Advantages of long-term evaluation of doxorubicin-induced cardiotoxicity using human iPSC-derived cardiomyocyte sheet tissues with continuous contractile force measurement under constant pacing

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With advancements in anticancer therapy, concerns over delayed cardiotoxicity are increasing, creating demand for precise in vitro systems to evaluate long-term cardiotoxic effects in drug discovery. In this study, we examined the impact of doxorubicin on the contractility of cell sheet tissues made from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) maintained at a steady pacing rate of 1 Hz. Using our system for continuous contractile force measurement over 5 days, tissues exposed to 0.3 µM doxorubicin exhibited progressive force decline and arrhythmias, despite no significant changes in 4 biomarkers, ANP, BNP, NT-proBNP, and cTnT, sampled post-measurement. These findings suggest that indirect biomarker-based assessment of the cardiotoxicity of doxorubicin may be challenging. Notably, an increased slope during the relaxation stage preceded reduction in contraction amplitude in 0.3 µM-exposed tissues. Further analysis, dividing the relaxation into early, middle, and terminal phases, indicated that doxorubicin induces a rapid force decline during the early phase, followed by a gradual decrease in the terminal phase. We discussed the mechanistic basis of this toxicity based on intracellular Ca2+ dynamics. These insights derive from a system that enables stable, long-term measurement of contractile force under a consistent beating rate, and such technological advancements promise to enable more reliable evaluation of delayed cardiotoxicity in future drug development. Thus, our rate-controlled, continuous force platform reveals early relaxation-phase changes not detected by soluble biomarkers and offers a more sensitive in vitro approach for preclinical cardiotoxicity screening.

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