Session S64.2

The E1784K Mutation in SCN5A and Phenotypic Overlap of Type 3 Long QT Syndrome and Brugada Syndrome: A Simulation Study

KQ Wang, YF Yuan*, S Kharche, HG Zhang

Harbin Institute of Technology
Harbin City, China

Introduction: E1784K mutation in SCN5A is reported as phenotypic overlap between type 3 Long QT syndrome (LQT3) and Brugada syndrome (BrS). However it is still unclear how the E1784K SCN5A gene mutation-induced changes at ionic channel level affect ventricular excitation waves at tissue level. In this study, we use a biophysically detailed computer model to underpin the functional impacts of the E1784K SCN5A gene mutation on action potential (AP), abnormal ECG and ventricular arrhythmia.
Methods: The ten Tusscher et al. models were modified to include a new formulation for the late sodium current (INaL). To simulate E1784K mutation, experimental data of Makita et al. and Wei et al. on the mutation-induced changes on INa and INaL channel currents were incorporated into the model. These mutation-induced changes include a decrease in the fast INa current density by 40%, a slowed down of its inactivation process by 200% and an increase in the current density of INaL by 3.5 folds. Single cell models were then incorporated into a one-dimensional multi-cellular tissue model to simulate propagation of ventricular excitation waves across the strand and reconstruct the pseudo-ECG.
Results: Simulations show that (1) during the repolarisation plateau phase of AP, the mutation-induced increase in the late inward sodium current prolongs significantly action potential duration (APD) and augments transmural heterogeneity of APD and of the effective refractory period (ERP), that increases the vulnerability of ventricular tissue to the genesis of unidirectional conduction block leading to arrhythmia risks; (2) The mutation modifies the Na channel inactivation producing a persistent inward current during the phase 2 of AP, which elicits prolongation of APD and the QT interval prolongation as seen in a typical LQT3 ECG. However, there is no obvious elevated ST-segment as observed in the BrS ECG. However, when additional increase in Ito was considered, the coved-type ST segment elevation was produced. While additional reduction in ICaL was considered, the saddle-back type ST segment elevation was produced. Both the coved-type and saddle-back type ST segment elevation are typical features of clinical ECG recorded in the carriers of E1784K mutation.
Conclusions: These simulations substantiated the causative link between the E1784K SCN5A mutation and phenotypic overlap of LQT3 and BrS. It also illustrated that the elevated ST segment in ECGs of E1784K mutation carrier can not be sufficiently accounted for by the mutation-induced changes in INa and INaL alone. It may arise from a combined action of the mutation-induced changes in sodium channel currents and possible increase of Ito and decrease of ICaL as observed experimentally in BrS. The non-uniform prolongation in the APD augments transmural heterogeneity of ventricular repolarization that increases the vulnerability of ventricular tissue to the genesis of arrhythmia risks.

(Abstract Control Number: 45)