The Ca2+ transient assay in human stem-cell-derived cardiomyocytes correctly detected cellular arrhythmias-like/early afterdepolarizations in 87.5% of high TdP-risk drugs, 54.5% of intermediate TdP-risk drugs, and 0% of low TdP-risk drugs.
Does a Ca2+ transient assay in human stem-cell-derived cardiomyocytes accurately detect drug-induced long QT and proarrhythmic risk of 28 CiPA compounds?
A Ca2+ transient assay using human stem-cell-derived cardiomyocytes is a viable, higher-throughput method for in vitro assessment of drug-induced long QT and TdP risk.
The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR, and Health and Environmental Sciences Institute (HESI) was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem-cell-derived cardiomyocytes (hSC-CMs). The potential proarrhythmic risks of the 28 comprehensive in vitro proarrhythmia assay (CiPA) drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+-sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of 2 commercially available hSC-CM lines (Cor.4U and CDI iCell Cardiomyocytes) at 3 different test sites. The Ca2+ transient assay, performed at the 3 sites using the 2 different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CiPA drugs and detected cellular arrhythmias-like/early afterdepolarization in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP-risk drugs (54.5%), and 0 of 9 low/no TdP-risk drugs (0%). The results were comparable among the 3 sites and from 2 hSC-CM cell lines. The Ca2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the microelectrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.
Lu et al. (Fri,) conducted a other in Drug-induced long QT and torsade de pointes (TdP) risk. 28 CiPA compounds vs. Vehicle (DMSO) was evaluated on Detection of cellular arrhythmias-like/early afterdepolarization (EADs). The Ca2+ transient assay in human stem-cell-derived cardiomyocytes correctly detected cellular arrhythmias-like/early afterdepolarizations in 87.5% of high TdP-risk drugs, 54.5% of intermediate TdP-risk drugs, and 0% of low TdP-risk drugs.