Modeling the mechanism of [Na+]i elevation in heart failure by a canine ventricular cell model

Numerous studies have found the phenomenon of [Na⁺]i elevation in cardiac myocytes in heart failure (HF), which may influence cardiac action potential (AP) and intracellular Ca²⁺ handling to induce cardiac arrhythmias. As one of the most important regulators in the cardiac myocytes, Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII), which could alter Na⁺ channel gating, was found to be over-expressed in HF. It may contribute to [Na⁺]i elevation in HF. For the purpose of this study, we developed a new canine epicardial cell model based on the framework of published Hund-Rudy dynamic (HRd) model. The effects of dynamic CaMKII regulation on fast Na⁺ current (INa) and late Na⁺ current (INaL) were incorporated into our model according to the recent experimental data. Simulation results suggested that the regulation role of CaMKII on INaL could elevate [Na⁺]i. The effect of COE on INa had a function of lowering [Na⁺]i in fact. However, it could not offset the trend of Na⁺ up-regulation by enhanced INaL. The magnitude of [Na⁺]i elevation was smaller than experimentally measured values. We speculate that other [Na⁺]i elevation mechanisms such as lowered Na⁺/K⁺ pump (INaK) or increased Na⁺/H⁺ exchange may happen in HF.