Cardiac voltage‐gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is responsible for the initial fast upstroke of the cardiac action potential ( Figure 1A ). This inward sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of sodium channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired sodium channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac sodium channel, the clinical and biophysical characteristics of inherited and acquired sodium channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac sodium channel disease.

Cardiac sodium channels are not homogeneously distributed throughout the myocardium, but show differential expression within the cardiac conduction system and across the ventricular wall. Nav1.5 protein expression is low to absent in the sinoatrial and atrioventricular nodes, but abundant in the His bundle, bundle branches and Purkinje fibers [ 15 , 16 ]. Furthermore, a transmural gradient is observed in left and right ventricle, with lower Nav1.5 labeling intensity and decreased functional sodium channel availability in the subepicardium as compared to the subendocardium [ 16 , 17 ]. During pathological conditions, this inhomogeneous sodium channel expression throughout the ventricular wall may promote transmural heterogeneity in conduction slowing and arrhythmogenesis [ 18 ]. In addition, differences in sodium channel inactivation properties have been described between atrial and ventricular myocytes [ 19 , 20 ]. Overall, the observed heterogeneity in sodium channel expression and function in different compartments of the heart has profound consequences not only for disease expressivity of cardiac sodium channelopathies, but also determines responsiveness to and efficacy of sodium channel blockade drug therapy (see later).

Cardiac sodium channel function is influenced by a large number of proteins, including the ancillary β‐subunit, which consists of a small C‐terminal cytoplasmic domain, a single transmembrane segment, and a large glycosylated N‐terminal extracellular domain ( Figure 1B ). Through a direct physical interaction with the α‐subunit Nav1.5, various β subunit isoforms (β1–β4 encoded by the SCN1B – SCN4B genes, respectively) may influence sodium channel density and kinetics in vitro [ 5 - 7 ]. Other proteins directly binding to and regulating Nav1.5 include ankyrins, fibroblast growth factor homologous factor 1B, calmodulin, caveolin‐3, Nedd4‐like ubiquitin‐protein ligases, dystrophin, and syntrophin [ 8 ], in addition to the more recently reported glycerol‐3‐phosphate dehydrogenase 1–like protein [ 9 ] and MOG1 [ 10 ]. Through their physical association with Nav1.5, these proteins modulate sodium channel trafficking, surface expression, gating, and kinetics. More specifically, sodium channels are not isolated units in the myocyte membrane, but are functional components of a macromolecular complex through which they associate with proteins that participate in cell adhesion, signal transduction, and cytoskeleton anchoring [ 8 ]. The functional relevance of such interactions is evidenced by the fact that mutations in these modulatory proteins are associated with sodium channel dysfunction and arrhythmia [ 11 ]. In addition, the anticancer drug taxol, which changes the properties of the cytoskeletal component tubulin, affects sodium current density and gating in vitro and is associated with increased occurrence of cardiac conduction disorders and arrhythmias in vivo [ 12 , 13 ]. Sodium channel density and kinetics are furthermore also regulated by phosporylation and glycosylation, and by changes in temperature [ 1 , 14 ].

The cardiac sodium channel is a member of the voltage‐dependent family of sodium channels and consists of a transmembrane pore‐forming α‐subunit associated with an ancillary modulatory β‐subunit. The α‐subunit protein Nav1.5 (encoded by the SCN5A gene) is made up of four internally homologous domains (DI‐DIV), each consisting of six transmembrane α‐helical segments (S1–S6) ( Figure 1B ). The positively charged S4 segment of each domain forms the voltage sensor, responsible for increased channel permeability (channel activation) during membrane depolarization [ 1 , 2 ]. The ion‐conducting pore of the channel is formed by the S5 and S6 segments of all four domains, and their interconnecting P‐loops are considered to contain the channels’ selectivity filter for sodium ions [ 3 ]. As the channel is activated, sodium ion influx commences, thereby depolarizing the cell membrane during the upstroke of the action potential, ultimately enabling activation of L‐type calcium channels, calcium influx, and myocardial contraction. Prolonged membrane depolarization initiates the processes of fast and slow inactivation, ultimately leading to sodium channel closure [ 1 , 2 ]. In physiological situations, activation and inactivation properties of sodium channels are tightly regulated, thus maintaining cardiac excitability. However, in the setting of sodium channel dysfunction, channel gating properties, and sodium current kinetics may be altered. As a consequence, sodium channel availability, and peak sodium current may be decreased, or the channel is not properly inactivated, resulting in a persistent (sustained), noninactivating sodium current during the action potential plateau [ 4 ]. As discussed below, these alterations in sodium channel function may have profound consequences for cardiac electrophysiological characteristics and arrhythmogenesis.

SCN5A Mutations and Cardiac Sodium Channelopathies

More than a decade ago, the first SCN5A mutation was reported in two unrelated long QT syndrome type 3 (LQT3) syndrome families [21]. In 1998, mutations in SCN5A were also described in patients with Brugada syndrome, a familial disease entity comprising specific ECG abnormalities (ST‐segment elevation in the precordial leads) and sudden death in the absence of QT‐prolongation or structural heart disease [22]. Overall, more than 150 SCN5A mutations have now been reported, the vast majority in patients with either LQT3 or Brugada syndrome. In addition, SCN5A mutations have also been described in association with other clinical syndromes, including cardiac conduction defect [23, 24], sick sinus syndrome [25], atrial standstill [26], and susceptibility to dilated cardiomyopathy and atrial fibrillation [27-29].

SCN5A Mutations Associated with LQT3 Long QT syndrome (LQTS) is characterized by prolonged QT intervals on the ECG, and increased risk for sudden death due to ventricular tachyarrhythmias, in particular torsades de pointes. Various subtypes of LQTS exist, each associated with distinct clinical features and underlying genetic defect. Patients with LQTS type 3 (LQT3, associated with SCN5A mutations) display arrhythmias predominantly during rest or sleep (at slow heart rates), and they are often relatively bradycardic [30]. Compared to other LQT subtypes, LQT3 patients are particularly at risk for sudden death, and cardiac arrest (rather than syncope) is often the first clinical event [31, 32]. Most SCN5A mutations associated with LQT3 typically disrupt fast inactivation of the sodium current, allowing for sodium channels to reopen, resulting in a persistent inward current during the action potential plateau phase [32]. Consequently, delayed repolarization and action potential prolongation occurs (Figure 2A), and early after‐depolarizations may subsequently trigger torsades de pointes and sudden death. Alternatively, SCN5A mutations less commonly cause LQT3 through reduced or destabilized slow inactivation, faster recovery from inactivation (causing increased sodium channel availability), and/or increased peak sodium current density [33-36]. Figure 2 Open in figure viewer PowerPoint (A) Alterations in sodium current characteristics underlying action potential (AP) and electrocardiographic (ECG) characteristics in long QT3 and Brugada syndrome. (B) Differences between action potential shape and duration between epicardial and endocardial myocytes in the right ventricle underlie ST‐segment elevation in precordial ECG leads (repolarization hypothesis). (C) Conduction delay in the right ventricular outflow tract (RVOT) underlying right precordial ST‐segment elevation. Since the RVOT AP is delayed with respect to the right ventricular (RV) AP, a potential gradient exists which is reflected in the right precordial ECG leads as ST elevation (reproduced in part from [37], with permission).

Brugada Syndrome and SCN5A Mutations Brugada syndrome is a familial disorder characterized by ventricular arrhythmias and sudden cardiac death occurring in otherwise healthy individuals at a relatively young age (<40 years). On ECG analysis, a typical pattern is observed comprising ST‐segment elevation in the right‐precordial leads V1–V3, which is unmasked or increased after administration of Class 1A or 1C antiarrhythmic sodium channel blocking drugs (ajmaline, flecainide), or during exercise [37]. Arrhythmias and sudden death occur mostly during rest or sleep, and arrhythmia incidence is higher in males than females [38]. Furthermore, episodes of fever and other factors may provoke or exacerbate the typical ECG pattern and promote onset of arrhythmias [39-41]. In about 10–20% of Brugada syndrome patients, a mutation in SCN5A has been identified, and more than 100 SCN5A mutations have now been linked to this disorder. In addition, mutations in the β‐subunits SCN1B and SCN3B, and the regulatory protein GPD1‐L have been described in some Brugada syndrome patients [9]. In general, SCN5A mutations associated with BrS are “loss‐of‐function” mutations, leading to reduced sodium channel availability, either through decreased trafficking and membrane surface channel expression, or through altered channel gating properties including disruption of activation, accelerated inactivation, and impaired recovery from inactivation [42, 43]. Reduced sodium current decreases action potential upstroke velocity (Figure 2A), leading to atrial and ventricular conduction slowing accompanied by prolongation of PR‐ and QRS‐intervals on the ECG. The right‐precordial ST segment elevation and its relation to arrhythmogenesis is less well understood, but two major hypotheses have been proposed [37, 38]. The repolarization disorder hypothesis involves increased transmural heterogeneity in action potential duration, which occurs preferentially in the right ventricle due to the more pronounced presence of the transient outward potassium current (Ito) in the right ventricular epicardium (Figure 2B) [38]. Alternatively, excessive conduction delay between the right ventricle and right ventricular outflow tract in the setting of sodium current reduction may cause a potential gradient underlying right precordial ST‐segment elevation (see Figure 2C) [37, 44]. The development of structural abnormalities in the myocardium in the setting of (and/or secondary to) sodium current reduction may further exacerbate right ventricular activation delay and subsequent ECG changes [45]. Conduction slowing secondary to sodium channel dysfunction preferentially affects the right ventricle, which may be due to the relative low redundancy in sodium channel availability in this part of the heart [16]. Thus, the right ventricle may be more susceptible to the deleterious effects secondary to sodium channel dysfunction, thereby promoting right ventricular arrhythmogenesis [44, 46]. Accordingly, arrhythmias in Brugada syndrome patients arise mostly from the right ventricle [47].

SCN5A Mutations Underlying Progressive Cardiac Conduction Defect (PCCD) and Sick Sinus Syndrome PCCD, also called Lenègre or Lev disease, is characterized by progressive conduction slowing through the His‐Purkinje system, with right and/or left bundle branch block and QRS‐widening, leading to complete AV block, syncope and sudden death. In some cases, inherited PCCD is associated with mutations in SCN5A[23, 48]. From a mechanistic point of view, SCN5A mutations underlying PCCD lead to reduced sodium channel availability (loss‐of‐function) similar to Brugada syndrome, and considerable overlap exists between these two clinical entities (see also below) [49]. Similarly, inherited sick sinus syndrome has also been associated with loss‐of‐function mutations in SCN5A[25, 50]. Although sodium channels are not considered essential for sinoatrial nodal pacemaking, they do however contribute to cardiac automaticity through the depolarizing effects of inward sodium current (albeit relatively small). In addition to reduced automaticity of sinoatrial pacemaking tissue, decreased sodium channel availability may also cause bradycardia by slowing or block of conduction from the central sinoatrial region to the surrounding atrial tissue [51]. Furthermore, sinus bradycardia may also occur in LQT3 patients with SCN5A gain‐of‐function mutations. Here, action potential prolongation secondary to increased persistent inward sodium current causes slowing of the sino‐atrial diastolic depolarization rate, resulting in a reduction of the sinus node pacemaker rate [52].

SCN5A Mutations Associated with Atrial Fibrillation and/or Dilated Cardiomyopathy Atrial fibrillation is the most prevalent clinical arrhythmia affecting mostly elderly patients with underlying structural cardiac abnormalities, but it may also occur as a hereditary disease in young patients with structurally normal hearts. Recently, both loss‐of‐function and gain‐of‐unction mutations in SCN5A have been described in this familial form, which are thought to induce atrial fibrillation through decreased atrial conduction velocity and increased atrial action potential duration and excitability, respectively. Dilated cardiomyopathy has also been reported in patients with SCN5A mutations [53, 54], often in combination with atrial arrhythmias and/or fibrillation [28]. The question remains whether arrhythmias and structural defects are a direct effect of sodium current alterations, or merely secondary to longstanding cardiac abnormalities. Although biophysical properties consistent with loss of sodium channel function have been observed in SCN5A mutations associated with DCM, a diverse spectrum of other sodium current characteristics have also been described, and very few commonalities between various SCN5A mutations related to DCM exist [54, 55]. Thus, the mechanisms underlying SCN5A mutation‐related DCM remain unclear, and may involve a complex interplay of altered sodium channel current (preexistent) myocardial structural abnormalities, and occurrence of long‐standing arrhythmias.