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Updates in Long QT Syndrome: Experience from the Stanford Inherited Cardiac Arrhythmia Clinic

Interview by Jodie Elrod

Interview by Jodie Elrod

In the next episode of The EP Edit podcast, we speak with Dr. Marco Perez, a cardiac electrophysiologist and associate professor of cardiovascular medicine at the Stanford University Medical Center in California. As director of the Stanford Inherited Cardiac Arrhythmia Clinic and director of the Stanford Cardiac Electrocardiography Laboratory, Dr. Perez’s research focus is to evaluate the fundamental causes of cardiovascular disease through the study of genetics and epidemiology. In this interview, he tells us about his work and research in long QT syndrome, a rare inherited arrhythmia. Enclosed here are the edited transcripts of the podcast.

Tell us about the Stanford Inherited Cardiac Arrhythmia Clinic. Approximately how many patients with long QT syndrome (LQTS) are seen on average?

Broadly speaking, we manage not just long QT syndrome, but all sorts of inherited arrhythmic conditions, and this includes ion channelopathies like long QT, which is the most common ion channelopathy, Brugada, CPVT, and so on, but we also manage a lot of patients who have arrhythmic disease who have inherited cardiomyopathies like hypertrophic cardiomyopathy (HCM), ARVD, and several others. We have about 130 patients that we follow just with LQTS, but if you add the other inherited ion channelopathies, there are several hundred [patients]. If you start looking at the inherited cardiomyopathies, for example, we have over 500 patients with HCM, and we manage the arrhythmic components of those diseases.   

What is the incidence of LQTS?

It’s not exactly well known. One estimate is about 1 in 2000, and that is based on screening in young infants with EKGs and genetic testing, but the true prevalence of long QT is a little hard to tell for a few reasons. One is because the diagnosis is based on prolongation of the QT interval, and that can come and go. So one day you can have a normal QT interval, and the next day it can be prolonged. So that is one of the reasons. The other reason is that it can be asymptomatic, so you can go a really long time in your life without feeling anything, and one of your very first manifestations could be sudden death. So a lot of people go through life not really diagnosed. One of the other challenges is that if somebody dies suddenly with LQTS, their autopsy is completely normal, because you cannot see the electrical abnormalities in the heart, and that becomes an issue. When we manage families and there is a sudden death in the family, they’ll come to our clinic and we’ll do a full evaluation, and one of the big questions is what the autopsy showed. Many times, the autopsy is completely normal, and so it makes us wonder if some of these families actually do have long QT syndrome. It can be quite a challenge sometimes to find the root cause.

What is the median age for first LQTS event?

Most people present before the age of 30. The median age really depends on what kind of population you look at. For example, if you look at pediatric registries, the median age is closer to the teenage years. If you look at broader registries that include adults, the median age is closer to about 21-22 years of age, but it can present anytime in life.

What percentage of all LQTS patients still have a negative genetic test or a variant of uncertain significance?

When we look at our genetic testing in these populations — let's say you make a clinical diagnosis and know that they definitively have LQTS, and that is based on an EKG and some symptoms they present with, or maybe they’ve got really clear signs of LQTS — in those patients, only 75% of the time do we get a genetic confirmation. In some ways, it sounds a little bit low, but believe it or not, it’s one of the cardiovascular conditions where the yield of genetic testing is actually the highest. So compared to, for example, Brugada syndrome, that yield is closer to 30%. So in terms of yield and genetic testing, 75% is actually pretty good. But it does mean that 25% of people who get their genetic testing done will not have a genetic confirmation. It doesn’t mean they do not have it, it usually means there is probably another genetic cause for their LQTS — we don’t know all the genes that cause LQTS. We have a list of about a dozen or so genes that we believe are linked to LQTS, and we test for all these genes when we do genetic testing, but even then, some of these patients just have a genetic abnormality that we just don’t know how to test for.   

What other challenges still exist for optimal genetic testing?

You alluded to one of them, which is that often when somebody gets a genetic test, they have a rare variation. LQTS is a rare inherited disorder, and we believe that the vast majority of these are caused by rare genetic variations. So when we test for them, we find rare genetic variants, but one of the big challenges is sometimes knowing how to interpret the results of the test. A very common and difficult scenario is that somebody with LQTS comes in and gets their genetic testing done, and there might be a rare genetic variant in one of the genes that has been well described. But that rare genetic variant might be new, so it may be that nobody else has ever described that very specific genetic variant and has never been reported. So now we have somebody who has a rare genetic variant, but we don’t know if it is actually disease causing, because there are rare genetic variations that don’t cause disease — just because a variation is rare doesn’t mean it is what we call pathogenic, which means that it causes disease. One of the big challenges that we have right now is knowing how to interpret some of these variants of unclear significance, because it’s never been seen before and we don’t know how to interpret it.

Discuss the concept of precision health at Stanford Medicine.

Rather than treating a patient like an average patient who should receive the most commonly prescribed medication or the treatment that works for most people, the idea behind precision medicine is that we can go beyond that — we can individualize the treatments and other things like prognosis for our patients, and that is based on very specific information. Broadly speaking, you take information about your particular patient, like their history or certain laboratory tests. In the case of genetic testing, you can take the information about the genetic variation. So you can use all of that information to go beyond the average therapy for the average patient and determine if you might have a therapy that would work better for your particular patient knowing a little bit more information — in this case, genetic testing — about the patient. LQTS is a really good example of this, because it is one of the few conditions where the results of a genetic test can actually influence the way that you manage a patient. When we do genetic testing for LQTS, we find out what kind of LQTS it is. There are about 12 different kinds of long QT syndromes, the most common being the first three, and there is a lot of information that we know now about how each of the different long QT syndromes — or at least the first three — behave and how some of them respond to medicines. A nice example for this is long QT-3, which is due to a problem with the sodium ion channel, and if we identify that is the gene that is involved, then there are therapies such as mexiletine that can be more effective in that kind of long QT syndrome. So that is the concept — you can start to target the best medication or the best intervention for your patient based on all of this detailed information.

How are advanced genetic editing tools and stem cell technologies also allowing clinicians to more precisely prevent or diagnose cardiac disease?

This is an area that is very exciting right now, and Stanford is doing a lot of the leading research. For example, here at Stanford we have a big initiative to do a stem cell bank of all of our inherited arrhythmic patients and other conditions as well, but the possibilities of what you can do with the stem cells at the moment lie more than anything on help with determining whether or not a rare variation is actually disease causing. So this gets back to the challenge of the variants of unclear significance. For example, we’ve done studies where we have taken a genetic variation that we identified in one of our long QT patients, we took his blood and were able to create some stem cells and differentiate them to cardiomyocytes, and then we were able to edit his genetic code to see what happened if we corrected the genetic variation in one of the long QT abnormalities that he had. We found that before correcting it, there were clear abnormalities at the cellular level, and after correction, those abnormalities went away — that gave us some more confidence that this genetic variation may be playing a role in our patient’s disease. So that is an example of how at the moment, stem cells and gene editing are helping us treat our patients.

This is more futuristic, but one area of what you can do — not for long QT, but we’ve done this for other conditions (for example, in patients with arrhythmic cardiomyopathy) — is to take a patient’s blood, de-differentiate it into stem cells and make cardiomyocytes from that, and then — this is the exciting part — take the stem cells and make muscle cells (essentially cardiomyocytes) from these stem cells to see how they behave in terms of arrhythmias. You can also try different medications. For example, we had a patient who had very severe arrhythmic disease with very frequent ventricular and atrial arrhythmias, so we derived some stem cells from her, created some cardiomyocytes, and then tried different medications. We were able to tell that there were certain types of medications that at least her stem cells were responding to, so now we’re taking that back to the clinic and seeing how she is responding to the different medications that were successful in the dish. So the concept is sort of a “patient in the dish” — meaning that you can try different things on the patient’s cells before you actually try it on the patient.      

Do wearable technologies also have a role in the management of LQTS?

I am one of the co-principal investigators on the Apple Heart Study, so we’ve been doing a lot of work trying to see how well wearable technologies like the Apple Watch can do things like detect atrial fibrillation. In the field of arrhythmias, at least for atrial fibrillation, it looks like we have this data suggestion that this wearable technology is doing a reasonably good job. In long QT syndrome, however, this has not been as well studied. There isn’t a lot of data on wearable technology and measurement of the QT interval. Theoretically, someday if we develop tools to measure the QT interval more accurately using wearable technology, you can imagine the day where somebody is monitored for their QT interval and if there is a significant prolongation in the QT interval, that could alert the patient that there could be some changes going on, but that hasn’t been studied quite yet. Measuring the QT interval can be a little bit tricky, and doing it accurately can be difficult, so we’re a little bit away from doing that with long QT syndrome, but we’ve made a lot of progress in other conditions such as atrial fibrillation.

Do you think there is a need for more specialized multidisciplinary clinical programs that combine focused expertise in cardiovascular medicine and genetics?

Absolutely, yes. Here at Stanford, I think one of the really special things that we have is that the inherited arrhythmia clinic is part of an umbrella organization with the Stanford Center for Inherited Cardiovascular Disease. What we’re really proud of is that within this umbrella organization, we have cardiovascular specialists in the different specialties, and we have cardiovascular physicians who specialize in the inherited cardiomyopathies, aortopathies, and lipid disorders. So we all work very closely together, and as you can imagine, there are a lot of inherited cardiomyopathy patients who need electrical care, and a lot of patients who get referred with arrhythmias actually end up having cardiomyopathies. Therefore, it is important to have this close relationship between the inherited arrhythmic disease specialists and the inherited cardiomyopathy specialists. We also have created an environment where we work very closely with a bigger team that includes genetic counselors, so they’re a very important part of our organization. Genetic counselors help us in many things, including taking multigenerational family histories, counseling our patients in terms of the risks and the benefits of doing genetic testing, helping us interpret our genetic variance, and communicating a lot of the nuances in genetic testing to our patients and their families. They help us reach out to family members who need testing or who could potentially provide more information about the nature of the disease. So they are a pretty critical part of our group. We also work very closely with pediatric specialists. We’ve differentiated ourselves into adult and pediatric CV specialists, so, for example, I see mostly adults, but I have colleagues in our organization who see kids. The issue is that adults with cardiovascular disease have kids who are at risk for these inherited disorders, and likewise, kids who are diagnosed with inherited disorders have parents who are at high risk for having them as well. So it’s important to work together in order to send uniform messages to the family about how we are going to screen them and how we are going to manage them, and that is a pretty important part of what we do. We have nurses who have been trained in managing, because when you manage a patient with LQTS, you’re actually not just managing that patient but the whole family. Our nurses sometimes manage very large families, and they help coordinate the care across families and across generations, so it becomes a really big team effort to help manage entire families.

Can you tell me more about your research at Stanford evaluating long QT?

I mentioned one of the important things that we do, which is the stem cell research, and we collaborate with folks like Joseph Wu and Sean Wu, who are specialists in stem cell research. Together with them, we have a pretty large bank of stem cells from patients with these disorders — not just long QT, but other inherited disorders. We are doing some pretty cutting-edge research in terms of gene editing to characterize rare genetic variants, such as the “patient in a dish” type of research, so that is one big aspect of what we’re doing. We participate in barter studies, so for example, we participated in a long QT research study headed by Rachel Lampert from Yale to better understand how exercise influences the risk of events in patients with long QT syndrome. One of the things that has been a challenge in the past has been to really understand how to counsel patients with long QT syndrome. To give you an example, in the older guidelines, when somebody was diagnosed with long QT syndrome, it was recommended that they not do any exercise at all — like, zero exercise. You can imagine, especially for younger patients, that this could be devastating. There has been a lot of work over the last several years to better understand the risk involved in patients with long QT who exercise. So this registry has really helped to better understand what the true risks are, and we’ve contributed pretty significantly to this study. We do other things like better understand how to measure the QT interval on the electrocardiogram, so for example, we have a study that we recently published to more accurately measure the QT interval during atrial fibrillation, which can be a challenge in some patients as well. So you can see it is a pretty broad scope of research that we do, from the basic and cutting-edge level, to the more clinical level.

Is there anything else you’d like to add?

LQTS is pretty rare condition, and not even a lot of electrophysiologists might be as comfortable managing some patients with LQTS, particularly when it comes to the genetic testing and interpretation. So there really is a strong push towards getting patients this specialized care, mainly for the reasons that we talked about, which include the fact that we have genetic counselors, the ability to do a lot of the interpretation and the counseling involved, and the managing of the families. There is not a ton of data in this space comparing outcomes in those who are managed at specialized facilities, but there are some data demonstrating that in the right setting of specialty care where patients are managed with genetic testing, appropriate risk stratification, and appropriate exercise recommendation, that the rate of sudden death in this population is miniscule. So at least with appropriate guideline-based and cutting-edge therapies, you can really minimize, almost to a negligible level, the rates of sudden cardiac death.

Thanks so much for sharing this information with me today!

Sure! 

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