The role of late I Na in development of cardiac arrhythmias

Abstract

Late I Na is an integral part of the sodium current, which persists long after the fast-inactivating component. The magnitude of the late I Na is relatively small in all species and in all types of cardiomyocytes as compared with the amplitude of the fast sodium current, but it contributes significantly to the shape and duration of the action potential. This late component had been shown to increase in several acquired or congenital conditions, including hypoxia, oxidative stress, and heart failure, or due to mutations in SCN5A, which encodes the α-subunit of the sodium channel, as well as in channel-interacting proteins, including multiple β subunits and anchoring proteins. Patients with enhanced late I Na exhibit the type-3 long QT syndrome (LQT3) characterized by high propensity for the life-threatening ventricular arrhythmias, such as Torsade de Pointes (TdP), as well as for atrial fibrillation. There are several distinct mechanisms of arrhythmogenesis due to abnormal late I Na, including abnormal automaticity, early and delayed after depolarization-induced triggered activity, and dramatic increase of ventricular dispersion of repolarization. Many local anesthetic and antiarrhythmic agents have a higher potency to block late I Na as compared with fast I Na. Several novel compounds, including ranolazine, GS-458967, and F15845, appear to be the most selective inhibitors of cardiac late I Na reported to date. Selective inhibition of late I Na is expected to be an effective strategy for correcting these acquired and congenital channelopathies.

Fig. 1

Late sodium channel current is the current flowing during the plateau of the cardiac action potential and is comprised of slowly inactivating sodium channel current, late re-openings, and bursting behavior of the sodium channels. Modified from Belardinelli et al. (2004), with permission

Fig. 2

The pathophysiological paradigm for enhanced late I_Na. In both acquired and congenital syndromes, impaired inactivation of the sodium channel leads to enhanced late I_Na, causing a rise in intracellular Na concentration, which leads to calcium overload conditions. Modified from Belardinelli et al. (2006), with permission

Fig. 3

I_Kr and I_Ks blockers and Late I_Na agonist promote transmural dispersion (TDR) of repolarization and prolonged Tpeak–Tend intervals in the ECG by producing a preferential prolongation of the M cell action potential duration. Block of late I_Na with mexiletine reduces TDR in these experimental models of the long QT syndrome. Each panel shows transmembrane action potentials recorded from M and epicardial (Epi) sites in canine left ventricular wedge preparations together with a transmural ECG recorded across the bath (BCL of 2,000 ms). Traces are recorded in the presence of the I_Ks blocker, chromanol 293B (LQT1), I_Kr blocker d-sotalol (LQT2), and late I_Na agonist, ATX-II (LQT3), plus increasing concentrations of mexiletine. Mexiletine produced a greater abbreviation of the M cell vs. epicardial action potential at every concentration, resulting in a reduction in transmural dispersion of repolarization in all three LQTS models. Modified from (Shimizu and Antzelevitch 1997b, 1998) with permission

Fig. 4

Effect of ranolazine to suppress d-sotalol-induced action potential prolongation and early afterdepolarizations in Purkinje fiber (a) and M cell preparations (b). Modified from Antzelevitch et al. (2004)

Fig. 5

GS-458967 abolishes early afterdepolarizations (EADs) and EAD-induced triggered activity elicited by exposure to ATX-II in a canine Purkinje fiber. (a) ATX-II (10 nM) elicited EADs and EAD-induced triggered activity at basic cycle lengths (BCLs) of 2,000, 2,500, 3,500, 4,500, and 8,000 ms. GS-458967 (30 nM) abolished all EADs and triggered activity. From Sicouri et al. (2013) with permission

Fig. 6

Mechanisms contributing to electrical instability and mechanical dysfunction in acquired and congenital conditions that enhance late I_Na