Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (-)-noradrenaline

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the beta(1)-adrenoceptor (AR) agonist (-)-noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non-failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t(50%)) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration-effect curves were established to (-)-noradrenaline at beta(1)-ARs in the absence or presence of OM. OM prolonged TPF and t(50%) in ventricular trabeculae (600 nM, 2 mu M, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (-)-noradrenaline (pEC(50) 6.05 +/- 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 mu M. Co-incubation with (-)-noradrenaline reduced TPF and t(50%), reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 mu M, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (-)-Noradrenaline reversed the negative diastolic effects, co-administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.

Automated summary

Omecamtiv mecarbil (OM) is a new drug for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. In human failing heart tissues, OM prolonged time to peak force and 50% relaxation time, reduced time dependent deterioration in contractile strength, and had no significant inotropic effect. Co-administration of (-)-noradrenaline with OM reversed the negative diastolic effects of OM and may limit ischemic side effects from titration of inotropes.