HiPSC-CMs from different sex and ethnic origin donors exhibit qualitatively different responses to several classes of pharmacological challenges

We investigated whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) created from diverse origins could have qualitatively (not just quantitatively) different responses to pharmacological reagents. Specifically, we challenged six hiPSC-CM syncytia made from a female Caucasian, a female black non-Hispanic, a female white non-Hispanic, a male Caucasian non-Hispanic, a male Asian Indian, and a male-Asian, respectively, with eight different classes of pharmacological reagents (hERG channel blocker cisapride and dofetilide, calcium channel opener FPL64176, β-adrenergic agonist Isoproterenol, HCN channel blocker Ivabradine, I_Ks current blocker L-000768673, sodium channel blocker tetrodotoxin, and calcium channel blocker verapamil). We focused our analysis and comparison on qualitative differences (e.g., yes or no), and, found the following: hiPSC-CMs from female donors were uniformly more sensitive to dofetilide or cisapride, whereas those from male donors of all races were less sensitive to the two typical hERG blockers; isoproterenol had no chronotropic effect at all in one line; and two lines reacted to tetrodotoxin at very low concentrations and were more sensitive to external stimulation. We conclude that not all hiPSC-CMs are suitable for drug testing in terms of cardiac safety assessment, and pre-set acceptance criteria need to be established before any hiPSC-CMs can be used in CiPA-style study to evaluate cardiac liabilities of drug candidates.