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Abstract
This review presents the roles of cardiac sodium channel NaV1.5 late current (late INa) 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 INa and initiate excitation-contraction coupling. Openings of Na(+) channels outside the upstroke contribute to late INa, a depolarizing current that persists throughout the action potential plateau. The small, physiological late INa does not appear to be critical for normal electrical or contractile function in the heart. Late INa does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na(+) loading. An increase of late INa, 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.
Highlights
This review presents the roles of cardiac sodium channel NaV1.5 late current in generation of arrhythmic activity
The detrimental electrical effects of an enhanced, pathological late INa are depicted in Figure 1, and include the following: (i) diastolic depolarization during phase 4 of the action potential (AP) that may lead to spontaneous AP firing and abnormal automaticity, especially of myocytes that are relatively depolarized and have low resting K+ conductance; (ii) an increase of AP duration, due to the depolarizing effect of an increased inward Na+ current during the AP plateau, and which may lead to early after-depolarizations (EADs) and triggered activity, as well as increased spatiotemporal differences of repolarization time, which promote reentrant electrical activity; and (iii) the indirect effects of a late INa-induced increase of Na+ entry to alter Ca2+ homeostasis in myocytes, which may lead to Ca2+ alternans and DADs
Voltageclamp studies of atrial myocytes demonstrated that an inward current is activated by a depolarizing ramp pulse and that the ramp-induced current is blocked by TTX and enhanced by ATX-II, consistent with its identification as late INa.[77]. These findings suggest that late INa is a cause of spontaneous diastolic depolarization and abnormal automaticity that may contribute to arrhythmogenesis in atrial myocytes and Purkinje fibres
Summary
The presence and potential importance of so-called noninactivating Na+ current in myocytes was recognized as early as 1979,1,2 the roles of this seemingly minor current in arrhythmogenesis were not identified until the demonstration that ‘gain of function’ mutations in the gene SCN5A enhance NaV1.5 late INa and cause the congenital long-QT syndrome type 3 (LQT3).[3,4] Pathological roles of late INa in the heart have been reviewed previously.[5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Of peak INa at a pacing rate of 1 Hz increased AP duration by nearly 2.2-fold and Na+ and Ca2+ concentrations in diastole by 34 and 52%, respectively, and was associated with spontaneous erratic releases of Ca2+ from the sarcoplasmic reticulum.[69] An increase of late INa in myocytes isolated from failing human and dog hearts is associated with spontaneous releases of sarcoplasmic reticular Ca2+ during diastole.[56] Drug-induced inhibition of late INa has been shown to reduce Na+dependent Ca2+ loading and contractile dysfunction of cardiac myocytes from both normal and failing hearts,39,47,56,63 – 65 and contractile dysfunction in the ischaemic heart.[70,71] One may conclude that an enhanced late INa can cause changes of Na+ entry and the transmembrane Na+ gradient that alter cardiac function. GS967 indicate that reduction of endogenous late INa in rabbit hearts and isolated ventricular myocytes is associated with a decrease of AP duration, a small but non-significant decrease in intracellular Na+, and no change in Ca2+.74
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