In Silico Investigation of the Functional Impact of SCN10A Mutations in Human Atrial Cells

In normal conditions, action potential (AP) in cardiac myocytes is initiated by peak sodium current 𝐼"#$, which become inactivated during depolarization, leaving a less pronounce current known as late sodium current (𝐼"#%), which has a relatively smaller amplitude (~0.5%) compared to the 𝐼"#$. A recent study has identified three gain-of-function mutations in the SCN10A channel (the gene encoding the voltage-gated sodium channel 𝑁𝑎(1.8, 𝐼"#% ) that have a correlation with the subsequent development of atrial fibrillation. However, the underlying mechanism responsible for the pro-arrhythmic effect of the gene mutations is unclear. This study aims to investigate the effect of the three gene mutations on atrial electrical action potentials. Hodgkin-Huxley (HH) formulation of late sodium channel current in human atrial cells was developed and validated against experimental data obtained by voltage clamp techniques. The formulation was then implemented in Colman et al. human atrial model to simulate atrial APs for wild type (WT) and mutation conditions. It was shown that A1073 and P1092 mutations prolong the action potential duration (APD) and elevate the plateau (phase 2) potential compared to WT. Such altered AP profiles may alter tissue’ s spatial heterogeneity, favoring the initiation and maintenance of atrial fibrillation, which warrants future study.