Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Na(v)1.5-subunit mutations

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 SCNIB c.590C>T) identified from two BrS patients, we generated two novel BrS iPS cell lines that carried missense mutations in SCN5A or SCNIB, 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 V-max, 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 SCNIB c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.