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Elife. 2017 Jan 30;6. pii: e19406. doi: 10.7554/eLife.19406.

Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells.

Author information

1
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
2
Department of Pharmacology and Systems Therapeutics, Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, United States.
3
Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
5
Cellectis Stem Cells, Paris, France.

Abstract

A large number of drugs can induce prolongation of cardiac repolarization and life-threatening cardiac arrhythmias. The prediction of this side effect is however challenging as it usually develops in some genetically predisposed individuals with normal cardiac repolarization at baseline. Here, we describe a platform based on a genetically diverse panel of induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop a cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting in vivo with extremely low or high changes in cardiac repolarization in response to a pharmacological challenge with sotalol. In vitro, the responses to sotalol were highly variable but strongly correlated to the inter-individual differences observed in vivo. Transcriptomic profiling identified dysregulation of genes (DLG2, KCNE4, PTRF, HTR2C, CAMKV) involved in downstream regulation of cardiac repolarization machinery as underlying high sensitivity to sotalol. Our findings offer novel insights for the development of iPSC-based screening assays for testing individual drug reactions.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01338441.

KEYWORDS:

arrhythmia; cardiotoxicity; human; human biology; induced pluripotent stem cells; medicine

PMID:
28134617
PMCID:
PMC5279943
DOI:
10.7554/eLife.19406
[Indexed for MEDLINE]
Free PMC Article

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