Myosin Inhibition in Non-obstructive Hypertrophic Cardiomyopathy: Lessons from ODYSSEY-HCM

The Phase III ODYSSEY-HCM trial evaluating the cardiac myosin inhibitor mavacamten in symptomatic non-obstructive hypertrophic cardiomyopathy did not demonstrate significant improvements in clinical endpoints, including the Kansas City Cardiomyopathy Questionnaire score and peak oxygen consumption. However, mavacamten significantly reduced pro-B-type natriuretic peptide levels and improved echocardiographic indices of diastolic and left atrial function, suggesting a potential biological effect. This apparent dissociation between biomarker improvement and clinical outcomes raises questions regarding patient selection, endpoint choice and dosing strategy. In addition, the observed decline in left ventricular systolic function in a substantial proportion of treated patients may have offset the benefits of improved diastolic performance and may have implications for arrhythmic vulnerability. In this viewpoint, the ODYSSEY-HCM trial is critically appraised and future directions for optimising myosin inhibition therapy in non-obstructive hypertrophic cardiomyopathy are discussed.