13 Nodal cells are densely packed within fibrous connective tissue. 14,15 The main body is crescent-shaped with a thinner tail of tissue extending below it. 13 However, nodal tissue capable of supporting pacemaker activity can be detected inferiorly as far as the most inferior aspect of the CT and the Eustacian ridge. 13 The histologically defined human SAN ranges from 8–21.5 mm in length. It is located 0.1–1 mm subepicardially within the posterior wall of the right atrium, closely opposed to the crista terminalis (CT), extending from near to the insertion of the superior vena cava (SVC) towards the inferior vena cava (IVC) (see Figure 2). The SAN in humans is a much more extensive and complex structure than originally described (e.g. 12 Tbx18-deficient mice have demonstrated a failure of this core SAN tissue to develop. 11 It drives progenitor cells in the sinus venosus to morphologically develop into a SAN core upon which Tbx3 then exerts its pacemaker programme of membrane ion channels. Tbx18 is another important T-box transcription factor which appears during embryogenesis in the sinus horns of the sinus venosus and disappears from this region prior to birth. 10 Null mutation of Shox2 in mouse embryos is lethal due to atrial malformation and severe bradycardia. 10 Nkx2–5 normally represses Tbx3 in the working myocardium and so Shox2 is associated with Tbx3 promotion. 10 Shox2 represses the activation of Nkx2–5, Nppa and Cx40 which are all genes involved with contractile working myocardium. The sinus venosus expresses a homeobox regulatory gene named Shox2. The SAN is derived from an area of the developing CCS called the sinus venosus. 8,9 The function of HCN channels within the SAN is discussed below. 8 These include key pacemaker genes, such as those encoding the low conductance gap junction connexin (Cx)45 and the hyperpolarisation-activated cyclic nucleotide-gated (HCN) membrane ion channel. Transgenic mice have been used to demonstrate its role in repressing working myocardial development and promoting a pacemaker programme of genes. Tbx3 is a T-box transcription factor found selectively within the CCS. 7 However, the CCS is derived from primary myocardium that is instead led down a different lineage directed by specific transcription factors ( Figure 1). During early embryogenesis as the heart tube forms, mesodermal cells quickly multiply and differentiate into working cardiomyocytes capable of contraction and fast conduction. The CCS is defined by a specific pattern of gene expression, differing to the surrounding ‘working myocardium’. The SAN is the uppermost part of the cardiac conduction system (CCS), a chain of specialised tissue that directs electrical impulses through the heart and thus co-ordinates the way it contracts. 6 In this article we summarise the mechanisms of SAN function and review the current evidence surrounding the pathophysiology of SND. 4,5 However, contemporary evidence suggests that electrical remodelling of molecular pacemaking mechanisms such as membrane ion channels and intracellular Ca 2+ cycling are important factors in SND. Historically it is attributed to fibrosis and cell senescence and this is often still quoted today. The pathophysiology of ‘idiopathic’ SND is still not clearly understood. The other 49 % were assumed to be intrinsic or ‘idiopathic’. One retrospective study of 277 patients presenting to the emergency department with compromising bradycardia showed that 51 % of cases were attributable to a treatable extrinsic cause such as an adverse drug reaction, electrolyte imbalance or acute myocardial infarction.
The aetiology of SND can be intrinsic, extrinsic or often a mixture of the two. 1 The prevalence of SND in the UK is around 0.03 % affecting all ages, but it is much more common in the elderly population. SND is the most common reason to have a pacemaker implanted, the indication for 27.5 % of all pacemakers implanted in the UK. Implantable electronic pacemakers are currently the only effective treatment.
However, early SND may be latent and individuals may remain asymptomatic. As a result, SND can lead to symptoms of reduced cerebral perfusion such as dizziness and syncope. SAN dysfunction (SND) in humans, also known as ‘sick sinus syndrome’, can manifest as pathological bradycardia and asystolic pauses. Located in the superior right atrium, it automatically produces cyclical electrical activity to initiate each heartbeat in normal sinus rhythm. The sinoatrial or sinus node (SAN) is the heart’s natural pacemaker.
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