The arrhythmogenic consequences of increasing late I-Na in the cardiomyocyte

This review presents the roles of cardiac sodium channel Na(V)1.5 late current (late I-Na) in generation of arrhythmic activity. The assumption of the authors is that proper Na channel function is necessary to the maintenance of the transmembrane electrochemical gradient of Na and regulation of cardiac electrical activity. Myocyte Na channels openings during the brief action potential upstroke contribute to peak I-Na and initiate excitationcontraction coupling. Openings of Na channels outside the upstroke contribute to late I-Na, a depolarizing current that persists throughout the action potential plateau. The small, physiological late I-Na does not appear to be critical for normal electrical or contractile function in the heart. Late I-Na does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na loading. An increase of late I-Na, due to acquired conditions (e.g. heart failure) or inherited Na channelopathies, facilitates the formation of early and delayed afterpolarizations and triggered arrhythmias, spontaneous diastolic depolarization, and cellular Ca-2 loading. These in turn increase the spatial and temporal dispersion of repolarization time and may lead to reentrant arrhythmias.