High-Throughput Optical Assays for Assessing Drug-Induced Q-T Prolongation in Human iPS Cell-Derived Cardiomyocytes

Prolongation of the Q-T interval, an important electrocardiogram (ECG) parameter, has been a major cardiac safety concern because it can lead to potentially fatal arrhythmia. The identification of compounds with potential Q-T prolongation liability is becoming critical in the discovery and selection of candidates for drug development. To assess the effects of compounds on the duration of cardiac action potentials, which are related to the Q-T interval, we have developed plate-based membrane potential dye and Ca2+ indicator assays using human induced pluripotent stem (iPS) cell-derived cardiomyocytes. With the use of sub-second fluorescence resonance energy transfer (FRET) probes, the change of membrane potential in cardiomyocytes can be monitored. To determine whether these assays are predictive for human cardiotoxicity, we have examined the pharmacological effects of selected reference drugs known to target different classes of cardiac ion channels and receptors. We have demonstrated that these optical assays are highly sensitive to the inhibition of cardiac ion channels and able to accurately track drug-induced change of action potential duration in human iPS-derived cardiomycocytes.