Pharmacological enhancement of repolarization reserve in human induced pluripotent stem cells derived cardiomyocytes.

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for many applications including safety pharmacology. However, a deficiency or complete absence of several K ⁺ currents suggests repolarization reserve is low in hiPSC-CMs. We determined whether a dual I _to and I _Kr activator can improve repolarization reserve in hiPSC-CMs resulting in a more electrophysiologically mature phenotype.
Methods and Results: Human iPSC were maintained on growth factor and differentiated into the cardiac phenotype by addition of selective Wnt molecules. Current and voltage clamp recordings in single cells were made using patch electrodes. Extracellular field potentials were made using a microelectrode array on hiPSC monolayers. Action potential recordings from hiPSC-CMs following application of an I _Kr inhibitor resulted in depolarization of the membrane potential and prolongation of the APD. A flattening of the T-wave was noted on the pseudo-ECG. In contrast, application of the I _Kr and I _to agonist, NS3623, resulted in hyperpolarization of the membrane, slowing of the spontaneous rate and shortening of the APD. Voltage clamp recording showed a significant increase in I _Kr ; no enhancement of I _to in hiPSC-CMs was noted. AP clamp experiments revealed that I _Kr plays a role in both phase 3 repolarization and phase 4 depolarization. mRNA analysis revealed that KCNH2 is abundantly expressed in hiPSC-CM, consistent with electrophysiological recordings.
Conclusions: Although NS3623 is a dual I _to and I _Kr activator in ventricular myocytes, application of this compound to hiPSC-CMs enhanced only I _Kr and no effect on I _to was noted. Our results suggest I _Kr enhancement can improve repolarization reserve in this cell type. The disconnect between a dramatic increase in I _to in adult myocytes versus the lack of effect in hiPSC-CMs suggest that the translation of pharmacological effects in hiPSC-CM to adult myocytes should be viewed with caution.
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