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

TLDR

The study evaluated whether human‑induced pluripotent stem cell–derived cardiomyocytes can serve as a reliable in‑vitro proarrhythmia model by testing 28 drugs across low, intermediate, and high torsades de pointes risk categories in a blinded multisite setting with two commercial cell lines and standardized protocols. Drug responses were used as predictors in logistic and ordinal linear regression models to classify torsades de pointes risk, with measurements obtained via multielectrode array or voltage‑sensing optical methods. Three predictors—arrhythmia‑like events and repolarization prolongation at maximum tested or clinical exposures—achieved an AUC of ~0.8, while cell line, site, and platform had minimal impact, confirming hiPSC‑CMs’ utility for detecting drug‑induced proarrhythmic effects within the Comprehensive In Vitro Proarrhythmia Assay framework.

Abstract

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.