Understanding Hypertrophic Cardiomyopathy (HCM)
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, characterized by an abnormal thickening of the heart muscle, particularly the left ventricle [1.5.4, 1.8.3]. This thickening, not caused by other factors like hypertension or valve disease, stiffens the heart muscle, making it harder to pump blood effectively [1.3.2]. HCM is a genetic condition, often caused by mutations in genes that code for sarcomere proteins—the machinery responsible for heart muscle contraction [1.8.5].
There are two primary types of HCM:
- Obstructive HCM (oHCM): Affecting about two-thirds of patients, this is where the thickened septum bulges into the left ventricular outflow tract (LVOT), blocking or reducing blood flow from the heart to the rest of the body [1.2.7]. This obstruction is a major cause of symptoms like shortness of breath and chest pain [1.2.1].
- Non-obstructive HCM (nHCM): In this form, the heart muscle is thickened, but it does not cause a significant blockage of blood flow [1.2.7].
The underlying problem at a molecular level is often an excessive number of actin-myosin cross-bridges, leading to a state of hypercontractility where the heart squeezes too forcefully and doesn't relax properly [1.3.7, 1.8.6]. This leads to symptoms ranging from mild to severe, including shortness of breath (dyspnea), fatigue, chest pain, palpitations, and an increased risk of atrial fibrillation, heart failure, and sudden cardiac death [1.3.4].
The Limitations of Traditional HCM Treatments
Until recently, the pharmacological management of HCM focused on alleviating symptoms rather than addressing the underlying hypercontractility [1.6.6]. Traditional therapies include:
- Beta-blockers: Considered first-line therapy, they slow the heart rate and reduce the force of contraction to lessen the workload on the heart [1.6.2].
- Calcium Channel Blockers: Drugs like verapamil and diltiazem also help relax the heart muscle and reduce its contractility [1.6.3].
- Disopyramide: An antiarrhythmic drug that can also reduce the strength of heart contractions [1.3.4].
While these medications can provide symptomatic relief for many, they are often insufficient and do not alter the natural history of the disease [1.2.1, 1.6.6]. For patients with severe, drug-refractory obstructive HCM, more invasive procedures have been the only option. These include surgical septal myectomy (an open-heart procedure to remove part of the thickened septum) and alcohol septal ablation (a catheter-based procedure to create a small, controlled heart attack to shrink the septum) [1.2.5]. These procedures carry significant risks and require specialized centers [1.7.6].
A Paradigm Shift: Cardiac Myosin Inhibitors
The development of cardiac myosin inhibitors marks a revolutionary change in HCM treatment. These drugs are the first to be specifically designed to target the fundamental cause of the disease: the hypercontractility of the heart muscle [1.2.5]. They work by selectively and reversibly binding to cardiac myosin, reducing the number of actin-myosin cross-bridges that can form. This action normalizes contractility, reduces the LVOT obstruction, and improves the heart's ability to fill with blood [1.3.5].
Mavacamten (Camzyos): The First-in-Class Breakthrough
Mavacamten, sold under the brand name Camzyos, became the first-in-class cardiac myosin inhibitor approved by the FDA in April 2022 [1.2.4]. Its approval was based on pivotal clinical trials like EXPLORER-HCM, which demonstrated significant improvements in symptoms, exercise capacity, and LVOT obstruction in patients with symptomatic oHCM [1.2.6]. The VALOR-HCM trial further showed that Mavacamten could substantially reduce the need for invasive septal reduction therapy in eligible patients [1.3.4].
Mavacamten is indicated for adults with symptomatic NYHA Class II-III obstructive HCM [1.3.2]. Due to its mechanism, it carries a boxed warning for the risk of heart failure from reducing the left ventricular ejection fraction (LVEF) too much. Therefore, it is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program that requires regular echocardiogram monitoring [1.2.2, 1.2.6].
Aficamten: The Next Wave of Innovation
Aficamten is another investigational cardiac myosin inhibitor that has shown promising results in late-stage clinical trials [1.2.7]. It works similarly to Mavacamten but has a shorter half-life, which may allow for more rapid dose adjustments and potentially a more favorable safety profile [1.3.7, 1.8.3].
Recent data from the MAPLE-HCM trial showed Aficamten was superior to the standard-of-care beta-blocker metoprolol in improving exercise capacity in patients with oHCM [1.4.1, 1.4.2]. The FDA is currently reviewing a New Drug Application for Aficamten, with a target decision date of December 26, 2025 [1.4.4]. It is also being studied for non-obstructive HCM in the ACACIA-HCM trial [1.4.3].
Comparison Table: New vs. Traditional Therapies
| Feature | Cardiac Myosin Inhibitors (Mavacamten) | Beta-Blockers | Calcium Channel Blockers |
|---|---|---|---|
| Mechanism of Action | Directly inhibits cardiac myosin to reduce hypercontractility and normalize force production [1.3.7]. | Block the effects of adrenaline, slowing heart rate and reducing contraction force [1.6.6]. | Block calcium from entering heart cells, relaxing muscle and slowing heart rate [1.6.6]. |
| Therapeutic Target | Targets the underlying pathophysiology of HCM [1.2.4]. | Symptom management by reducing cardiac workload [1.6.1]. | Symptom management by reducing cardiac workload [1.6.1]. |
| Primary Indication | Symptomatic obstructive HCM (NYHA Class II-III) [1.2.6]. | First-line therapy for symptomatic HCM [1.6.2]. | Used for symptomatic HCM, often when beta-blockers are not tolerated or effective [1.6.2]. |
| Key Side Effects | Reduced Left Ventricular Ejection Fraction (LVEF), risk of heart failure, dizziness, fainting [1.3.2]. | Fatigue, bradycardia (slow heart rate), low blood pressure, dizziness. | Constipation, dizziness, headache, edema (swelling). |
| Monitoring | Requires REMS program with regular echocardiograms to monitor LVEF [1.2.2]. | Routine clinical follow-up for heart rate and blood pressure. | Routine clinical follow-up for heart rate and blood pressure. |
Conclusion: A New Era in HCM Management
The arrival of cardiac myosin inhibitors like Mavacamten, and the anticipated approval of Aficamten, has transformed the treatment landscape for hypertrophic cardiomyopathy. For the first time, clinicians can offer patients a medication that addresses the root cause of their condition, moving beyond simple symptom control [1.6.1]. These targeted therapies have been shown to improve quality of life, increase exercise capacity, and in many cases, help patients avoid or delay the need for invasive heart surgery [1.3.4]. While careful monitoring is essential, these new medications represent a significant and hopeful step forward for thousands of individuals living with HCM.
Visit the American Heart Association for more information on hypertrophic cardiomyopathy.
