Pro-arrhythmic effects of increased late sodium current in failing human heart

Heart failure (HF) induces remodeling in cellular ionic channel kinetics, calcium and sodium cycling in the ventricle. In the present study, we investigated the effects of late Na⁺ current (I_NaL) on rate-dependent electrical activity of failing human ventricle by characterizing rate-dependent I_NaL and [Na⁺]_i, action potential duration (APD) prolongation, and early afterdepolarizations (EADs). Transmural ventricular APD dispersion and conduction velocity restitution (CVr) of 1-D virtual tissue were also investigated. In addition, the developed model was used to simulate ventricular electrocardiograms (ECG) under normal and HF conditions by using a 2-D idealized model. The results were in good accordance with experimental observations: under the HF condition, enhanced I_NaL contributed to the reverse rate-dependent (RRD) effects, APD prolongation and EADs generation in cells, and increased dispersion of APD and slowed down conduction in 1-D tissue. ECGs under normal and HF conditions were compared, demonstrating the importance of enhanced I_NaL which could be responsible for the increased arrhythmia susceptibility in human HF.