Assessing drug-induced long QT and proarrhythmic risk using human stem cell-derived cardiomyocytes in a Ca2+ imaging assay: Evaluation of 28 CiPA compounds at three test sites


Abstract
Introduction
The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR and 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).

Methods
The potential proarrhythmic risks of the 28 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 two commercially available hSC-CM lines (Cor.4U® and CDI iCell® Cardiomyocytes) at three different test sites.

Results
The Ca2+ transient assay, performed at the three sites using the two different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CIPA drugs and detected cellular arrhythmias-like/EAD 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 three sites and from two hSC-CM cell lines.

Conclusion
The Ca 2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the micro-electrode 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.

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