Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Nav1.5-subunit mutations  

作　　者：Yue Zhu Linlin Wang Chang Cui Huiyuan Qin Hongwu Chen Shaojie Chen Yongping Lin Hongyi Cheng Xiaohong Jiang Minglong Chen 

机构地区：[1]Department of Cardiology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China [2]Department of Cardiology,the Affiliated Brain Hospital of Nanjing Medical University,Nanjing Chest Hospital,Nanjing,Jiangsu 210029,China

出　　处：《The Journal of Biomedical Research》2021年第5期395-407,I0004-I0007,共17页生物医学研究杂志（英文版）

基　　金：supported by the Natural Science Foundation of Jiangsu Province of China(Grant No.BK20160134 to LW and BK20191071 to CC);National Natural and Science Foundation of China(Grant No.81900295 to CC);Special Foundation for Clinical Science and Technology of Jiangsu Province(Grant No.BE2017754 to HWC).

摘　　要：Brugada syndrome(BrS)is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death.Considering that its heterogeneity in clinical manifestations may result from genetic background,the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs)may help to reveal cell phenotype characteristics underlying different genetic variations.Here,to verify and compare the pathogenicity of mutations(SCN5A c.4213G>A and SCN1B c.590C>T)identified from two BrS patients,we generated two novel BrS iPS cell lines that carried missense mutations in SCN5A or SCN1B,compared their structures and electrophysiology,and evaluated the safety of quinidine in patient-specific iPSC-derived CMs.Compared to the control group,BrS-CMs showed a significant reduction in sodium current,prolonged action potential duration,and varying degrees of decreased Vmax,but no structural difference.After applying different concentrations of quinidine,drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration(ETPC).The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A or SCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.

关 键 词：human iPSCs Brugada syndrome disease modeling QUINIDINE SCN5A SCN1B 

分 类 号：R541.7[医药卫生—心血管疾病]