Pathological roles of the cardiac sodium channel late current (Late ina)

Abstract

The causes, consequences, and potential therapeutic benefit of inhibiting cardiac late sodium current are reviewed. Myocardial sodium channels enable electrical excitability and impulse conduction in the heart. Depolarization induces sodium channel openings and a large inward Na+ current that forms the upstroke of the cardiac action potential (AP). The cardiac AP is characterized by a long plateau phase during which Na+ channels are inactivated. Disruption of the process of Na+ channel inactivation, even when it affects only a small fraction of Na+ channels, results in a late or persistent inward Na+ current (late INa) that flows throughout the AP plateau. The magnitude of late INa is normally small but an increase can have pathological consequences. Both inherited (congenital) and acquired diseases may cause late INa to be enhanced. Mutations in genes encoding Na+ channel alpha and beta subunits and channel-associated proteins are causes of an enhanced late INa and LQT3 syndrome. Ischemia, heart failure, oxidative stress, and increased activities of certain protein kinases are associated with an increase of late INa. The consequences of an increased late INa include prolongation of the duration of the AP and facilitation of early after-depolarizations, and increased loading of myocytes with Na+. Myocyte Na+ loading leads to Ca2+ loading via Na+ /Ca2+ exchange, delayed after-depolarizations, and activation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII). CaMKII activation is associated with phosphorylation of the Na+ channel that further increases late INa, creating a potential positive feedback loop. Inhibition of late INa ameliorates electrical and mechanical dysfunction caused by LQT3 syndrome, ischemia, heart failure, and Na+ /Ca2+ overload. In these settings, the advantages of reducing an enhanced late INa may include: increased repolarization reserve associated with decreased AP duration and variability; decreased occurrences of early and delayed afterdepolarizations and triggered arrhythmias; improvements of myocardial Ca2+ handling, ventricular diastolic relaxation, and contractile efficiency.