry the mutation but you don't necessarily have the disease. There's also a concept called variable expressivity which means that the same mutation or similar mutations can cause different phenotypes. So mutations in the cardiac sodium channel NAV1-5 or SCN5A can cause Brugada syndrome, conduction disease, long QT syndrome or some combination of the above and this is an example of variable expressivity in SCN5A where different mutations scattered through the gene can cause multiple different syndromes and in fact some of the mutations can cause either for example long QT syndrome or conduction disease or Brugada syndrome in the same person or in different people in the same family. A genetic condition is called autosomal dominant if a single copy of the mutation is sufficient to cause the disease. So you have two copies of each gene, a single copy is enough to cause disease. Males and females will be genotypically affected equally although the penetrance may vary by sex. An autosomal recessive condition on the other hand is one where the affected individuals inherit mutant alleles from both parents, either the same mutation called consanguinous or different disease mutations that knock out the two copies of the gene called compound heterozygosity. Males and females are again affected usually equally and the parents may or may not have any phenotype at all. Sometimes the parents will have a milder version of the phenotype that is more severe in individuals who get two copies of the mutation. Finally a condition is X-linked if the mutation is on the X chromosome. In that case males are predominantly affected, Duchenne muscular dystrophy being a good example of that. Females will be heterozygous for the condition because they have two X chromosomes and they may have a milder version of the phenotype. Finally genetic conditions can be mitochondrial and since mitochondria pass from mother to egg to child this has pure maternal inheritance. Most mitochondrial conditions are syndromic meaning they affect multiple different organ systems and we're not going to talk about those today. Now monogenic arrhythmia syndromes is the majority of what we're going to talk about. They have genetic heterogeneity and phenotypic variability so multiple different mutations can cause similar conditions and the phenotype can vary despite having similar or the same mutations. A general problem with our field, there's been no randomized trials of therapy really for any of the conditions that we're going to talk about. A randomized trial was attempted for CPVT but it had to be stopped because of poor enrollment which means that risk stratification schemes are needed and they're not based on randomized controlled trials. They're largely based on data derived from registries. Now with all of these conditions the first reports of long QT syndrome, short QT syndrome, etc. reported severe phenotypes because the people who initially came to medical attention were people who are really sick and in this case really had a lot of arrhythmias. As we became able to identify relatives who had it, as we became able to test for these genetically larger populations were studied and it became clear that the prognosis in many individuals is much more benign. In general for the inherited arrhythmia syndromes the prognosis depends on a combination of how severe is the EKG phenotype and do you have symptoms and or arrhythmias and or sudden death. Now genetic mutations can either cause the gene not to work or cause the gene to work differently. Genes not working cause loss of function mutations while genes that do something that they're not supposed to are gain-of-function mutations. As you can imagine it's a lot easier to make a mutation that just makes a gene not work and not express. So loss of function mutations causing these conditions are much more common. Okay we talked about mutations versus polymorphisms. Just to emphasize again mutations that cause monogenic diseases must be rare. A common variant can't be a mutation because it would cause it in too many people. Mutations tend to change the protein structure and function significantly. Their sequence of the area they change is conserved usually across species so usually down within vertebrates and sometimes beyond and the mutations will co-segregate in families meaning that everyone who has the condition will have the mutation and not necessarily everybody who has the mutation will have the condition because that's incomplete penetrance. In addition you'll often seen de novo mutations that cause disease. So you'll find somebody who has the mutation and neither of their parents have it and they have the disease and their parents don't suggesting that the mutation is causal. Polymorphisms on the other hand can either be rare or common. We define common as usually more than 1% of people have that allele. They may or may not affect the protein sequence and or structure or function. If they do they can act as modifiers of either inherited or common conditions. We have 3 billion base pairs of DNA and there are over a million variants that all of us have that make us different from each other. The most common ones I said are single nucleotide polymorphisms or SNPs. There are many examples in the literature of associations between SNPs and multiple medical conditions including arrhythmia susceptibility. Unfortunately most of them don't reproduce when you study them in other populations and may or may not be real. I've listed a couple of common ones for you. The S1103Y polymorphism in the cardiac sodium channel has been associated with LONQT and arrhythmia and sudden infant death syndromes specifically in African Americans where it's more common and a number of variants have been associated with atrial fibrillation. A quick review on cardiac electrophysiology. So all of our cells are batteries and all of our cells have sodium potassium pumps and the sodium potassium pump pumps sodium out and potassium in. So intracellular potassium is about 140 millimolar, blood potassium is about 5 millimolar and the other hand blood sodium is about 140 millimolar and intracellular sodium is about 20 millimolar. We then have proteins in the cell membrane called potassium channels. These potassium channels are permeable only to potassium so potassium flows down its concentration gradient from 140 millimolar inside to 5 millimolar outside. That leaves behind a negative charge and eventually the inside of the cell becomes sufficiently negative as to prevent the bulk flow of potassium from inside to outside. There is an equation called the Nernst equation that gives you the equilibrium of at what concentration difference which voltage leads to the cessation of bulk flow. If you plug 140 and 5 into it you'll get minus 90 millivolts as the equilibrium potential of the voltage at which bulk potassium stops flowing and that is the resting membrane potential of our cells. Most of our cells live their lives at minus 90 millivolts. If you're a liver cell you live your life at minus 90 millivolts until your host goes out drinking and you die at which point your voltage goes up to zero millivolts. If you're a heart cell, a skeletal muscle cell, a brain cell, a smooth muscle cell you use changes in voltage as a mechanism of signaling. So how do you change voltage? You have what's called natural potential so you close potassium channels and you open sodium channels. Sodium is 140 millimolar outside, 20 millimolar inside. Sodium rushes in, positive charges accumulate, voltage goes up to about plus 10 or plus 20 millivolts. You then close the sodium channel, if you're the heart you open some calcium channels, some calcium comes in, you open a few potassium channels and you hang out at zero millivolts for about .3 seconds or 300 milliseconds. You then open a new set of potassium channels and you go back down to minus 90 millivolts and reset for the next, waiting for the next action potential. The surface EKG as everybody on this review knows is the manifestation of the cellular action potentials at the body surface. So the P wave is the spread of electrical activation across the atrium from the SA node towards the AV node. In the middle of the P wave half of the atrium is at plus 10 millivolts, the other half of the atrium is still in its resting state. The PR interval is when the whole atrium is depolarized. Then activation spreads through the ventricle and that is the QRS complex, the middle of the QRS being when half of the ventricle is depolarized and half is still at the resting state. The ST segment is when the whole ventricle is depolarized and the T wave is dyssynchronous repolarization of different parts of the ventricle. If we talk about a condition called long QT syndrome, that is when the QT interval is too long, what's the most common reason the QT interval is too long? Because the action potential is too long. What makes the action potential too long? We could have that the potassium currents that are supposed to terminate the action potential are broken and don't work and so the action potential is too long or the sodium or calcium currents that are supposed to close that started the action potential don't close correctly and lead to the action potential being too long. That would lead to prolongation of the action potential, prolongation of the QT interval and long QT syndrome. And it turns out that is the molecular basis of long QT syndrome. You have potassium currents that don't close, potassium channels that don't close, sodium and calcium currents channels that don't open, and accessory proteins that help the channels either open or close appropriately. So most of the genes that have been identified are genes in channels and channel related genes. Now clinically the only important long QT genes really are the top three here. They're KCNQ1 which is the potassium channel we talked about earlier that encodes for the IKS or the slowly activating delayed rectifier current that is important in terminating the action potential and shortening the action potential in the presence of adrenergic stimulation and increased heart rate. HERG or KCNH2 gene which is the more rapid component of delayed rectifier current that has a huge role in acquired long QT syndrome but it's also a cause of inherited long QT syndrome. Together these two cause about 90 percent of the genetically identifiable long QT syndrome. Then there's sodium channels that don't close properly and so we gain a function mutation and these cause several percent, three, four, five percent of genetically identifiable long QT syndrome and then all these rest are really rare and none of them cause anywhere near one percent of the residual causes of long QT syndrome. Okay so clinically long QT syndrome comes in three forms, autosomal dominant or Romano-Ward, autosomal receptive or Gervais-Lange-Nielsen syndrome and acquired. Gervais-Lange-Nielsen syndrome is associated with congenital deafness. Why is that? It's because the IKS current encoded by KVL-QT1 is present in hide cells but it's also present in the cells in the inner ear that make endolymph. So if you have two dead copies of the KVL-QT1 gene you will not be able to make endolymph and you'll be congenitally deaf. There's also the acquired form of long QT syndrome which is much more common and we'll talk about in a little bit. Clinically long QT causes syncope, sudden death, seizures and important to note sudden infant death syndrome. So sudden infant death syndrome is in a baby who dies suddenly. Most of us think that the more common cause is a pulmonary and central nervous system which is in fact the case but up to a third of the cases of SIDS are arrhythmias from ion channel mutations as has been shown by molecular autopsies. So if you have a long QT or a Brugada gene and you have an arrhythmia and die suddenly as a baby you'll be classified as SIDS. Now for long QT syndrome it's diagnosed by long QT by QT prolongation on EKG and corrected QT usually by Bizette's formula but can be by the other formulas too. We usually measure QT in leads 2, V5 and V6. A corrected QT of greater than 480 milliseconds is considered abnormal. Normal is less than 440 milliseconds in men and 450 milliseconds in adult women and there's a that which tells you there's a big gray area between 440 and 480 milliseconds and long QT is associated with a specific type of ventricular tachycardia called toissade de point which is a ventricular tachycardia with a rotating axis giving it a sine wave type appearance. In addition VT I mean long QT syndrome can be associated with macroscopic T wave alternance so this is where every other bead has an alternating T wave morphology that's very that's visible on a baseline electrocardiogram. You don't need a special T wave alternance equipment to try to identify it. Okay a question what is the phenotype of homozygous long QT syndrome mutations and on the left we have the phenotype for you know homozygous for long QT1 or KCNQ1 KVLQT1 channel on the right long QT2 which is KCNH2 and ERR. So A deafness and severe symptoms from LQT1 and early and severe symptoms if you're homozygous for LQT2. B deafness and mental retardation for long QT1 and incompatible with life for long QT2. C mental retardation and severe symptoms for long QT1 and early symptoms and heart block for long QT2. D deafness syncope and syndactyly for long QT1 and early symptoms and woolly hair for long QT2. E deafness and severe symptoms for long QT1 and incompatible with life for long QT2. So the best answer here is deafness and severe symptoms for long QT1 and early and severe symptoms for long QT2. So it's you know in general if you have less of a less potassium currents your symptoms will be more severe and that's true for both but KCNQ1 mutations also make the end you know prevent the inner ear from making endolymph if you have no functional channels. Okay let's talk a little about potassium channel mutations which are the most common cause of long QT syndrome. So potassium channel subunits you know make up the channels but it takes four subunits that co-assemble to make a functional channel. So if you have wild type subunits if you have two copies of wild type subunits you put four of them together and you make functional channels. Now many of the mutations that cause long QT syndrome you know from potassium channels are loss of function mutations meaning that they just make a dead channel the channel you know or they just don't make the channel at all the channels truncated etc. If that's the case then you have half as much half as many subunits you have half as many channels and you'll have half as much protein and having half as and half as much current and having half as much current may be enough to cause a cause long QT syndrome and that's referred to as haploinsufficiency. You just have less functional channels. However because potassium channels you know co-assemble to make functional channels there's another way that is more they can get more severe disease. If the mutation leads to a subunit that is expressed that can co-assemble with the other subunits but prevents the channels from functioning then you will also get a lot of dead channels but because if only one bad mutant subunit is enough to take out the tetramer then 15 16th of the channels will be non-functional. So this is what we call dominant negative you know so a mutation that makes a subunit that can get to the that can be made can get to the membrane can co-assemble with other sub with normal subunits but form a dead channel are actually much worse than haploinsufficiency and we see that clinically although we don't actually use it yet in terms of making clinical decisions. Now mutations can cause loss of function by basically making the channels not open or close that would be by gating. They can make the channels not be made but one thing that's become obvious is they can also make channels that look and work pretty well but can't make it to the membrane so they get produced but they have mutations that make them not recognizable by the machinery that actually gets them from the sarcoplasmic reticulum and the Golgi where they're made out to the surface membrane and those are trafficking defects and it turns out especially for long QT2 HERG that trafficking defects are the most common cause of dysfunctional channels and if you could actually get the channels out to the membrane it would actually work and so that's one thought on how you can actually treat you know long QT2 long QT syndrome would be to identify drugs or equivalent that will actually help the channels get out to the membrane. Now that is loss of function from potassium channels. Long QT syndrome for sodium channels is the opposite. It is channels that don't close properly. It is a gain of function problems so normally you get the potassium sodium channels open for a couple milliseconds and then they close really quickly and the residual current when you get 10, 20, 50, 100 milliseconds out is less than way less than one percent of the total amount of current. However, mutants that cause long QT syndrome lead to a residual current where the channels don't close completely and you can get up to three percent residual current downward is current here you know and this is this ongoing inward current you know counteracts the outward potassium current and leads to acute actual potential and QT prolongation in sodium channels. How common is long QT syndrome? Well we have some data so the Italian group under Schwartz by Schwartz et al basically did EKGs on tens of thousands of infants and you know they did this between 2001 and 2005 and during that time they looked to see how many of those infants had prolonged QT intervals and you can see that you know QT corrected is greater than 470 milliseconds were present in about 30 of these infants you know and in a more borderline range of 460 to 470 were present in another 28 and all of these when they repeated the EKGs on the babies who had long QT prolongation still had it on their repeat QT prolongation. They went then went and genotyped the infants looking for long QT mutations and they identified long QT mutations in 16 of the you know sort of of these 59 or so infants and then they there was one other that they were clinically able to definitively diagnose as long QT syndrome. So that led to 17 genetically identifiable long QT babies out of 43,000 which is about one in 2,500. Now clearly we can't identify a mutation in everyone so the clinical frequency of long QT syndrome is going to be higher than that and the estimate that we use for white people is about one in 2,000 is the incidence of carrying sort of a long QT mutation and having long QT syndrome. I mentioned that there's three common types of long QT syndrome long QT1 and long QT2 which are potassium channel mutations and long QT3 which is a sodium channel mutation. The EKGs although they all have long QT differ and people who are good at it can look at the EKG and guess the genetic cause. In long QT1 the EKG looks basically normal everything is proportional it's just the QT interval in the T wave and the ST segment is a little bit longer a little bit wider than normal and this is the condition where at slow heart rates the QT interval the corrected QT is quite normal but the problem is that the QT doesn't shorten when the heart rate goes up and you then end up with a corrected QT that's long that's too long. So the EKG looks normal but the QT is too long at fast heart rates. In long QT type 2 you usually see abnormal T waves especially in the precordial leads but also elsewhere you can see bifid T waves inverted T waves just funny looking T waves. In long QT3 this is the sodium channel problem the QRS is normal the T wave is normal but the ST segment is just too long and so like I say you can oftentimes look at the EKG and take a pretty good guess and people are good at it can get it right about 80% of the time. Now there are also genotype phenotype correlations in terms of you know sort of what brings out arrhythmias. So long QT1 this is the one where the QT corrected is too long with exercise so not surprising here people get in trouble get arrhythmias get sudden death when they're exercised. So long QT1 is one of the causes of sudden death in kids on soccer courts. Long QT2 can cause problems with exercise but it also causes problems specifically with noises loud noises. So this is a condition where the alarm close clock goes off and somebody wakes up and dies you know or you know sort of loud noises you know doorbells trigger you know arrhythmias and sudden death we don't exactly know why that is the case. Long QT3 which is the sodium channel problem sodium channel mutations tend to be associated with conduction disease they tend to be associated with bradycardia and long QT3 most of the sudden death happens at night when people are asleep. Now it turns out pacemakers don't necessarily prevent this so people still if they're you know have a problem need a defibrillator but these are bradycardic dependent arrhythmias in general. Clinically what brings out arrhythmias and sudden death well one of the strongest predictors is QT interval or corrected QT interval. So multiple groups have shown that a corrected QT interval of greater than 500 milliseconds correlates with risk of sudden death and in some circumstances may be an indication for a defibrillator. Now because you carry a long QT gene does not automatically mean that you will have a QTC prolongation for example long QT1 at slow heart rate the QTC will tend to be normal but if the QTC is normal it doesn't mean that you have a zero risk of sudden death but it does mean that the risk of sudden death is markedly lower than if the QTC is prolonged. There are other things that predict other you know sort of types of channels that have a higher likelihood of sudden death that includes mutations that are in regions of the gene that are more likely to cause them to be dominant negative as we talked about before and that's mutations that are in the transmembrane region that control gating mutations that change the amino acid sequence are more likely to you know to cause you know dominant negative effects than ones that just create no completely non-functional you know truncated channels and same thing things in the poor region. Although this is true generally we don't have a library of mutations at this point so we don't clinically yet use this to determine who gets what type of therapy. How do we risk stratify Long QT syndrome? Well we try to identify from EKG characteristics and symptoms who is at highest risk of sudden death. So people who've had aborted sudden death are at highest risk and in the United States we would place defibrillators in somebody who had aborted sudden death. That's not true in Europe as we'll talk about in a minute. Beta blockers are extraordinarily good therapy for Long QT especially for Long QT1 and in many places in Europe even with aborted sudden death you would get a trial of beta blockers before you got a defibrillator. The extent of QT prolongation we talked about predicts sudden death. If you have symptoms which means arrhythmia or you have ventricular tachycardia on therapy which means for Long QT1 and Long QT2 on a beta blocker that predicts a high risk of sudden death and would aim one towards a defibrillator pathway. And then what the genetic mutation is and Long QT3 which is the sodium channel mutation you know tend to potentially have a worse prognosis at least in part because beta blockers don't work nearly as well or potentially don't work at all and you know we'll talk about that again in a second. Okay a couple other facts about Long QT syndrome. So pregnancy does not increase the risk of arrhythmias and sudden death in women but for Long QT type 2 the Herg mutations the risk goes up significantly in the early postpartum period so after delivery and for some period thereafter and it's important that those women be treated you know with beta blockers during that period of time when they're at higher risk. If your sibling died your sister died of Long QT syndrome and you carried the gene does that put you at higher risk? The answer is no. It's been reasonably well studied having a sibling or a first degree relative who died of sudden death doesn't increase your risk that's different for example than hypertrophic cardiomyopathy where a family history of sudden death is predictive of sudden death. That being said if somebody comes in your office and is 30 years old and said you know my brother died of Long QT syndrome at 28, my sister died at 27, my mom died at 33, I'm 30 and carry the gene what do you think? The answer there is I think you should have a defibrillator because you know it's never been studied in people who are from particularly malignant families and there's every reason to believe that malignant families do exist. Okay by sex who's at highest risk? Well it tracks with who has Longer QT intervals so before puberty boys have Longer QT intervals than girls and they're at higher risks of arrhythmias if they have Long QT if they carry Long QT syndrome mutations. After puberty women have higher have Longer QT intervals and higher risk of arrhythmias than men. After as people age the hormonal differences that lead to the difference in QT interval gradually go away so in general the risk of arrhythmic event tends to go down after age 40 and the differences between sex does go away to a large degree by the time one reaches old age. But QTC duration predicts risk at all ages. How about response to beta blockers? Well Long QT type 1 has a very good prognosis in people on beta blockers, and failure to suppress arrhythmias on beta blockers is a predictor of badness, arrhythmias, and syndromic cardiac event. And predictors of failure of beta blocker therapy, having your first arrhythmia at a very young age, having a very long corrected QT interval despite beta blockade, and being long QT type 3 because there's not good evidence that beta blockers actually significantly decrease risk in patients who are long QT type 3. Now interestingly, natalol, which is a long-acting non-cardioselective beta blocker, appears to be superior to all the other beta blockers, including propranolol, which is a similar class of drug. So we use that preferentially in patients with long QT syndrome. Again, a couple of the references that have shown this are listed here. How do you manage long QT syndrome? Well beta blockers are considered almost curative in long QT type 1, and they are effective in long QT type 2. If one is worried, one can do an exercise test or a Holter on beta blockers and see that it suppressed QT prolongation or QTC prolongation by suppressing heart rate and suppressed arrhythmias. Again, as I mentioned before, beta blocker effect is less certain in long QT type 3, and if one thinks one's high risk, a defibrillator would be appropriate. Now sodium channel blockers can be used for recurrent VT in long QT type 3 patients, but they're not necessarily an alternative to a defibrillator. Sympathectomy is the ultimate beta blockade and is highly effective in appropriate patients. Exercise restriction is considered less likely more recently, especially in people on medical therapy. And defibrillators in the U.S., we put them in for survivors of cardiac arrest, people who have syncope, so documented ventricular arrhythmias on therapeutic doses of beta blockers. If you have a very high risk because you're very young with syncope or you have Gervais-Lange-Nielsen syndrome with a very long QT, then one should consider placement of a defibrillator. The placement of a defibrillator is often not an easy decision. If you have an ischemic cardiomyopathy and you're 70 years old and you have an ejection fraction of 30% and we talked about primary prevention defibrillators, we really need an arrhythmic death rate of about 5% a year to make it worthwhile to place a defibrillator because there's a competing risk of non-arrhythmic death in those patients. If you have a 20-year-old who just had their first kid and you have long QT syndrome and you have an estimated life expectancy of 60 years, is a 1% a year risk of sudden death acceptable? And the answer is probably no. And so then shared decision-making on whether it makes sense to have a defibrillator or whether it doesn't in people who are at significant risk is appropriate, especially as defibrillators have lower morbidity, subcutaneous defibrillators are available, etc. There are gene-specific therapies for long QT syndrome. We talked about beta blockers for long QT1. Long QT2 is HERG mutations. It turns out that HERG mutations cause less IKR current and that the HERG channel doesn't work well when extracellular potassium is low. So one therapy is raising extracellular potassium, and you can do that by putting people on potassium supplements and spironolactone. And it turns out that does shorten the QT interval. There's no randomized data to show that you prevent sudden death by doing it. Finally, long QT3 are sodium channel mutations, and some of the mutant sodium channels are better blocked by sodium channel blockers like maxillitin and flecainide. And so it turns out that some of these mutations with long QT, you give them patients therapeutic doses of maxillitin or flecainide, and the QT interval will shorten. Again, there's no randomized data to show that you prevent sudden death, and we know that occasionally you will bring out Grugada syndrome, which is a sodium channel deficiency syndrome by putting people on maxillitin or flecainide who have mutations. And so that becomes sort of a concern. And again, if somebody has an indication for a defibrillator for primary prevention, they should have a defibrillator. Maxillitin and flecainide, though, are very good in some patients with malignant arrhythmias, ventricular tachycardia, storm, et cetera. And I emphasize again, aside from beta blockers, no pharmacological therapy has been shown to prevent sudden death in long QT syndrome or in any of the other inherited cardiomyopathies. An EKG of a subtype of long QT syndrome, this is a 28-year-old woman who presented with intermittent weakness, and this is her electrocardiogram. And this is an example of Anderson-Tewell syndrome or long QT type 7. So long QT 7 or Anderson-Tewell is most notable for very prominent U waves, and the U waves can fuse into the T wave and give the appearance of severe long QT syndrome for a severely prolonged QT interval. And this is caused by mutations in the KCNJ2 gene, which is the potassium channel that sets the resting membrane potential. So people have mutations in this gene, their resting membrane potential is too high, and they're susceptible to tons of ventricular ectopy and arrhythmias such as bidirectional ventricular tachycardia, also seen in catecholaminergic polymorphic ventricular tachycardia. Interestingly, these patients tend to have a lot of high-grade ventricular ectopy, commonly seen by pediatricians, but fortunately, sudden death is quite rare. And these arrhythmias respond to flecainide, which is actually a stabilizer of the sarcoplasmic reticulum calcium relief channel. And beta blockers have a relatively minimal effect at suppressing the arrhythmias. I'll briefly mention acquired long QT syndrome. So acquired long QT syndrome is caused by drugs, drug-induced long QT, but can also be caused by severe global ischemia, electrolyte abnormalities, intracranial events such as bleeds. Here, the corrected QT interval is normal at baseline or with exercise, but in the presence of the drug or after a cardiac incel, people develop marked prolonged QT and potentially arrhythmias that get better. Most of these patients do not have a mutation in one of the known long QT genes, and genetic testing does not make sense in them. This is likely polygenic vulnerability. The idea here is decreased repolarization reserve. All of us have more potassium channels than we need. The idea is these people have less than most of us, and the drugs that cause this tend to bind to the HERG potassium channel, and because that channel has a promiscuous pore that binds to a lot of drugs, so those people, you block some of the HERG current, and they end up getting marked QT prolongation only in the setting of drugs. How do you treat it? Stop the drug, although not every drug will cause the same phenotype in every person. You try to avoid acquired long QT drugs in those people, and genetic testing would only be done for people who have a family history of long QT syndrome who present this way or who have persistent prolonged corrected QT after you stop the drug. That's enough for long QT syndrome. If you like long QT syndrome, you'll love short QT syndrome. It is the exact opposite, meaning the QT corrected is very short. The definition is less than 360 milliseconds in men and 370 in women, but the early cases that were first identified had incredibly short QT intervals in the 300 or 280 millisecond range sometimes, and here the QT is always short, so it's short at fast heart rates, it's slow heart rates, so the corrected QTC becomes really short at slow heart rates. The T middle to T end is very short in these people. They have very spiky T waves, which can lead to double counting on defibrillators. There's no pharmacotherapy that's been proven to prevent sudden death, and if the QT is very, very short, these are very sort of morbid conditions. Quinidine and Sotolol can prolong the QT interval, which can be useful and make your defibrillator work better, but again, there's no evidence that putting people on these drugs actually prevents sudden death as primary prevention. The genes that cause short QT, I'd do exactly what you think they are. Long QT is not enough potassium current. Short QT is too much potassium current at the wrong time, so these are potassium channels that stay open when they're not supposed to, and in some cases, calcium channels that close too soon, so you have too little inward calcium current, and like many of these conditions, there are scoring systems that you can use to try to decide whether somebody clinically has short QT syndrome. There are well-known scoring systems, the Schwartz system for long QT syndrome. We don't use it as much now in the days of genetic diagnosis, but we still can use it, and in short QT syndrome, I've given you an example of one of the scoring algorithms where you can get definitely short QT, probably short QT, and probably not. Okay, we'll talk a little bit about Brugada syndrome. So Brugada syndrome is one of the inherited arrhythmia syndromes that causes sudden death at night or at rest. Although it is autosomal dominant, meaning it is genetically equally common in men and women, the clinical syndrome is much more common in men, at least 5 or 10 to 1. It's also more common in Southeast Asia, where it is the most common cause of sudden death in young men. In fact, in some villages in Southeast Asia, where it is known that this causes sudden death in young men, in families that are affected, one of the treatments that has developed is for young men to dress up as women at night, because it's known that women don't die, to try to fool the deities that lead to sudden death. As with most therapies in this condition, there's been no randomized controlled trials to see whether dressing up as a woman at night prevents sudden death in men. The EKG is classic, and I'll show you many examples in a minute. J point of elevation in leads, V1 to V3 with a right bundle branch block pattern. So it looks like an acute anterior wall MI with a right bundle branch block. It's exacerbated by sodium channel blockers, and we use them diagnostically, procainamide in the United States, and ashmaline, a stronger blocker in Europe, because this is a sodium channel deficiency syndrome, not enough sodium current. Beta blockers make it worse, beta agonists and exercise make the phenotype less severe. The EKG changes in arrhythmias can be provoked by fever. So people will often show up with syncope and Brugada syndrome EKGs when they're febrile, that go away when they're not febrile. The EKG in general can change day to day, it is dynamic. Some days you can have a completely affected one, some days you can have a completely normal EKG. It's 20% of cases are caused by mutations, loss of function mutations in the cardiac sonogen on NAV1-5. If you look really closely by cardiac MRI or pathology, you can often see subtle defects in the septum corresponding to the location of the EKG changes. These are some of the genes that have been associated with Brugada syndrome. The only one that is clearly causal in a monogenic way on NAV1-5 or cardiac sodium channel mutations, this is likely because we have a huge excess of the amount of cardiac sodium current that we need in our heart. So to have a phenotype, you have to get rid of at least about half or more of the sodium current. And the only genetic mistake that can really take out half of the sodium current is having half of the sodium channel genes not work. But other genes and genetic mutations in inward and outward currents that lead to less sodium current, less calcium current, or more potassium out current can cause the phenotype. This is the EKG that are associated with Brugada syndrome. They're listed as type 1, type 2, and type 3 Brugada syndrome EKGs. The only one that is diagnostic is type 1. It is a, you know, coved ST elevation with an inverted T wave. The saddleback types, which are type 2, which is a saddleback, you can sit in it with a right underbranch plug pen, upright T wave with at least 2 millimeters of ST elevation, and type 3 is less, same as type 2 with less than 2 millimeters of ST elevation. These are not diagnostic of Brugada syndrome because they are present in a reasonable fraction of the general population. If you look at the EKGs of young black men, you will see this quite commonly in the precordial leads and it is not necessarily Brugada syndrome. You can bring out the EKG pattern by putting the leads 1 or 2 into spaces higher, specifically leads V1 and V2, and as I mentioned, you can give patients sodium channel blockers, which will bring out the condition. This is an example, a baseline EKG, which is, you know, sort of a type 3 Bailey Brugada EKG pattern. You move the leads up and now you see an EKG pattern that is diagnostic of Brugada syndrome. You put the leads in baseline position, but you do a procainamide challenge, again, diagnostic for Brugada syndrome. Procainamide plus the leads up, you know, unequivocal Brugada syndrome. Beta agonists make the EKG more normal, and even when you go up to higher leads, they make the ST elevation go away. Symptoms are the best predictor of arrhythmias in Brugada syndrome, and this is just one of many studies showing that patients with sudden death, the likelihood of recurrent sudden death in Brugada syndrome is quite high, so sudden death with Brugada syndrome means you get a defibrillator, but syncope raises your risk of sudden death a lot. Unfortunately, sudden death can be the first presentation of asymptomatic patients. A lot of tests have been used to try to risk stratify the risk of sudden death in somebody who has a Brugada syndrome gene or has Brugada syndrome on procainamide testing, but not at baseline. This includes a signal average dKT, which some studies have shown is predictive. Programmed electric stimulation, which the results are conflicting. Some studies have shown that if you have inducible ventricular fibrillation, you have a high risk of going on to arrhythmias, syncope, and sudden death. Other studies have not shown that, and the difference between the studies is not at all obvious. Finally, a recent study showed that sodium channel blockers, if you have a lot of ST elevation when you use a procainamide or an Ashmolean challenge, or you have inducible arrhythmias, that that predicts arrhythmias and potentially sudden death. Again, it hasn't been confirmed enough to be absolutely useful clinically, but maybe one mechanism of predicting. What's the mechanism of ST elevation in Brugada syndrome? Well, a couple mechanisms have been proposed, but the bottom line is that you have part of the height depolarized and part of the height not depolarized at the same time. The classic mechanism proposed by Ancelovich is this. The action potentials in the epicardium, the outer wall of the heart, are shorter than action potentials in the endocardium, the inner wall of the heart. That's because the epicardium has extra potassium channels. If you don't have enough sodium channels, it is possible in the epicardium that these early potassium channels will be enough to abort the action potential. Now you have an action potential that is really short in the epicardium, yet still pretty normal in the endocardium. That can lead to reactivation of the epicardium, something called type 2 reentry, and the initiation of ventricular tachycardia, and leads to the ST elevation on EKG. An alternative mechanism is just very, very slow conduction caused by the sodium channel mutations that leads to inexcitability of the epicardium, you know, in the septum in the right ventricle. And that is an alternate, and many now favor this as the major cause of Bugatti syndrome. Functionally, it doesn't make much difference, and they're going to act the same. Preventing the blocking the potassium currents in the epicardium is one potential way to lengthen the action potential and prevent, you know, aborted action potentials in, you know, in Bugatti syndrome, and that is what quinidine could do. And quinidine has been shown to be effective in eliminating the Bugatti EKG pattern in some individuals, and is used for VT storm or incessant ICD shocks, with a reasonable amount of success in many people. That says, again, there's no evidence that it should be used for primary prevention of sudden cardiac death. Electrophysiologists can ablate anything, and this appears to be a problem with the septum. So, can you ablate the right ventricle and the septum? And the answer is yes. And one can improve the EKG, and in some cases of patients with malignant arrhythmias, one can eliminate or markedly decrease the arrhythmic burden. Again, no evidence for this as a treatment for primary prevention of sudden death in patients who don't have arrhythmias, and I don't think it should be used as an alternative to a defibrillator. There's many approaches to the treatment of Bugatti syndrome, but the bottom line is that, you know, if you have symptoms, you know, that are malignant and you have Brugada syndrome, you should consider getting a defibrillator. If you're not sure from the EKG, you should test, you know, to see whether you actually have Brugada syndrome and a type one pattern. If you have an inducible type one pattern with, for example, a drug test, but it's normal at baseline and you don't have symptoms, you do not qualify and should not get a defibrillator. On the other hand, you know, if you do have a baseline type one pattern, then the question of does, should one get a defibrillator is a difficult question. That's the group that we all struggle with the most and additional mechanisms to risk stratify that group would be greatly appreciated. And partly that's because we're not very good at predicting who's going to die suddenly. If you look at people who either died or almost died suddenly with a, you know, from Brugada syndrome, the bottom line is you wouldn't necessarily have put defibrillators in most of them, you know, if you had seen them, you know, a week or two or a month or two before they showed up. You know, so even though, you know, we can predict some people are at high risk, there's still a reasonable group who don't have any of the predictive symptoms or EKG signs who still will present with sudden death. It's, you know, the most common age of presentation is 30 to 40, but you can present younger and you can present older and we have many examples of patients where that is in fact the case. So recently it's been shown that Brugada syndrome is really polygenic. So genetic testing, unlike the other arrhythmia syndromes where you can identify mutations in 50, 60, 70% of patients, if you show up with Brugada syndrome, we're only going to find a mutation in 20 to 30% of you. In addition, genome-wide studies have shown that there were a lot of common variants that associate with Brugada syndrome, including variants in other potassium channels and transcription factors, showing that, you know, that genes that affect the amount of sodium current that you have, you know, basically are going to affect whether you have Brugada syndrome and it's unusual to have a single genetic mistake that's going to be enough to bring out, to cause Brugada syndrome all by itself. There are families where we specifically identified a sodium channel mutation and a variant in another sodium channel-related gene that probably go together to make the pre-epple symptomatic and, as I mentioned, only mutations in NAF1-5 of the chi external channel reached the threshold for causality as a monogenic syndrome in Brugada syndrome. We talked about the action potential before. The action potential, you know, sodium channel, sodium current going in and then leads to opening of calcium channels, and calcium channels lead to release of calcium from the internal stores, the sarcoplasmic reticulum, and this leads to contraction in cells. Mutations in the calcium release mechanism lead to catecholaminertic polymorphic ventricular tachycardia. These are the most common mutations, autosomal dominant, in the ryanin receptor, which is the calcium release channel of the SI. This leads to a normal EKG at baseline, but in the setting of exercise or isopropyl, which load the SI with calcium, you get abnormal release, which leads to depolarization, extra action potentials, and arrhythmias. The common rhythm disturbance is bidirectional VT, which is ventricular tachycardia with every other BP and alternating PBC morphology. Beta blockers are effective. Flecainide, which stabilizes the sarcoplasmic reticulum, is also effective. Sympathectomy, as an ultimate beta blocker, is also very effective. Calcium channel blockers, interestingly, don't work so well and aren't the first line of a second-line therapy. Defibrillators work, but as you can imagine, you know, defibrillators lead to catecholamine mean release, which can lead to VT storm in this condition, so you want to pharmacologically treat these patients as well or preferentially. There are autosomal recessive versions, with the most common one being caused by mutations in calcium question, which is the calcium storage protein in the SI. There are other inherited arrhythmia syndromes that have been identified recently. One of them is early repolarization syndrome, so early repolarization are, you know, sort of J-point and early ST elevation in leads that are not the precordial leads, which are the leads that cause Brugada syndrome, or they're associated with Brugada syndrome. And you know, it turns out if you have this on your EKG, you're a couple-fold more likely to have sudden death, but still sudden death is unlikely. You know, sudden death in the general population is very rare, so having a five times higher risk of sudden death than normal is still pretty rare. So having this, although it predicts sudden death on a population basis, isn't particularly useful, and there are likely benign types of early repolarization and non-benign types, and we're not particularly good at telling the difference at the moment. There are mutations in some of the same ion channels that cause Brugada syndrome have been identified in patients and families with early repolarization. Inherited conduction disease exists. The genes, some of the genes that are associated with, you know, both, you know, sort of inherited bradycardia and inherited forms of heart block are listed here. Again, these are rare and not as well identified and won't, you know, probably be asked on any of the exams. I won't talk much about the inherited myopathies. I'll just mention arrhythmogenic right ventricular cardiomyopathy, which is now arrhythmogenic cardiomyopathy of the right ventricle, left ventricular, or biventricular type, and this is largely a disease of the desmosome, and the arrhythmic phenotype is really identical to the other inherited arrhythmia syndromes, but these come along with them with ventricular dysfunction, you know, that, you know, causes heart failure in addition to the arrhythmic symptoms, and again, as I mentioned, this is a disease of the desmosome, and this is a list of, you know, sort of the task force criteria, you know, and with a scoring system of major and minor criteria that can let you do, you know, identify, you know, ARVC and their, you know, right ventricular contractile dysfunction or dilation. Their myocyte loss with fibrosis by either autopsy or biopsy. Repolarization changes, such as T-inversions, B1 to B3. Depolarization changes, which are this little extra bump or epsilon wave in B3 and B4. Arrhythmias that initiate in the right ventricle, so they have a left bundle branch block pattern, sort of family history or genetics, you know, and treatment here is the same as treatment for, you know, myopathies and beta blockers and defibrillators as necessary for the arrhythmias. Signal average EKG can be useful. I won't say much about hypertrophic cardiomyopathy, which is, you know, sort of the most common of the, you know, inherited arrhythmia conditions associated with cardiomyopathies. So somebody shows up with, in one of these inherited myopathies, how do you treat it? Well, you can, in many cases, the appropriate treatment is nothing. And to watch it, you have a Brugada syndrome gene, but a normal EKG at baseline, and you had positive testing with propanamide. No therapy is appropriate. Avoid sodium channel blockers. Long QT, avoid potassium channel blockers. Avoid acquired long QT medications. Competitive sports is interesting. ARVC is the one condition where competitive sports have clearly shown that you should avoid them. You know, for a lot of the other conditions, the guidelines have been liberalized, allowing people to participate in sports. The question of whether, you know, people still want you to participate in sport, because even if the risk of sudden death is low and not exacerbated by exercise, like in Brugada syndrome, there's still a chance you might die while you're exercising, and there's some medical legal implications for that to happen at your local college or high school. The question, you know, pharmacologic treatment, beta blockers, and long QT syndrome being a pretty good example of it. You know, flecainide and beta blockers and CPPT. We talked about defibrillators, and these are decisions based on the individual condition. And finally, you know, some of these conditions go all the way to artificial hype devices, VAT, ventricular assist devices, and to transplant. It's not a common indication for transplant, but it does happen. Inherited, somebody shows up with a family history and a risk of inherited, one of these inherited arrhythmia syndromes. How do you work it up? You check a history, you know, looking for syncope, palpitations, aborted sudden death, but also for, you know, heart failure, cardiomyopathies, presence of defibrillators, etc. You know, you do have to ask people whether they have, you know, sort of a history of sudden death. I had a patient who, you know, sort of was here because a family member had, you know, sort of Brugada syndrome. And the, you know, sort of at the end of the interview, I said, anything else you should tell me? And the patient's husband said, you know, you should probably tell the doc about that time you stopped breathing. I was like, stop breathing? He goes, yeah, she slumped over on the couch, stopped breathing, turned blue. I gave her CPR for about 20 seconds, and then she woke up, and we decided not to do anything about it. And I was like, okay, that's useful. When would you like your defibrillator? So, like I say, potentially things you should ask for. Family history, sort of again, family history of sudden death, pacemakers, defibrillators, family history of sudden infant death syndrome, because, you know, those, you know, can be caused by the arrhythmia, by arrhythmia mutations in iron channel genes. EKG helps identify long QT, short QT, Brugada, arrhythmogenic right ventricular cardiomyopathy. ECHO or MRI can be useful in the conditions that are cardiomyopathies with arrhythmias. Stress tests for catecholaminergic polymorphic VT and long QT type 1. Drug testing with sodium channel blockers for Brugada syndrome and beta agonists for catecholaminergic polymorphic VT. And maybe program stimulation looking for, you know, inducible V-fib for Brugada syndrome. Inherited, you know, how do you screen families? We're not very good at this, but the recommendations are to do cascade screening. So, do clinical screening on first, all first degree relatives of somebody who is affected with one of these conditions and anyone in the family who has any symptoms suggesting that they might be affected. And then if you find somebody you do, you screen all their first degree relatives. Now, in addition, there are mandatory reporting genes. So, if somebody gets whole exome or whole genome sequencing for you being a funny looking kid or equivalent, and you identify a mutation in one of these genes, which include almost all of the common long QT and Brugada and CPVT genes, then those genetic mutations are reported to the patient or family, depending on the age of the patient. And then people will get screened and show up and you often say, hey, I have a Sonia channel mutation, what should I do? And you treat them like anybody else who shows up who's asymptomatic usually with these. Should you do pediatric EKGs on all kids? We as a country have chosen not to. We don't have enough pediatric cardiologists to read them all. And the number of false positives exceed the number of true positives. So, you're going to muck up a whole bunch of kids' lives to identify a relatively small number of kids who are actually affected. And testing school age athletes, the University of Iowa and many universities will do testing looking for inherited forms of sudden death, you know, at least history, physical, put a stethoscope on your chest, do maybe do an EKG, maybe do an echo. The question of does this really make sense? And if you're going to do it, you know, is the risk of, you know, sort of sudden death really higher in a college basketball game in an auditorium, in a big auditorium where there's a AED sitting at the bench than it is in a pickup basketball game, you know, for somebody out in the community. Not clearly in the question of should everybody be screened, you know, if it could be affordable is a good question. Genetic testing is available. It can pick up over 50% of mutation pickup in people who clearly have the condition in all the conditions except Brugada syndrome. You always test a person who has the clinical condition if you don't know whether they have a genetic mutation because you want to, if you don't find a mutation, you won't know whether the test isn't good enough or whether they actually don't have it. So, you test somebody who's affected. If you identify a mutation, you then cascade screen, you know, through the family and it can be done with a relatively cheap blood test instead of with ECHOs and EKGs and Holters, et cetera. The main benefit to genetic testing is for the family, not for the, necessarily for the individual. If you have Long QT syndrome, you still have Long QT syndrome whether we identified the gene or not, although it may help direct therapy if we identify it's Long QT1. There's multiple ways of genetic testing using whole exome or whole genome sequencing. It doesn't matter which one you use. And, you know, oftentimes, unfortunately, we identify variants and we're not sure whether they're causal. And I mentioned before, you can look in the prior literature, you can look for evidence in other families, you know, and evidence in the genetics, whether it's causal or not, but oftentimes you don't know for sure. Once you identify a mutation, you can do carrier testing of relatives. And if you do, you know, in relatives, if you know the genetic mutation, you can do either clinical testing or genetic testing or both. The advantages of genetic testing is if you identify carriers, you can tell them drugs to avoid. There are some treatments that you might use in asymptomatic people such as beta blockers and Long QT1 carriers. Oftentimes, though, you don't know whether you should or you shouldn't. And the best part of genetic testing is if you know the gene that runs in a family and you identify somebody in the family who doesn't have it, you can tell them that as long as you're sure you're right, you can tell them that you don't need to worry about getting it. They can't give it to their kids. They don't need ongoing clinical testing and they just don't need to worry about it. Problems, it is still pricey to do the initial genetic testing a few thousand dollars, although insurance is increasingly covering the primary testing of somebody who's affected. A negative test in a proband is useless. So if somebody has a condition and they test negative, it doesn't mean they don't have the condition, it just means the test didn't work. You know, I mentioned that there's variants that we don't know whether pathological or not, and you just don't need to ignore them, you know, until they're proven one way or another. Therapies aren't proven in asymptomatic carriers. Although health insurance is protected independent of genetics, life insurance isn't. So if you identify somebody as a carrier, you might hurt their insurability, you might damage their careers. And remember, this is still a young field and, you know, we're still wrong and correcting mistakes every now and then. I will just spend 30 seconds talking about common forms of, you know, heritability in sudden death. So a number of studies have shown that if a relative of yours died suddenly, whether it's from ischemic disease, an MI or not, that your risk of sudden death is higher, showing that there are common genetic variants that are inherited that lead to an increased risk of sudden death. Again, usually not actionable in most people, you know, because the risk of sudden death remains quite low. You know, this is presumably variants in, you know, sort of the millions of SNPs that we all have. And as one example I'll give you, you can look at the QT interval and identify the genetic predictors of the QT interval in normal people. And these are variants in ion channels and ion channel related genes that predict a reasonable fraction of the QT variability in the population. And, you know, and then you can come up with allele risk scores where you can, you know, check these, you know, 15 or so variants and identify people who have longer QTs or shorter QTs based on them. And then if you take people with genetic long QT syndrome and you use this genetic risk score, you can actually identify people who are going to be, have longer QT intervals and be at higher risk of sudden death than people who have the common variants that predict a shorter QT interval and sudden death. People now can walk in, can send away their DNA, a buckle swab and get, you know, everything you wanted to know about your genome back. And sometimes that will include, you know, the inherited arrhythmia genes. And so people will show up and say, hey, my testing on 23andMe showed this. And so we need to deal with an increasing amount of those. These are some of the websites that can be used to identify, you know, sort of what medicines you should avoid if you have long QT syndrome or Brugada syndrome. And with that, I will just briefly summarize that mutations in ion channels and ion channel related genes cause a variety of inherited forms of sudden cardiac death, the inherited arrhythmia syndromes. The genome mutations lead to characteristic EKG abnormalities, symptoms, susceptibility to diagnostic tests and utility of therapies. Structural mutations lead to inherited cardiomyopathies that are also associated with high risk of sudden death. Symptoms and clinical testing drive the risk of sudden death and the need for invasive therapies, usually meaning defibrillators. Clinical and genetic testing is useful in identifying family members at risk for arrhythmias and sudden cardiac death. And rare and common genetic variants can modify the risk in both inherited and acquired forms of heart disease and risk of sudden death. And with that, I'll stop. Thank you all very much.
Video Summary
The video discusses inherited ion channelopathies, particularly long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, which can cause sudden cardiac death. Dr. Barry London explains the genetic basis of these syndromes and their associated EKG abnormalities and symptoms. He emphasizes the importance of genetic testing for identifying at-risk individuals and the need for clinical testing and screening for family members. Dr. London also discusses the management of these syndromes, including the use of medications, defibrillators, and other interventions. He highlights the role of risk stratification in determining the appropriate treatment approach and mentions the involvement of common genetic variants in increasing the risk of sudden cardiac death. The video concludes by emphasizing the need for further research in the field and the importance of genetic counseling for individuals and families with inherited ion channelopathies. Overall, the video provides a comprehensive overview of these syndromes and their implications for sudden cardiac death.
Keywords
inherited ion channelopathies
long QT syndrome
Brugada syndrome
catecholaminergic polymorphic ventricular tachycardia
sudden cardiac death
genetic testing
EKG abnormalities
symptoms
management
medications
defibrillators
genetic counseling
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