The E1784K mutation in SCN5A and phenotypic overlap of Type 3 Long QT syndrome and Brugada syndrome: A simulation study

The E1784K mutation in SCN5A was reported as a phenotypic overlap between the Type 3 Long QT syndrome (LQT3) and the Brugada syndrome (BrS). However it is still unclear if the E1784K mutation-induced changes at ionic channel level is sufficient to account for the two phenotypic and how they affect ventricular excitation waves at tissue level. In this study, we used a biophysically detailed computer model to underpin the functional impacts of the E1784K mutation on ventricular action potential (AP), abnormal ECG and arrhythmic genesis. The simulation results suggested that augmented transmural heterogeneity of APD and ERP under the E1784K mutation condition aggravates arrhythmia risks. The E1784K mutation is insufficient to produce the phenotypic overlap between LQT3 and BrS, which may arise from a combined action of the mutation-induced changes in sodium channel currents and possible increase of I_To or decrease of I_CaL as seen in BrS.