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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 β(1)–adreno...

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Detalles Bibliográficos
Autores principales: Dashwood, Alexander, Cheesman, Elizabeth, Wong, Yee Weng, Haqqani, Haris, Beard, Nicole, Hay, Karen, Spratt, Melanie, Chan, Wandy, Molenaar, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085933/
https://www.ncbi.nlm.nih.gov/pubmed/33929079
http://dx.doi.org/10.1002/prp2.760
Descripción
Sumario: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.