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dc.contributor.authorDashwood, A
dc.contributor.authorCheesman, E
dc.contributor.authorWong, Y
dc.contributor.authorHaqqani, H
dc.contributor.authorMolenaar, P
dc.date.accessioned2020-07-21T00:33:04Z
dc.date.available2020-07-21T00:33:04Z
dc.date.issued2020
dc.identifier.issn1557-3117
dc.identifier.doi10.1016/j.healun.2020.01.427
dc.identifier.urihttp://hdl.handle.net/10072/395650
dc.description.abstractPURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
dc.languageeng
dc.publisherElsevier BV
dc.relation.ispartofpagefromS358
dc.relation.ispartofissue4
dc.relation.ispartofjournalThe Journal of heart and lung transplantation
dc.relation.ispartofvolume39
dc.subject.fieldofresearchCardiorespiratory Medicine and Haematology
dc.subject.fieldofresearchcode1102
dc.titleDetermining the Properties of Omecamtiv Mecarbil on Human Explanted Cardiac Trabeculae and Its Interaction with Current Inotropes via the Beta 1-Adrenoceptor
dc.typeJournal article
dc.type.descriptionC2 - Articles (Other)
dcterms.bibliographicCitationDashwood, A; Cheesman, E; Wong, Y; Haqqani, H; Molenaar, P, Determining the Properties of Omecamtiv Mecarbil on Human Explanted Cardiac Trabeculae and Its Interaction with Current Inotropes via the Beta 1-Adrenoceptor, The Journal of heart and lung transplantation, 2020, 39 (4), pp. S358
dc.date.updated2020-07-21T00:30:50Z
gro.hasfulltextNo Full Text
gro.griffith.authorDashwood, Alexander M.


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