Omecamtiv mecarbil suppresses the cardiac myosin working stroke from 5.4 nm to 0.4 nm and prolongs actomyosin attachment 5-fold, leading to increased myocardial force via cooperative thin-filament activation.
Omecamtiv mecarbil increases myocardial force output through cooperative thin-filament activation by OM-inhibited myosin molecules, despite suppressing the myosin working stroke.
Absolute Event Rate: 0.4% vs 5.4%
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 performance. Here we show, via single-molecule, biophysical experiments on cardiac myosin, that OM suppresses myosin's working stroke and prolongs actomyosin attachment 5-fold, which explains inhibitory actions of the drug observed in vitro. OM also causes the actin-detachment rate to become independent of both applied load and ATP concentration. Surprisingly, 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.
Woody et al. (2018) studied Heart failure (in vitro biophysical model). Omecamtiv mecarbil vs. No omecamtiv mecarbil was evaluated on Myosin working stroke size. Omecamtiv mecarbil suppresses the cardiac myosin working stroke from 5.4 nm to 0.4 nm and prolongs actomyosin attachment 5-fold, leading to increased myocardial force via cooperative thin-filament activation.