Hypertrophic Cardiomyopathy Treatment Options

Podcast Transcript

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Dr. Nissen:
I'm Dr. Steve Nissen and I'm here with two of my colleagues, Dr. Milind Desai who's in our imaging section in the Department of Cardiovascular Medicine and Dr. Nick Smedira, who is a cardiac surgeon who has tremendous expertise in surgically treating a hypertrophic obstructive cardiomyopathy. And together, we're going to talk about the options for treatment of this disorder. So let's begin with Dr. Desai, so what is a hypertrophic obstructive cardiomyopathy or HOCM? What is it? And how do you diagnose it?

Dr. Desai:
So HCM hypertrophic cardiomyopathy, it is a disease that has been described for the last 60 odd years, which is where the heart muscle... There is exuberant hypertrophy of the heart muscle, which is typically not explained by other factors like hypertension. A fascinating aspect of this is that it results in almost 70% of patients. It results in obstruction to the flow of blood, which is dynamic. The meaning of dynamic... It's not a fixed obstruction. There will be times when there is no obstruction to the flow of blood, but then there's other times when there's significant obstruction to the flow of blood due to a phenomenon called systolic anterior motion of the mitral valve or SAM wherein the mitral leaflet is dragged into the outflow track causing obstruction of the flow of blood. So it is also commonly seen in fairly young patients, but we have recognized that it can be prevalent in the full age spectrum.

Dr. Nissen:
And a familial predisposition.

Dr. Desai:
And there is a familial predisposition in an autosomal dominant mode. The rate with which we see it in the communities has long been thought to be about one in 500 prevalence, but recent data is emerging where it says the prevalence could be as high as one in 200 in these patients.

Dr. Nissen:
So it's pretty common.

Dr. Desai:
It is very common.

Dr. Nissen:
So how do patients present?

Dr. Desai:
Patients often are asymptomatic. They don't know, you may pick it up on an abnormal electrocardiogram, which could be dramatically abnormal. The symptomatic patients very often present with progressive shortness of breath, dizziness, lightheadedness, often they present with syncope, passing out and rarely they also present with sudden cardiac death. So which is what causes a lot of angst because a lot of these patients are young.

Dr. Nissen:
Okay. Let's talk from just a moment about traditional medical treatments.

Dr. Desai:
So traditionally once the diagnosis is made, and once you identify that they have obstruction to the flow of blood causing a lot of their symptoms, the first thing we do is initiate lifestyle modifications. So the things that increase outflow tract obstruction, the dynamic obstruction. So what we tell patients not to do isometric exertion or avoid dehydration, avoid excess of alcohol intake, avoid sudden changes in position. These are some of the lifestyle modifications that work well in many patients, if these don't work or rather, you need something more, than traditionally we have relied on medications that slow the contractility of the heart and/or reduce the heart rate, sort of like beta blockers, something like Atenolol Metoprolol.

Dr. Desai:
If these drugs don't work in some patients or they have side effects, then we can use certain type of drugs called calcium channel blocker. The most common being Verapamil. The third line, if these things don't work or you have maxed out on the dosages, then people have tried Disopyramide, which can also reduce the gradient and reduce the contractility. Now, an important thing that needs to be said around the medical therapy is none of these really have been tested in a randomized control trial so-

Dr. Nissen:
And of course they don't change the anatomy.

Dr. Desai:
And they do not change the anatomy.

Dr. Nissen:
Yeah. So now you have patients that, they haven't responded to medical therapy, and I'm going to turn to Dr. Smedira because you've probably had as much experience as anybody in the world. You've got a surgical option that works really pretty well. And maybe you could describe for us what you do and what the results look like.

Dr. Smedira:
Sure. I think one of the... What should I say? New understandings that we've developed here at the Cleveland Clinic and Milind sort of hinted to that, we've been primed for 60 years to think of hypertrophy as sort of the sine qua non of what you need to understand the problem of obstruction with the difficulty of the blood getting out of the heart and what we have tried to evolve our thinking to, from a surgical perspective, is there are multiple reasons why you can have obstruction and classically it's, the septum gets thick or hypertrophied, which leads to obstruction. But what imaging studies have shown and what we have identified which leads to my answer to your question, is it can be a combination of the muscle and the mitral valve. They are sorted together and define the channel for the blood to leave the heart.

Dr. Smedira:
If it gets thick, you can get obstruction. If the mitral valve is slightly off axis, too long, too mobile, you can get obstruction. So using the imaging studies, it guides me to think through the surgical techniques, which traditionally have been, just cut the thick muscle, do extensive myectomy. And we have modified and extended the myectomy. Probably 80 plus percent of our patients that's all they need. But as we became more attuned to the fact that you can have obstruction without hypertrophy and our long standing expertise in mitral valve repairs here at the Cleveland Clinic, we've now combined resection or removal or thinning of the septum, if possible, with a number of different surgical techniques to modify the behavior of the mitral valve, which leads to us being able to expand valve saving. So we can avoid valve replacement operations in patients with a combination of muscle and valve generating obstruction.

Dr. Nissen:
And how good are the results? I mean do people feel better? Can they exercise more? How good is this operation?

Dr. Smedira:
Yeah, it's probably one of the most rewarding operations I do. Patients, when we follow them out longterm have a return to normal functional capacity, like any other person in the U.S. that does not have obstruction and their life expectancy is exactly the same. The mitral valve intervention seemed to be quite durable. I don't know if we'd consider them permanent, but they're very, very successful. Our rate of needing a pacemaker in the average patient is 1% or less. So it's a very safe, reliable, and durable operation.

Dr. Nissen:
But it is open heart surgery, for sure?

Dr. Smedira:
It's definitely open heart surgery. We have to go through the middle, although we are exploring and certain conditions doing robotic approaches, especially if they have coexisting mitral valve disease, but it is open heart surgery. You do have to go on the heart lung machine. I do have to stop your heart to work on it.

Dr. Nissen:
Does the muscle ever regrow?

Dr. Smedira:
No, the best of my knowledge and what I tell every patient is once you reach a certain age, there's not a capacity to regenerate muscle. Although, as you know, we've done many, many studies here to put in stem cells and all sorts of things with the idea that... hopeful that they could regenerate the way to make sure that patient doesn't have [inaudible 00:08:56] , is to do an extensive myectomy, to take a significant amount of muscle and the skill that's required for the myectomy is to have imaging experts that tell me how thick it is, and then the experience to know exactly how much to take. So I make it thin enough, but not too thin.

Dr. Nissen:
It's really a highly specialized procedure that's probably best done by people who do a lot of them. Would you agree with that?

Dr. Smedira:
There's no doubt. You're working inside the heart, it's a very narrow, a lot of vital structures on either side. You have to take enough, but you can't take too much.

Dr. Nissen:
Yep. Now, so the three of us are working on a potential alternative to surgery and it's a new medications and maybe Milind you can talk about what this drug is and how it works.

Dr. Desai:
Yeah. So yes, like you mentioned we've had excellent track record with surgery and, and excellent results. Patients feel like a million bucks, but it is still open heart surgery. So to push the envelope of science forward, I mean we've been working with this new drug. There's a new drug out that is being currently developed Mavacamten. Essentially what this drug does is it works at microscopic level. Essentially what patients have with hypertrophic cardiomyopathy is, they have thick myocytes at a microscopic level that are contracting, that are in a state of hyper contractility. There is something called the bridges. There are bridges in between these different myocytes and studies have shown that in hypertrophic cardiomyopathy, there are a lot more bridges that are moving a lot. And so there's a lot of expenditure of energy. And so essentially there's some chaotic moment at a high expenditure of energy and results in stiffness or noncompliance of the heart in a big picture.

Dr. Nissen:
So it's stiff and it's hyper contractile?

Dr. Desai:
It's hyper contractile and it is stiff and it uses more energy. So this new drug essentially we think, or studies have shown at a fundamental level. And now in patient related study where it reduces the contractility, it reduces the energy utilization, it reduces the functioning of those bridges that I mentioned. And it has the potential of reducing or improving compliance of the heart or-

Dr. Nissen:
Does it affect the gradient?

Dr. Desai:
Yes. So an important thing that we have seen is that the fundamental problem of symptom cause in hypertrophic obstructive cardiomyopathy is the gradient. What it does is it has been shown to dramatically reduce the outflow tract gradients in multiple studies that have led up to now.

Dr. Nissen:
What about your relieving symptoms?

Dr. Desai:
There is a significant improvement in symptoms and functional capacity now because in obvious thought processes, if it is going to reduce contractility, could it reduce your heart function overall ejection fraction? That obviously has been a concern, but it has been studied well in multiple patients in multiple studies. And the concern it does not cause significant reduction in ejection fraction in vast majority, vast, vast majority of the patients, yet it results in a substantial reduction in gradient and the patients feel better. Yeah.

Dr. Nissen:
And so the study that the two of you are going to be doing together, what's the design, what does it look like?

Dr. Desai:
So the study you're referring to, it's called the VALOR-HCM trial. And essentially the concept is a little bit innovative. It is obviously a randomized controlled trial and blinded study where we hope to recruit about a hundred patients or so in about 15 sites, all experience HCM centers with excellent septal reduction therapy programs throughout the USA. And the plan is we want to blind half a group to placebo, half a group to Mavacemten. These are all simply obstructive hypertrophic cardiomyopathy patients that have advanced symptoms that are maxed out on tolerated medical therapy like we talked about.

Dr. Desai:
So they are close to end of the road where their next option is essentially either surgery or alcohol septal ablation. And we plan to randomize them into two groups for the first 16 weeks where one group will get placebo, one group will get the drug and we will reevaluate them at 16 weeks to see how they are doing, the hope or the hypothesis is that this drug, because it significantly reduces the gradient and improves the dynamics, the patients will feel better and we may be able to a stave off a surgical procedure.

Dr. Nissen:
At least in some of them.

Dr. Desai:
At least in some of them.

Dr. Nissen:
Yeah. And so this is an interesting and innovative approach. I think all of us involved here do not expect this to replace surgery, but it may allow at least some of the patients to have relief of their symptoms. Maybe either delay surgery or maybe avoid it entirely if their symptoms get a lot better. So it will be an interesting study to complete it's about to start. And it's great that we have both a surgeon and a non surgeon that are experts in this disease, working together, advancing medicine. And I think it's an exciting development. So thank you all for watching and thanks to both of you for helping everybody understand what's going on. What's really new with hypertrophic cardiomyopathy.

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