These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.
Pubmed for Handhelds
PUBMED FOR HANDHELDS
Search MEDLINE/PubMed
Title: Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Author: Patel D, Stohlman J, Dang Q, Strauss DG, Blinova K. Journal: Toxicol Sci; 2019 Jul 01; 170(1):167-179. PubMed ID: 30912807. 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.[Abstract] [Full Text] [Related] [New Search]