Transcript
Announcer:
You’re listening to GLC on ReachMD. This activity, titled ‘Non-Obstructive HCM in Focus: Symptoms, Quality of Life, and Unmet Therapeutic Need,’ is provided by Global Learning Collaborative.
Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements, as well as the learning objectives.
Dr. Michels:
Symptomatic non-obstructive hypertrophic cardiomyopathy is a distinct clinical meaningful phenotype within the spectrum of hypertrophic cardiomyopathy, yet it's often unrecognized, and today we'll delve into its clinical features and impact on patients' quality of life. My name is Michelle Michels. I'm a cardiologist based in Rotterdam, The Netherlands, and I'm joined here today by my colleague.
Dr. Masri:
Hi, everyone. My name is Ahmed Masri. I'm a cardiologist from Portland, Oregon.
Dr. Michels:
We're going to start with a case. So I brought a specific case from my own outpatient clinic that I'd like to discuss with Dr. Masri. It's a 32-year-old male, and he was referred from a general hospital with chest pain and shortness of breath on exertion. And on echo, he has a clear phenotype of hypertrophic cardiomyopathy with a maximal wall thickness of 24 mm.
Very good left ventricular ejection fraction of 68%, a pseudonormal diastolic function, an E/e' of 16, and a left ventricular outflow tract gradient of 19 mm Hg. And, well, I think my first question is, Ahmed, what do you think about a case like this? So this is a symptomatic young man who is limited in his everyday life by chest pain and shortness of breath with hypertrophic cardiomyopathy.
Dr. Masri:
Great. Thank you, Michelle. This is a typical case or typical presentation that we see when patients come into the office with symptoms. And I think the most important piece to understand is the timeline of symptoms. You know, when they started, how they progress over time, and to integrate this within the echo which you nicely laid out already for us.
One important piece is to make sure that we exhaust all the tools at our disposal to rule out having any form of obstruction. Because, as we all are aware, obstruction in the LVOT can happen at rest with provocation, with Valsalva, or with exercise. And when it happens with exercise, you know, the principle is that the patients have to be limited. Some patients do obstruct with exercise, but they're not limited. They can do more than most people can on exercise, and they obstruct by then. So ruling out related obstruction is really important since we can treat that already now, and we have options for it. And the second piece after then is to make sure that we think about what else could this be.
So ruling out these phenocopies, ruling out the things that could present as non-obstructive HCM and trying to control the risk factors that come with the disease. And then finally, aside from thinking about the symptoms, we then need to risk stratify the patient for the risk of sudden death. And that can involve multiple different things, including heart monitor, ambulatory monitor, cardiac MRI, and trying to understand the family history a bit more as well as the imaging phenotype a little bit more.
Dr. Michels:
I think these are all very important aspects of hypertrophic cardiomyopathy. So I only mentioned the left ventricular outflow tract gradient during rest. But we also put the patient on a bicycle, and there was no significant obstruction. So it was a maximum of 25 on exercise, and he could not exercise to the normal goal of his age.
So he's severely restricted. He comes from a family with hypertrophic cardiomyopathy. We completely risk stratified him. Also, we performed a CMR, and we didn't find any signs of a phenocopy, which I think is very important. And we also did genetic testing, and then we found out that he is actually a carrier for myosin heavy chain variant, which, I think, is, with his phenotype and his age and a positive family history, I think we kind of expected the genetic results to come back positive.
But we do have an absence of significant left ventricular outflow tract obstruction with a severely limited young male patient with, well, substantial symptoms. The big question is what are we going do with this patient now? I think it's also good if we can talk a little bit more about the quality of life and the burden of disease.
But maybe first, Ahmad, what do you think of the genetic test results of this patient?
Dr. Masri:
I agree with you. It's fairly expected. Not every young patient or significant, severe phenotype at a young age requires to be genetically positive, but that's usually the case. And usually, as you alluded to, almost 80%, 85% of these patients either have a myosin heavy chain variant, or they have a myosin binding protein C3 variant.
And genetics help us in many different ways, but hopefully, even in the future, we might be looking at really genetically targeted therapies as well. That's why this is becoming more and more relevant.
Dr. Michels:
Yeah. Thank you very much. Yeah, and on a more, more personal note, I think symptom burden in non-obstructive hypertrophic cardiomyopathy can really have a substantial impact on the patient's quality of life even in the absence of left ventricular outflow tract obstruction.
So, Ahmad, how would you assess a patient like this in your everyday clinical practice?
Dr. Masri:
Yeah, great question. I think one of the biggest issues that we see from the referrals we get is that there is general lack of understanding of the difference between having shortness of breath in the absence of overt heart failure and congestion versus not. And I think a lot of us dismiss these symptoms in the absence of overt heart failure, which shouldn't be the case because these patients are limited.
And so we would dive deeper into their shortness of breath circumstances: how it happens, what really provokes it, what comes after. Chest pain in this condition is really important. It's a very complicated pathophysiology, but there are multiple reasons why patients could get chest pain, and it could be debilitating.
This is a younger patient, but if it's someone in their 40s and 50s, we need to make sure that we rule out concomitant significant coronary artery disease if someone has significant chest pain. And then, probably the biggest issue, all of these symptoms essentially converge on creating significant exercise intolerance and limitations in their daily living, which affects patients in many different ways.
Aside from the fact that they themselves are unhappy, they also become metabolically affected by this. And that's part of, probably, the story why you have so many patients with obesity with HCM and other comorbidities as well. And then measuring it, of course. Every time someone comes in the clinic, the simplest way of measuring it is by the narrative, but also NYHA class, since some therapies now are approved based on NYHA class.
And, in certain practices, if you have the ability to do patient-reported outcomes, such as Kansas City Cardiomyopathy Questionnaire or similar to that, I think that could be useful because you could track patients over time and understand what is going on between them. And really, an important piece is that discrepancy that happens between sometimes what you're looking at in the clinic and the reality that patients live in.
And one should not discount that because, again, you look at someone in the clinic, we're used to seeing patients with advanced cardiomyopathies or heart failure with reduced ejection fraction. They have physical and clinical signs that tell you how sick they are. In this scenario, the patient could look healthy in your office, but they are significantly limited; and that requires really a dive.
Dr. Michels:
I completely agree. So this is not a disease that happens overnight, so they tend to adjust their everyday clinical life. They stop doing certain exercise or use the car more often. And this, well, you should pay attention to that, I think. Ask a couple of more questions. And as for KCCQ, well, we don't routinely use it, but I think it can be very helpful, especially over time.
And do you think that there's also a role for biomarkers in these patients to get a better sense of how they're actually doing?
Dr. Masri:
Definitely. I think some biomarkers are better established than others. For example, in our practice, we use NT-proBNP essentially in every patient. It is becoming really an important marker of one really understanding what is going on, because it's very uncommon to have severe symptoms and your NT-proBNP, for example, is normal.
But also, it's an excellent surrogate for what you would expect to find in terms of diffuse fibrosis, interstitial fibrosis, and impairment of exercise capacity. And the difference of NT-proBNP in HCM compared to other heart failure diseases is that it actually is pretty steady, stable, and, again, as we mentioned, these patients have exercise intolerance, but they don't swell up at rest. They don't swell up in response to a meal here or there. So it's a very different marker behavior.
And I can tell you that, aside from just understanding symptoms, selecting patients for therapy, also, it has helped us over the years to keep track of it over time. And sometimes things happen. Patients develop other diseases, other conditions on the background of HCM, and tracking NT-proBNP can actually help you integrate their symptoms with a more objective marker as well.
And then in some other clinical trials, it was one of the most important predictors when it comes to the response to therapies. The reduction in NT-proBNP early on is a very important marker that the patient should respond and feel better in terms of their feel and function.
And then we also do look at high-sensitive troponin. If not for anything—it's useful, but if not for anything so that you establish a baseline for the patient so that when they go with chest pain or with some other symptoms to an emergency room or to another physician's office, they already have that baseline checked.
Dr. Michels:
That's very important, I think, because if they end up in the emergency room with chest pain and they have elevated troponin, that often leads to clinical difficulties. So I think that's really important.
So we have this patient with non-obstructive hypertrophic cardiomyopathy, well, clearly symptomatic, and, I think, what's a problem currently is that we actually don't have a specific treatment for non-obstructive hypertrophic cardiomyopathy.
So what are your, in your opinion, the current treatment options for these kind of patients?
Dr. Masri:
Yeah, that's probably the biggest issue, correct? We still think that underdiagnosis is a big, big problem in HCM. But on top of that, I think for specifically non-obstructive HCM, that we do not have any therapies that are currently available to us that actually have shown to be successful in a clinical trial.
If we actually dig deep into the evidence, there are suggestions that the guideline-recommended potential options that we can try, such as beta-blockers, actually could be detrimental to patients' ability to exercise and do things. And it's not a large multicenter in the case of non-obstructive HCM, but there is one in the case of obstructive HCM as well.
And so I think we should be careful there. So in our own practice, the guidelines, typically what they recommend is that you could try things such as beta-blockers, calcium channel blockers. If someone has congestion and requires a diuretic, you can use that. But for the sole purpose of improving their exercise capacity and symptoms, long ago we have seen that beta-blockers and calcium channel blockers actually don't help that much.
So we've stopped using them routinely except on a case-by-case basis when there's another reason we need to use them. Chest pain might be slightly different. I think sometimes in the absence of obstruction, chest pain, it's a hit or miss, but it can respond to either verapamil or ranolazine. Palpitations can respond to beta-blockers. So there are exceptions, but in general, for the sole purpose of improving exercise capacity and shortness of breath, really, we unfortunately do not have much right now in the case of being able to offer patients.
And contrast and compare that to obstructive HCM, where we right now have cardiac myosin inhibitors that can address the underlying disease pathophysiology and help us treat patients better and make them feel better.
So what do you think about that, Michelle? What do you think? What do you do in your practice?
Dr. Michels:
Yeah, so I completely agree. I've been trained to use beta blockade quite often and calcium channel blockers. We almost stopped using beta-blockers now, especially in young patients, because we are experiencing that you often make them worse. As for the chest pain, we don't have ranolazine available in The Netherlands, so we currently use verapamil.
Sometimes this does do the trick. And what we currently prescribe quite often are SGLT2 inhibitors, because they have been approved for heart failure with preserved ejection fraction. And sometimes patients do respond well, or at least they feel some relief. But there's, I think, a great unmet need.
And I think for many cardiologists, especially the non-hypertrophic cardiomyopathy cardiologists, they often see non-obstructive hypertrophic cardiomyopathy as a less severe disease. But in my opinion, it's a more difficult disease to manage than the obstructive hypertrophic cardiomyopathy patients.
And if you also look at the big registries, these are also the patients that do have ventricular arrhythmias and tend to develop heart failure if they age. So yeah, I think we're struggling. And that brings us to my next question because there are some targeted agents under investigation for non-obstructive hypertrophic cardiomyopathy, and there was one positive trial recently presented and published.
What can you tell us about these developments in the treatment of non-obstructive hypertrophic cardiomyopathy?
Dr. Masri:
Yeah. You know, despite the disappointing couple of decades in this condition, I think now we finally are at a point where we can say we have a positive trial and positive evidence for benefit for the patients. And so the idea centers again back on the sarcomere, which is the contractile unit that produces force, and in HCM, that force is disordered; that is being produced really excessively.
And so targeting that could result in reduction in the needs of the myocardium in terms of energy and metabolism but also can help in inducing relaxation and supporting lusitropy as well. And so that's where the cardiac myosin inhibitors come into play, by really counteracting this excessive actin-myosin interaction in hypertrophic cardiomyopathy.
Now the recently positive trial called ACACIA-HCM showed that aficamten can lead to a significant improvement in feel and function, as well as symptoms and biomarkers, echocardiographic measure of diastolic dysfunction, and then overall, from a responder perspective, patients responded well.
So that was really positive news. Again, first trial ever to show that. It's been a difficult space to really try and figure something out for these patients. And so obviously aficamten is not available yet for this indication. The trial just reported recently, as you alluded to. Prior to that, though, we had also another trial called ODYSSEY-HCM, which looked at mavacamten, the first-in-class cardiac myosin inhibitor, that was trialed before aficamten, and that trial did not show benefit from mavacamten.
And so what's important here is that to really avoid the urge to be extrapolating things. I think it's important in contractility modulation in the cardiac myosin inhibitor era to really treat medications separately as individual drugs rather than as a class and understand their benefits, their risks, and their indications separately, because I don't think we should be grouping such drugs.
And on the horizon in the near future, there are multiple new initiatives that are trying to address non-obstructive HCM as well. There is EDG-7500. There is BHP-1893. We also have ninerafaxstat, which is a modulator of energy. We also have a combined SGLT1 and 2 inhibitors as well, sotagliflozin, that is currently being looked at, and we have some gene-targeted therapies, including an anti-fibrotic agent that targets long noncoding RNA called Wisper, and that's HTX-001. I think the future is going to be bright in this condition. We're probably looking at needing multiple agents to address this underlying complex process of non-obstructive HCM.
But, overall, focusing on the current future, I think the ACACIA-HCM delivered really important results for us and for our patients, hopefully trying to mitigate the frustration that we all feel in the office when we just say, "Unfortunately, there's nothing that I can give you right now beyond what we've already tried."
Dr. Michels:
Yeah, thank you very much. You gave a great overview of, well, what's currently out there, but also what's, well, coming up the next year. So I do agree that I think the future looks bright for hypertrophic cardiomyopathy. Mavacamten and aficamten are probably not the end, but I think it's the start of a new era in the treatment of hypertrophic cardiomyopathy, and hopefully also for non-obstructive hypertrophic cardiomyopathy.
So, Ahmad, before we wrap up, let's each offer a final take-home message. What do you hope our listeners will leave with today? What's the most important thing?
Dr. Masri:
Looking at the current rather than the future, I think making sure that you work up patients with left ventricular hypertrophy and especially with exercise intolerance, you rule out obstructive HCM in patients who you think they have non-obstructive HCM, and then considering what else can be done for these patients from risk factor perspective and from other treatments as well.
And considering, really, ongoing clinical trials, I think you could really make huge difference in some of these patients' lives much earlier than when the therapy becomes commercially available.
Dr. Michels:
I do agree with your points. I think it's really important that we also make sure that we rule out phenocopies, especially in non-obstructive hypertrophic cardiomyopathy—we touched upon that in the beginning—because hypertrophic cardiomyopathy is not the only disease where we see positioned therapies entering the therapeutic space but, for example, also in cardiac amyloid provocation, you mentioned.
And I think the other thing that we have to take into account is the more general cardiovascular risk factors, like obesity, that we also have to target that in order to improve our patients.
So I think this wraps it all up for today. I want to thank our audience for listening in, and thank you, Ahmad, for joining me and for sharing all of your valuable insights and expertise.
Thank you very much.
Dr. Masri:
Thank you. It's been a pleasure as always.
Announcer:
You have been listening to GLC on ReachMD. This activity is provided by Global Learning Collaborative.
To receive your free CE credit or to download this activity, visit ReachMD.com/CME. Thank you for listening.
In support of improving patient care, Global Learning Collaborative (GLC) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. 
Global Learning Collaborative (GLC) has been authorized by the American Academy of Physician Associates (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 0.50 AAPA Category 1 CME credit(s). PAs should claim only the credit commensurate with the extent of their participation in the activity. 
Global Learning Collaborative (GLC) designates this activity for a maximum of 0.50 contact hour(s)/0.05 CEUs of pharmacy continuing education credit. 
