Contemporary Management of Hypertrophic Cardiomyopathy: Key Challenges, Recent Advances, and Future Directions

Interview With Ahmad Masri, MD, MS

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EP LAB DIGEST. 2024;24(9):22-23.

In this interview, EP Lab Digest speaks with Ahmad Masri, MD, MS, from the Hypertrophic Cardiomyopathy (HCM) Center at Oregon Health & Science University about contemporary management of HCM, including recent advances, pharmacologic treatment options, new guidelines, and future directions. 

Could you tell us about the Hypertrophic Cardiomyopathy Center at OHSU and its mission? What unique resources or expertise does the center offer to patients with HCM?

Thank you for having me here today. It is a pleasure to chat with you about HCM. My name is Ahmed Masri, and I am a cardiologist at the Center for Hypertrophic Cardiomyopathy at OHSU. At our center, we have a multidisciplinary program that is designed to provide the whole spectrum of care for patients with HCM. We provide resources as well to our partners across the Pacific Northwest. We are a Center of Excellence as designated by the Hypertrophic Cardiomyopathy Association. We collaborate closely with them as well as with other centers across the country to help care for patients. HCM is a genetic disease, and if patients move, this network can really help us take care of patients across different states and all over the United States, even globally. 

In terms of some of the things we provide, we offer the whole spectrum of care for HCM, from evaluating patients and their family genetics, to all types of imaging modalities, and treatments, which are broken down into symptomatic management with medications, more specialized medications such as research-based or investigational therapeutics, and surgical interventions such as septal myectomy or any other needed surgeries. We also provide services for alcohol septal ablation. 

From the electrophysiological (EP) aspect, we also have electrophysiologists who focus on advanced and complex EP issues related to HCM, from atrial fibrillation and ventricular arrhythmias, which are very common in later stages of HCM, and as such, really do comprise an important aspect of the care of these patients. 

What are some of the key challenges in managing HCM?

I think one of the biggest issues that we come across is under-recognition, because patients do not typically develop the classic heart failure phenotype of not only having shortness of breath, but also leg swelling or volume overload, and on exam you have some signs and symptoms of that. Their heart failure symptoms such as dyspnea, limited exercise capacity, and ability to do things in life are frequently not recognized, and as such, the disease itself is not recognized and undiagnosed.

So, the first step is finding and diagnosing the disease. From there, things get easier, because once you recognize the disease, even if patients do not have local access to some of the therapies or treatment that are needed, then they at least have a diagnosis and can reach out. That is why our focus is not just to be a referral center where people come to be evaluated or treated. There are patients who can travel and there are others who cannot come from far away. So, we provide open access to their physicians and caretakers to allow for communication and help through the process. 

Another challenge is related to treatment and access to genetic evaluation, which I think is really limited. This is driven by both not having the service in many places, but also the current structure for reimbursement by Medicare and Medicaid for genetic counselors is fairly limited. So, that is another big challenge that we come across. Then finally, and at least this is getting better, but for patients who continue to have symptoms, their only traditional option if they have obstruction is open heart surgery such as septal myectomy or alcohol septal ablation. For patients with non-obstructive HCM, if they have advanced disease, it becomes kind of a waiting game. If they progress, then we proceed to heart transplant if the patient is eligible. 

So, those are some of the key challenges that we have in HCM. If I may add another one, it is in the EP space where some patients with HCM have significant burden of arrhythmias, and typical antiarrhythmics or catheter-based approaches sometimes might not be enough for these patients. That is one of the reasons why we offer advanced therapies such as heart transplant, because their arrhythmias cannot be controlled.

What are some of the most exciting recent advances in the understanding of HCM? What novel pharmacological agents show promise for treating HCM? 

Some of the advances were built on our better understanding of how the disease itself manifests and the underlying pathophysiology of the disease. It used to be thought that thickening was the primary problem in HCM. But over the years, it was discovered to be hypercontractility, so the heart was working too much. It does not have the checks and balances that make it essentially modulate how much it works. If you are sitting while watching TV, your heart should not be working too hard. If you are running a marathon, then you should recruit more muscle fibers and sarcomere units to allow you to produce more power. However, that is not the case in HCM. You could be watching TV and your heart is working as if you are running a marathon. That essentially leads to subsequent thickening, and thickening over time that goes unchecked leads to fibrosis and scar tissue. So, new drugs were developed to target this underlying concept of hypercontractility to have more control over how many of these power units, the sarcomere, are available to engage and produce more power. They are called cardiac myosin inhibitors, and 2 drugs are fairly well advanced in development. Mavacamten is commercially available and still in development for some other indications, and aficamten is in development and recently also reported positive phase 3 trials, so we expect to see this submitted to the US Food and Drug Administration sometime soon. So, those are 2 drugs that are fairly advanced, with one being available commercially and the other in advanced stages. Right now, both are for hypertrophic obstructive cardiomyopathy as a medical option to treat patients so they do not have to go directly to surgery or alcohol septal ablation, collectively known as septal reduction therapies.

How have recent guidelines (The 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy) influenced the management of HCM?

The recent guidelines were revised because of mavacamten becoming commercially available. The guidelines before this were in 2020, so not a lot of things have changed aside from the cardiac myosin inhibitors in HCM, which led to this new iteration of the guidelines. 

So, with the new guidelines, mavacamten or cardiac myosin inhibitors are referred to because you do not want to issue a new edition of the guidelines every time you have a new cardiac myosin inhibitor. In the guidelines, cardiac myosin inhibitors in general (mavacamten being commercially available) are now a second-line therapy that can be offered to patients after they continue to have symptoms and obstruction despite the use of beta-blockers or calcium channel blockers. Mavacamten was put at the same level in the guidelines as disopyramide and septal myectomy. Probably more data down the road will change that hierarchy of how things are, but it also approaches what we do in the clinic nowadays. In the clinic we tell patients that we will first try beta-blockers and calcium channel blockers. But really, you can tell upfront who is going to benefit from that with mild obstruction and mild symptoms and who is going to continue to have symptoms. However, it must be done. Then, the next step is to have a detailed discussion with patients about options. We used to use disopyramide a lot, but we use it less now because of its side effect profile. So, it comes down to mavacamten or septal reduction therapies. Patients tend to pick and choose based on what works for their lifestyle and values, how they think about one intervention with the possibility of seeing relief from further intervention and evaluation, or being on a medical therapy that could spare them the need for open heart surgery, for example. Everyone is different. It is difficult sometimes to guess which direction patients will go, but I think that is our responsibility as physicians and as HCM practitioners who are taking care of these patients to provide them with all the options and together have shared decision-making on choice of therapy.

Where do you see the future of HCM management heading in the next 5-10 years?

It has been wonderful to see all the interest, excitement, and advances that are happening in HCM. Many people who have paid attention to this space over the decades have seen many trials that have not been successful or showed that medications were successful in relieving symptoms and improving exercise tolerance. As such, this is really a great time and it is good for our patients that we can offer them more options. I think over the next decade we will be looking at more and more understanding of the underlying pathophysiology and mechanisms leading to HCM and opening the door on more therapies to be used in this space, not just in the cardiac myosin inhibitor category. I think that is only one category. Mavacamten is a step in the right direction, but I think we will continue to evolve from there and develop more medications. We already have a total of 4 drugs in this category that are being developed, with mavacamten being one of those, but we are also looking at improvement in interventional approaches. For example, alcohol septal ablation has its own limitations and so there are newer techniques that are being developed.

I am of the opinion that these will always continue to be kind of a backup salvage approach, because once you have really effective and safe medical therapies, you might not want to go down that route. The biggest unmet need in HCM is non-obstructive HCM. There are no proven therapies whatsoever in this space. Even though the guidelines say to try beta-blockers and calcium channel blockers, they are not effective for the majority of these patients. As such, myosin inhibitors are being looked at for non-obstructive HCM. We are also thinking about gene therapy. In HCM, almost 40% of patients have some underlying genetic mutation that could expand their disease process. Whether we can get to a point where we can get those gene therapies or gene editing products to target some of these underlying issues in HCM is a big advancement in the space. We already have a few programs. We have 2 programs for myosin-binding protein C3 or MYBPC3 HCM that are already undergoing Phase 1 evaluation. We will have a better understanding of their safety and efficacy as time goes by. 

Finally, I think devices are improving. A lot of patients with HCM end up needing defibrillators or pacemakers or requiring an intervention of their arrhythmia. Technology is improving quickly in this space. I think this will be helpful for patients with HCM, given the fact that many of those who require defibrillators are young, active patients. So, more developments in the device space will be very useful. 

The transcripts have been edited for clarity and length.