Short-term electrical stimulation promotes partial functional and morphological maturation of human-induced pluripotent stem cell-derived cardiomyocytes enabling cardiotoxicity risk mitigation at early-stage drug discovery for cardiac contractility modulation.

In drug discovery, assessing cardiac contractile force is crucial because of its association with the development of cardiovascular events and heart failure. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising in vitro model for drug discovery, particularly for assessing proarrhythmic risk. However, the availability of robust in vitro models to evaluate cardiac contractility has been limited. Here, we demonstrate that subjecting hiPSC-CMs to electrical stimulation for 48 h using a multielectrode array system induces partial functional and morphological maturation, as evidenced by a positive force-frequency relationship, increased conduction velocity of depolarization signals and improved sarcomere orientation with distinct Z-bands compared to unstimulated controls. We confirmed that electrical stimulation enables the evaluation of the positive inotropic effects of drug compounds with diverse pharmacological actions. The functional maturation induced by the electrical stimulation was observed across different facilities. The method also effectively detected prolonged QT intervals. These findings demonstrate the utility of the electrical stimulation for 48 h for hiPSC-CMs using the multielectrode array assay system to assess drug-induced contractile function and detect prolonged QT intervals in a single experiment, thereby enhancing the early-stage assessment of cardiotoxicity in drug discovery.