Electrophysiological and pharmacological analysis with LQT2 patient (453delC‐KNCH2)‐derived induced pluripotent stem cell‐derived cardiomyocytes

Abstract

Objective Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising options for cell-based cardiac repair and in vitro models of human cardiomyocytes. The hiPSC-CMs are used as a diagnostic disease modeling and drug toxicity screening platform. Because hiPSCs retain the genetic information of the cells from which they are derived, cells differentiated from iPSCs can potentially recapitulate the disease phenotype. Methods In this study, we investigated the electrophysiological properties of hiPSC-CMs derived from a LQT2 patient with mutation in the KNCH2 gene (453delC-KNCH2) for hERG channel (LQT2 453delC-iPSC-CM). Results The genomic DNA analysis of LQT2 453delC-iPSC-CM confirmed the heterozygous mutation of 453delC KCNH2. The mRNA expression of cardiac ion channels and ventricular markers were analyzed to verify cardiomyocyte maturity. In the whole-cell patch clamp study, LQT2 453delC-iPSC-CMs showed smaller amplitude of hERG-type K+ current (IKr) and prolonged action potential duration compare to the control hiPSC-CMs. The results were consistent with the loss-of-function mutation of KCNH2 and LQT2 phenotype. In a multi-electrode array (MEA) study, TdP risk was compared between the control hiPSC-CMs and LQT2 453delC-iPSC-CMs. High, intermediate, and low risk TdP drugs were applied, and the drug-induced changes of field potential were analyzed to compare TdP risk. Conclusion The data set might be helpful for the drug investigation in the LQT syndrome and the development of patient-specific antiarrhythmic strategies.