In Silico Investigation of the Functional Effects of Long QT Syndrome Variant 3 on Electrical Conduction at PVJ

Cunjin Luo1 and Ying He2
1University of Essex, 2University of Nottingham


Recent studies suggested that long QT syndrome variant 3 (LQT3) is caused by mutations in the human KPQ-related gene (SCN5A), resulting in the production of late sodium currents (INaL) during the AP plateau, and prolonging the action potential and extending the QT interval of the ECG. However, ionic mechanisms underlying cardiac arrhythmias of LQT3 are incompletely understood. Our goal was to investigate the functional effects of LQT3 on the electrical wave conduction at the Purkinje-ventricle junction (PVJ). We defined the late sodium ion current (INaL) based on the TNNP model. We then changed its slow-deactivation gate variable and can generate a stable and significant late sodium current to simulate the action potential of cardiomyocytes under LQT3. We used the S1S2 protocol to obtain the dependence curve of APD and ERP and the CV recovery curve to investigate the mechanism of LQT3-induced arrhythmia. In the simulations, compared with 1.25 Hz of electrical stimulation, the measured APD90 did not change noticeably at 0.5 Hz, but was reduced at 2.66 Hz. At 3.33 Hz, 1:1 response of electrical excitation wave propagation to stimuli failed in the control condition, but was sustained in LQT3 conditions. This suggested that increased INaL prolongs the APD and ERP, which facilitates the conduction of electrical excitation waves. This study may account for the initiation of ventricular arrhythmia under LQT3 conditions.