Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that shows promising results in the management of systolic heart failure. It binds to the myosin heads, resulting in increased ATPase activity and improved energy utilization.
We aimed to investigate the in vitro and in vivo effects of OM on heart function.
The effects of OM on the aortic flow, coronary flow and aortic pressure were measured in isolated working heart preparations, in vitro. OM was also administered in the jugular vein to measure its effects on the heart function (by echocardiography) and blood pressure (invasive measurement), in vivo.
OM evoked a dose dependent (0, 200, 600 and 1200 µg/bkg) decrease in aortic flow (59±4, 63±6 ml/min; no flow above 600 µg/bkg dose, respectively), coronary flow (23±1, 25±2, 13±2 and 6±2 ml/min, respectively) and in aortic pressure (103±1, 93,6±1, 54±6 and 34±6 mmHg, respectively). However, there was a dose dependent increase in ejection fraction (EF) (from 70±2, 72±4, 78±5 to 82±8%, respectively to the doses mentioned above), a decrease in E/A ratio (2±0,05, 1,8±0,1, 1,5±0,03, respectively, while it was not measurable at the highest dose), and an increase in isovolumetric relaxation time (22±2, 32±0,8, 35±1,8 and 51±2 in ms, respectively) as determined by echocardiography. The 1200 µg/bkg dose significantly decreased both systolic and diastolic blood pressure (to 41±9% and to 37±11%, respectively) as determined by invasive measurements. Finally, we found that a high dose of norepinephrine (5µg/bkg) reverses the decrease in systolic and diastolic blood pressures (to 132±10 % and to 117±9%, respectively), along with improving the diastolic dysfunction (E/A ratio back to 1,69±0,05 and IVRT to 20,83±0,7 ms).
In conclusion, high doses of OM significantly increase systolic function, in vivo. However, it also results in diastolic dysfunction, in vivo, and seriously decreased cardiac output, in vitro, which leads to severe hypotension, in vivo. Our data suggest that OM should be used carefully in the clinical practice. Moreover, we propose that high dose of norepinephrine can be utilized to overcome the hypotension and diastolic dysfunction if it develops.