Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Abstract

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

“…Supporting a direct mechanism, SUMOylation of Na V 1.5 produces I LATE in the absence of hypoxia in membrane patches excised from cells, basal levels of Na V 1.5 SUMOylation are low under control conditions in iPS-CMs, and hypoxia leads to SUMOylation of the channels with the same time course as the increase in I LATE . Furthermore, SUMOylation produces changes in the gating of single Na V 1.5 ion channels, macroscopic I Na , and APDs like those described in human heart and in animal models with hypoxia (Chadda et al, 2017;Austen et al, 1963;Thung et al, 1962;Brown et al, 2014); and the effects are suppressed by the mutation of Na V 1.5 K442, the application of SENP1 deSUMOylase, or the application of ranolazine, an inhibitor of I LATE .…”

“…spatiotemporal changes in repolarization that promote reentrant arrhythmias, including ventricular TdP (Gaur et al, 2009;Shryock et al, 2013;Chadda et al, 2017). Medications like ranolazine that suppress I LATE minimize disruption of Ca 2+ homeostasis, reducing EADs and DADs (Maier and Sossalla, 2013).…”

“…In patients with an ischemic and failing heart, sudden infant death syndrome (SIDS), and mutations in SCN5A, the gene that encodes the Na V 1.5 channel, which produces long QT syndrome, the size of I LATE can increase to 4%-5% of peak I Na (Bennett et al, 1995;Plant et al, 2006;Belardinelli et al, 2015). Furthermore, acute hypoxia and ischemia have been recognized to increase I LATE in cardiac myocytes (Saint et al, 1992;Ju et al, 1996;Carmeliet, 1999;Belardinelli et al, 2006) prior to slower processes like remodeling (West, 2017), and excess I LATE has been shown to be pro-arrhythmic because it prolongs action potential duration (APD), reducing repolarization reserve, increasing suscepti-bility to after-depolarizations, and causing a predisposition to torsades de pointes (TdP), a ventricular dysrhythmia that is lethal when sustained (Gaur et al, 2009;Shryock et al, 2013;Chadda et al, 2017). Thus, increases in I LATE above baseline by just 0.3% to 1% predisposition to sudden cardiac death (Bennett et al, 1995;Belardinelli et al, 2015).…”

Acquired long QT syndrome in chronic kidney disease patients

“…Mexiletine has a significant therapeutic effect on refractory TdP and that it can shorten the QT interval of the basic ECG. The enhanced late sodium channel currents (I Na-L ) can potentially cause pro-arrhythmic phenotypes [111]. Enhanced I Na-L can be observed in acquired conditions, such as hypertrophic cardiomyopathy, heart failure and drug-induced arrhythmias [112,113].…”

Late sodium current in human, canine and guinea pig ventricular myocardium

“…Initially I Na-late was believed to be a consequence of the overlapping steady-state activation and inactivation functions of the Na + current (window Na + current) [17], now it is better explained by the slow inactivation kinetics of a small fraction of cardiac Na + channels (mode-II gating, bursting and late openings) [4,6]. In spite of its relative importance, many aspects of I Na-late are still poorly understood.…”