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

抄録

　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 torsade-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 7 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 experimental 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.