Open AccessEffects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
Author(s) -
Dashwood Alexander,
Cheesman Elizabeth,
Wong Yee Weng,
Haqqani Haris,
Beard Nicole,
Hay Karen,
Spratt Melanie,
Chan Wandy,
Molenaar Peter
Publication year - 2021
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.760
Subject(s) - inotrope , diastole , cardiology , lusitropy , medicine , heart failure , contractility , nifedipine , calcium , blood pressure
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 β 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 β 1 ‐ARs in the absence or presence of OM. OM prolonged TPF and t 50% in ventricular trabeculae (600 nM, 2 µM, 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 µM. Co‐incubation with (−)‐noradrenaline reduced TPF and t 50% , reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, 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.