025 Determining the Effects of Omecamtiv Mecarbil on Human Failing Ventricular Trabeculae and Interaction With (-)-Noradrenaline Via the β1-adrenoceptor

Abstract

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. However, OM had negative diastolic effects and evidence of ischaemia at supratherapeutic doses. To assist translation to clinical practice we investigated OMs effect on ventricular trabeculae from explanted human failing hearts, specifically; contractile dynamics, interaction with the β1–adrenoceptor (AR) agonist (-)-noradrenaline and arrhythmia genesis. Ventricular trabeculae from explanted failing hearts were paced under tension and incubated with or without a single concentration of OM for 120 mins. Time to peak force (TPF) and 50% relaxation (t50%) were recorded. Cumulative concentration-effect curves were established to (-)-noradrenaline at β1-ARs in the absence or presence of OM, whilst β2-AR, α1-ARs and neuronal uptake were blocked. Stimulators were switched off and trabeculae observed for arrhythmic contractions. OM prolonged TPF and t50% in ventricle (600 nM, 2 mM, p<0.001) but had no effect on inotropic force. OM did not affect the generation of arrhythmic contractions. The potency of (-)-noradrenaline (pEC50 6.05±0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 μM. (-)-Noradrenaline reversed the negative diastolic effects of OM at maximal β1-AR effect. In ventricular trabeculae from explanted human failing hearts, OM prolonged TPF and t50%, but had no effect on contractile force, generation of arrhythmic contractions or potency of (-)-noradrenaline at β1-ARs. The competing diastolic effects of OM and (-)-noradrenaline may prove clinically important. If used together in patients with cardiogenic shock.