A voltage-sensitive dye assay using hiPSC-CMs successfully detected conduction slowing and drug-induced TdP-like rotors for high- and intermediate-risk compounds, whereas low-risk compounds did not.
Can a voltage sensitive dye-based high-throughput screening assay using hiPSC-CMs accurately detect drug-induced proarrhythmia mechanisms such as Torsades de Pointes?
A voltage sensitive dye-based high-throughput assay using hiPSC-CMs can successfully detect drug-induced proarrhythmia mechanisms, validating its utility for preclinical drug safety screening.
We validated 3 distinct hiPSC-CM cell lines-each of different purity and a voltage sensitive dye (VSD)-based high-throughput proarrhythmia screening assay as a noncore site in the recently completed CiPA Myocyte Phase II Validation Study. Blinded validation was performed using 12 drugs linked to low, intermediate, or high risk for causing Torsades de Pointes (TdP). Commercially sourced hiPSC-CMs were obtained either from Cellular Dynamics International (CDI, Madison, Wisconsin, iCell Cardiomyoyctes2) or Takara Bio (CLS, Cellartis Cardiomyocytes). A third hiPSC-CM cell line (MCH, Michigan) was generated in house. Each cell type had distinct baseline electrophysiological function (spontaneous beat rate, action potential duration, and conduction velocity) and drug responsiveness. Use of VSD and optical mapping enabled the detection of conduction slowing of sodium channel blockers (quinidine, disopyramide, and mexiletine) and drug-induced TdP-like activation patterns (rotors) for some high- and intermediate-risk compounds. Low-risk compounds did not induce rotors in any cell type tested. These results further validate the utility of hiPSC-CMs for predictive proarrhythmia screening and the utility of VSD technology to detect drug-induced APD prolongation, arrhythmias (rotors), and conduction slowing. Importantly, results indicate that different ratios of cardiomyocytes and noncardiomyocytes have important impact on drug response that may be considered during risk assessment of new drugs. Finally, we present the first blinded CiPA hiPSC-CM validation results to simultaneously detect drug-induced conduction slowing, action potential duration prolongation, action potential triangulation, and drug-induced rotors in a proarrhythmia assay.
Rocha et al. (Fri,) conducted a other in Drug-induced Torsades de Pointes. Voltage-sensitive dye (VSD)-based high-throughput proarrhythmia screening assay was evaluated on Detection of drug-induced conduction slowing, action potential duration prolongation, action potential triangulation, and drug-induced rotors. A voltage-sensitive dye assay using hiPSC-CMs successfully detected conduction slowing and drug-induced TdP-like rotors for high- and intermediate-risk compounds, whereas low-risk compounds did not.