Sodium channel (dys)function and cardiac arrhythmias

Abstract

Cardiac voltage-gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is responsible for the initial fast upstroke of the cardiac action potential. This inward sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of sodium channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired sodium channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac sodium channel, the clinical and biophysical characteristics of inherited and acquired sodium channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac sodium channel disease.