Abstract 15707: MYK-491, a Novel Small-Molecule Cardiac Myosin Activator Increases Cardiac Systolic Function and Preserves Mechanical Efficiency: Pre-Clinical in vivo and in vitro Evidence

IntroductionCardiac myosin motors have been shown to efficiently convert ATP to mechanical force. MYK-491 is a novel small-molecule selective allosteric activator of cardiac acto-myosin that leverages such efficiency, increasing the number of force-producing cross-bridges while preserving their detachment dynamics. As such, MYK-491 could increase systolic performance without affecting resting tension. These in vivo and in vitro experiments evaluated the acute responses to MYK-491 in healthy dogs and human-derived cardiomyocytes (hiPSC-CMs).MethodsIn vivoBeagle dogs (n = 6) were chronically instrumented for arterial pressure and LV pressure-volume (LVPV) recordings. Systemic/LV hemodynamics, geometry, and load-independent function were examined before/following MYK-491 (3 mg/kg PO). In vitroFunctional (cellular morphology and engineered-tissue tension) as well as metabolic responses to MYK-491 (at matching concentrations) were studied in hiPSC-CMs.ResultsIn conscious dogs, MYK-491 increased (P