Cardiac late Na⁺ current: proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress.

Abstract

Myocyte sodium channel current that persists throughout the plateau of the cardiac action potential is referred to as late sodium current (I(Na-L)). The magnitude of I(Na-L) is normally small, but can increase significantly in common acute and chronic pathological settings as a result of inherited and/or acquired Na(+) channelopathies that alter channel opening and closing (ie, gating), location (trafficking), or anchoring and interactions with cytoskeletal proteins. An increase in I(Na-L) reduces repolarization reserve in atrial and ventricular myocytes and prolongs the action potential duration and the QT interval. An enhanced I(Na-L) is a cause of long QT syndrome 3. I(Na-L) may be a cause of afterdepolarizations, triggered arrhythmias, and spontaneous diastolic depolarization-induced automaticity. In addition, enhancement of I(Na-L) increases both the temporal and the spatial dispersion of repolarization in the myocardium and may lead to spatially discordant action potential duration alternans, wavebreak, and reentrant arrhythmias. Positive feedback loops between increases in I(Na-L) and the activity of Ca(2+)/calmodulin-dependent protein kinase II appear to contribute to the genesis of arrhythmias and to certain abnormalities of the ischemic heart. In this review, we discuss some of the more relevant experimental results, clinical findings, and insights from cellular and animal models that highlight the role of I(Na-L) in the genesis of arrhythmias, long QT syndromes, and intracellular Ca(2+) homeostasis.