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Toxicol Sci. 2019 Jul 1;170(1):167-179. doi: 10.1093/toxsci/kfz076.

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

Author information

1
Office of Science and Engineering Laboratories.
2
Office of Device Evaluation, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland.
3
Office of Biostatistics.
4
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.

Abstract

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

KEYWORDS:

CiPA; MEA; iPSC-CMs; optogenetics; pacing; proarrhythmia

PMID:
30912807
DOI:
10.1093/toxsci/kfz076

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