Abstract 17625: Modeling the Long QT Syndrome with Human Induced Pluripotent Stem Cells
The development of strategies to generate patient specific human induced pluripotent stem cells (hiPSCs) offers a new paradigm for modeling human disease and individualized drug testing. The congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific hiPSCs line from a LQTS type 2 patient (displaying the A614V missense mutation in the KCNH2 gene). The generated hiPSCs were coaxed to differentiate into the cardiac lineage. Detailed gene expression, immunostaining, and electrophysiological studies confirmed the cardiomyocyte phenotype of the LQTS hiPSCs-CMs. Thorough whole-cell patch-clamp and extracellular recordings (multielectrode array mapping technique) demonstrated significant prolongation of the action potential duration (APD90= 1060±103 vs. 411±94 ms; n=6, p<0.05) and field potential duration (1047±70 vs. 666±97 ms; n=10, p<0.05) in the LQTS hiPSCs-CMs when compared to healthy hiPSCs-CMs (Fig.1A). Such a prolongation is characteristic of the LQTS phenotype. Importantly, the LQTS derived cells also displayed marked arrhythmogenicity; characterized by the development of early after depolarizations (EADs) in 15/24 cells and sustained triggered arrhythmias in 6/24 cells (Figs. 1A-B). Finally, the LQTS hiPSC-CMs were used to validate the potency of pharmacological agents that may either aggravate (E-4031, Cisapride, Chromanol) or ameliorate (Nifedipine) the disease phenotype. Our study illustrates, for the first time, the ability of the hiPSCs technology to model the abnormal functional phenotype of an inherited disorder. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized-medicine), and aid in the development of new therapeutic strategies.
- © 2010 by American Heart Association, Inc.