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

wei wang, Shanzhuo Zhang, Kuanquan Wang
Harbin institute of technology


Introduction: The enhancement of the late sodium current (INaL) has been demonstrated to contribute to cardiac arrhythmias. However, its arrhythmogenic mechanism at the cellular and tissue level remains incompletely elucidated. In this study, a multiscale human ventricular model was used to investigate the mechanistic influence of enhanced INaL on cardiac electrophysiology and arrhythmias. Method: The O’Hara-Rudy model of human ventricular cells was implemented for simulations. At the cellular level, we simulated and analysed the influences of pathological enhanced INaL to different degrees on cardiac action potential characteristics, ion currents, intracellular ion concentration homeostasis and action potential duration (APD) restitution properties for all three ventricular cell types: endocardial, midmyocardial and epicardial cells. At the tissue level, a heterogeneous 1-D strand was constructed to find out the impact of enhanced INaL on APD dispersion variations. Finally, the vulnerable windows (VWs) were calculated to evaluate the role of the pathological INaL in cardiac arrhythmia. Results: The cellular simulations revealed the role of augmenting INaL in the prolongation of APD, the reverse of Na+-Ca2+ exchanger, the accumulation of intracellular Na+ concentration and changes in ICaL and Ca2+ transients. The enhanced INaL also steepened the APD restitution curves of all cell types, demonstrating a promoting role in the reverse rate dependent APD prolongation. In addition, the APD spatial gradient, as well as the VW, increased with the growth of INaL in the tissue simulations, indicating increased heterogeneity of the tissue, which is a predisposing factor of cardiac arrhythmias. Conclusion: Our simulation data provides a detailed mechanistic insight into the pro-arrhythmic role of the enhanced INaL at both cellular and tissue levels. These findings are consistent with previous experimental studies, adding a theoretical basis for the mechanism of cardiac arrhythmia related to the late sodium current.