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Cardiovascular Research 2007 74(3):356-365; doi:10.1016/j.cardiores.2007.01.009
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Copyright © 2007, European Society of Cardiology

SCN5A and sinoatrial node pacemaker function

Ming Leia,*, Henggui Zhangb, Andrew A. Gracec and Christopher L.-H. Huangc

aCardiovascular Group, School of Medicine, The University of Manchester, Manchester, M13, 9NT, UK
bBiological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester, M60 1QD, UK
cCardiovascular Biology Group, Departments of Biochemistry and Physiology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK

* Corresponding author. Division of Cardiovascular and Endocrine Sciences, The University of Manchester, Manchester, M13, 9NT. Tel.: +44 161 2751194; fax: +44 161 2751183. Email address: ming.lei{at}manchester.ac.uk

Received 29 October 2006; revised 1 January 2007; accepted 9 January 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 
The SCN5A gene encodes specific voltage-dependent Na+ channels abundant in cardiac muscle that open and close at specific stages of cardiac activity in response to voltage change, thereby controlling the magnitude and timecourse of voltage-dependent Na+ currents (iNa) in cardiac muscle cells. Although iNa has been recorded from sinoatrial (SA) node pacemaker cells, its precise role in SA node pacemaker function remains uncertain. This review summarizes recent findings bearing upon: (i) Sinus node dysfunction resulting from genetic mutations in SCN5A; (ii) Sinus node function in the murine cardiac model with targeted disruptions of the SCN5A gene; (iii) Experimental and computational evaluations of the functional roles of iNa in SA node pacemaker function. Taken together, these new observations suggest strong correlations between SCN5A-encoded Na+ channel and SA node pacemaker function.

KEYWORDS SA node; Pacemaker activity; Voltage-dependent Na+ channels


   1. Introduction
Top
 Abstract
 1. Introduction
2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 
SCN5A directs the synthesis of cardiac-type voltage-dependent Na+ channels (Nav1.5) abundant in the heart and important in initiation of cardiac activity. The resulting synchronized contractions in the atrial and ventricular chambers of the heart then produce the normal rhythmic heartbeat. However, the possible roles of this voltage-dependent Na+ current, iNa, generated by SCN5A-encoded Na+ channels in sinoatrial (SA) node pacemaker function have been uncertain [1–5]. Such current only exists in some and not all pacemaker cells and in any case may be inactivated at the relatively positive membrane potentials observed in these cells [1–3]. Block of iNa by tetrodotoxin (TTX) has little or no effect on action potential (AP) generation in the leading pacemaker cells in the SA node [2,6–10]. Yet recent evidence suggests strong correlations between human SA node dysfunction (SND) and Nav1.5 Na+ channel defects [11–13]. Thus, loss-of-function mutations in the SCN5A gene occur in pedigrees with familial sick sinus syndrome (SSS) [11]. Furthermore, a murine model with targeted disruptions of the SCN5A gene also replicates the major features of clinically observed SSS [14].


   2. Mechanisms of SA node pacemaker function
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 
Electrical excitation in the mammalian heart originates in specialized pacemaker cells located in the SA node. These cells display unique action potential (AP) waveforms characterized by the lack of a stable diastolic potential. Instead, a slow, pacemaking, diastolic depolarization that follows action potential (AP) termination drives the membrane potential back towards the re-excitation threshold. The processes that determine the rate of this diastolic depolarization in turn set the rate and rhythm of the normal heartbeat. Extensive voltage-clamp studies, principally in rabbit SA node, have established that such diastolic depolarization results from the balance between inward (depolarizing) and outward (hyperpolarizing) ionic currents and their activation and deactivation [3]. This may involve a range of membrane currents (Fig. 1) that include decay of the outward delayed rectifier K+ current (iK) in the presence of an inward Na+ background current (ib,Na), and activation of the hyperpolarization-activated inward current (if), the inward L- and T-type Ca2+ currents (iCa,L and iCa,T) and, probably, sustained inward current (ist). The Na+–K+ pump (iNaK) and the Na+–Ca2+ exchanger (iNaCa) currents also contribute to pacemaker function. Finally, alterations in intracellular Ca2+ homostasis also influence SAN pacemaker rates (for reviews see [3,10,15,16]). Recent progress in genomics has led to the discovery of a large number of their corresponding encoding genes (Table 1), which has further contributed to our understanding of the molecular basis of normal SA node pacemaker function and sinus node dysfunction. For example mutations in the ion channel genes, SCN5A [11] and HCN4 [17] have been implicated in familiar sinus node dysfunction.


Figure 1
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  		Fig. 1 Ion channels involved in SA node pacemaker function. A, expression of ion channels and carriers and intracellular calcium handling proteins in SA node cells. B, SA node pacemaker action potentials result from complex interactions between: (1) Decay of "outward" potassium currents. (2) Activation of "inward" (Na, f, Ca) currents.

 

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  		Table 1 Relationship of ionic currents, channel subunits and channel genes in the SAN

 

   3. SCN5A mutation and sinus node dysfunction
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 
Sick sinus syndrome (SSS) was first described nearly 40 years ago as a complicating arrhythmia following cardioversion by Lown [18]. SSS has been attributed to dysfunction in the SAN and is characterized by inappropriate sinus bradycardia, sinus arrest, or chronotropic incompetence [19–21]. It accounts for approximately ~50% of one million permanent pacemaker implants every year worldwide [22]. Although it may accompany underlying cardiac disease, it can occur at any age, but most commonly occurs in the elderly without apparent heart disease [23]. Patients with SSS may experience syncope, pre-syncope, palpitations, or vertigo; however, they often are asymptomatic or have subtle or nonspecific symptoms related to the decreased cardiac output that occurs with the bradyarrhythmias or tachyarrhythmias. SSS can produce a variety of electrocardiographic manifestations that may include atrial bradyarrhythmias, atrial tachyarrhythmias, and alternating bradyarrhythmias and tachyarrhythmias. Supraventricular bradyarrhythmias may include sinus bradycardia, sinus arrest with or without junctional escape, sinoatrial exit block, ectopic atrial bradycardia, and atrial fibrillation with slow ventricular response. Despite extensive efforts to define SSS in terms of abnormal automaticity, exit block, or impaired intraatrial conduction and excitability, it has until recently primarily remained largely an electrocardiographic diagnosis.

Several recent studies [11,13,24,25] link ion channel defects to familial sinus bradycardia syndromes. Fourteen SCN5A mutations contributing to familiar SSS have been identified (Fig. 2 and Table 2). For example, an onset of atrial bradycardia, atrial standstill and a prolonged His-ventricle conduction time in the third or fourth decade have been attributed to coinheritance of a heterozygous SCN5A mutation (D1275N) and a specific haplotype in the connexin-40 promoter in a small Dutch kindred [24]. Failure of the SCN5A allele alone to confer a clinical phenotype supported an argument favoring a digenic inheritance [11].


Figure 2
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  		Fig. 2 Membrane topology of the {alpha} subunit of Nav1.5, with the N-terminal end to the left, and the C-terminal end to the right of the scheme, showing the location of 14 identified mutations from SSS families. The four homologous domains (DI–DIV) of the {alpha} subunit each contain 6 segments (marked 1 to 6) of which segments 5 and 6 are the pore-lining segments and the S4 helices serve as voltage sensors.

 

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  		Table 2 Summary of identified SCN5A mutations related to SSS

 
Benson et al. [11] screened SCN5A as a candidate gene in ten patients from families diagnosed with congenital SSS on the basis of disorders of cardiac rhythm and conduction during the first decade of life. Heterozygous SCN5A mutations occurred in 50% of these patients, suggesting that congenital SSS segregates as a recessive disorder of the cardiac Na+ channel [11]. Three families showed an autosomal recessive transmission of the phenotype with complete penetrance. Mutation carriers were asymptomatic, but some exhibited evidence for latent cardiac conduction system disease (e.g. first degree atrioventricular block). Two of the six mutations associated with congenital SSS produced non-functional Na+ channels when expressed in stable mammalian cells [11]. The remaining mutations were associated with mild to severe channel dysfunction. Such findings suggested that loss-of-function or significant impairments in channel gating characteristics leads to a reduced myocardial excitability in some forms of congenital SSS [11]. Interestingly, six compound heterozygous mutations (G1408R, P1298L; T220I, R1623X; delF1617,R1632L) were also identified in individuals from three kindreds in this study [11]. Diagnosis of SSS in these individuals was at very young ages (2 to 9 years old), which suggests that these compound mutations may cause more severe dysfunction of Na+ channels. Smits et al. [25] described the biophysical features of another mutation of SCN5A, E161K, identified in individuals of two non-related families with single symptoms or symptoms in combination of bradycardia, sinus node dysfunction, generalized conduction disease and Brugada syndrome [25].

Recently, a novel mutation (R878C) of SCN5A associated with SSS was reported in a three generational Chinese family whose phenotype showed an autosomal dominant transmission of disordered cardiac rhythm and conduction with reduced penetrance [26]. Screening of SCN5A as a candidate gene in all the family members demonstrated a heterozygotic mutation C -> T transition at nucleotide 2826 encoding cysteine in place of arginine 878 (designated as R878C) which is located in S5 of domain II in the pore forming region of the Nav1.5 channel (Fig. 2 and Table 2) in four individuals from this kindred [26].

Finally, a gain-of-function, 1795insD, mutation, has been associated with sinus bradycardia and sinus pauses together with phenotypic characteristics of SND with inherited long-QT syndrome (LQT3) as observed in humans [13]. Veldkamp et al. [13] reported persistent inward currents over the voltage range traversed by the SA node action potential in measurements of whole-cell Na+ currents (iNa) in HEK-293 cells expressing either wild-type or 1795insD channels, and Na+ channels from 1795insD mutants showed negative shifts in their voltage-dependence of inactivation. Computer modelling then predicted that such features would slow sinus rates to give a situation in which LQT3 Na+ channel mutations that result in persistent inward current (ipst) in turn leading to sinus bradycardia and sinus pauses in addition to QT prolongation [13]. Thus, membrane potentials in SAN cells start to oscillate at plateau potentials and fail to repolarize if ipst is increased above a critical level. Thus, Na+ channel mutations displaying an ipst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SAN cells to repolarize under conditions of extra net inward current. It suggests that intrinsic or extrinsic factors generating little additional net inward current during the plateau phase, either by decreasing outward current or increasing inward current, can induce the transition from relative bradycardia into sinus node dysfunction. Therefore, both loss of function [11] and gain of function [13] changes in Nav1.5 may lead to sinus node dysfunction. Interestingly, the identified mutations responsible for SSS are all located at positions of trans-membrane segments or extracellular links although they occur in all four domains (see Fig. 2) in contrast to the locations of LQT mutations [27].


   4. Analysis of hearts from heterozygous SCN5A knockout mice
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 
Genetic defects in the SCN5A encoding cardiac Nav1.5 Na+ channels have been described in patients with the familial SSS [11], Brugada and Lev-Lenègre syndromes [12,28] and long QT syndrome type 3 (LQT3). However, the specific mechanisms for the observed sinus node dysfunction in these conditions have not been clarified. Papadatos et al. [29] established mice with a null mutation in the Na+ channel gene, SCN5A, using homologous recombination in embryonic stem cells. This provided an experimental system that permitted assessment of the physiological contribution of Na+ channels to cardiac impulse initiation and propagation. Homozygous disruption of the cardiac Na+ channel in SCN5A–/– mice led to severe, lethal, defects in ventricular morphogenesis. Comparisons of phenotypes in wild-type (WT) and SCN5A+/– hearts using in vivo surface electrocardiogram (ECG) recordings and ex-vivo epicardial recordings in isolated Langendorff-perfused preparations demonstrated impaired action potential propagation, conduction block, and re-entrant arrhythmias reflecting a decreased total Na+ conductance. These defects in impulse initiation and conduction provided a basis for an understanding of the pathophysiology of several pleiotropic clinical phenotypes [27,30–32]. Accordingly, the basis for isolated cardiac conduction disease [32], progressive cardiac conduction disorder [30], and the arrhythmogenic substrate in idiopathic ventricular fibrillation [33] could be viewed in terms of slowed myocardial conduction [34].

Subsequent studies in this heterozygous SCN5A+/– mouse model explored for possible electrophysiological roles for cardiac SCN5A-encoded Na+ channels in SA node function [35]. They demonstrated that targeted genetic disruption of SCN5A-encoded Na+ channels, confirmed by a reduced immunochemical expression of SA node Na+ channels in SCN5A+/– hearts [35], resulted in a sinus bradycardia, slowed SA conduction and sinoatrial exit block thereby replicating major but previously unexplained features of clinically observed SSS [14]. Long-term telemetric ECG recordings demonstrated depressed mean rates and persistent SA block in intact SCN5A+/– mice. Findings from mouse SA node pacemaker cells then directly demonstrated possible roles for the SCN5A Na+ channel in both conduction and pacing. Whole-cell patch clamp analyses demonstrated similar steady-state activation and inactivation properties in SCN5A+/– and WT but reduced maximum SCN5A+/– Na+ currents (~30%) [35]. The latter findings matched the ~50% reduction of iNa observed in ventricular SCN5A+/– myocytes [29] in this mouse model, which mostly contain Nav1.5 channels, provided that Nav1.5 does not account for all the iNa observed in SA node cells. In addition, SCN5A+/– SA node preparations exhibited similar activation patterns but significantly slower SA conduction and more frequent sinoatrial–atrial conduction block than WT (Fig. 3). Furthermore, isolated WT and SCN5A+/– SA node cells demonstrated contrasting correlations between cycle length, diastolic depolarization rate, maximum upstroke velocity and action potential amplitude, and cell size. Thus, small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SA node cells in the reduced pacemaker rate that was observed in SCN5A+/– myocytes. Finally, all these findings were successfully reproduced in a model that implicated iNa directly in action potential propagation through the SA node and from SA node to atria as well as in modifying heart rate through a coupling of SA node and atrial cells, whose features also closely replicated features of clinical sinus node dysfunction.


Figure 3
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  		Fig. 3 Activation sequence and sinoatrial conduction in WT and Scn5a+/– mice. Isochrones at 2 ms intervals and activation times in milliseconds are shown. Points a, b and c exemplify sites on the leading pacemaker site in the centre of the SA node, the periphery of such sites, and atrial muscle, AM, respectively, from which extracellular potentials could be taken. SVC, superior vena cava. SEP, interatrial septum. IVC, inferior vena cava. RA, right atrial appendage. CT, crista terminalis. The figure is adapted from Fig. 4 in Lei et al. J Physiol (Lond). 2004;559(3):835–848. [35].

 
Recently, Remme et al. [36] characterized a novel transgenic murine model for the human mutation 1798insD. Heterozygous, Scn5a1798insD/+ mice showed significantly lower heart rates, bradycardic episodes, and increased PQ interval, QRS duration, and QTc intervals compared to WT mice. The Na+ channel blocker flecainide induced a marked sinus bradycardia and/or sinus arrest in the majority of such Scn5a1798insD/+ but not WT mice [36]. Whole-cell patch-clamp analyses of ventricular myocytes isolated from Scn5a1798insD/+ hearts displayed prolonged action potentials, a 39% reduction in peak Na+ current density and similar reductions in action potential upstroke velocity. Scn5a1798insD/+ myocytes also displayed slower time courses in their Na+ current decays despite an absence of significant differences in their steady-state voltage-dependence of activation and inactivation, slow inactivation, or recovery from inactivation compared to WT [36]. Furthermore, Scn5a1798insD/+ myocytes showed a larger TTX-sensitive persistent inward current compared with wild-type myocytes. Thus, the mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype [36]. Their results directly demonstrated in the murine model that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac Na+ channel disease.


   5. Experimental evaluation of the roles of Na+ channel isoforms in SA node pacemaker function
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
6. Computational analysis of...
 7. Summary
 References
 
Most cardiac Na+ channels are tetrodotoxin (TTX)-resistant (KD, 2–6 µM) SCN5A-encoded Nav1.5 channels. However, recent studies have demonstrated a presence of neuronal (Nav1.1, Nav1.3 and Nav1.6) TTX-sensitive (KD, 1–10 nM) Na+ channel isoforms in the myocytes of both ventricles and SA node in several species including mouse, rat, rabbit and dog [37,38,39,40]. Thus recent investigations identified two distinct, TTX-resistant (putative Nav1.5) and TTX sensitive current components in mouse SA node pacemaker cells [37]. These showed activation thresholds at –70 and –60 mV, current peaks at –30 and –10 mV, with current densities of ~22 and ~18 pA pF–1, respectively. TTX-sensitive iNa inactivated at the more positive potentials but activated late during the pacemaker potential in action-potential clamped cells. Fig. 4 shows that Nav1.5 was absent from the centre but present in the periphery of the SA node in mouse [37]. Nanomolar TTX concentrations (10 or 100 nM), that block neuronal iNa, slowed pacemaker function in both intact SA node preparations and isolated SA node cells without significant effects on SA node conduction. In contrast, micromolar TTX concentrations (1–30 µM), which block both cardiac and neuronal iNa slowed both pacemaker function and SA node conduction [37]. These findings implicated both neuronal and cardiac isoforms in pacemaking, but only the cardiac Nav1.5 isoform in action potential propagation from the SA node to the surrounding atrial muscle. Despite the progress in identifying the role of voltage-gated Na+ channels in SA node pacemaker function, important aspects of the biogenesis of those channels such as species-dependent transcription and splicing as well as age-dependent and gender-specific features are still poorly understood. For example, Zimmer and colleagues recently identified significant differences in the expression levels of TTX-sensitive Na+ channel isoforms in the hearts of different mammalian species (Blechschmidt, S., Haufe, V., and Zimmer, T.; personal communication) and even a species-dependent splicing of Nav1.5 [41]. Similarly, SA nodal cells may express the different Na+ channel isoforms in a species-dependent manner which could contribute to the variability of SAN AP wave forms of different mammalian species [10,37]; however, so far there is no information of such species dependent roles of the different Na+ channel isoforms in the SA node.


Figure 4
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  		Fig. 4 Labelling of Cx43, desmoplakin, HCN4, Nav1.5 in SA node sections of murine heart. A: schematic diagram of a section. B: double labelling of Cx43 and desmoplakin (DP). C: labelling of HCN4. D: labelling of Nav1.5. SVC, superior vena cava. SEP, interatrial septum. IVC, inferior vena cava. RA, right atrial appendage. CT, crista terminalis. "c", centre of SA node, "p", periphery of SA node. The figure is adapted from Fig. 5 in Lei et al. J Physiol (Lond). 2004;559(5):394. [37].

 

   6. Computational analysis of possible functional roles of iNa in SAN pacemaker and conduction function
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
7. Summary
 References
 
These experimental results concerning the possible roles of iNa in initiation and conduction of pacemaker activity prompted computer modelling studies of their function in multicellular SA node and atrial tissue [42]. They used approaches developed from pioneering work (Noble [43]) in which families of biophysical models of electrical activity of cardiac cells used experimental data on ion current kinetics to reproduce the electrical changes observed in intact tissue. Such models included mathematical analyses of the automaticity properties of sinoatrial pacemaker cells [44–48] that were applied initially to rabbit SA node cells. These were extended to the regional differences in SA node activity as reflected in variations in maximal diastolic potential, amplitude, action potential duration, maximal upstroke velocity and diastolic depolarization rate [49] and the relatively depressed pacemaker properties shown by peripheral, as opposed to central SA node, cells [45] in tissue regions closest to the atrium, as well as the persistence of such phenomena in tissue section preparations cut from the SA node [50] and therefore entirely detached from neighbouring atrium.

Two possible hypotheses have been suggested for these observed regional differences. Of these, the mosaic model [51] conjectured that the electrophysiological properties of pacemaker cells in the SA node are uniform throughout the SA node and the apparent regional differences in electrical activity in the SA node to which such atrial cells may be electrically coupled are the result of a progressive decrease in the percentage of intermingling atrial cells towards the centre giving rise to a progressive decrease in their hyperpolarizing influence from the periphery towards the centre. However, this hypothesis predicted action potential waveforms from the centre and periphery of SA node cells that did not match experimental findings [52]. Computer simulation using the mosaic model failed to predict action potentials for the centre and periphery of SA node cells that showed characteristics consistent with those recorded experimentally [42]. In the simulations the mosaic based central cell model had faster pacemaking rates and larger up-stroke velocities that were contradictory to experimental observations.

In contrast, a gradient model attributes the regional differences in electrical properties of SA node cells to gradients in their ionic channel current densities [10,47,52]. This predicted action potential properties that successfully reproduced experimental findings [47]. Initial studies using the latter approach initially assumed [47] values for iNa channel current density based on the experimental data demonstrating regional differences in the TTX-resistant iNa across the SA node [2]. They predicted large channel currents in the periphery of the SA node in contrast to small or absent currents in its centre. Subsequent studies incorporated the observation that the centre of the SA node in some mammals, such as rat and mice, shows additional distinct TTX-sensitive Na+ channels [35,37,38] correlating with small but nonzero iNa in the centre of the SA node. Such findings prompted modifications of the original Zhang et al. central cell model to incorporate this new data on iNa [42].

These computations represented the behaviour of the intact SA node tissue and surrounding atrial muscle in terms of a one-dimensional string of cells extending from the centre to the periphery of the SA node then onto atrial muscle cells as a simplified representation of an ideal multicellular model for the complex structure of the intact SA node and the surrounding atrium. Such a system can be represented by a model based on a one-dimensional partial differential equation for the intact SA node and surrounding atrial muscle (Table 3). This assumed a string of SA node cells 1.5 mm in length, and a string of atrial cells 9 mm in length. The former incorporated both the anatomical and electrical heterogeneities of the SA node whose central cells (capacitance 20 pF) are smaller than those in the periphery (capacitance 65 pF) (Eq. (2)). Each node is modelled by the equations of Zhang et al. [47]. The ionic current densities of cells are functions of their cell capacitance (Eq. (3)). The modelling assumed a SAN centre of radius 0.75 mm with TTX-sensitive neuronal Na+ channels with a uniform maximal current density of 10 pA pF–1. The surrounding SAN periphery was given an annular radius of 1.5 mm and both neuronal and cardiac Na+ channels whose density increased from the centre (10 pA pF–1) to the periphery (60 pA pF–1). The cells in the atrial string were modelled by the Earm–Hilgemann–Noble equation [53]. Electrotonic interactions within the tissue were modelled by the diffusive interactions of membrane potentials (Eqs. (4) and (5)Go). Non-flux boundary conditions were adopted for both ends of the model (Eqs. (1) and (6)Go). Ds and Da are diffusion parameters that model the cell-to-cell electrotonic coupling and scale the conduction velocity of the action potential in the SA node and the atrial muscle. Ds was set at 0.6 cm2 s–1, giving an SA node conduction velocity of ~0.03 m s–1 and Da was set at 1.25 cm2 s–1 to give an atrial muscle conduction velocity of 0.62 m s–1. Coupling at the junction of the SA node and atrial muscle was modelled by Ds. The models (Eqs. (1) (2) (3) (4) (5) and (6)GoGoGoGoGo) were coded in Fortran and numerically solved by an explicit Euler method with a three-node approximation of the Laplacian operator, a 0.1 ms time step and space steps of 0.05 mm for SA node tissue and 0.3 mm for atrial muscle. The chosen time and space steps proved sufficiently small for a stable and accurate solution.


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  		Table 3 One-dimensional model of the intact SA node

 
The functional roles of iNa in SA node pacemaker function and conduction were studied by systematic simulations of the effects of a progressive iNa block. These predicted that a 35% block of iNa in a 2 mm length of the peripheral part of the SA node, increased cycle length and therefore reduced pacemaker rate by 41 ms and increased sinoatrial conduction time by 18.4 ms [35]. Fig. 5A–E illustrate modelled AP waveforms in successive myocytes under control conditions (A), following a 100% reduction of iNa confined to the SA node centre (B), and successive 35% (C), 70% (D) and 80% (E) reductions of iNa selectively in the SA node periphery. Such manoeuvres both increased the time intervals between successive APs corresponding to decreasing pacemaker rate, (B), and decreased conduction velocity (C) ultimately producing a conduction exit block of AP propagation from SA node into the atrium (D) culminating in a complete termination of SA node pacemaker activity (E). Such modelling reproduced experimental results: blocks of TTX-resistant iNa as well as TTX-sensitive iNa by micromolar TTX produced a greater slowing of pacemaker activity than block of TTX-sensitive iNa alone by nanomolar TTX in the intact SA node. Together these findings are consistent with roles for both TTX-resistant and TTX-sensitive iNa, in SA node pacemaker function [35] not only through impulse initiation, but also impulse propagation through the SA node and between the SA node and atria.


Figure 5
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  		Fig. 5 Simulated effects of iNa block from the SA node on initiation and conduction of pacemaker activity on a one-dimensional model of the SAN and atrial muscle (AM). A: APs displayed along the length of SAN and atrial string. The AP is first initiated in the SAN centre then propagates via its periphery towards atrium. B: Effect of selectively blocking iNa in the SAN centre by 100% increases CL by 11 ms compared to the control. C–E: APs with progressive selective reductions of iNa in peripheral SAN by 35% (C), 70% (D) and 80% (E). The Figure is adapted from Fig. 6 in Lei et al. J Physiol (Lond). 2005;567(2):397.[35].

 

   7. Summary
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
References
 
In conclusion, the SCN5A Na+ channel is expressed in the peripheral SA node. Genetic defects in Nav1.5 channels underlie some categories of inherited sinus node disease. Recent new observations, suggest a strong correlation between SCN5A-encoded Na+ channel function and SA node pacemaker function. This appears, firstly, to involve pacemaker potentials through a mechanism that involves the coupling of electrical events between pacemaker cells and cells surrounding them within the SA node: any impairment of impulse initiation accounts for the observed sinus bradycardia. They also appear to be involved in impulse propagation through the SA node and between the SA node and atria disorders in which may block conduction.


   Acknowledgements
 
This work is supported by the Wellcome Trust, the British Heart Foundation, Medical Research Council and Biotechnology and Biological Sciences Research Council and The Chinese National Natural Science Foundation.


   Notes
 
Time for primary review 28 days


   References
Top
 Abstract
 1. Introduction
 2. Mechanisms of SA...
 3. SCN5A mutation and...
 4. Analysis of hearts...
 5. Experimental evaluation of...
 6. Computational analysis of...
 7. Summary
 References
 

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