Late sodium current and calcium homeostasis in arrhythmogenesis

Abstract

The cardiac late sodium current (I_Na,late) is the small sustained component of the sodium current active during the plateau phase of the action potential. Several studies demonstrated that augmentation of the current can lead to cardiac arrhythmias; therefore, I_Na,late is considered as a promising antiarrhythmic target. Fundamentally, enlarged I_Na,late increases Na⁺ influx into the cell, which, in turn, is converted to elevated intracellular Ca²⁺ concentration through the Na⁺/Ca²⁺ exchanger. The excessive Ca²⁺ load is known to be proarrhythmic. This review describes the behavior of the voltage-gated Na⁺ channels generating I_Na,late in health and disease and aims to discuss the physiology and pathophysiology of Na⁺ and Ca²⁺ homeostasis in context with the enhanced I_Na,late demonstrating also the currently accessible antiarrhythmic choices.

Keywords: Voltage-gated sodium channels; calcium homeostasis; calcium signaling; cardiac arrhythmias; delayed afterdepolarization; early afterdepolarization; late sodium current; sodium current; sodium homeostasis.