Talking Tall Rounds®: Inherited Cardiomyopathies

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series brought to you by the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic.

Wilson Tang, MD:

Good morning, everybody. Welcome to Tall Rounds. Today's topic is on inherited cardiomyopathies, and it is an important cause of heart failure and sudden death across all age groups.

Wilson Tang, MD:

Patients with inherited cardiomyopathies are frequently asymptomatic or they're often unsuspected, and yet they may be diagnosed incidentally or as a result of family screening. With the broad adoption of genetic testing, we started to approach many of them over the course of the last decade and we approached these complex inherited heart conditions with experienced multidisciplinary teams that take care of patients and their families, both in the adult and the pediatric world.

Wilson Tang, MD:

So today we'll discuss some common approaches and challenges in the multi-generational care of at-risk patient families of patients with inherited cardiomyopathy.

Wilson Tang, MD:

We'll start with a case. A 47-year-old woman diagnosed with non-obstructive hypertrophic cardiomyopathy back in 1984 when she was young, after an episode of sudden cardiac death from VT, she survived and received an ICD. At that time, they actually still used an endocardial patch. She subsequently had multiple generator changes and has been followed by our electrophysiology staff for some time. Over the last decade, she has progressive symptoms of heart failure because of the restrictive cardiomyopathy and stage three diastolic dysfunction. She was admitted with recurrent atrial flutter and AFib with pre-syncope events and ICD shocks despite having an ablation and had elevated NT-proBNP levels.

Wilson Tang, MD:

This is an echocardiogram you can actually see, there is a cardiac hypertrophy, biatrial enlargement, and very stiff heart. So she was readmitted that about two years ago with a low output state to the heart failure ICU with elevated filling pressures and impaired cardiac index. Balloon pump was placed and she was listed and subsequently underwent heart transplant and has been doing well since.

Wilson Tang, MD:

Now, at the time when she saw us about 10 years ago, we actually referred them to our genetic counselors who elicit the family history that she has a paternal uncle that died suddenly at the age of 25. Parents are both healthy though and had had clinical screening that did not see any abnormalities in echocardiogram. She did have the daughter at that time with normal echocardiogram. Genetic testing at that time showed a troponin T mutation with a substitution of lysine-2 glycine-93, the residue position with intron missense change.

Wilson Tang, MD:

And at that time, it was found to be likely disease-causing. Although the genetic testing report mentioned that this was a completely novel discovery. Interestingly, Titan mutations, sorry, not Titan. Troponin T mutations have been recognized over the past decades to be an important trigger of arrhythmogenesis and restrictive cardiomyopathy, and in part, because of its increased calcium sensitivity. And we actually see the area in 93 as close to the most common genetic variant of at the position 94, which has been associated with hypertrophic cardiomyopathy, as well as arrhythmogenesis.

Wilson Tang, MD:

So the family actually deferred genetic testing until she was 12 years old for their personal decision in part also, because at that time, that variant in ClinVar was still deemed variant of unknown significance because it was first described and has no prior reports. The daughter actually has had annual echo and EKG monitored locally with slight change detected in 2017 when the ventricular dimensions start to become slightly hypertrophy. However, she had a syncopal event during sports training exactly as the same age as her parent and as her mother, and the MRI during that time did not show any scar. Nevertheless, because of the event, she had an ICD placed. She's currently treated with metoprolol and she's healthy and at senior high school right now. So this case actually highlights that the genetic variant obviously when diagnosed, allows us to actually gain insights into the reason why both her and her mother, the outpatient and her daughter had such manifestation.

Milind Desai, MD MBA:

I think we will continue with the theme of looking at a bigger picture as it relates to at-risk family members. Here are my conflicts. I am running a clinical trial sponsored by Bristol Myers Squibb in the HCM space.

Milind Desai, MD MBA:

So some simple math as it relates to hypertrophic cardiomyopathy, genetic testing, and everything is great, but let's just walk through this. This is autosomally transmitted. As of right now, there's about a hundred thousand patients diagnosed with HCM in United States of which two-thirds are obstructive, and the rest walk around with a diagnosis of non-obstructive. Assuming a prevalence of one in 500, there's about 600,000 other patients, human beings in the United States that could potentially have HCM that have not been diagnosed. And if you base this, if you expand this math globally, there's about 16 million of which almost 14 million are undiagnosed. So there's a lot to be done. There's a lot to be done in this space in cardiomyopathy, in inherited cardiomyopathy space.

Milind Desai, MD MBA:

So how do you deal with HCM family members? As was detailed, it is crucial to take a detailed three-generation family history, strongly recommend discussion with a genetic counselor, and then they can decide whether or not to do further the genetic testing. A lot of people have different beliefs and values, but the genetic counselors I find are incredibly helpful, recommend screening of all first-degree relatives. A lot of times patients will say, "Can I get my grandkid tested?" I'm like, "Let's start with your kids and your siblings before we jump onto grandkids." And as we will talk, it could be using a combination of genetic testing and/or clinical screening with imaging.

Milind Desai, MD MBA:

So genetic testing, it is beautiful. It is fine and dandy, there's lots and lots of genes that have been identified in the context of HCM. A lot of seminal work done in this. How do you deal with genetic counseling? So obviously you need to start with the index case and you hope when you order the gene testing that the genetic testing is positive, because then you can do something about it. If the genetic testing is positive, then as has been alluded to, you go with targeted testing of that gene mutation. Too often, what we have is a negative genetic test or my favorite, variant of unknown significance, where I have no idea what to do. So what we do, we still have to be physicians and take care of the patient as well as their family members. So targeted testing in gene-positive patients, gene negative patients. What I tell them is science may not have evolved around right now. Maybe come back in three to five years. Variant of unknown significance, same conversation.

Milind Desai, MD MBA:

So genetic testing in HCM, lots of genes identified. However, this is based on Mayo and Toronto data. If you take a hundred patients that look like HCM, the gene-positive rate is less than 40%. So we still have to be physicians in the rest of the 60 plus percent of patients that walk into your clinic. Please remember that.

Milind Desai, MD MBA:

There's lots of work being done. This is just a slide I've taken from this large multi-center share registry. The whole purpose of this is to show that there's science evolving, lots of stuff going on and more work to come, more results will be available. The important thing is I am not aware of a single genetic mutation that puts you at a higher risk than others. So that is the key thing to remember.

Milind Desai, MD MBA:

What do you do with genotype positive, phenotype negative patient, either in proband or family member? The question I ask is, is this really phenotype negative? Just because there's no hypertrophy does not make them "no HCM."

Milind Desai, MD MBA:

Does exercise advance progression? Is the risk for sudden cardiac death similar to that in overt HCM? Should they get prophylactic therapies? What about athletic activities? There's no real conclusive answers. There's only strong opinions and quotation guidelines, which are generally based on consensus opinions.

Milind Desai, MD MBA:

This is the case that we saw years ago now, genetic positive, phenotype negative. This person was told he has nothing going on. He was MYBPC3 positive and true symptoms, no diagnosis until we provoked him. And the only thing we found is there's no hypertrophy, this very abnormal papillary muscle, this was one of the earlier ones that we diagnosed, which led to our developed understanding of that whole field of non-hypertrophic obstructive HCM variant.

Milind Desai, MD MBA:

Clinical screening of asymptomatic relatives of first-degree relatives, typically it is EKG and echo, impedes as will be discussed, you do this every one to two years, all other children and adolescents every two to three years; in adults, we recommend every three to five years. However, cannot underscore the importance of one thing. When in doubt, if the phenotype looks a little funky, go for the gold. Go for, do a stress echo, do a CMR, go for a full evaluation. Don't just stop at an EKG and an echo.

Milind Desai, MD MBA:

This is publication from a few years ago now, which suggested that echo alone clearly by the nature of its creation, CMR would be a little bit more sensitive than echo. So when in doubt, if you do not see the walls, well, go for a CMR. Don't hesitate in suspicious cases. Lifestyle sports, for most patients with HCM, mild to moderate intensity, recreational exercise is okay for athletes. Shared decision-making is crucial before you clear them, and who are gene-positive, phenotype negative. I think there's more and more data that suggests it is okay to participate in sports of course, shared decision-making is crucial.

Milind Desai, MD MBA:

Pregnancy, again, it is... I always say it is safe. In an experienced center, you will be well managed. But it is also important to manage comorbidities so that things don't crop up down the road, because you are adding fuel to the fire.

Milind Desai, MD MBA:

Moderate intensity, aerobic activity is beneficial. This is data from Michigan, which suggests you're more active, your peak VO2 is better. And if there's one thing you need to learn, higher the peak VO2, the better you are going to do in life.

Milind Desai, MD MBA:

So this is a recently published data from the VANISH trial where the authors, Cleveland Clinic was also part of this trial, gave Valsartan in early-stage hypertrophic cardiomyopathy, and they found all the markers, E over E prime, wall thickness and diastolic volume, BNP, everything trended in the right direction in the Valsartan group versus a placebo group.

Milind Desai, MD MBA:

The last thing is the business of genetics and gene editing, et cetera. This is still a concept that is being developed, evolving, but there's data that suggests you can influence the passing downstream of HCM by doing some gene editing. More to come in this space as the years go by. Thank you.

Shahnawaz Amdani, MD:

I'll try to sum up my clinical practice in the next seven minutes, so buckle up your seatbelts. I have no disclosures. So the two main objectives of my talk are to discuss the challenges that I face in my role as a pediatric cardiomyopathy specialist when I'm caring for children with inherited cardiomyopathy or who are at risk for inherited cardiomyopathy, and then briefly highlight some pediatric-specific cardiomyopathies that I encounter when I'm taking care of these patients.

Shahnawaz Amdani, MD:

So just to start off, the annual incidence of pediatric cardiomyopathies, these is extremely low. So it's 1.1 to 1.5 per a hundred thousand children and the gene yield, or the gene positivity yield is probably the highest for those with pediatric HCM, and it's still less than 60%, but it's precipitously lower for children with dilated cardiomyopathies or non-compaction cardiomyopathies, or restrictive cardiomyopathies. And I think that's where, leveraging what we have at our institution where there's the seamless transition between pediatric and adult providers is so important because as you see in the last sentence, even in the most experienced centers, there are patients who fall off in the transition from screening, when you have a child screening, the adult and so on and so forth.

Shahnawaz Amdani, MD:

And in these two studies, what they identified was less than 70% of at-risk relatives completed gene testing when there was a gene-positive proband, and less than 60% completed cardiac screening, which is essentially recommended for everyone.

Shahnawaz Amdani, MD:

So the first challenge that I have when I'm discussing with the patient is to highlight, with the help of a genetics team, is the presence of a pathogenic variant, does not mean that the patient will manifest that phenotypically as has been highlighted throughout the talk and that underscores the importance or the concept of variable penetrance. And then the second aspect is that not all family members, this is a common question that gets asked to me when I'm looking at multiple children, is not all will have the same manifestation clinically or at the same point in time. And that's why continued surveillance is so important. And that underscores the principle of variable expressivity.

Shahnawaz Amdani, MD:

There are two types of genetic testing that I use in my clinic. One is called the diagnostic testing that Joseph talked about in which I have a clinical suspicion for a child with some form of cardiomyopathy and I order a dedicated gene panel to identify the underlying gene. And then the second is what we call is a risk predictive testing or cascade testing. When one of my colleagues have identified the proband with a pathogenic or likely pathogenic variant, and all we are trying to do is identify if the child under my care has the same exact pathogenic mutation.

Shahnawaz Amdani, MD:

I think this cannot be emphasized enough. I think the concept that you're testing a vulnerable population group, and we'll get to that in a little bit, understanding that giving a child a genetic diagnosis that they're going to carry on for life carries a huge emotional burden and a psychological burden, not only for the child, but for the family in a condition where there is variable penetrance and expressivity is extremely important. And I think that's where we leverage as a group of clinicians with a lot of expertise here at the clinic. And again, highlighting that a positive gene test cannot predict who will develop the phenotypic manifestation nor the severity of the manifestation of the disease. This is extremely important and very different than what my adult colleagues practice, patient autonomy. For all of our adults, they can give consent for whatever testing that is required, but even in our pediatric practice or in my practice, I do take assent, which is making our children, especially our teenagers, understand the rationale for the genetic testing and the implications of the genetic testing, and then getting expressed approval when it's possible.

Shahnawaz Amdani, MD:

But then, the challenge that I face is I'm often facing these neonates, infants, young toddler who are not even able to provide assent, but where a genetic diagnosis is important and can alter the outlook of the disease. So just to give you two specific examples, I took care of a child who had a homozygous MYBPC3 mutation and Amish, had severe infantile hypertrophic cardiomyopathy. And these patients typically do need a heart transplant. And he did undergo heart transplant and is thriving since then. And then the other patients with dystrophin mutation who have Duchenne muscular dystrophy, in this particular condition, early initiation of an ACE inhibitor can delay the progression or onset of cardiomyopathy. And in these circumstances, we often do have to go undergo genetic testing without their assent.

Shahnawaz Amdani, MD:

Important to highlight this. I think all of us in this room understand that when you're testing for a gene condition, especially with the rapid proliferation of what genes can be tested, Joseph, correct me if I'm wrong, but the primary gene pile that we use has 86, the Pan Cardiomyopathy panels has 86, 87 genes. And then you can test for an additional 36 genes. So you may find certain variance, not of uncertain, significance, but really medical significance. That is unrelated to the reason the genetic testing was ordered. And in those circumstances, having that strong multidisciplinary team and leaning on our genetic counselors and the geneticists is so important.

Shahnawaz Amdani, MD:

So again, I think in specific to children, when I'm making a phenotypic diagnosis, what I do know from the limited literature that we have in children is there is a lot of genetic overlap between the different kinds of cardiomyopathies. And hence, we typically start off with a pan cardiomyopathy panel, and in cascade testing is relatively easier in which you're just screening for the pathogen variant that was identified in the first-degree relative who has the phenotypic manifestation. So, yeah, so just sort of highlighting very quickly about the pediatric considerations and the kids that we've taken care of. Unlike our adult colleagues, where we have certain inherited genes that are associated with certain phenotypes, there are a lot of syndromic and inherited and inborn aneurysm, metabolic and neuromuscular diseases that we take care of. So the first one is Pompe’s disease in which you have an infant with severe HCM, it's a glycogen storage disease, enzyme replacement therapy in this circumstance can, can reverse some of the cardiac manifestations. And that's why diagnosing it is so important.

Shahnawaz Amdani, MD:

Then we have a full cohort of Danon disease here, again, LAMP2 mutation where the patients have skeletal and myopathies and intellectual disabilities. The males are often more affected than females and the cardiac manifestation, again, is HCM. Often, these patients do end up undergoing heart transplant.

Shahnawaz Amdani, MD:

Then we have RASopathies that was touched upon a little bit, kids with Noonan syndrome, they have certain phenotypic manifestations that are extracardiac that would give you the di-, a hint as to what the syndromic or the other association is. They have short stature, they have HCM, but they also have pulmonic stenosis, and atrioventricular septal defect, kids that we take care of with muscular dystrophies. Again, Duchenne muscular dystrophy patients typically have early cardiorespiratory failure in the second decade and have dilated cardiomyopathies. There has been an increasing trend in the pediatric age group to support some of these kids if they have limited respiratory involvement to put a DT-VAD, which is typically not done in pediatrics. But then our kids with Becker's who typically manifest more in the adulthood, and I'm sure my adult colleagues see them.

Shahnawaz Amdani, MD:

Again, taking care of kids with mitochondrial disease, they are rapidly evolving, can have multiple organ systems affected. I've had patients who we've lost because they had multiple organ systems affected, but then kids like Kearnes-Sayre syndrome, where you have cardiac conduction issues like complete AV block or ventricular tachycardia, the phenotypic manifestation here is dilated cardiomyopathy, but they also have ocular manifestations.

Shahnawaz Amdani, MD:

Specific to POTS syndrome, this is a specific type of syndrome in which you have LV non-compaction is the cardiac manifestation, but you... It's X linked, so more prevalent in boys. It has associated with TAZ mutation and these patients have neutropenia and skeletal myopathy.

Shahnawaz Amdani, MD:

And then finally Friedreich's ataxia, which is patients have not only HCM as the cardiac manifestation, but they also have arrhythmias, dysarthria and ataxia. And again, what I'm trying to highlight is that these are different syndromes all within the inherited cardiomyopathy umbrella, where it's extremely important to involve a multidisciplinary team, a pediatric cardiomyopathy specialist like myself, is just one member, but then you have neuromuscular specialists, neurologists, geneticists and counselors who are extremely important taking care of these children, and the overall outlook for these children is very different. So the overall trajectory in which they progress is so different.

Shahnawaz Amdani, MD:

Addressing family hesitation, a common question that gets asked to me, which is as simple as what are the costs associated with it? Would the insurance cover this? And I think that's where our genetic counselors are so valuable in explaining, and in many cases offsetting some of these costs.

Shahnawaz Amdani, MD:

And then the fear about genetic discrimination, as was mentioned by my colleagues before, in fact there is a specific act called The Genetic Information Nondiscrimination Act came out in 2008, which bars the use of genetic information in health insurance and employment. And this is extremely vital for a kid, a child who you diagnosed at age 12 with a genetic condition could face, not only psychological trauma, but discrimination if this information were to get disclosed to other colleagues and future employers.

Shahnawaz Amdani, MD:

And then the psychosocial effects. So this is, I think the part that I struggle with the most. I have a child right now who I'm taking care of, a LMNA mutation has a... His father had multiple aborted arrests, had ICD, eventually underwent a transplant. And now with this diagnosis, which was after his assent, he's now severely depressed that he has the pathogenic mutation, although he has no phenotypic manifestations. And I think that's where my role is more of a counselor and a guide in explaining to him that there is no need to limit activities at this point, just continued surveillance is required.

Shahnawaz Amdani, MD:

Again, one thing that comes through in this talk with all of my colleagues here is that at the Clinic, we are well-positioned to take care of the most complex patients with cardiovascular disease, from birth to adulthood, and I think we should leverage that. Genetic testing should be considered for children who have high pretest probability and throwing a fishnet out there with whole exam sequencing is probably not the smartest idea. And the timing of testing, I think that's where the American Medical Association Ethics comes into play, is you have to understand as the specialist, the likelihood of the pediatric phenotypic expression, the availability of therapies and the psychological distress to the child and the family by disclosing a genetic condition that may not manifest itself in the pediatric realm.

Shahnawaz Amdani, MD:

Shared decision-making is extremely, extremely, extremely important. I know Dr. Desai touched on it. In my practice, if the patients are gene-positive, phenotype negative, I let them practice competitive sports without any restriction. But again, having that engaging conversation, calling in the families, calling in the child, making them a part of the collective decision-making is extremely important. And these kids are going to have more children. And I know it was touched upon before, but reproductive counseling is extremely important. And so children want to have kids and they do want to have kids and live their lives. You want to make sure that they are well-positioned and have had a chance to talk to our genetic counselors. Thank you so much for your attention.

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