Cardiac myosin inhibitors in hypertrophic cardiomyopathy

Abstract

Mavacamten, the first selective and reversible cardiac myosin inhibitor (CMI), has been introduced to the clinical arena for the treatment of obstructive hypertrophic cardiomyopathy (HCM). By reducing excessive actin-myosin cross-bridging, this agent decreases myocardial contractility and alleviates the dynamic left ventricular outflow tract (LVOT) obstruction in obstructive HCM. In the EXPLORER-HCM trial, mavacamten significantly improved exercise capacity, symptoms, and LVOT pressure gradients, while the VALOR-HCM trial proved it can obviate the need for septal reduction therapy in patients who were deemed to be candidates for septal reduction therapy. Notably, long-term data (MAVA-LTE study) has demonstrated sustained benefits up to 180 weeks, with < 10% experiencing transient reductions in left ventricular ejection fraction < 50% and only 1.3% of permanent discontinuation rate. Aficamten, a next-generation CMI with a shorter half-life, has also demonstrated comparable efficacy. Reverse remodeling following treatment was noted in both agents. In nonobstructive HCM, preliminary studies (MAVERICK-HCM trial and cohort 4 of REDWOOD-HCM trial) have reported improvements in cardiac serum biomarkers and symptoms. However, the preliminary results from phase 3 trials (ODYSSEY-HCM trial) revealed that primary endpoints were not met in nonobstructive HCM. Regarding safety, both were generally well tolerated. Although an LVEF reduction occurred in some patients, it was reversible with a dose reduction or a short-term drug cessation. These results emphasize careful dosing strategy with regular echocardiographic monitoring. Real-world data have also demonstrated consistent efficacy and safety across varying ethnic groups without new safety signals. CMI is a major advance in HCM management. However, future studies must provide data on hard clinical outcomes, such as heart failure hospitalization or death. Ongoing trials comparing CMI to traditional first-line therapies, such as β-blockers, will clarify their potential role as an initial therapeutic option.

Keywords: Cardiac myosin; Cardiac myosin inhibitor; Cardiomyopathy, hypertrophic; Diastolic dysfunction; Review; Therapeutics.

Fig. 1

Sarcomeres of (A) normal heart and (B) hypertrophic cardiomyopathy (HCM). In a healthy heart, 40% to 50% of myosin heads are in an “off” state. Conversely, in HCM, only 15% to 20% of myosin heads are in an “off” state with increased actin-myosin cross-bridge. This state induces hypercontractility and diastolic dysfunction in the heart

Fig. 2

A real-world example of 54-year-old man who showed complete response after 2-month of mavacamten treatment. A Resting left ventricular outflow tract pressure gradient decreased from 67 mmHg to a negligible level, and that with Valsalva maneuver also decreased from 103 mmHg to a similarly low level. Correspondingly, his symptoms improved from New York Heart Association class II to class I. B Cardiac magnetic resonance revealed that his septal wall thickness significantly decreased from 17 to 15 mm after 6 months of mavacamten therapy

Fig. 3

Data from Korean prospective multicenter real-world study demonstrating cardiac reverse remodeling after a median mavacamten treatment of 21 weeks. Violin plots showing (A) changes in left ventricular (LV) ejection fraction, (B) changes in maximal LV wall thickness, (C) changes in left atrial (LA) volume index, and (D) changes in mitral septal E/e’ ratio