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A new system for profiling drug-induced calcium signal perturbation in human embryonic stem cell-derived cardiomyocytes

Lewis, Kimberley, Silvester, Nicole C., Barberini-Jammaers, Steven, Mason, Sammy, Marsh, Sarah A., Lipka, Magdalena and George, Christopher 2015. A new system for profiling drug-induced calcium signal perturbation in human embryonic stem cell-derived cardiomyocytes. Journal of Biomolecular Screening 20 (3) , pp. 330-340. 10.1177/1087057114557232

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Abstract

The emergence of human stem cell–derived cardiomyocyte (hSCCM)–based assays in the cardiovascular (CV) drug discovery sphere requires the development of improved systems for interrogating the rich information that these cell models have the potential to yield. We developed a new analytical framework termed SALVO (synchronization, amplitude, length, and variability of oscillation) to profile the amplitude and temporal patterning of intra- and intercellular calcium signals in hSCCM. SALVO quantified drug-induced perturbations in the calcium signaling “fingerprint” in spontaneously contractile hSCCM. Multiparametric SALVO outputs were integrated into a single index of in vitro cytotoxicity that confirmed the rank order of perturbation as astemizole > thioridazine > cisapride > flecainide > valdecoxib > sotalol > nadolol ≈ control. This rank order of drug-induced Ca2+ signal disruption is in close agreement with the known arrhythmogenic liabilities of these compounds in humans. Validation of the system using a second set of compounds and hierarchical cluster analysis demonstrated the utility of SALVO to discriminate drugs based on their mechanisms of action. We discuss the utility of this new mechanistically agnostic system for the evaluation of in vitro drug cytotoxicity in hSCCM syncytia and the potential placement of SALVO in the early stage drug screening framework.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Sage
ISSN: 1087-0571
Funders: Wellcome Trust, British Heart Foundation
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 7 October 2014
Last Modified: 28 Jun 2019 02:45
URI: http://orca-mwe.cf.ac.uk/id/eprint/68060

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