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Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell–Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome
- Liang, Ping;
- Sallam, Karim;
- Wu, Haodi;
- Li, Yingxin;
- Itzhaki, Ilanit;
- Garg, Priyanka;
- Zhang, Ying;
- Termglichan, Vittavat;
- Lan, Feng;
- Gu, Mingxia;
- Gong, Tingyu;
- Zhuge, Yan;
- He, Chunjiang;
- Ebert, Antje D;
- Sanchez-Freire, Veronica;
- Churko, Jared;
- Hu, Shijun;
- Sharma, Arun;
- Lam, Chi Keung;
- Scheinman, Melvin M;
- Bers, Donald M;
- Wu, Joseph C
- et al.
Published Web Location
http://ac.els-cdn.com/S0735109716351634/1-s2.0-S0735109716351634-main.pdf?_tid=4d24a26a-c70e-11e6-9a69-00000aab0f01&acdnat=1482277672_cc35168440e0535974098323bbbecc9dNo data is associated with this publication.
Abstract
Background
Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder.Objectives
The objective of this study was to examine single cell mechanism of Brugada syndrome using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).Methods
This study recruited 2 patients with type 1 BrS carrying 2 different sodium voltage-gated channel alpha subunit 5 variants as well as 2 healthy control subjects. We generated iPSCs from their skin fibroblasts by using integration-free Sendai virus. We used directed differentiation to create purified populations of iPSC-CMs.Results
BrS iPSC-CMs showed reductions in inward sodium current density and reduced maximal upstroke velocity of action potential compared with healthy control iPSC-CMs. Furthermore, BrS iPSC-CMs demonstrated increased burden of triggered activity, abnormal calcium (Ca2+) transients, and beating interval variation. Correction of the causative variant by genome editing was performed, and resultant iPSC-CMs showed resolution of triggered activity and abnormal Ca2+ transients. Gene expression profiling of iPSC-CMs showed clustering of BrS compared with control subjects. Furthermore, BrS iPSC-CM gene expression correlated with gene expression from BrS human cardiac tissue gene expression.Conclusions
Patient-specific iPSC-CMs were able to recapitulate single-cell phenotype features of BrS, including blunted inward sodium current, increased triggered activity, and abnormal Ca2+ handling. This novel human cellular model creates future opportunities to further elucidate the cellular disease mechanism and identify novel therapeutic targets.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.