Human-induced pluripotent stem cell-derived cardiomyocytes have limited I(Ks) for repolarization reserve as revealed by specific KCNQ1/KCNE1 blocker

OBJECTIVE: We investigated if there is I(Ks), and if there is repolarization reserve by I(Ks) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). DESIGN: We used a specific KCNQ1/KCNE1 channel blocker, L-000768673, with an IC(50) of 9 nM, and four hERG-specific blockers, astemizole, cisapride, dofetilide, and E-4031 to investigate the issue. RESULTS: L-000768673 concentration-dependently prolonged feature point duration (FPD)―a surrogate signal of action potential duration―from 1 to 30 nM without pacing or paced at 1.2 Hz, resulting from I(Ks) blockade in hiPSC-CMs. At higher concentrations, the effect of L-000768673 on I(Ks) was mitigated by its effect on I(Ca-L), resulting in shortened FPD, reduced impedance amplitude, and increased beating rate at 1 µM and above, recapitulating the self-limiting properties of L-000768673 on action potentials. All four hERG-specific blockers prolonged FPD as expected. Co-application of L-000768673 at sub-threshold (0.1 and 0.3 nM) and threshold (1 nM) concentrations failed to synergistically enhance the effects of hERG blockers on FPD prolongation, rather it showed additive effects, inconsistent with the repolarization reserve role of I(Ks) in mature human myocytes that enhanced I(Kr) response, implying a difference between hiPSC-CMs used in this study and mature human cardiomyocytes. CONCLUSION: There was I(Ks) current in hiPSC-CMs, and blockade of I(Ks) current caused prolongation of action potential of hiPSC-CMs. However, we could not demonstrate any synergistic effects on action potential duration prolongation of hiPSC-CMs by blocking hERG current and I(Ks) current simultaneously, implying little or no repolarization reserve by I(Ks) current in hiPSC-CMs used in this study.