Arrhythmogenic Mechanism of the Enhanced Late Sodium Current in Human Ventricular Myocytes - a Simulation Study

Abstract

The enhancement of the late sodium current (I NaL ) has been demonstrated to contribute to the cardiac arrhythmias. However, its arrhythmogenic mechanism at the cellular and tissue level remains incompletely elucidated. In this study, the O’Hara-Rudy model of human ventricular cells was implemented for multi-level simulations. At the cellular level, the influences of the pathological enhanced I NaL on cardiac action potential characteristics, ion currents, intracellular concentration homeostasis and action potential duration (APD) restitution properties were simulated and analyzed. At the tissue level, a heterogeneous one dimensional (1D) strand was constructed to find out the impact of enhanced I NaL on APD dispersion and the vulnerable windows (VWs). The simulations revealed the role of augmenting I NaL in prolonging the APD, steepening the APD restitution curves, increasing the heterogeneity of the tissue and widening the VWs. Our simulation data provides a detailed mechanistic insight into the pro-arrhythmic role of the enhanced I NaL at both cellular and tissue levels.