Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Nav1.5-subunit mutations
Yue Zhu1
Linlin Wang2
Chang Cui1
Huiyuan Qin1
Hongwu Chen1
Shaojie Chen1
Yongping Lin1
Hongyi Cheng1
Xiaohong Jiang1
Minglong Chen1
1.Department of Cardiology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China2.Department of Cardiology,the Affiliated Brain Hospital of Nanjing Medical University,Nanjing Chest Hospital,Nanjing,Jiangsu 210029,China
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.
机标关键词：
分类号：R541.7(心脏、血管（循环系）疾病)
论文发表日期：2021-09-30
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：13( 395-407 )
英文信息