BACKGROUND: Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs 
systolic ejection time and increases ejection fraction through myosin ATPase 
activation. We hypothesized that a potentially favorable energetic effect of 
unloading the left ventricle, and thus reduction of wall stress, could be 
counteracted by the prolonged contraction time and ATP-consumption.
METHODS AND RESULTS: Postischemic left ventricular dysfunction was created by 
repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In 
both groups, systolic ejection time and ejection fraction increased after OM 
(0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous 
infusion). Cardiac efficiency was assessed by relating myocardial oxygen 
consumption to the cardiac work indices, stroke work, and pressure-volume area. 
To circumvent potential neurohumoral reflexes, cardiac efficiency was 
additionally assessed in ex vivo mouse hearts and isolated myocardial 
mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase 
in unloaded myocardial oxygen consumption in healthy and postischemic pigs, 
respectively. Also, the oxygen cost of the contractile function was increased by 
63% and 46% in healthy and postischemic pigs, respectively. The increased 
unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts 
and explained by an increased basal metabolic rate. Adding the myosin ATPase 
inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen 
consumption in the OM-treated hearts.
CONCLUSIONS: Omecamtiv mecarbil, in a clinically relevant model, led to a 
significant myocardial oxygen wastage related to both the contractile and 
noncontractile function. This was mediated by that OM induces a continuous 
activation in resting myosin ATPase.