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

Unveiling the Lack of Inotropic Response of Human Induced Pluripotent Stem Cell-Derived... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Applied In Vitro Toxicology Mary Ann Liebert

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

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

Applied In Vitro Toxicology , Volume 6 (2): 7 – Jun 1, 2020

Abstract

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.

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Publisher
Mary Ann Liebert
Copyright
Copyright 2020, Mary Ann Liebert, Inc., publishers
ISSN
2332-1512
eISSN
2332-1539
DOI
10.1089/aivt.2020.0002
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Applied In Vitro ToxicologyMary Ann Liebert

Published: Jun 1, 2020

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