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Sudden Death - What's in Your Genes?
Sudden Death - What's in Your Genes?
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When I was a fellow, I was sent from clinic down to the exercise lab to supervise stress tests on a couple 10 and 12-year-old boys. They were brothers, and their grandmother had died suddenly, and their mother had had a cardiac arrest while she was exercising. And they ended up having something called Long QT syndrome. I'll explain in a little bit. But that really got my attention about how little we knew about family transmission and familial diseases and how we could detect them and treat them and protect families from sudden death. So how many people here have ever been to an inherited arrhythmia clinic? Okay. That's called learning needs, in my humble opinion. So this is actually a part of EP for people who usually work in the sort of procedural end of things. And it's a growth area for sure because our recognition and utilization of genetic testing is increasing. And genetics is migrating into cardiovascular like it did years ago with cancer and before that with maternal fetal health. So the geneticists and genetic expertise is now embedded within our field. And in fact, it's richest in EP compared to other disciplines. The only other one would be heart failure. So here's my start. Okay. This hasn't changed. So we'll start with a case. So these are three lovely Google images, versions of Rod. And what you can see is that, you know, when you're turned, you know, when the photographer says turn a little, you know, and they take your picture, right? So this is proof. The two on the left, you know, he's very handsome and good looking and well thought through. The one in the middle looks like his sort of, either his booking picture or the one for the audition for the serial killer movie, you know? We'll go with 44. So, but here's an example of something that happens. So let's just pretend that Rod has a cardiac arrest and he's lucky enough to make it. He's got a history of borderline blood pressure. You would think that he would have heart disease because usually 90% of people have evidence of heart disease out of the gate. But it turns out not to be the case. He has an angiogram and an echocardiogram that are unremarkable. But interestingly with this, he gets resuscitated, he comes back from the dead, and then he says, but my nephew died playing hockey. So that's maybe a Canadian moment, but anyway. Although Jay Boomeaster did this recently, but fortunately in public. But as is often the case, he doesn't know a lot about the details. You know, when something horrible like that happens, families sometimes sort of knuckle in and don't talk very much about the medical implications of this. And so then the question is, a guy who's had a cardiac arrest, who's got family trouble maybe, you know, what should we do? How do we look into that? How would we determine if there's a genetic basis for this? So here we go. So a little bit about terminology, okay? So if you have a cardiac arrest, so this is a sudden collapse, if you like, this is how things can turn out. So first of all, if you're lucky, one of those right now, survival's between 5 or 10%. But if you are unlucky, like most people, you have sudden death, okay? Or sudden cardiac death is the other terminology for it, okay? Then if it's unexplained and the coroner activates a pathologist to say, let's do an autopsy, okay, because we didn't see this coming, so we better do an autopsy and figure out what's going on. That happens for two reasons. One is to rule out foul play. And the second is to try to establish the cause of death, because it could theoretically have implications for the patient's family. So autopsy rates are going down like crazy, and that's because they cost money, and because most of the time, somebody who dies that's not completely unexpected, people are simply not curious, as long as there's reasonable grounds to assume there's no foul play. So then the next thing that happens, if you have an autopsy and that doesn't show anything, then you convert from sudden cardiac death to sudden arrhythmic death, okay? And because you can't autopsy the EKG or the rhythm, the next best thing that you can do is you can autopsy the genes. So we now routinely do and recommend genetic testing for people who have a sudden arrhythmic death. So you can extract DNA from a bunch of different tissues, either blood at the time of autopsy or other DNA-rich tissues. And so we now routinely do genetic testing. And I'll talk a bit about genetic testing and the fact that the process is actually cumbersome, but the technology is actually quite straightforward, okay? On the other hand, if you're one of those lucky people who survives, you get a cardiac evaluation. And again, 90% of people, it's going to turn out to be coronary disease or they have a cardiomyopathy. And not that those aren't important, but those do have a genetic component to them, but not dominantly. But there may be a genetic phenotype. And so for instance, if you've inherited your cholesterol or you have inherited other parameters that have an inherited component to them, then that may be evident. And then you would undergo genetic testing. So for instance, if your cholesterol is nine, oh, sorry, hang on, I don't know the standard units, only the metric units, but anyway. If you have an extraordinarily high cholesterol, you probably have familial hypercholesterolemia, that's one in 500, or maybe even one in 200. And those people have infarcts when they're 25 years old. And those people can be genetically tested, their family can be screened and treated, and that would be an explanation. But if you have an unexplained cardiac arrest, like our 44-year-old patient, then the latest thing is we are now exploring genetic testing to try to explain that with some really interesting recent research in this area. So this has been a passionate interest of mine since this all started, and so we evaluate patients for unexplained cardiac arrest, and when we look hard, this is the outcome of it. And what happens in this situation is if you look hard and you do genetic testing and you look for all these genetic conditions, if you like, about half the time you can find an explanation, and the other half of the time you don't find anything. So they're either one and done or it's going to come back, and then maybe it will manifest and tell you what the cause is. And if you look at that list on the right of what those genetic conditions are, I'll explain that in just a second, but these are the kind of things that you can have that can cause a cardiac arrest, it can be unheralded, like happened for our guy, or cause the sudden death of a young nephew who's the hockey player. So this is the kind of family we would like to meet in the clinic. We all get a little smirk and chuckle from it, but this is the kind of family we meet almost every week. So mom and dad come in and their 17-year-old son died playing hockey. Grandparents or kids come in and their young or middle adult person, like if that case I presented, if he died at home, which is where you don't usually survive cardiac arrest at home, then we'd be talking to the family to say what's the cause, are other family members at risk, and every once in a while what happens is a second family member dies and then they find help. And that's a horrible situation, obviously, that it took two events to happen for that to be brought to attention. So I'm going to tell you a little bit about the beating of the heart. So this tells you the difference. This tells you how much smarter Jagsing is than I am, right? So my pictures are all like real simple, like cartoons and stuff like that. So I'm really trying to keep it simple. So he is a heck of a lot smarter than me. But here's my little analogy to explain this, okay? So every heart cell, if you like, has a switch, it has an electrical impulse. It flicks on and off at every heartbeat. And your heart's a bit like a toilet. I know it sounds sort of goofy, but really what it is is it pumps blood like toilets pump water, right? Fills up, flushes out very quickly, slowly fills back up, gets ready for the next heartbeat, okay? Toilets need to be reliable, just like our hearts, right? And they're very important. You can't live without one in your house, okay? So here's a very crude schematic. This is not the Jagsing diagram. This is the Andrew Kron diagram, okay? And so we have, on the top is like, you know, inside the bloodstream, if you like, or outside the heart cell, okay? And on the inside is the inside of the heart cell. And the little blue line is the cell membrane. And through that, although it's not technically perfect, what you have is you have the flow of potassium and sodium and calcium, okay? Most of the calcium is inside the cell, if you're interested. And then it's in a certain kind of perfect balance. It's almost like Goldilocks, not too hot, not too cold, okay? And so in these genetic conditions, basically what's happened is you've lost one of those signaling processes, okay? So for instance, if you don't have enough potassium, then what happens is that the flushing works fine. That's mostly sodium. But the potassium, because it's slow, it takes longer to generate your, to fill back up, the toilet to fill back up. So then you get long QT, okay? If your problem is with sodium, you don't have enough sodium, okay, then things don't quite go right with, if you like, firing, okay? So then what you do is you get brugada, okay, if you've heard that terminology, okay? And if you fail to fix your calcium and take it back into the part of the, if you like, the spark plug inside the cell, then you get something called catecholaminergic polymorphic ventricular tachycardia. Don't worry, there won't be a quiz. The easy brief word is CPVT, but that's kid cardiac arrest during exercise kind of condition. And then you get this kind of concerning looking ECG. So if you step back and look at the field of cardiogenetics, which is a sort of emerging conceptual field, this is a diagram I made about 10 years ago, and we're slowly populating it. You can be born with heart disease, that's congenital. You can have it inherit arrhythmia, which is what we focus on. You can have it inherited cardiomyopathy, and you can inherit other things like lipids or neuromuscular disorders. And what we're focused on are the things that are arrhythmias, because we're EPs. We bucket in those cardiomyopathies that typically present with an arrhythmia. So most people might be familiar with arrhythmogenic right ventricular cardiomyopathy, or ARVC. It's now in a bucket of something called arrhythmogenic cardiomyopathy, renamed. And so at the top left are these syndromes, okay? And what these syndromes are, are these are, one of the genes that's involved in your toilet schematics is just not working properly, okay? So you fail to make the proper sodium channel or potassium channel or calcium regulation or those kinds of things. And then you can get, your QT can be too long or too short, et cetera, et cetera. So the key thing with these things is they tend to run in families. A couple things. One is only a quarter to half of these people are ever symptomatic. So you'll see somebody like the 17-year-old kid who collapses on the ice, and one of his or her parents has the same condition, but is well. They have a mild version of it, and then it's worse in the next generation. So it's common to have people who don't realize that they're at risk or have the condition. Most people will never be troubled by their condition. So that's one thing. The second thing is the sudden death rate's 5 to 25%, okay? That might seem relatively low, but quite frankly, if you have sudden death in a 17-year-old, the life, life years lost, the tragedy, the social impacts are dramatically different than if their grandparents dropped dead. I'm sorry to be ageist, but the reality is they're horrific situations that leave families scarred forever. And again, the important thing is at least half of the people will have it and not know. And that's why it's, I laugh, I have a brother who's a family doctor, and I say I'm a family doctor too, because you have to get beyond the person in front of you to the family around them. And not to be critical, but the American health system has a tendency to silo patients within their own care and not families, so that unless families are in the same health system, there are barriers to the ability to exchange information and care and advocate for family screening. So there's a lot more inherited arrhythmia organization outside of the United States because of the insurance system that does that. And Canada's a better situation that way, because everybody has the same health plan. So we all share the same sort of system, if you like. And then importantly, most of these people, because of course, if the minority are symptomatic and many are unrecognized, treatments are simple, right? So there are things like there's some drugs that make these conditions worse. There's some simple drugs like beta blockers that are 10 cents a day. Occasionally we use ICDs, but ICDs are not what happens for most of these people. They happen in the highest risk people or people who have had problems, okay? So if we can find these people, we can protect them very effectively. So the inherited arrhythmia clinic's not like your usual clinic. So it's sort of bizarre. I sometimes go to clinic without a stethoscope. That's not your typical way. And so I've shown you two pictures here. So the picture at the bottom there, so at the very back is the little guy in the green hat. So he's eight. He has a fraternal twin. Unfortunately, he had a fraternal twin, and they were coming out of an ice rink. They were horsing around with a couple friends, and his brother collapsed and had 15 minutes of attempted resuscitation before the ambulance got there and didn't survive. So he has that thing called CPVT. So we found this out by getting his DNA, doing genetic testing, finding the culprit gene that causes CPVT, and then testing, and so does his mother. And in fact, we found eight family members among about 40 that we've tested who have this condition who are now protected because it's a simple medical treatment for protection. But the sad thing is there's a face missing on their family picture, a terribly sad thing. But what you see in that picture there at the back are three people who are the family, and then the other people around are adult and pediatric EPs, genetic counselors, nursing, and research staff. So this is a team sport. This is a multidisciplinary clinic for sure. On the right is why at least half the time it's quite complicated. So on the right, for example, is a grandma, dad, and daughter. And grandma got a pacemaker like any old lady whose heart goes too slow and develops heart block. So then it turns out that dad keeps coming in and getting repeat coronary angiograms because he has brugada. He always has brugada on his EKG, and nobody can figure it out, but because he doesn't always go to the same emergency room when something funny happens, he gets repeated angiograms in different hospitals. But he's got brugada. So then his daughter then develops syncope, and it turns out she has long QT. They all share the same genetic mechanism that manifests itself three different ways in one family. So if you don't connect those dots, this very complicated thing, which is a good research question is how can it be so different in three members of the same family make for individual care that doesn't identify the genetic nature of it? So this is a nice series from Mike Ackerman's group that looks at the genetic predisposition to cardiac arrest. And if you take cardiac arrest patients and you look at whether there's an inherited cause, the older you get, the less likely that's the case. So if you look on the left, 90% of their cardiac arrest in people under the age of 10 are genetically driven. And by the time you're in your 40s and 50s, it's very much the minority. So it sort of teaches us that the younger they are, the more extreme they are, the more likely they are to be genetic. So when we do genetic testing, we started doing genetic testing around 1995. We literally said there's a gene that causes long QT syndrome, and we would test one gene. And then we figured out that, in fact, several genes can cause long QT syndrome. We're now up to testing 17 genes. And then some of the technology really changed to be able to really fast track and make this simpler. We could test more genes. We could do it much more reliably, and so on. So in 2012, we were testing about 20 different genes for in the cardiac space. We now test 200 routinely. And then the other cool thing is that some of these technologies mean we can test the entire genetic sequence for $500, and it'll be 200 soon enough. So this notion that genetic testing is something in the future or there's some kind of big barrier, I mean, it's more expensive to go to the emergency room, register at triage, and leave than to have a genetic test, right? So it's not about cost, right? It's about the process of acquiring and using the information and what to do with it. And genetic counselors are the key because they're really the educators that help to explain the nature of genetic testing because the interpretation is complex. So they counsel and consent patients. Most of the time now, we collect sputum, not blood, so it's not even a needle. Right now, it's done in commercial labs, mostly in the U.S. and in Europe. Your own environment's important to figure out, but it's common for the price of this to be in the order of $1,000 to $1,500. This is a fairly dynamic area where pricing changes every about a month or two. Family members are tested, and they're only tested for what's going on in the family, so it's very cheap. Oftentimes, the company will actually give away the test, and it doesn't take very long, and the issue is insurance coverage. And that's a good offline conversation because it's not a short one about the battle that people go through to try to get coverage to be able to do this. One of the key things your EP will do if you're interacting with the EP is not so much necessarily the genetic testing, but in fact, the clinical testing around this. And so I sort of laugh and say that, you know, just like men are from Venus and women are from Mars or the other way around, that EPs are different. You know, in our place, we have an EP lab next to the cath lab. And when you shout out VT, the EP lab goes, hooray, and does the wave, right? And in the cath lab, they panic, right? So EPs like to make trouble, okay, because their problems are typically lurking in the weeds, and we're trying to bring out that. So we like to provoke. That's the sort of principle of stimulation in the EP lab. So the secret sauce is provocation. So this is an example of we use, for instance, exercise to bring out evidence of long QT. Remember, I said half of these people don't have, like, half of these people don't have a long QT on their EKG when they have long QT. But exercise brings it out in about 90% of people. So exercise is one mechanism by which we do this. We also do it with drugs. So this is an example of that. This is, in fact, that 44-year-old person who had this ECG. And for those of you who don't read ECGs, we're sort of focusing on, again, the big spike, that's the flush, and it's the filling. It's the ST segments after that. So if you look here, it looks a little funny. There's something called ST elevation here in V2 that you see right here, okay? But if we put the recording leads a little higher to look at what that signal looks like higher in the heart, it starts to look concerning for something called brugada, okay? And then if we give procainamide, there's the provocation, okay? We now have clear-cut evidence of brugada. And if you look in the high leads, we have worrisome evidence of brugada that's very dramatic. But unlike a myocardial infarction, if we exercise the patient or give them isoproterenol, we can make it much better. We can, in fact, basically normalize it. Okay? So here's your test that shows this person who had, hmm, wonder why he had the cardiac arrest, has now got evidence of brugada. So we now have a diagnosis. It also helps because it makes a plan. Brugada patients have a very specific plan if they have a recurrence. If they get ICD shocks, they don't need the usual treatment, they need different treatment. So this kind of testing helps to identify this, and now we know what to look for in the family. So the key message is this is, in fact, family medicine. And so one of the things that we do is we have a whole platform of systems for communicating information through patients to their families. And so our most common referral is actually our own letter to the patient that's then faxed back to us saying, please see this patient's sister who you know. Review the records, provoke with things like exercise and pharmacology and genetic testing when you see a phenotype, and again, risk prediction often leads to the ability to deliver very effective therapies that are often very simple, and then make a shock plan based on making a diagnosis from the patient. Thank you.
Video Summary
In this video transcript, the speaker discusses the importance of identifying and treating genetic conditions related to heart disease. The speaker shares their own experiences with patients who have genetic conditions, such as Long QT syndrome, and emphasizes the need for increased awareness and access to inherited arrhythmia clinics. The speaker explains the process of genetic testing and the role of genetic counselors in educating patients and families. They also highlight the importance of provocation testing, such as exercise and drug stimulation, in diagnosing and treating these conditions. The speaker concludes by emphasizing the importance of family medicine and the need for comprehensive communication and collaboration among healthcare providers to ensure effective treatment and protection of individuals with inherited arrhythmias.
Keywords
genetic conditions
heart disease
Long QT syndrome
inherited arrhythmia clinics
genetic testing
genetic counselors
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