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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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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
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author Dashwood, Alexander
Cheesman, Elizabeth
Wong, Yee Weng
Haqqani, Haris
Beard, Nicole
Hay, Karen
Spratt, Melanie
Chan, Wandy
Molenaar, Peter
author_facet Dashwood, Alexander
Cheesman, Elizabeth
Wong, Yee Weng
Haqqani, Haris
Beard, Nicole
Hay, Karen
Spratt, Melanie
Chan, Wandy
Molenaar, Peter
author_sort Dashwood, Alexander
collection PubMed
description 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.
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spelling pubmed-80859332021-05-07 Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline Dashwood, Alexander Cheesman, Elizabeth Wong, Yee Weng Haqqani, Haris Beard, Nicole Hay, Karen Spratt, Melanie Chan, Wandy Molenaar, Peter Pharmacol Res Perspect Original Articles 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. John Wiley and Sons Inc. 2021-04-30 /pmc/articles/PMC8085933/ /pubmed/33929079 http://dx.doi.org/10.1002/prp2.760 Text en © 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Dashwood, Alexander
Cheesman, Elizabeth
Wong, Yee Weng
Haqqani, Haris
Beard, Nicole
Hay, Karen
Spratt, Melanie
Chan, Wandy
Molenaar, Peter
Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title_full Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title_fullStr Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title_full_unstemmed Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title_short Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
title_sort effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
topic Original Articles
url 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
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