Heart failure is a life-threatening condition that occurs when the heart muscle 
becomes weakened and cannot adequately circulate blood and nutrients around the 
body. Omecamtiv mecarbil (OM) is a compound that has been developed to treat 
systolic heart failure via targeting the cardiac myosin heavy chain to increase 
myocardial contractility. Biophysical and biochemical studies have found that OM 
increases calcium (Ca2+) sensitivity of contraction by prolonging the myosin 
working stroke and increasing the actin-myosin cross-bridge duty ratio. Most 
in vitro studies probing the effects of OM on cross-bridge kinetics and muscle 
force production have been conducted at subphysiological temperature, even 
though temperature plays a critical role in enzyme activity and cross-bridge 
function. Herein, we used skinned, ventricular papillary muscle strips from rats 
to investigate the effects of [OM] on Ca2+-activated force production, 
cross-bridge kinetics, and myocardial viscoelasticity at physiological 
temperature (37°C). We find that OM only increases myocardial contractility at 
submaximal Ca2+ activation levels and not maximal Ca2+ activation levels. As 
[OM] increased, the kinetic rate constants for cross-bridge recruitment and 
detachment slowed for both submaximal and maximal Ca2+-activated conditions. 
These findings support a mechanism by which OM increases cardiac contractility 
at physiological temperature via increasing cross-bridge contributions to 
thin-filament activation as cross-bridge kinetics slow and the duration of 
cross-bridge attachment increases. Thus, force only increases at submaximal Ca2+ 
activation due to cooperative recruitment of neighboring cross-bridges, because 
thin-filament activation is not already saturated. In contrast, OM does not 
increase myocardial force production for maximal Ca2+-activated conditions at 
physiological temperature because cooperative activation of thin filaments may 
already be saturated.