【Introduction】 Evaluation of drug-induced cardiotoxicity is important to avoid adverse effects, such as arrhythmia and contractile dysfunction, which is considered to result in heart failure, in non-clinical and clinical studies. For example, BMS-986094, which was developed as a Hepatitis C virus nucleotide polymerase (non-structural 5B) inhibitor, was withdrawn from phase 2 clinical trials because of unexpected heart failure by long-term administration. Although animal models have been widely used to assess cardiac contraction, in vitro models are expected to assess human-specific contraction. We have previously developed the methods to assess cardiac contraction using motion analyses in human iPS cell-derived cardiomyocytes (hiPSC-CMs). Here we assessed whether BMS-986094 induced chronic contractile dysfunction in hiPSC-CMs.
【Methods】 We used iCell cardiomyocyte 2.0 (CDI). Motion analyses were performed using a cell motion imaging system (SI8000, Sony). Calcium imaging was performed using Fluo-8/AM.
【Results】 We found that BMS-986094 decreased both contraction and relaxation velocity by 96 h exposure, while acute exposure with BMS-986094 had little effects. In contrast, sofosbuvir, which has the same drug target, had little effect during 6-day exposure. Next, we analyzed the effect on calcium transient. BMS-986094 decreased calcium transient at 96 h, while sofosbuvir did not affect.
【Conclusion】 Thus, the imaging analysis of hiPSC-CMs would be useful to assess the chronic contractile dysfunction in human.