Patient-specific iPSC-derived cardiomyocytes reveal variable phenotypic severity of Brugada syndromeResearch in context
Yaxun Sun,
Jun Su,
Xiaochen Wang,
Jue Wang,
Fengfeng Guo,
Hangyuan Qiu,
Hangping Fan,
Dongsheng Cai,
Hao Wang,
Miao Lin,
Wei Wang,
Ye Feng,
Guosheng Fu,
Tingyu Gong,
Ping Liang,
Chenyang Jiang
Affiliations
Yaxun Sun
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
Jun Su
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Xiaochen Wang
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Jue Wang
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Fengfeng Guo
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Hangyuan Qiu
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
Hangping Fan
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Dongsheng Cai
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
Hao Wang
Prenatal Diagnosis Center, Hangzhou Women's Hospital, Hangzhou, 310008, China
Miao Lin
Department of Cardiology, Wenzhou Central Hospital, 325000, Wenzhou, China
Wei Wang
Jiangxi Provincial Cardiovascular Disease Research Institute, Jiangxi Provincial People's Hospital, Nanchang, 330006, China
Ye Feng
Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China
Guosheng Fu
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
Tingyu Gong
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China; Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, China
Ping Liang
Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China; Corresponding authors. 268 Kaixuan Road, North Block of the Central Building, Room 404, Hangzhou, 310029, China.
Chenyang Jiang
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Corresponding author. 3 Qingchun East Road, Hangzhou, 310016, China.
Summary: Background: Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the genotype–phenotype correlations are not completely matched. Clinical phenotypes of a particular SCN5A variant may range from asymptomatic to SCD. Here, we used comparison of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from a SCN5A mutation-positive (D356Y) BrS family with severely affected proband, asymptomatic mutation carriers (AMCs) and healthy controls to investigate this variation. Methods: 26 iPSC lines were generated from skin fibroblasts using nonintegrated Sendai virus. The generated iPSCs were differentiated into cardiomyocytes using a monolayer-based differentiation protocol. Findings: D356Y iPSC-CMs exhibited increased beat interval variability, slower depolarization, cardiac arrhythmias, defects of Na+ channel function and irregular Ca2+ signaling, when compared to controls. Importantly, the phenotype severity observed in AMC iPSC-CMs was milder than that of proband iPSC-CMs, an observation exacerbated by flecainide. Interestingly, the iPSC-CMs of the proband exhibited markedly decreased Ca2+ currents in comparison with control and AMC iPSC-CMs. CRISPR/Cas9-mediated genome editing to correct D356Y in proband iPSC-CMs effectively rescued the arrhythmic phenotype and restored Na+ and Ca2+ currents. Moreover, drug screening using established BrS iPSC-CM models demonstrated that quinidine and sotalol possessed antiarrhythmic effects in an individual-dependent manner. Clinically, venous and oral administration of calcium partially reduced the malignant arrhythmic events of the proband in mid-term follow-up. Interpretation: Patient-specific and genome-edited iPSC-CMs can recapitulate the varying phenotypic severity of BrS. Our findings suggest that preservation of the Ca2+ currents might be a compensatory mechanism to resist arrhythmogenesis in BrS AMCs. Funding: National Key R&D Program of China (2017YFA0103700), National Natural Science Foundation of China (81922006, 81870175), Natural Science Foundation of Zhejiang Province (LD21H020001, LR15H020001), National Natural Science Foundation of China (81970269), Key Research and Development Program of Zhejiang Province (2019C03022) and Natural Science Foundation of Zhejiang Province (LY16H020002).
