Omecamtiv mecarbil (OM) is a selective cardiac myosin activator (myotrope), 
currently in Phase 3 clinical investigation as a novel treatment for heart 
failure with reduced ejection fraction. OM increases cardiac contractility by 
enhancing interaction between myosin and actin in a calcium-independent fashion. 
This study aims to characterize the mechanism of action by evaluating its 
simultaneous effect on myocyte contractility and calcium-transients (CTs) in 
healthy canine ventricular myocytes. Left ventricular myocytes were isolated 
from canines and loaded with Fura-2 AM. With an IonOptix system, contractility 
parameters including amplitude and duration of sarcomere shortening, contraction 
and relaxation velocity, and resting sarcomere length were measured. CT 
parameters including amplitude at systole and diastole, velocity at systole and 
diastole, and duration at 50% from peak were simultaneously measured. OM was 
tested at 0.03, 0.1, 0.3, 1, and 3 µmol\L concentrations to simulate therapeutic 
human plasma exposure levels. OM and isoproterenol (ISO) demonstrated 
differential effects on CTs and myocyte contractility. OM increased 
contractility mainly by prolonging duration of contraction while ISO increased 
contractility mainly by augmenting the amplitude of contraction. ISO increased 
the amplitude and velocity of CT, shortened duration of CT concurrent with 
increasing myocyte contraction, while OM did not change the amplitude, velocity, 
and duration of CT up to 1 µmol\L. Decreases in relaxation velocity and 
increases in duration were present only at 3 µmol\L. In this translational 
myocyte model study, therapeutically relevant concentrations of OM increased 
contractility but did not alter intracellular CTs, a mechanism of action 
distinct from traditional calcitropes.