title: Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.
abstract: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland; ksenia.blinova@fda.hhs.gov.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Blinova
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.
authors.forename: Jayna
authors.initials: J
authors.lastname: Stohlman
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.|US Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, Maryland.|BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vicente
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.
authors.forename: Dulciana
authors.initials: D
authors.lastname: Chan
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: University of Glasgow, Glasgow, UK.|Clyde Biosciences, Glasgow, UK.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Hortigon-Vinagre
authors.affiliation: University of Glasgow, Glasgow, UK.|Clyde Biosciences, Glasgow, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Zamora
authors.affiliation: University of Glasgow, Glasgow, UK.|Clyde Biosciences, Glasgow, UK.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Smith
authors.affiliation: Zenas Technologies, Metairie, Louisiana.
authors.forename: William J
authors.initials: WJ
authors.lastname: Crumb
authors.affiliation: Division of Biochemical Toxicology, US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
authors.forename: Li
authors.initials: L
authors.lastname: Pang
authors.affiliation: Division of Biochemical Toxicology, US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
authors.forename: Beverly
authors.initials: B
authors.lastname: Lyn-Cook
authors.affiliation: Axion BioSystems, Atlanta, Georgia.
authors.forename: James
authors.initials: J
authors.lastname: Ross
authors.affiliation: Axion BioSystems, Atlanta, Georgia.
authors.forename: Mathew
authors.initials: M
authors.lastname: Brock
authors.affiliation: Axion BioSystems, Atlanta, Georgia.
authors.forename: Stacie
authors.initials: S
authors.lastname: Chvatal
authors.affiliation: Axion BioSystems, Atlanta, Georgia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Millard
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.
authors.forename: Loriano
authors.initials: L
authors.lastname: Galeotti
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, Maryland.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland; ksenia.blinova@fda.hhs.gov.|US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology, Silver Spring, Maryland.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D057170:Translational Research, Biomedical
keywords: CiPA; Cor.4U.; MEA; VSD; iCell; iPSC-CM