Hypertrophic cardiomyopathy (HCM) has become increasingly prevalent worldwide, especially in the era of genetic screening. However, the recent introduction of cardiac myosin inhibitors (CMIs) and their proven efficacy in reducing the degree of left ventricular outflow tract obstruction (LVOTO) and outcomes in obstructive HCM are becoming key factors in deciding treatment strategy and escalation. The severity of obstruction can vary with changes in preload, afterload, and contractility. Other complications of HCM include LVOTO, diastolic dysfunction, and exercise intolerance.¹ Therefore, the mainstay of symptom-directed treatment for obstructive HCM has historically been either beta-blockers or calcium channel blockers (CCBs).²

Recently, CMIs have ushered in a new chapter of pharmacologic treatment for HCM by not only optimizing physiological loading conditions but also altering the structural makeup at the level of the sarcomere. The EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) results demonstrated the benefit of mavacamten for symptom improvement in these patients, laying the groundwork for the next-in-class CMI aficamten.³ With the positive results from the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) trial demonstrating improvement in symptoms and decrease in LVOTO with aficamten use compared with placebo, the next logical step was to compare this therapy head on with the current first-line treatment.⁴

The MAPLE-HCM (Metoprolol Versus Aficamten in Patients With Left Ventricular Outflow Tract Obstruction on Exercise Capacity in HCM) trial was an international, double-blinded, double-dummy trial in which 175 adult patients with symptomatic obstructive HCM were randomly assigned to receive aficamten plus placebo or metoprolol plus placebo to test the hypothesis that aficamten monotherapy could provide greater symptomatic benefit compared with beta-blocker monotherapy.⁵ Eighty-eight patients received aficamten (daily dose of 5 mg up to 20 mg) plus placebo or metoprolol (daily dose of 50 mg up to 200 mg) plus placebo. The primary endpoint was change in peak oxygen uptake by cardiopulmonary exercise testing at week 24, with secondary endpoints including change in New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, left ventricular outflow tract (LVOT) gradient, and N-terminal pro–B-type natriuretic peptide level. By week 24, the aficamten group showed a change in peak oxygen uptake of 1.1 mL/kg of body weight, which was significantly improved compared with a change of -1.2 mL/kg in the metoprolol group. Additionally, the aficamten group demonstrated a noteworthy change in LVOT gradient of -40.7 mm Hg compared with only -3.8 mm Hg in the metoprolol group. In fact, aficamten showed improvements in all endpoints except for left ventricular mass index, with similar rates of adverse events.

This trial mirrored the SEQUOIA-HCM trial in showing improvement in peak oxygen uptake and common secondary endpoints studied in cardiomyopathy trials at 24 weeks, although the MAPLE-HCM trial results additionally emphasize the stark contrast in these outcomes compared with the current guideline-recommended first-line beta-blocker monotherapy. Although nonvasodilating beta-blockers/CCBs can provide symptom benefit in patients with HCM, the long-standing limitation has been inability to make any change at the structural level. CMIs have been shown to significantly improve LVOTO itself, likely leading to physiological benefit shown in these trials with peak oxygen uptake. Additionally, 12% of patients taking metoprolol in the MAPLE-HCM trial had to be dose reduced to 0 mg because of unacceptable adverse effects including lightheadedness, bradycardia, and fatigue, whereas only one patient in the aficamten group was reduced to 0 mg because of lightheadedness. Furthermore, CMIs can also delay the need for invasive procedures, as shown in the VALOR-ACH (Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy) trial results, in which mavacamten decreased eligibility for septal reduction therapy in patients taking maximally tolerated medical therapy. The main limitation of the MAPLE-HCM trial was the short treatment period. Longer-term outcomes of aficamten should be studied, although the study duration for mavacamten was 30 weeks in the EXPLORER-HCM while still showing benefit. The MAPLE-HCM trial also only analyzed one nonvasodilating beta-blocker (metoprolol).

In summary, although guidelines currently advocate for beta-blockers/CCBs as first-line therapy for patients with symptomatic obstructive HCM, CMIs are novel therapies that approach this disease at the myocardial cell level, leading to improvement in quality of life and prevention of long-term sequalae of HCM such as heart failure and invasive procedures.

References

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2. Writing Committee Members, Ommen SR, Ho CY, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(23):2324-2405. doi:10.1016/j.jacc.2024.02.014
3. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769. doi:10.1016/S0140-6736(20)31792-X
4. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. doi:10.1056/NEJMoa2401424
5. Garcia-Pavia P, Maron MS, Masri A, et al. Aficamten or metoprolol monotherapy for obstructive hypertrophic cardiomyopathy. N Engl J Med. 2025;393(10):949-960. doi:10.1056/NEJMoa2504654