Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes

• DOI: 10.1093/toxsci/kfz076
• Publication Date: 2019-03-25T08:19:04Z
• Authors: Dakshesh Patel; Jayna Stohlman; Qianyu Dang; David G Strauss; Ksenia Blinova
• Keywords: Risk; 0301 basic medicine; Dose-Response Relationship, Drug; Induced Pluripotent Stem Cells; Cell Culture Techniques; Drug Evaluation, Preclinical; Models, Cardiovascular; Arrhythmias, Cardiac; Optogenetics; 03 medical and health sciences; Pharmaceutical Preparations; Heart Rate; Predictive Value of Tests; Torsades de Pointes; Humans; Myocytes, Cardiac

Cardiac side-effects are one of the major reasons for failure drugs during preclinical development. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been proposed as a model predicting drug-induced arrhythmias under Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Field potential duration (FPD) spontaneously beating iPSC-CMs is commonly corrected rate using formulas originally derived from clinical QT–RR relationship that not thoroughly validated use with iPSC-CMs. In this study, channelrhodopsin-2 was expressed allowing recordings both and optically paced (0.8, 1, 1.5 Hz pacing rate) microelectrode array system (Maestro, Axion Biosystems). After optimizing intensity (>1 mW/mm2), (15 ms) frequency stimulating light pulses, we recorded iPSC-CMs' responses to 28 blinded CiPA compounds clinically characterized risk causing ventricular arrhythmia (Torsade de Pointes or TdP). Drug-induced FPD prolongation data along arrhythmia-like events were used build logistic regression model, separating high intermediate TdP low-or-no drugs. The area receiver operator characteristic curve drug prediction identical 0.8 Hz-paced (AUC = 0.96; 95% CI [0.9, 1]), while it slightly lower 1 0.88; [0.76, 1] 0.93; [0.84, 1], respectively). optical did offer substantial improvement proarrhythmic when compared nonpaced sample