Highlights
Aficamten monotherapy demonstrated a superior reduction in both resting and Valsalva left ventricular outflow tract (LVOT) gradients compared to metoprolol.
Significant reverse cardiac remodeling was observed with aficamten, including a reduction in left atrial volume index and maximal wall thickness.
Markers of diastolic function, such as the E/e’ ratio, improved significantly more with aficamten than with the current gold-standard beta-blocker.
Aficamten therapy led to a notable resolution of mitral valve systolic anterior motion and a reduction in the severity of mitral regurgitation.
Introduction: A New Era in HCM Management
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, characterized by myocardial hypertrophy that cannot be explained solely by loading conditions. In its obstructive form (oHCM), the thickened septum causes a physical impediment to blood flow leaving the left ventricle, leading to debilitating symptoms such as dyspnea, chest pain, and exercise intolerance. For decades, the pharmacological management of oHCM has relied on non-vasodilating beta-blockers, such as metoprolol, and calcium channel blockers. These agents focus on slowing the heart rate and reducing the force of contraction to alleviate the gradient. However, they do not target the underlying molecular pathophysiology of the disease.
The emergence of cardiac myosin inhibitors represents a paradigm shift. Following the success of mavacamten, aficamten—a next-generation, selective cardiac myosin inhibitor—has entered the clinical arena. While the SEQUOIA-HCM trial established aficamten’s efficacy against placebo, the MAPLE-HCM study provides the first head-to-head comparison against the long-standing first-line therapy, metoprolol.
The MAPLE-HCM Study Design
MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM) was a multicenter, randomized, double-blind study. It enrolled 175 participants with a mean age of 58 years. The population was symptomatic (NYHA class II or III) with significant LVOT obstruction, defined by a resting gradient of at least 30 mm Hg or a Valsalva gradient of at least 50 mm Hg, and a preserved left ventricular ejection fraction (LVEF) of at least 55%.
Participants were randomized to receive either aficamten (starting at 5 mg, titrated up to 20 mg based on echocardiographic monitoring) or metoprolol succinate (starting at 50 mg, titrated up to 200 mg). The study duration was 24 weeks, with serial echocardiography used to evaluate changes in cardiac structure, hemodynamics, and valvular function.
Comprehensive Echocardiographic Results
Hemodynamic Improvements: LVOT Gradients
The primary hemodynamic objective in oHCM is the reduction of the LVOT gradient. At 24 weeks, aficamten demonstrated a profound reduction compared to metoprolol. The mean difference in resting LVOT-G was -30 mm Hg (95% CI: -37 to -23 mm Hg; P < 0.001), and the difference in Valsalva LVOT-G was -35 mm Hg (95% CI: -44 to -26 mm Hg; P < 0.001). These data suggest that aficamten is significantly more potent at relieving the mechanical obstruction that defines the disease state.
Structural Remodeling: Left Atrial and Ventricular Changes
One of the most striking findings of the MAPLE-HCM study was the evidence of reverse cardiac remodeling. The left atrial volume index (LAVI) is a critical marker of chronic left ventricular filling pressures and is strongly associated with the risk of developing atrial fibrillation and heart failure. Patients treated with aficamten saw a reduction in LAVI of -7.0 mL/m2 relative to those on metoprolol (P < 0.001).
Furthermore, maximal wall thickness (MWT) decreased by 1.0 mm in the aficamten group compared to the metoprolol group (P = 0.02). While a 1 mm change may seem modest, it represents a significant structural shift within a 24-week period, suggesting that myosin inhibition may alter the natural progression of myocardial hypertrophy.
Valvular Dynamics: Mitral Regurgitation and SAM
The Venturi effect caused by high-velocity flow through a narrowed LVOT often pulls the mitral valve leaflets toward the septum—a phenomenon known as systolic anterior motion (SAM). This leads to both increased obstruction and significant mitral regurgitation (MR). Aficamten treatment resulted in a significant decrease in both SAM and MR at week 24. By addressing the hypercontractility at the sarcomere level, aficamten stabilizes the hemodynamic environment, thereby improving valvular competence.
Safety and Physiological Considerations: The LVEF Trade-off
As a cardiac myosin inhibitor, aficamten works by reducing the number of active actin-myosin cross-bridges. This inherently reduces the force of contraction. In MAPLE-HCM, aficamten therapy resulted in a modest reduction in LVEF (-4% compared with metoprolol). Additionally, absolute global longitudinal strain (GLS) and global circumferential strain decreased. However, it is crucial to note that there was no significant change in resting cardiac output between the groups. This suggests that the reduction in LVEF reflects the drug’s mechanism of action—normalizing the hyperdynamic state—rather than causing clinical heart failure, provided that LVEF remains within a safe range.
Clinical Implications and Expert Commentary
The results of MAPLE-HCM challenge the long-held dominance of beta-blockers as the mandatory first-line therapy for oHCM. Clinicians have traditionally reached for metoprolol due to its familiarity and low cost, but it often fails to provide adequate gradient relief or halt structural progression. The superior performance of aficamten across almost every echocardiographic measure—hemodynamics, remodeling, and diastolic function—positions it as a potentially superior first-line option for symptomatic patients.
Expert consensus suggests that while beta-blockers remain useful for heart rate control, they may be relegated to a supportive role in patients who require more robust gradient reduction. The favorable remodeling seen with aficamten, particularly the reduction in left atrial size, may have long-term benefits in reducing the burden of atrial fibrillation, though longer-term outcome studies are needed to confirm this.
Conclusions
The MAPLE-HCM trial provides robust evidence that aficamten monotherapy is superior to metoprolol in improving the echocardiographic profile of patients with symptomatic obstructive HCM. By significantly lowering LVOT gradients, reducing left atrial volumes, and improving diastolic function, aficamten addresses the multi-faceted pathophysiology of the disease more effectively than traditional beta-blockade. While careful monitoring of LVEF is required, the overall profile of aficamten suggests it will play a central role in the future of HCM care.
Funding and Trial Registration
This study was funded by Cytokinetics, Inc. ClinicalTrials.gov Identifier: NCT05767346.
References
1. Hegde SM, Wang X, Garcia-Pavia P, et al. Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM. J Am Coll Cardiol. 2025 Dec 16;86(24):2452-2467. doi: 10.1016/j.jacc.2025.08.022.
2. Maron MS, Hellawell JL, Lucove JC, et al. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Three-Year Results From the REDWOOD-HCM Open-Label Extension. JACC Heart Fail. 2024.
3. Maron BJ, Desai MY, Nishimura RA, et al. Management of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):390-414.