Cardiac Sodium Channel (Dys)Function and Inherited Arrhythmia Syndromes

Normal cardiac sodium channel function is essential for ensuring excitability of myocardial cells and proper conduction of the electrical impulse within the heart. Cardiac sodium channel dysfunction is associated with an increased risk of arrhythmias and sudden cardiac death. Over the last 20 years, (combined) genetic, electrophysiological, and molecular studies have provided insight into the (dys)function and (dys)regulation of the cardiac sodium channel under physiological circumstances and in the setting of SCN5A mutations identified in patients with inherited arrhythmia syndromes. Although our understanding of these sodium channelopathies has increased substantially, important issues remain incompletely understood. It has become increasingly clear that sodium channel distribution, function, and regulation are more complicated than traditionally assumed. Moreover, recent evidence suggests that the sodium channel may play additional, as of yet unrecognized, roles in cardiomyocyte function, which in turn may ultimately also impact on arrhythmogenesis. In this chapter, an overview is provided of the structure and function of the cardiac sodium channel and the clinical and biophysical characteristics of inherited sodium channel dysfunction. In addition, more recent insights into the electrophysiological and molecular aspects of sodium channel dysregulation and dysfunction in the setting of SCN5A mutations are discussed.