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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Card Electrophysiol Clin. Author manuscript; available in PMC 2011 December 1.
Published in final edited form as:
Card Electrophysiol Clin. 2010 December 1; 2(4): 499–507.
doi:  10.1016/j.ccep.2010.09.001
PMCID: PMC3076695
NIHMSID: NIHMS253534

Genetics of sick sinus syndrome

Jeffrey B. Anderson, MD, MPH1 and D. Woodrow Benson, MD, PhD2

Background

Sick sinus syndrome (SSS) was first described over four decades ago as a complicating arrhythmia following cardioversion1 and shortly thereafter its electrocardiographic features were defined.2 The disorder is characterized by persistent inappropriate sinus bradycardia, episodes of sinoatrial block and/or chronotropic incompetence.3 Episodes of atrial tachycardia coexisting with sinus bradycardia (tachycardia-bradycardia syndrome) are also common in this disorder.4 See Figure 1. Despite extensive efforts to better understand the mechanism of SSS in terms of abnormal automaticity, sinus node exit block, or impaired intra-atrial conduction and excitability, this has remained largely an electrocardiographic diagnosis.4

Figure 1
Electrocardiographic findings in sick sinus syndrome.

The sinoatrial (SA) node is a complex structure and its proper function requires an intricate arrangement of cellular and molecular components. SSS, a misnomer, once thought to be simply a problem with the automaticity initiated within the SA node, can be secondary to a number of different molecular, cellular and structural abnormalities. For example, the SA node core, where automaticity arises, may be working properly with abnormal conduction from the SA node to the remainder of the atrium. As will be discussed in this review, patients diagnosed with SSS may have problems with automaticity, propagation of electrical impulses from the SA node to the remainder of the heart, abnormalities related to autonomic influences on the SA node, or a combination of these problems. SSS may occur in the absence of structural heart disease, but “atrial disease” is a recurring theme whether in the elderly with acquired heart disease or young survivors of congenital heart disease surgery. Patients of any age with SSS may exhibit varied symptoms including presyncope or syncope, activity intolerance and SSS may even be the cause of sudden cardiac arrest. The course of SSS can be intermittent and unpredictable, related to the severity of the underlying heart disease. While SSS is more common in the elderly and in those with structural heart disease, its true incidence is unknown as the features of SSS have not been evaluated in the general population in a standardized manner.3

Sinus node architecture and physiology

Gross and microscopic anatomy

Keith and Flack first described the SA node in 1907. Of their findings they wrote, “There is a remarkable remnant of primitive fibres persisting at the sinoauricular junction in all the mammalian hearts examined…in them the dominating rhythm of the heart is believed to normally arise.”5 The anatomical and histological structure of the SA node is conserved across vertebrates.5 The SA node is a right atrial structure that is subepicardial and can be located at the junction of the crista terminalis at the superior cavoatrial junction.6 It is shaped like a flattened ellipse and the prominent SA nodal artery passes through its body. Multiple autonomic nerves course to both its poles.7 The SA node is an extensive structure, encompassing tissue from the superior to the inferior vena cava8 and the size and tissue thickness of the SA node varies between species.6 In humans, the SA node lies beneath the epicardial surface with a layer of atrial muscle between the SA node and the endocardium.9 This layer of atrial muscle, along with connective tissue in the region of the SA node, are thought to protect the area against high wall stresses.10 Microscopically, the SA node is characterized by a complex pattern of cells within a fibrous stroma. Near its periphery there is an outer coat of working atrial myocytes. The function of the specialized cells of the SA node is conduction rather than contraction; therefore, they are smaller, have fewer contractile elements, and expend less energy than surrounding myocytes.7 See Figure 2.

Figure 2
A. Schematic diagram of dorsal view of rabbit heart showing location and extent of central (red) and peripheral (blue) sinus node tissue. Reproduced from Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding ...

Molecular architecture

The molecular organization of the SA node is complex but serves as a template to understand the characteristics that allow for its role as the primary pacemaker in the heart.1112 Figure 3 shows a section cut through the SA node. SA node tissue arises from the intercaval region and persists to the endocardial surface near the crista terminalis (CT) and overlaps the atrial muscle. In the atrial muscle, Cx43 is expressed and Cx45 is absent. In contrast, in the SA node core, Cx43 is absent and Cx45 is expressed while in the periphery of the SA node , both Cx43 and Cx45 are expressed. Atrial muscle expresses atrial natriuretic peptide (ANP) but not neurofilament, and the SA node core and periphery express neurofilament but not ANP. Neurofilament is a cytoskeletal protein found in nerve cells. Because it is expressed in the SA node and other cardiac pacemaker/ conducting tissues but not in the rest of the heart, it has been suggested that these tissues are neural in origin.13 On the basis of these markers, three cell types can be identified: ANP-negative/neurofilament-positive/Cx43-negative/ Cx45-positive central cells, ANP-negative/neurofilament-positive/Cx43-positive/Cx45-positive peripheral cells, and ANP-positive/neurofilament-negative/Cx43-positive/Cx45-negative atrial cells. It is important to minimize electrotonic coupling. 14

Figure 3
Schematic diagram illustrating molecular architecture of the SA node. The anatomical section is through the crista terminalis (CT) and intercaval region of rabbit showing the relative relation of CT with SA node periphery and SA node core. The distribution ...

Gap junctions and connexins

Electron microscopy has demonstrated the presence of gap junctions in the SA node as well as in other myocardial tissue. Gap junctions are made up of serially linked channels (connexons) contributed to by two opposing cell membranes. These junctions allow for the passage of small molecules (<1 kDa) between two adjacent cells.10 Each connexon is composed of six transmembrane proteins called connexins. In cardiac tissue, three main connexin isoforms are found: Cx40, Cx43, Cx 45.14 A fourth connexin, Cx30.2, has been identified in murine conduction tissue; its human orthologue is Cx31.9.14 There is regional and tissue specific expression of different connexin isoforms within the heart; See Figure 4. Cx40 is mainly expressed in the atrial myocytes, the AV node, His-bundle and in the ventricular conduction system. Cx43 is expressed in atrial and ventricular myocytes and within the distal portions of the ventricular conduction system. Cx43 is also expressed in SA node periphery but not at its core.10 There is localization of Cx45 in the SA node, the AV node, His bundle and bundle branches. Although the structures of connexin isoforms are similar, the biophysical properties of the channels they form are very different.1516 For example, gap junction conductance follows the sequence of Cx40> Cx43> Cx45> Cx30.2/Cx31.9 consistent with better conductance in atrial tissue compared to that at the SA node core.17 The differences in electrical properties of gap junctions help explain regional differences in electrical conduction. In addition there are regional differences in the total number of gap junctions participating in cellular communication. Gap junctions are sparsely found in the SA node and seen in great quantity in atrial tissue.18

Figure 4
Chamber specific expression of Cx40, Cx43, and Cx45 in the mouse heart. From Jansen JA, van Veen TA, de Bakker JM, van Rijen HV. Cardiac connexins and impulse propagation. J Mol Cell Cardiol. Jan 2010;48(1):76–82; with permission.

Gap junctions in the SA node play a role in both automaticity and transfer of electrical impulses to the surrounding myocardium.19 At the SA node core Cx45 is the predominant connexin in gap junction proteins.20 There are few total gap junctions found at the SA node core18, where little coupling is necessary for synchronization of electrical impulses of individual cells.21 In the periphery of the SA node Cx40 and Cx43 are both expressed. Studies in mice using knock-out models of Cx43 and Cx45 demonstrated no significant heart rate abnormalities but, Cx40-/- mice did display breakthrough activation of pacemaker activity at locations distant from the SA node, as seen in wild type mice.22 Haploinsufficiency or deletion of Cx43 has also been shown to have no effect on SA nodal function.23 The fact that the SA node seems to function well, even with reduced expression or absence of apparently essential connexins, supports the thought that little coupling is needed for electrical propagation within the SA node itself.14

Connexins play an important role in electrical propagation through atrial tissue. Murine models haploinsufficient or deficient for Cx43 show no changes in electrical impulse propagation through the atria.24 There have been mixed results in studies of Cx40 knock-out mice and the effect on atrial electrical impulse propagation.2526 While the deficiency of Cx40 or Cx43 expression may not itself lead to decreased atrial electrical propagation, there does seem to be a relationship between impulse propagation velocity and the ratio of atrial Cx40 and Cx43 expression.2728

Ion channels, handling proteins, and receptors

Sodium and calcium current

The inward sodium current (INa) is responsible for the initial upstroke of the action potential within atrial myocardium. Within the SA node core there is an absence of INa, resulting in a slow initial upstroke of the action potential.29 Blockade of INa with tetradotoxin, in the rabbit, results in no effect on electrical activity recorded from the SA node core.30 The cardiac isoform of the channel responsible for INa is most abundantly expressed in atrial muscle and has been shown to be expressed in lower amounts within the SA node and to be absent from the SA node core in a murine model.31

Two separate inward Ca2+ currents have been identified in SA node core tissue. A long lasting current (ICaL) and a transient current (ICaT) serve separate roles in action potential formation. ICaL is the main contributor to the initial upstroke of the action potential in the SA node core and also plays a role in the plateau portion of the action potential. Cav1.2 is the principle isoform responsible for ICaL in atrial myocardial tissue. In the SA node, however, Cav1.3 is the principle isoform.32 ICaT contributes to the last two thirds of the diastolic depolarization. Blockage of both calcium currents have been shown to suppress spontaneous electrical activity in the SA node core.30, 33

Potassium currents

The hyperpolarization-activated cyclic nucleotide-gated (HCN) family (HCN1–4) of ion channels is responsible for If. These channels are directly regulated by cAMP.34 This current is inward in direction and carries both Na and K ions. If increases when cellular cAMP levels are elevated during sympathetic stimulation and decreases when levels are reduced during vagal stimulation.35 Further evidence of the contribution of If to automaticity has been documented in observation of a decrease in automaticity in both humans and rodents when If is specifically blocked with the selective If inhibitor ivabradine.3638 Two of the four known genes encoding HCN channel subunits, HCN2 and HCN4, are pre- dominantly expressed in the heart.39 The most abundant isoform of this channel within the SA node is HCN4 and HCN4 is more abundant within the SA node than in the atrial myocardium. Human genetic40 and pharmacologic36, 41 studies have suggested a significant role for HCN4 subunits in SA nodal pacemaking in humans and rodents. However, targeted deletions of HCN4 in adult mice were found to cause sinus pauses but to have no effect on heart rate regulation.42 Similar observations were made in adult heterozygous knock-in mice expressing a cAMP binding–deficient HCN4 subunit.43

Besides the HCN family, there are several potassium currents that are important in SA nodal function. The transient outward potassium current (Ito) activates and inactivates quickly and is responsible for the initial phase of repolarization and, in part, determines the duration of the action potential.8 In the rabbit, Ito has been shown to be present at a higher density in the SA node than in atrial myocardium.10 Delayed-rectifier potassium currents are also important in determining the duration of the action potential initiated in the SA node. During SA nodal action potential formation there are rapid and slow delayed rectifier potassium currents (IKr) and (IKs). Both help to further repolarization and determine maximum diastolic potential.44 The inward rectifier potassium current (IK,1) participates in stabilization of the resting potential in myocardium. The maximum diastolic potential of the sinus node is significantly more electrically positive than that of the surrounding atrial tissue. Several isotypes of the inward rectifier potassium channel are present in myocardial tissue. KV1.4 is primarily found in atrial myocardium and KV4.2 is primarily found in sinus nodal tissue.32

Calcium handling proteins

There are several proteins involved with calcium movement within SA node and atrial tissue. The arrival of the action potential leads to an increase in cytoplasmic Ca brought about by and influx of extracellular Ca. This Ca influx triggers a further release of calcium-mediated calcium release from the sarcoplasmic reticulum (SR) by way of the ryanodine receptor (RyR).45 The cardiac ryanodine receptor (RyR2) mRNA and protein are expressed within the SA node core but is more abundant in the periphery of the SA node as well as in atrial tissue.46 Once the membrane begins to repolarize Ca begins to be removed from the cytosol back to the SR by means of the sarcoplasmic reticulum Ca pump, SERCA2a.45 SERCA2a is present within the SA node core but more abundantly in the periphery of the SA node as well as in atrial tissue.46 While the majority of Ca release from the SR occurs during action potential formation (depolarization) there is some slow Ca release from the SR during diastolic repolarization. Within the SA node core this occurs as a result of high cAMP levels.44 The release of Ca from the SR during diastolic depolarization activates a Na/Ca exchanger which results in an inward current that contributes to depolarization. Three isoforms of the Na/Ca exchanger (NCX) have been identified, NXC1-NCX345 but only NCX1 has been identified in pacemaking cells from several animals and is present in equal concentration within the SA node and atrial tissue.46 If intracellular stores of Ca are depleted, the influx of extracellular Ca can be augmented by TRPC (transient receptor potential canonical) channels. These channels have been identified in the SA node in the mouse and may be involved in pacemaking.47

Receptors

Adenosine, adrenergic, and muscarinic receptors are all present in SA nodal tissue. Adrenergic α1a, α2a, α2b, and α3 adenosine receptors have all been identified. Alpha-1 and alpha-2 adrenergic receptors are all detectable at varying levels within the SA node. Of the muscarinic receptors, M2 are present in SA nodal tissue and M1 receptors have not been detected.46 The presence of these receptors within the SA node gives some evidence as to the pharmacologic mechanism of action on the SA node of these classes of medications.

Physiology

The SA node is the physiological pacemaker in the human heart and is predominantly responsible for autonomous heart beat generation. The complex mechanisms underlying SA nodal automaticity remain incompletely understood. However, heart rate control is regulated through control of SA nodal automaticity by the autonomic nervous system; cholinergic stimulation slows spontaneous SA nodal activity and β-adrenergic stimulation accelerates spontaneous SA nodal activity.48

The action potential, initiated in the SA node core, propagates first into the SA node periphery and then into the surrounding atrial tissue. The speed of action potential propagation increases as distance from the SA node core increases. Following electrical impulse propagation, there is stable resting electrical potential in the atrial myocardium. In the SA node, however, the tissue is more depolarized and there is further time-dependent depolarization, leading to initiation of the next action potential upon reaching threshold. There is minimization of electronic coupling between the SA node and the surrounding atrial tissue. While there is no distinct border between the SA node and the surrounding atrial tissue, the periphery of the SA node is surrounded by a layer of connective tissue. There is also poor electrical conduction velocity in the SA node core as compared to conduction velocity in atrial tissue. These two properties act to protect the SA node from electrical activity in the atrium that may suppress its pacemaking functions.49

Genetic origins of sick sinus syndrome

From this discussion of the complex molecular makeup of the SA node, SSS may result from a number of genetic abnormalities leading to mutations in proteins important for its function. Family clustering of SSS has been reported and both autosomal recessive (MIM #608567) and dominant (MIM #163800) forms have been described. However, to date only a few examples have been identified.

HCN ion channels are important in the automaticity of the SA node core. HCN4 mutations have been identified in two studies of patients with SSS manifesting as marked sinus bradycardia and chronotropic incompetence.40, 50 Using HCN4 as a candidate gene, both studies identified a heterozygous 1-bp deletion (1631delC) in axon 5 of the human HCN4 gene. The mutant (HCN4-573X) is predicted to have a truncated C-terminus and lack the cyclic nucleotide–binding domain. COS-7 cells transiently transected with HCN4-573X coda exhibited normal intracellular trafficking and membrane integration of HCN4-573X subunits. However, patch-clamp experiments showed that HCN4-573X channels mediated If-like currents that were insensitive to increased cellular cAMP levels. Co expression experiments identified a dominant-negative effect of HCN4-573X subunits on wild-type subunits. Together, these data indicate that the cardiac If channels are functionally expressed but with altered biophysical properties. To study the pathogenesis of HCN4-573X, Align and colleagues 43 generated mice with heart-specific and inducible expression of a human HCN4-mutation (573X). They found that conditional expression of the mutation causes elimination of the cAMP sensitivity of If and decreases the maximum firing rates of SAN pacemaker cells. In conscious mice, hHCN4–573X expression leads to a marked reduction in heart rate at rest and during exercise. Despite the complete loss of camp sensitivity of If, the relative extent of SAN cell frequency and heart rate regulation are preserved. These results demonstrate that cAMP mediated regulation of If determines basal and maximal heart rates but does not play an indispensable role in heart rate adaptation during physical activity.

Sodium channels are essential for orderly progression of action potentials from the SA node core, through its periphery, and to the surrounding atrial tissue. Abnormalities in the genes coding for sodium channels have been examined in families with SSS. Inherited abnormalities in the alpha-subunit of INa are associated with three distinct channelopathies: congenital long QT syndrome51, idiopathic ventricular fibrillation5152, and progressive cardiac conduction system disease.5354 Recent reports of mutational analyses have revealed more than 200 distinct mutations in SCN5A, of which at least 20 mutations are associated with SSS.55 In addition to this variable expressivity, heterozygous SCN5A mutations have also shown incomplete penetrance. Compound heterozygous SCN5A mutations have also been shown to be associated with a recessive form of congenital SSS.4 Benson and colleagues 4 identified individuals with SSS characterized by sinus bradycardia and loss of atrial excitability (atrial standstill). Compound heterozygous nucleotide changes in SCN5A were identified in five individuals from three kindreds who carried the diagnosis of SSS. Because SCN5A is not expressed in the SA node and SA node action potentials are not dependent on SCN5A, primary dysfunction of the SA node seems unlikely. However, since SA node dysfunction caused by failure of impulses to conduct into adjacent atrial myocardium (exit block) has been suggested as a cause of SSS (43, 44) it has been speculated that this is a plausible mechanism to explain this SCN5A-linked disorder.

In addition, certain genetic variants of Cx40 with accompanying SCN5A mutations have been shown to be result in the atrial standstill phenotype.56 Groenewegen and colleagues 57 studied a large family with atrial standstill. They identified heterozygosity for a mutation in SCN5A, a G→A substitution in the first nucleotide of codon 1275 leading to the substitution of Asp by Asn (D1275N). Each family member affected by atrial standstill shared this haplotype; however this mutation was identified in some unaffected relatives as well. In addition, direct sequencing of the coding region of the Cx40 gene revealed changes in the proximal promoter: a G→A change at 44 nucleotides upstream of the transcription start site, and an A→G change in exon 1 at 71 nucleotides downstream of the transcription start site. Genotyping of all relatives revealed homozygosity for these base changes in all affected individuals as well as in unaffected relatives. While mutations in both SCN5A and Cx40 were seen in affected and unaffected individuals the occurrence of the SCN5a-D1275N mutation and the rare Cx40 genotypes were only seen in the individuals with atrial standstill and in none of the unaffected relatives.57 By themselves, the effect of each mutation is sufficient to result in the rare phenotype of atrial standstill. The mutation in SCN5A interferes with electrical impulse generation and the mutation in Cx40 leads to impairment of propagation of any electrical activity.57

Molecular biopacemaker

SSS can result in various clinical symptoms including presyncope or syncope, chronotropic incompetence or significant sinus bradycardia or sinus tachycardia that cause activity intolerance or even sudden death. The current treatment options for sinus node dysfunction include medical management to control tachyarrythmias and implanted pacemakers to counter bradyarrhythmia or sinus arrest. Implanted pacemakers are well tolerated but do require invasive placement and have a limited generator life, leading to multiple invasive procedures for replacement if needed at a young age. In the post-genomic era, there has been some interest alternative molecular therapies for individuals with SSS.

The SA node is highly adapted to its role as the primary pacemaker. Its mix of ionic currents fits it for the pacemaking function, but in addition its poor electrical coupling protects it from the inhibitory hyperpolarizing influence of the surrounding atrial tissue. Studies to date indicate the challenges to developing a biopacemaker. Several groups over the past several years have explored the possibility of a biological pacemaker which would ultimately replace implanted pacemakers. Proposed strategies include gene therapy, transplantation of donor excitable myocardium, and the delivery of modified embryonic stem cells to the heart. Fetal and neonatal cardiac cells have been shown to functionally integrate and act as an ectopic pacemaker when transplanted into the myocardium of dogs, pigs, and guinea pigs.5859 Gene therapy approaches that have been discussed include overexpression of beta-adrenergic receptors, suppression of the potassium inward-rectifier current, IK1, and inserting the pacemaker gene, HCN2, into the atrium using adenoviral or naked plasma vectors.60 Another approach in the biologic treatment of SA node dysfunction is the possibility of engraftment of embryonic stem cells that have been differentiated into cardiac myocytes, into atrial tissue.61

While each of these biologic approaches have shown some promise in addressing the problem of SSS they each address specific parts of a complex system. The intricacy of the anatomic and molecular design of the sinoatrial node allows for its function as the primary pacemaker of the heart. This complex design includes not only the differences in cellular makeup compared to surrounding atrial tissue but differences in cellular makeup within the SA node itself. Each part of the SA node, at a cellular and subcellular level, plays an individual role in the initiation and propagation of electrical impulses that create normal electrical physiology within the heart. Addressing one piece of this complex puzzle is a start to creating a solution for SA node dysfunction, but a complete solution will need to include a group of interventions that create a similar configuration to the SA node.

Summary

The SA node exhibits complex cellular and molecular structure and its proper function requires an intricate arrangement of its architecture. A better understanding of the genetic and molecular makeup of the SA node has led to improved understanding of its function as primary cardiac pacemaker and the abnormalities that may lead to sick sinus syndrome, a common clinical problem. Recently, genetic studies have begun to identify the molecular underpinnings of SSS. Taken together, these findings promise improved diagnosis and alternative therapies for SSS.

Footnotes

The authors have no financial relationships to disclose

No external funding was utilized for this manuscript

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