title: Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells.
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.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Stillitano
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Jens
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Kong
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Geng
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Stuart
authors.initials: S
authors.lastname: Scott
authors.affiliation: Cellectis Stem Cells, Paris, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Reynier
authors.affiliation: Cellectis Stem Cells, Paris, France.
authors.forename: Ma
authors.initials: M
authors.lastname: Wu
authors.affiliation: Cellectis Stem Cells, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Valogne
authors.affiliation: Cellectis Stem Cells, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Desseaux
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Joe-Elie
authors.initials: JE
authors.lastname: Salem
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Dorota
authors.initials: D
authors.lastname: Jeziorowska
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Noël
authors.initials: N
authors.lastname: Zahr
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States.|Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Jean-Sébastien
authors.identifier: 0000-0001-5463-6117
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D054715:Cardiotoxins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology*; D008403:Mass Screening / Q000379:methods*; D008954:Models, Biological; D035842:Research Subjects
chemical_list: D000889:Anti-Arrhythmia Agents; D054715:Cardiotoxins
keywords: arrhythmia; cardiotoxicity; human; human biology; induced pluripotent stem cells; medicine