Concentration dependent effects of Aficamten on isolated canine left ventricular cardiomyocytes

Abstract

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases characterised by abnormal thickening and hyperdynamic contractility of the left ventricular (LV) myocardium. Currently available approaches provide symptomatic relief to the patients but lack precision in targeting the underlying cause of the disease: excessive sarcomere contractility. Aficamten, a new-generation myosin inhibitor, may offer a potential breakthrough by aiming restoration of proper contractility within the sarcomere. Our aim was to analyse the concentration-dependent effects of Aficamten on the contractile function and on the Ca2+ homeostasis of enzymatically-isolated canine LV cardiomyocytes. The negative inotropic effect of Aficamten was characterised by the reduction in fractional shortening, duration of contractions, and systolic ejection time. Velocities of both contractions and relaxations were decelerated, which could further contribute to the reduction in contractility. Aficamten did not exert any significant influence on the parameters of systolic intracellular Ca2+ concentration changes (i.e. Ca2+ transients) regardless of the applied drug concentration. Our results confirmed that Aficamten exerts its negative inotropic effects by selective modulation of the activity of sarcomeric myosin, portraying it as a highly promising therapeutic option for HCM. Current and future clinical trials are expected to clarify further technical details and hopefully support the clinical introduction of direct myosin inhibitors in the management of HCM.