Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells
Francesca Stillitano,
Jens Hansen,
Chi-Wing Kong,
Ioannis Karakikes,
Christian Funck-Brentano,
Lin Geng,
Stuart Scott,
Stephan Reynier,
Ma Wu,
Yannick Valogne,
Carole Desseaux,
Joe-Elie Salem,
Dorota Jeziorowska,
Noël Zahr,
Ronald Li,
Ravi Iyengar,
Roger J Hajjar,
Jean-Sébastien Hulot
Affiliations
Francesca Stillitano
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States
Jens Hansen
Department of Pharmacology and Systems Therapeutics, Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, United States
Chi-Wing Kong
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States
Ioannis Karakikes
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States
Christian Funck-Brentano
Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France
Lin Geng
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States
Stuart Scott
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
Stephan Reynier
Cellectis Stem Cells, Paris, France
Ma Wu
Cellectis Stem Cells, Paris, France
Yannick Valogne
Cellectis Stem Cells, Paris, France
Carole Desseaux
Cellectis Stem Cells, Paris, France
Joe-Elie Salem
Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France
Dorota Jeziorowska
Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France
Noël Zahr
Sorbonne Universités, UPMC Univ Paris 06, AP-HP, INSERM, CIC-1421, Institute of Cardiometabolism and Nutrition, Paris, France
Ronald Li
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Stockholm, Sweden; Dr. Li Dak-Sum Centre, The University of Hong Kong – Karolinska Institutet Collaboration in Regenerative Medicine, Pokfulam, Hong Kong
Ravi Iyengar
Department of Pharmacology and Systems Therapeutics, Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, United States
Roger J Hajjar
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, United States
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
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.
