International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment

• Published in: Cell reports (Cambridge) 2018-09, Vol.24 (13), p.3582-3592
• Main Authors: Blinova, Ksenia, Dang, Qianyu, Millard, Daniel, Smith, Godfrey, Pierson, Jennifer, Guo, Liang, Brock, Mathew, Lu, Hua Rong, Kraushaar, Udo, Zeng, Haoyu, Shi, Hong, Zhang, Xiaoyu, Sawada, Kohei, Osada, Tomoharu, Kanda, Yasunari, Sekino, Yuko, Pang, Li, Feaster, Tromondae K., Kettenhofen, Ralf, Stockbridge, Norman, Strauss, David G., Gintant, Gary
• Format: Article
• Language: English
• Subjects: Cardiotoxicity; Cell Line; Cellular Reprogramming; CiPA; comprehensive in vitro proarrhythmia assay; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - standards; drug-induced ventricular arrhythmia Torsade de Pointes; Electrophysiology - methods; Electrophysiology - standards; hiPSC-CM; human-induced pluripotent stem cell-derived cardiomycotes; Humans; Induced Pluripotent Stem Cells - cytology; Membrane Potentials - drug effects; microelectrode array; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Torsades de Pointes - chemically induced; voltage-sensitive dyes
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.08.079

To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves ∼0.8). hiPSC-CM line, test site, and platform had minimal influence on drug categorization. These results demonstrate the utility of hiPSC-CMs to detect drug-induced proarrhythmic effects as part of the evolving Comprehensive In Vitro Proarrhythmia Assay paradigm. [Display omitted] •28 drugs classified by torsadesproarrhythmic risk studied in blinded experiments•Two commercial human cardiomyocyte lines used with 5 devices across 10 sites•Repolarization effects evaluated using microelectrode array and voltage-sensing dyes•Statistical model predicted proarrhythmic risk from electrophysiologic responses Blinova et al. tested human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for improving torsades de pointes arrhythmia risk prediction of drugs in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative. This validation study confirms their utility based on electrophysiologic responses to 28 blinded drugs, with minimal influence from cell lines, test sites, and electrophysiological platforms.