Key result
Omecamtiv mecarbil suppresses cardiac myosin working stroke by ~93%, explaining its calcium sensitization and motility inhibition.
Absolute Event Rate: 0.4% vs 5.4%
Omecamtiv mecarbil increases myocardial force output through an unanticipated mechanism of selective myosin suppression and cooperative thin filament activation, rather than direct myosin activation.
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.
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Woody et al. (2018) studied this question. Omecamtiv mecarbil vs. Absence of omecamtiv mecarbil was evaluated on Myosin working stroke size (nm). Omecamtiv mecarbil suppresses the cardiac myosin working stroke from 5.4 nm to 0.4 nm and prolongs actomyosin attachment 5-fold, explaining its calcium sensitization and motility inhibition effects.
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