Unveiling the Lack of Inotropic Response of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Isoproterenol by Chronic External Stimulation

Introduction: The lack of positive inotropic response to isoproterenol has been a caveat in the utilization of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for cardiac safety studies. Materials and Methods: We adopted two empirical, chronic ∼2-week pacing procedures to examine if chronic external stimulation could enhance a positive inotropic response of hiPSC-CMs to isoproterenol in a 2D environment. We also tested other typical pharmacological properties of hiPSC-CMs after chronic pacing training. Results: We found that hiPSC-CMs showed positive inotropic response to isoproterenol and forskolin treatment after chronic pacing training. But, this was only relative to the after-training baseline, inferring that chronic external stimulation can restore a related regulatory state in hiPSC-CMs. The after-training hiPSC-CMs showed no response to proarrhythmic agents—cisapride and dofetilide—at clinically relevant concentrations. This is consistent with recent acute pacing studies, therefore indicating it as a consequence of pacing itself (chronic or acute). Another surprising finding was that ranolazine at 100 μM did not induce early afterdepolarizations in after-training hiPSC-CMs. Despite those differences, the pacing training did not alter all pharmacological responses of hiPSC-CMs, as evidenced by responses to verapamil, FPL64176, and ivabradine. Conclusion: We concluded that chronic pacing training may restore hiPSC-CMs' positive ionotropic response to isoproterenol and reduce their proarrhythmic sensitivity. Indeed, chronic pacing training provided a new tool to use current hiPSC-CMs for fit-for-purpose studies in positive ionotropic-related cardiac safety assessment of drug candidates.