Positive Cardiac Inotrope, Omecamtiv Mecarbil, Activates Muscle Despite Suppressing the Myosin Working Stroke

Abstract

Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Although initially described as a direct myosin activator, subsequent studies are at odds with this description and do not explain OM-mediated increases in cardiac output. Single-molecule, biophysical experiments on cardiac myosin show that OM suppresses myosin's working stroke and prolongs actomyosin attachment 5-fold, which explain inhibitory actions of the drug observed in vitro. Surprisingly, the increased myocardial force output in the presence of OM can be explained by cooperative thin filament activation by OM-inhibited myosin molecules. Selective suppression of myosin is an unanticipated route to muscle activation that may guide future development of therapeutic drugs.