Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
Abstract 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 β1...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2021-05-01
|
Series: | Pharmacology Research & Perspectives |
Subjects: | |
Online Access: | https://doi.org/10.1002/prp2.760 |
id |
doaj-b72fc90c024c4b669e467a550e0991fe |
---|---|
record_format |
Article |
spelling |
doaj-b72fc90c024c4b669e467a550e0991fe2021-06-10T09:28:33ZengWileyPharmacology Research & Perspectives2052-17072021-05-0193n/an/a10.1002/prp2.760Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenalineAlexander Dashwood0Elizabeth Cheesman1Yee Weng Wong2Haris Haqqani3Nicole Beard4Karen Hay5Melanie Spratt6Wandy Chan7Peter Molenaar8Heart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaCardio‐Vascular Molecular & Therapeutics Translational Research Group University of Queensland Brisbane QLD AustraliaHeart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaHeart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaQueensland University of Technology Brisbane AustraliaQIMR Berghofer Medical Research Institute Brisbane QLD AustraliaHeart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaHeart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaHeart Lung Institute The Prince Charles Hospital Chermside QLD AustraliaAbstract 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 β1–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 (t50%) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration‐effect curves were established to (−)‐noradrenaline at β1‐ARs in the absence or presence of OM. OM prolonged TPF and t50% 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 (pEC50 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 t50%, 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.https://doi.org/10.1002/prp2.760arrhythmiabeta‐adrenoceptorcontractilitydiastoleheart failureinotrope |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alexander Dashwood Elizabeth Cheesman Yee Weng Wong Haris Haqqani Nicole Beard Karen Hay Melanie Spratt Wandy Chan Peter Molenaar |
spellingShingle |
Alexander Dashwood Elizabeth Cheesman Yee Weng Wong Haris Haqqani Nicole Beard Karen Hay Melanie Spratt Wandy Chan Peter Molenaar Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline Pharmacology Research & Perspectives arrhythmia beta‐adrenoceptor contractility diastole heart failure inotrope |
author_facet |
Alexander Dashwood Elizabeth Cheesman Yee Weng Wong Haris Haqqani Nicole Beard Karen Hay Melanie Spratt Wandy Chan Peter Molenaar |
author_sort |
Alexander Dashwood |
title |
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_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_sort |
effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline |
publisher |
Wiley |
series |
Pharmacology Research & Perspectives |
issn |
2052-1707 |
publishDate |
2021-05-01 |
description |
Abstract 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 β1–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 (t50%) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration‐effect curves were established to (−)‐noradrenaline at β1‐ARs in the absence or presence of OM. OM prolonged TPF and t50% 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 (pEC50 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 t50%, 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. |
topic |
arrhythmia beta‐adrenoceptor contractility diastole heart failure inotrope |
url |
https://doi.org/10.1002/prp2.760 |
work_keys_str_mv |
AT alexanderdashwood effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT elizabethcheesman effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT yeewengwong effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT harishaqqani effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT nicolebeard effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT karenhay effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT melaniespratt effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT wandychan effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline AT petermolenaar effectsofomecamtivmecarbilonfailinghumanventriculartrabeculaeandinteractionwithnoradrenaline |
_version_ |
1721385293492256768 |