Standardization and validation of human iPSC-derived cardiomyocyte-based assays for in vitro cardiac safety studies are currently assessed by the Comprehensive in vitro Proarrhythmia Assay (CiPA) consortium. Within CiPA, the acute effects of reference compounds (30±2 minutes after addition) are evaluated. However, besides acute effects on ion channels, especially chronic cardiotoxicity is a serious issue in the clinic.
In this study, we assessed both acute and chronic effects of a set of reference compounds on the electrophysiology and impedance of human iPSC-derived cardiomyocytes.
While ion channel inhibitors, e.g. hERG-channel blocker E4031, clearly caused acute drug effects on the electrophysiology of cardiomyocytes, other compounds affected the electrophysiology or impedance only after longer incubation times. For example, lapatinib, a tyrosine kinase inhibitor significantly increased the impedance peak width after 16h (54%, P≤0.01) to 24h (114%, P≤0.0001) incubations. In addition, the antiprotozoal drug pentamidine did not cause any acute effects, but induced a field potential duration prolongation exclusively from 12 hours after treatment caused by disruption of hERG protein trafficking in the cardiomyocytes.
Taken together, our results show that studying both acute and chronic drug-effects in hiPSC-derived cardiomyocytes enables a better understanding of the wide range of drug-induced cardiotoxicities that can occur and will help to explain the cellular mechanisms behind late onset drug-induced cardiomyopathy.