Abstract 18442: Modeling Drug-Induced Long QT Syndrome with Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes
A high number of drugs have the undesirable side effects of prolonging cardiac repolarization which can trigger life-threatening cardiac arrhythmias. However, methods to predict drug-induced QT prolongation (diLQT) are suboptimal. In addition, the risk of developing diLQT varies markedly among subjects. Multiple mutations in genes encoding ion channels have been reported to underlie the congenital form of the long QT syndrome (LQTS). However, most people who have life-threatening diLQTS do not have mutations in LQTS genes and the risk of developing diLQT is more likely associated with a predisposing genetic background with multiple genetic factors affecting the cardiac repolarization reserve.
We investigated whether induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) from subjects with quantitative measure of diLQT in vivo can recapitulate the phenotype in vitro thereby providing a model system for diLQT. We prospectively evaluated cardiac repolarization of 126 healthy subjects in response to a pharmacological challenge with a single oral dose of Sotalol 80mg. We collected skin fibroblasts from twenty subjects with the most extreme responses to Sotalol (10 subjects with high-sensitivity (high-S) and 10 with low-sensitivity (low-S); change in QTcf: 48.5±7.1ms vs. 0.2±4.8ms). iPSCs were successfully generated in 17 of the 20 individuals. All experiments were then performed in a blinded fashion without knowledge of the associated clinical phenotype. Cardiac differentiation resulted in the generation of iPSC-CMs with appropriate cardiac channel expression and response to a hERG blocker in lines from 14 subjects. iPSC-CMs were then tested in increasing concentrations of Sotalol. The different recordings (using multielectrode array or action potential duration) showed a significantly higher response to Sotalol in iPSC-CMs from high-S as compared to low-S subjects (maximal response to Sotalol: 52±6% vs. 29±6% in high-S vs. low-S, p<0.02). Five of the 7 lines derived from the high-S group displayed arrhythmias in response to sotalol stimulation while arrhythmias only occurred in one of the lines from the low-S group.
This study suggests that patient-specific iPSC can be used to model the functional abnormalities observed in diLQTS.
Author Disclosures: F. Stillitano: None. M. Kong: None. I. Karakikes: None. C. Funck-Brentano: None. S. Reynier: None. W. Ma: None. E. Laurent: None. A. Papadopoulos: None. Y. Valogne: None. C. Desseaux: None. N. Zahr: None. R. Li: None. R.J. Hajjar: None. J. Hulot: Research Grant; Significant; Cellectis Stem Cells, Celladon. Honoraria; Modest; Imaxio, Daiichi Sankyo.
- © 2014 by American Heart Association, Inc.