Abstract
Omecamtiv mecarbil (OM) is a first in class selective myosin activator, developed to increase contractile force without altering intracellular calcium concentrations in patients with advanced heart failure (AHF). We sought to investigate the effect of OM on contractility, arrhythmia genesis and interaction with Beta 1-adrenoceptor (B1AR) inotropes directly on explanted human failing heart. Trabeculae from 7 explanted hearts with AHF were dissected and set up to contract at 1 Hz. Trabeculae were incubated with or without OM (600 nM or 2 µM) for 120 mins. Cumulative concentration-effect curves were established to (-)-noradrenaline at B1ARs in the presence of the B2AR blocker (50 nM ICI 118,551) and phenoxybenzamine to block α1ARs and neuronal uptake. Contractile force and duration were recorded and observed for spontaneous contractions. OM prevented time dependent reduction (fade) in contractile force (Fig A, P=0.013 at 120mins). Trabeculae exhibited a concentration dependent increase in systolic ejection time (SET), associated with increased stroke volume, but this reduces the time for diastole. (Fig B). The concentration of (-)-noradrenaline required for 50% of maximal contractile force, the LogEC50, remained unchanged in the presence of OM (Mean LogEC50: -6.1 (control), -6.2 (600 nM), -6.1 (2 µM); P=0.7). (-)-Noradrenaline reversed OM mediated increases in SET. There was no significant increase in spontaneous contractions with OM concentrations up to 2 µM. OM maintains contractile force, independent of a B1AR mediated mechanism, without an increase in spontaneous contraction. In isolation OM increases SET at the cost of diastolic performance. Concomitant B1AR activation by (-)-noradrenaline normalises SET, improving ventricular filling. This finding may prove clinically relevant, especially when titrating traditional inotropes which increase metabolic demand.
Published Version
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