[MUSIC] In this module, I'm going to start the discussion around a set of diseases call the long QT syndrome, or in my view, they should be called the long QT syndromes because there are a number of different subtypes. In this particular module, I'm going to talk about the background for the disease. And in the next module we'll talk a little bit about the way in which that influences management of those patients and how that has implications for drug development and also for managing other kinds of patients. One of the reasons that I want to talk about the long QT syndrome is because I have a special laboratory interest in that, so we've contributed a little bit to this literature that I'll tell you about. The story that I'm going to tell you starts with a family that is seen with a 17 year old daughter, who during a softball game, collapses and is unable to be resuscitated from a fatal, abnormal heart rhythm. Her autopsy shows that her heart is normal. Death in a young athlete is not an uncommon event. This a series of over 1000 cases from an investigator in Minnesota. And one of the commonest causes are diseases that affect the function of the heart, cardiomyopathies, hypertrophic cardiomyopathies, dilated cardiomyopathies. Those are relatively evident at autopsy and among the causes, there's a minority of subjects in whom the cause is not evident at autopsy because the heart is actually structurally and as near as anybody can tell otherwise normal. Obviously it's not because there patients develop fatal abnormal rhythms as the cause for their cardiovascular collapse. So this is the family tree of this family. The deceased young girl is shown in black, and there is another death in the family at a young age in a paternal great aunt. And she died, had recurrent seizures and died at age 24. And I will say that sometimes the abnormal rhythms that come up in the long QT syndrome can present a seizure like activity. So it's not uncommon for doctors to take care of patients with arrhythmias to encounter patients in whom the initial diagnosis is a seizure disorder, and it turns out that it's an abnormal rhythm. This is the electrocardiogram of one of the deceased siblings. And the cardiogram shows, I've blown up a piece of it on the bottom, and that cardiogram shows a really striking prolongation of the QT interval that's indicated on the slide there. And in fact, it's not actually very clear where the QT interval ends. It could actually be quite a bit longer than that, because there's a little sort of trailing tail. And people have big fights about exactly how to measure the QT interim but in this case it in incontrovertibly long. Normal values are shown on this slide along with the QT values that are obtained across this family, so when the family has electrocardiograms, the girl's brother has a QT interval of 435, which is in the border zone, as you can see from the table. The father has a QT interval of 410, and the mother has a QT interval of 390. Those are both normal. On the other hand, the paternal grandmother has a QT interval of 475, which is a little on the long side and suggests that this may be an dominant disease that's transmitted from the grandmother and with variable penetrance through the father, so that's what we have. Let me talk a little bit about the history of Prolonged QT syndrome. One of the major contributors to our understanding of this disease has been an investigator in Italy named Peter Schwartz. And he published a paper in 1985, laying out the state of the arch. And the most important part is in the upper left-hand panel that shows what has come to be known as the Schwartz criteria for deciding whether a patient is affected with the long QT syndrome or not. Subsequent versions of this table have included a point system so to decide whether somebody is or is not effected. And of course with genetic testing those systems have become a little less interesting. The graph on the upper-right shows his particular person experience with the use of other beta blockers or an intervention called Left Sympathectomy or blockade to remove sympathetic to all or part of the heart. And the contention is that patients who have had these anti-sympathetic maneuvers do much better than patients who have no treatment and that's shown in the table on the bottom overtime both with data from 1975 and data from 1985. Very high mortality rate in untreated patients, lower mortality rate in patients receiving beta blockers. Often these events occur with exercise and so there's this idea of the beta blockers ought to be particularly effective. These kinds of data lead people to believe that the fundamental defect would be a defect in sympathetic signaling to the heart. And that turns out to be not the case but an interesting idea to start with and clearly identifies a set of interventions. So let me talk a little bit about the molecular basis for the long QT syndrome. There is the QT interval on the surface electrocardiogram and when we see a QT interval like that, we can infer that there are individual cells that have signals called action potentials, that are shown on the top. And the duration of an action potential roughly corresponds to the duration of the QT interval. Duration of action potentials in the ventricle, the main pumping chambers of the heart. Now of course there is heterogeneity across those action potentials, and that turns out to be quite important for some people's thinking about long QT syndrome, and the genesis of arrhythmias. I'm not going to touch on that part here, but there will be references that will be provided, and those will discuss that part further. So when we think about what shapes the QT interval we have to think about what shapes the action potential at the level of the individual cell. And that long plateau, that part from the fast upstroke that's mediated by fast inward sodium current is mediated by a balance between inward currents through sodium and calcium channels and outward current through potassium channels. Channels are tiny r proteins that are embedded in the cell membrane, whose mission in life is to transmit ions from one side of the cell to the other. And so when I see, or when an investigator sees a QT interval that is long, you have to infer that there's action potential prolongation in at least some cells in the ventricle. And when you infer that, what you say is well there's only two ways that action potential can get long, one is to have an increase in inward currents, or in the other way is to have a decrease in outward currents. That's fundamental elect cardiac electrophysiology. So it turns out that the vast majority of patients with Long QT syndrome had mutations and the genes that encode cardiac ion channels. And the most common are called LQT1 and LQT2, and those result in decreases in individual potassium currents that are shown on this table that are called IKR and IKS. And that's pretty irrelevant for the purposes of this discussion. The third common category is a mutation in the gene that encodes the cardiac sodium channel, which we call SCN 5A. And those mutations result in an increase in sodium current. So again, increase in inward current or decrease in outward current results, in almost all cases of the congenital Long QT Syndrome. There's a long list of rare, rare variants in many, many other genes, most of which interact with other potassium channels or sodium channels to change their function. So this is a disease of ion shells. And most cases are caused by mutations in one of those three at the top of this table. So there are some really interesting implications of understanding the fact that there are subtypes and they're shown on this slide again from Doctor Schwartz who started to investigate the possibility that individual subtypes of this disease, all of whom look pretty much the same when you see them individually because their QT intervals on their resting cardiogram are normal, may have different clinical manifestations. So patients with LQT1 form, one of the potassium channel related forms often have their events and event is a cardiac arrest or an episode of fainting due to abnormal heart rhythm during exertion. Patients with the sodium channel related form the LQT3 form tend to have events during sleep. Similarly, there's this mythology that if someone dives into the water, or someone has an event while they're swimming, they almost always have the LQT1 form. And that is true. On the other hand, there's a different form where patients have their event after an auditory stimulus. These are young children and they often will faint during a fire alarm at school or when the telephone rings at home or when an alarm clock rings. And so that is a pretty typical story for the LQT2 form. So these are interesting clinical tidbits that tell us a little bit about the different subtypes. So is there any importance in identifying the subtypes a little bit? This is a very large study from a registry that took place in Italy and studied 647 patients from 193 families and what you can see is a couple of things. Number one, patients with the LQT1 form are the commonest. They're about 350 of those and they, most of those patients, by the time they reach 40, have not had anything go wrong with them. So you could say, well this is a pretty benign disease, on the other hand a disease that kills young athletes, or a disease that causes potentially fatal fainting spells, syncope in a third of affected subjects is not so benign. The other two forms tend to have more events as you can see from the graph. And what we know is that the most important predictor of events among mutation carriers is how long their QT interval is. Patients with very long QT intervals to start with are at much higher risk than patients with very low, much shorter QT intervals. The question of exactly how to treat them, what the best way to treat them is very controversial, and I'm not going to get into that, clearly beta blockers are one mainstay of treatment. And one of the reasons that they are a mainstay of treatment is shown on this slide. I'll come back to that slide that I skipped in a second, but it's shown on this slide If you look at patients who receive beta blockers, there tends to be much less events among patients receiving beta blockers who had so called LQT1 form compared to the other two forms. There's physiologic rational for that, turns out the potassium channel that's encoded by the LQT1 disease gene is regulated by adro-energic stress. So it may be that before we had genetics, what we had was a collection of disease subtypes, most of whom have mutations in a gene that is regulated by adro-energic stimulation, and is therefore respond to beta blockers. The other forms don't respond as well as great controversy about whether they respond at all because we don't have placebo on this slide but clearly we have a better response in LQT1. I skipped this slide before so I'll come back to it. One of the other interesting things about this disease is that knowledgeable cardiologists can actually look at the electrocardiogram and try to guess from the electrocardiogram what the specific disease gene is. It's a little bit of an intellectual exercise, because at the end of the day, genetic testing is the way to find that out, not by guessing. But there is this interesting association between various patterns, and I suggest that the pathophysiology of the diseases are a little bit different across individual subtypes. So come back to this family. The fact that this girl had her event while she was playing softball suggests that this is the LQT1 form related to the potassium channel called KCMQ1. We didn't have material from the autopsy, that would have been the best way to do genetic testing. In principle, you do genetic testing in an individual who has clearly the phenotype. So that would have been the girl who died but in the absence of the girl who died, we'd do genetic testing on the person who's most obviously affected, which is her sister and the sister turns out to have a mutation in KCNQ1. That's not a single point mutation, but actually deletes three nucleotides, so results in deletion of a single amino acid, a phenylalanine at position 340 in the protein. So what do I take away, and we do genetic testing in the rest of the family and here are some interesting results. First of all, as we thought before, the grandmother and the father are carriers. The father has a normal QT interval and yet he had a daughter who died and a daughter who has manifests the disease. So that's called variable penetrance and I'll talk a little bit in a subsequent module about what might be influencing that. The other interesting part is that the brother has a QT interval, that's 435 in the border zone, but in fact does not carry the mutations. So he's off the hook. And that's important because if he thinks about having children, his children have a 50% chance of inheriting an abnormal allele where he to have one. But he doesn't so he's fine. The affected sister has to think about when she has children 50% of them will be mutation carriers, whether they have a severe phenotype or not is something that we don't yet know how to predict. So what does this part have to do with individualizing care? First of all, as we understand the nuances of a disease like the Long QT Syndrome, we understand the problems of variable penetrance, we understand problems of variable molecular subsets and how they respond to disease. And as I'll talk about in the next module, there are also implications for what kind of commonly used medications might actually affect risk in mutation carriers. So all of this has come because of our understanding of the fundamental basis of the disease itself and understanding the fundamental basis of the disease itself is then informed the way doctors who take care of patients with abnormal heart rhythms think about these ion channels and how they might go wrong, not only in the Long QT syndrome, but in other kinds of diseases where abnormal rhythms turn out to play a big role. [MUSIC]
