Talking Tall Rounds®: Inherited Arrhythmia's
Dr. Peter Aziz and Dr. Oussama Wazni highlight the contemporary & collaborative management of inherited arrhythmia’s.
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- Introduction by Moderators: Peter Aziz, MD & Oussama Wazni, MD
- Case Presentation: Benjamin Hammond, MD
- Overview of Ion Channel Physiology: David R. Van Wagoner, PhD
- Phenotype of Arrhythmia Disorders: Peter Aziz , MD
- Indications for Device Therapy: Mandeep Bhargava, MD
- Sports Participation: Michael Emery, MD
- Surgical Management – Sympathectomy: Siva Raja, MD, PhD
- Genetic Testing and Counseling: Joseph Liu, MS
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Talking Tall Rounds®: Inherited Arrhythmia's
Podcast Transcript
Announcer:
Welcome to the Talking Tall Rounds series brought to you by the Sydell and Arnold Miller Family Heart, Vascular, and Thoracic Institute at Cleveland Clinic.
Oussama Wazni, MD:
Morning, everyone, and thank you very much for attending today's Tall Rounds. I want to give a lot of credit to Peter Aziz, who's here to my left. Peter is the Pediatric Electrophysiologist and also Genetic Electrophysiologist here at the clinic in our group, and also, in Pediatric Cardiology. So thank you Peter for arranging this. Today we have a great session. We're going to talk about contemporary and collaborative management of inherited arrhythmias from ion channels to sympathectomy, and genetic testing and indications for defibrillators.
Peter Aziz, MD:
Want to use what Dr. Van Wagoner discussed in terms of ion physiology and action potentials and translate to the bedside. That's the goal of this brief talk. And I'll move a bit fast, given the length of time. We have a case presentation here, an 11-year-old with a family history of sudden death. She initially presented, as a matter of fact, with non-channelopathic symptoms of chest pain, she was an otherwise healthy child at the time. In examining her and in revealing history, we discovered that her paternal uncle died in his dorm room at 18 years of age. It was after his alarm sounded, his roommate reports that there was some strange breathing that was noted, and the patient was found to be unresponsive thereafter. This was tabulated as a sudden explained death. Of course, this happened years ago, and that's the amount of information that we had.
Peter Aziz, MD:
Getting an ECG on our 11-year-old patient perhaps was insightful in terms of what happened to her uncle. If we look at this ECG, it shows a normal sinus rhythm, but if you examine lead II a bit more closely, you see here — without using calipers, hopefully — that the QTc here is prolonged at 510 milliseconds, and this is a case of long QT syndrome. So long QT syndrome, from a broad scope of epidemiology and patient presentations, happens in about one in 2,500 patients. In the ion channelopathy world, that's quite frequent, so we do see quite a bit of long QT syndrome. It's a leading cause of autopsy negative sudden death. Cases about a thousand a year in the United States, and mostly in young children, typically about eight to 10, that's the peak. The hallmark presentation is syncope without a prodrome, and the hallmark arrhythmia is torsades, one that we'll see a handful of times today.
Peter Aziz, MD:
Long QT syndrome genotypes are pretty specific, so long QT1, long QT2, and long QT3 are the prototypes of long QT genotypes. Dr. Peter Schwartz years ago described what triggers exist in each long QT syndrome: long QT1 is predominantly triggered by exercise, in terms of events; long QT2 can have emotional triggers or sleep; and long QT3 is predominantly affecting patients in their sleep. Examining this in a table format, the three genotypes of 1, 2, and 3, you see that long QT1 is the predominant and most common form, effects the KCNQ1. All of these affect different phases of the action potential, Dr. Van Wagoner demonstrated how the potassium ion channels behave a bit differently than sodium ion channels in long QT3, and that's demonstrated here between 1, 2, and 3. The triggers can be different, the response to exercise can be different, and therefore, the efficacy of beta blockade can also be different. Where in long QT1, exercising catecholamines seem to be the predominant trigger, beta blockers tend to have the best efficacy.
Peter Aziz, MD:
The clinical diagnosis at the bedside, we oftentimes employ the Schwartz score. Again, Peter Schwartz, a pioneer in long QT syndrome, described this point assessment system for long QT syndrome. Patients that have a score of three or higher typically, at least, are assigned an intermediate risk of having the diagnosis of long QT syndrome, anything higher than four, that risk increases in terms of the probability of having long QT syndrome. There are various factors involved in this Schwartz score, having a QTc above 480 already starts you off at a points score of three, other things like torsades, having a family history, having syncope, are all employed in the Schwartz score.
Peter Aziz, MD:
Exercise testing is another bedside test that we oftentimes use, where you can reflect the differences in long QT1 and long QT2 relative to controls. One common misconception is that patients that are normal will shorten their QTc in exercise. That's actually not true, the long QT2 patients will actually decrease their QTc at peak and early exercise, and their QTc will increase later, and we've developed some lines in the sand, as it were, for what constitutes an abnormal repolarization pattern in QTc exercise. The treatment nadolol tends to be the basis of all therapy in long QT syndrome, particularly in long QT1 and 2.
Peter Aziz, MD:
Avoidance of medications that prolong the QT interval, we oftentimes find that patients that make it through the pediatric years without symptoms will oftentimes present themselves in adulthood after having exposure to a repolarization offending agent, and there are very easy ways, there are even iPhone apps, to be able to assess what is okay to use and what is not. Then device therapy really is for the small subset of populations, and I'm going to leave that one alone, because Dr. Bhargava is going to be speaking more about device therapy for our channelopathy patients.
Peter Aziz, MD:
Moving on to our next patient: 12-year-old that had exertional syncope. This patient was coming down a waterside at a waterpark, had syncope coming down the side, and landed in the pool unconscious. A lifeguard on the scene pulled the patient out of the pool though. CPR was not initiated and fortunately, the patient woke up spontaneously. Had a normal ECG and echocardiogram and negative family history, was seen initially in an ED in Atlanta. Just before discharge from the ED, had this very pathognomonic rhythm that we've seen a glimpse of in Dr. Hammond's presentation, this is bidirectional VT, and really should steer us into the direction of CPVT.
Peter Aziz, MD:
CPVT oftentimes presents with polymorphic VT, or in the case that we just saw, bidirectional VT. Clinical features, it's a cause of sudden cardiac death in the setting of emotional or physical stress. Just to add a clinical point to Dr. Hammond's presentation, the patient was described to have an event of torsades on link transmission during sleep, but I would argue that that patient was not sleeping at the time. We can think about what they were doing at the time, however, the heart rate was about 150 or so in sinus tachycardia before the event. So she was clearly not in REM sleep at the time. So exercise stress can be the key here to diagnosis in CPVT. If somebody has exertional syncope and everything otherwise looks the same, an exercise test needs to be employed to assess phenotype.
Peter Aziz, MD:
The phenotype is strong. 30% will have at least one cardiac event, 80% will have at least one syncopal event on presentation, so oftentimes these patients have already had a pretty significant presentation before they're diagnosed. Prevalence is about a quarter of that of long QT syndrome, one in 10,000, so not as common, and as Dr. Van Wagoner discussed, there are essentially four genes that are affected and proteins that are affected in long QT syndrome, RyR2 being the most predominant, calsequestrin, calmodulin, triadin can also be affected. Treatment is nadolol. If patients have breakthrough on nadolol, we move flecainide. If there's breakthrough flecainide, we call Dr. Raja and employ his services for sympathectomy. And then the ICD in this patient population is a difficult topic, and I'll let Dr. Bhargava tackle that one.
Peter Aziz, MD:
Next is a 10-year-old with a family history of sudden death. Excuse the clarity of this ECG, it's one of the rare, very spontaneous and very profound Brugada syndrome patterns that we have in our arsenal. I have not seen a phenotype this strong before this patient. This is a patient that had eight siblings, four of which died suddenly in their sleep. He also had syncope and the parents attributed his syncope to his mourning the loss of his siblings, rather than there may be a confounding factor here that might be at play. Again, this is Brugada syndrome. These are the Brugada genes, we typically look at SCN5A as the culprit, however, SCN5A is a elusive masquerader. It can cause various phenotypes, Brugada being one of them, long QT3 being another. Taking this from bench to bedside, what we typically look at in the ECG, in a patient, at the bedside is the three patterns: the Coved pattern, the Saddleback pattern, and type three is sort of a mix between the two, though, not as profound.
Peter Aziz, MD:
What Chen and Priori discovered and published in JACC years ago, is that different parts of the myocardium are behaving in depolarizing differently with various action potentials, and as Dr. Van Wagoner discussed, what we see on the ECG is sort of a mirroring of all of those action potentials at once. When there's that dispersion, we get what we see on the ECG. A very elegant study by Dr. Zhang in Circulation showed the different action potential patterns in depolarization in Brugada patients. In normal patients there's uniformity, the right ventricle depolarizes at essentially the same time, whereas if somebody has Brugada, the action potentials in the right ventricular outflow tract, in particular, are much later than they are on the rest of the heart, and that perhaps provides a reasoning for why we see what we see in V1 and V2 on an ECG.
Peter Aziz, MD:
Risk in treatment, risk stratification, EP study is controversial. We can use provocative testing to illicit phenotype in those that are silent, and there are many Brugada patients that don't have demonstrable phenotype. Treatment, there's not great evidence that quinidine works, though, it certainly is a historical drug that's been used. Avoidance of sodium channel blockers, much like in the long QT syndrome, we want to avoid medications that prolong the QT, we want to avoid medications that affect the sodium ion channel. Ablation is a bit of a newcomer, and then again, ICD therapy we'll table for a later discussion.
Peter Aziz, MD:
The key takeaways here is that we have to use the concept of the patient is broad. The patient that you see in your clinic may or may not have the phenotype that will lead you to a diagnosis, and therefore, this has to be really a family approach, you’re not treating the patient, you're treating the patient, their first few relatives that are likely affected, and then you follow that cascade down the line. I think therein really lies the fruit of finding phenotype, and we're fortunate here to use our resources, which is basic science, genetics, sports cardiology, EP surgery. And again, I hope this presentation will demonstrate the efficacy of that team collaboration. Thank you very much.
Michael Emery, MD:
So I am a sports cardiologist, I'm not an electrophysiologist, but I think it highlights the importance of a multidisciplinary approach to the management of these types of patients, specifically, when we start to talk about recreational or even competitive athletic participation in patients that have been diagnosed with these disorders. So I'm going to focus mostly on long QT syndrome, where we have a little bit more data and information, and a little bit on CPVT as we move through this. So these are the faces of sudden cardiac death in athletes. These are what no one wants to see. These are heart wrenching, gut wrenching, and tough for anyone to take in, whether that's an athlete on the field receiving CPR, the young athlete with an obituary, or good news, like Fabrice Muamba, who survived his on the field sudden cardiac arrest after an hour of resuscitation. He in fact did have long QT syndrome that was not detected, because it wasn't manifest all the time on multiple screening ECGs.
Michael Emery, MD:
So comparison of causes of sudden cardiac death in athletes, ion channelopathies are a known cause, hovering around two to 3%, depending upon which registry you look at, but in more contemporary studies, there's this large population of unexplained death, which is called sudden arrhythmic death syndrome, which didn't have an identifiable substrate, but probably represents a large proportion of undiagnosed channelopathies. So multiple pathways play into particularly long QT syndrome, we often think about fevers and medications, but that ultimate pathway at the end is that increased sympathetic drive to the heart, prolonging the QT, which is where exercise fits in, particularly, in long QT1.
Michael Emery, MD:
So what do the guidelines say? Often the Bethesda guidelines are referred to, this was published 2005. Channelopathies were lumped under multiple arrhythmias here, and in the same year, the 2005 European Society of guidelines came out. These were the classic paternalistic, non-data driven, and basically it said that if you had long QT syndrome, you were restricted from sports. US guidelines left some room for genotype-positive truly phenotype-negative, whereas the European guidelines said, "Even if you were genotype-positive with zero evidence of a phenotype, you should be restricted." But these really lacked evidence, they were before the guidelines used things like classes of evidence and levels of recommendations, they were really based upon expert opinion and they were grounded in the "art of medicine" because there wasn't a whole lot of science at the time.
Michael Emery, MD:
Things have evolved since that time and there have been a few publications, particularly on long QT syndrome and return-to-play. The first came out in 2013 from Dr. Ackerman at the Mayo Clinic, and he had an experience with 60 long QT syndrome athletes who continued to participate despite recommendations from the Bethesda guidelines, not necessarily recommendations from Dr. Ackerman though. So you can tell that looking at the Bethesda classification here, these low 1A sports have low dynamic, low static. These are things like golf, curling and bowling. Whereas when we increase the dynamic component or increase the static component, those are the more active sports: basketball, weightlifting, running-type of events, and there was a high number of these athletes in that sector. So in his cohorts — and remember, this is Dr. Ackerman's cohort — no increased long QT triggered cardiac events, there was one athlete who experienced two events during competitive sports who admitted to being non-compliant to beta blocker medication. So that boiled down to one cardiac event per 650 athlete years.
Michael Emery, MD:
Our own Dr. Aziz also published some data in 2015 on 103 people who participated in competitive, recreational, and physical education. A little more than half of these were asymptomatic, so genotype-positive phenotype-negative. All were treated aggressively with beta blockers, you'll see this theme come up again. There were no deaths or long QT syndrome cardiac events reported during participation. There were 12 long QT syndrome competitive athletes participating contrary to Bethesda guidelines, but there were zero events in 755 patient years.
Michael Emery, MD:
One more study has been published, more recently in 2017, 172 — so we keep getting larger numbers of registry-style case series. These were all phenotype-positive, 66 recreational, 106 competitive athletes. Again, we see a really high number of very active individuals participating in a wide array of athletics. Again, all on beta blockers, I'm going to come back to that again. There were 13 cardiac events in this group with no deaths, so that's 13 cardiac events in 1,203 patient years. Nine of those events of the 13 actually occurred during activities of daily living, not competitive or recreation events, four during recreational-type sporting events, and zero during competitive events. So pretty good success from these limited studies. This is just a brief recollection that in the newer guidelines, we have things like level of evidence. You'll note, level of evidence C is going to come up again, which is small case series, which I just presented to you, versus expert opinion and a lot of class 2A versus class 2B recommendations.
Michael Emery, MD:
So in 2015, the ACC updated their guidelines for sport participation. Now, there's a specific task force just for cardiac channelopathies, it was brought out of the rest of the arrhythmic-type disorders. And we have class 1 recommendations for evaluation in a comprehensive center with experience dealing with these, and those that are symptomatic, being asymptomatic for three months before any further consideration is made. Those are class one. We have then genotype-positive phenotype-negative, consideration for participation in all competitive sports with appropriate precautionary measures. This now is given a class 2A recommendation with level of evidence C. Then we have manifest long QT syndrome, symptomatic or manifest on multiple ECGs may be considered now, not totally restricted, with a class 2B recommendation. So things have progressed since 2005.
Michael Emery, MD:
Just last year, the ESC published some updated guidelines, let's have a look at what they say. They do have some class 1 recommendations now that really revolves around treating them aggressively and making sure that they are seen by experts. A 2B recommendation for shared decision making should be considered for sport participation in genotype-positive phenotype-negative. Recall that in 2005, they said, if you were genotype-positive, you were absolutely a hundred percent restricted. They did not go as far though as saying that appropriately treated manifest long QT can still participate. Briefly about CPVT, 2015 ACC guidelines really recommend restriction at this time if you have manifest CPVT. In fact, the 2020 ESC guidelines didn't discuss CPVT at all.
Michael Emery, MD:
But there has actually been one study published since then, again from Dr. Ackerman at the Mayo Clinic, on competitive sports participation on a single center experience, small cohort, 21 athletes with CPVT who remained active and 42 non-athletes who were either non-athletes to start with or discontinued their athletic participation, all appropriately treated. And what they saw was not a significant difference in the event rate between those who continued to participate and those who were not participating in athletics. Now, that event rate is still higher than classical long QT syndrome, but not different between the two in a single center with expertise, and the time-to-event rate was about the same between the two groups as well.
Michael Emery, MD:
So this really then boils down to shared decision making. I've talked about it once or twice, or I brought it up once or twice, and this is one of the more valued roles I think in sports cardiology and our contribution to this multidisciplinary team, and really has to rely on knowledge of the appropriate diagnosis, expertise in that cardiac condition, humility to say that we don't know everything and that we need to seek other opinions in a lot of cases, respect for patient priorities and recognize the patient's voice and opinion in this, so not being absolutely paternalistic, which the 2005 guidelines were. Teamwork, this is a team-based approach, multi-disciplinary approach, and communication, communication to the patient, the school, if there's a school involved, the parents, and multiple resources along the way.
Michael Emery, MD:
So some general sum up exercise in cardiac channelopathies. They really require a comprehensive evaluation and a management by specialists with experience and expertise. I can't stress that enough, particularly when we're talking about sports participation, that these athletes be thoroughly evaluated by experts and thoroughly worked up. This is not a random genetic test and off you go, this is not 12 and a half of BID metoprolol and off you go, these patients were aggressively treated with nadolol and/or sympathetic denervation when they were presented in the published case series. There have been no reports in the US of genotype-positive truly phenotype-negative, having their sentinel cardiac event during sports, so in the US, there are no restrictions. Avoidance of QT prolonging drugs, Dr. Aziz talked about this. We talk extensively about electrolyte and hydration replenishment, avoidance of dehydration, avoiding those hyperthermic febrile illnesses, and then when we talk about sports, not only that, we talk about core temperature changes with heat and training in sport participation and how that may increase your susceptibility.
Michael Emery, MD:
We talk acquisition of an AED as part of the athlete's personal sports safety gear, so they have their bag with their shoes and their mitt and their own AED, rather than having to rely on an institution to provide that. Establishing an emergency action plan with the school and team officials, I can't overemphasize how an emergency action plan is important. Then respecting the patient and family autonomy and that shared decision making approach. Thank you
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