Inherited sodium channelopathies: models for acquired arrhythmias?

VOLTAGE-GATED Na channels, transmembrane proteins that produce the ionic current responsible for the rapid upstroke of the cardiac action potential, are key elements required for rapid conduction through the myocardium and maintenance of the cardiac rhythm. As such, inherited mutations in SCN5A, the gene encoding the human cardiac Na channel (hH1; Fig. 1), are associated with a range of life-threatening disorders of cardiac rhythm. Moreover, the subset of mutations that decrease hH1 function in some cases provoke tachyarrhythmias (14) and in other cases bradyarrhythmias (37), highlighting the complex relationship between the Na channel and cardiac rhythm. It is also notable that inherited mutations that reduce Na channel function seem to sensitize patients to the proarrhythmic effects of antiarrhythmic drugs with Na channel-blocking properties (34). Studies are now examining the potential link between acquired proarrhythmic complications of drug therapy in patients experiencing myocardial ischemia [i.e., the Cardiac Arrhythmia Suppression Trial (CAST) trial (15)] and the functional defects seen in the inherited Na channel syndromes. Hence, the Na channelopathies are expanding our understanding of the proarrhythmic mechanisms caused by loss of Na channel function and may shed light on the common acquired rhythm disorders associated with coronary occlusion and structural heart disease.