title: Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell-derived cardiomyocytes.
abstract: Functional changes to cardiomyocytes are a common cause of attrition in preclinical and clinical drug development. Current approaches to assess cardiomyocyte contractility in vitro are limited to low-throughput methods not amenable to early drug discovery. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) were used to assess their suitability to detect drug-induced changes in cardiomyocyte contraction. Application of field stimulation and measurement of cardiac contraction (IonOptix edge detection) and Ca(2+) transients confirmed hiPS-CMs to be a suitable model to investigate drug-induced changes in cardiomyocyte contractility. Using a live cell, fast kinetic fluorescent assay with a Ca(2+) sensitive dye to test 31 inotropic and 20 non-inotropic compounds in vivo, we report that hiPS-CMs provide a high-throughput experimental model to detect changes in cardiomyocyte contraction that is applicable to early drug discovery with a sensitivity and specificity of 87% and 70%, respectively. Moreover, our data provide evidence of the detection of this liability at therapeutically relevant concentrations with throughput amenable to influencing chemical design in drug discovery. Measurement of multiple parameters of the Ca(2+) transient in addition to the number of Ca(2+) transients offered no insight into the mechanism of cardiomyocyte contraction.
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK Amy.Pointon@astrazeneca.com.
authors.forename: Amy
authors.initials: A
authors.lastname: Pointon
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Harmer
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Ian L
authors.initials: IL
authors.lastname: Dale
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bowes
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pollard
authors.affiliation: *Translational Safety, Discovery Safety, Drug Safety and Metabolism and Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield SK10 4TG, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Garside
mesh_terms: D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism
chemical_list: D002118:Calcium
keywords: cardiotoxicity; drug discovery and development; hiPS-CMs