The sinoatrial or sinus node (SAN) is the heart's natural pacemaker.Located in the superior right atrium, it automatically produces cyclical electrical activity to initiate each heartbeat in normal sinus rhythm. SAN dysfunction (SND) in humans, also known as 'sick sinus syndrome', can manifest as pathological bradycardia and asystolic pauses. As a result, SND can lead to symptoms of reduced cerebral perfusion such as dizziness and syncope.However, early SND may be latent and individuals may remain asymptomatic. Implantable electronic pacemakers are currently the only effective treatment. SND is the most common reason to have a pacemaker implanted, the indication for 27.5 % of all pacemakers implanted in the UK. 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. The aetiology of SND can be intrinsic, extrinsic or often a mixture of the two. 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 other 49 % were assumed to be intrinsic or 'idiopathic'. The pathophysiology of 'idiopathic' SND is still not clearly understood.Historically it is attributed to fibrosis and cell senescence and this is often still quoted today. 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. 6 In this article we summarise the mechanisms of SAN function and review the current evidence surrounding the pathophysiology of SND. Development of the Sinoatrial NodeThe 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. The CCS is defined by a specific pattern of gene expression, differing to the surrounding 'working myocardium'. During early embryogenesis as the heart tube forms, mesodermal cells quickly multiply and differentiate into working cardiomyocytes capable of contraction and fast conduction.7 However, the CCS is derived from primary myocardium that is instead led down a different lineage directed by specific transcription factors (Figure 1). 7Tbx3 is a T-box transcription factor found selectively within the CCS.Transgenic mice have been used to demonstrate its role in repressing working myocardial development and promoting a pacemaker programme of genes.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. 8,9 The function of HCN channels within the SAN is discussed below.The SAN is derived from an area of the developing CCS called the sinus venosus. The sinus venosus expresses a homeobox regulatory gene named Shox2.10 Sho...

SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing can be accelerated by the over-expression of HCN2 or HCN212. This provides proof of concept for the use of SAP tissue as a substrate for biopacemaking in the treatment of SSS.

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, I f , in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I f , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and I f in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment. Heart failure is a major health problem affecting ~ 26 million people worldwide and is one of the leading causes of hospitalisation in USA and Europe, resulting in over 1 million admissions/year as a primary diagnosis 1. Heart failure patients often have a relatively fast heart rate (> 70 beats/min) 2,3. β-blocker and ivabradine treatment received by heart failure patients lowers the heart rate 4,5 , which may or may not be the mechanism underlying the protective effects of these medications 4. Nevertheless, and paradoxically, bradyarrhythmias (excessively slow heart rates and rhythms) account for up to half of the deaths of end-stage heart failure patients 6-8. In the human and animal models, there is dysfunction of the pacemaker of the heart, the sinus node, in heart failure: there is a decrease in the intrinsic heart rate (the heart rate set by the sinus node in the absence of autonomic nerve activity) and an increase in the corrected sinus node recovery time (a frequently used measure of the functioning of the sinus node) 9-13. The dysfunction of the sinus node in heart failure has been attributed to fibrosis 14 and also remodelling of ion channels and corresponding ionic currents underlying the functioning of the sinus node 10,11,15,16. In particular, it has been attributed to a downregulation of the important pacemaker ion channel, HCN4, and the corresponding funny current, I f 11,15 ; however, the cause of the remodelling is not known.

Key points The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers. AbstractThe sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P < 0.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3 ± 7.2 ms to 6.9 ± 0.8 ms, P < 0.01; root mean square of successive differences of RR intervals fell from 41.7 ± 8.2 ms to 6.1 ± 1.2 ms, P < 0.01; standard deviation of points perpendicular to the line of identity of Poincaré plots (SD1) fell from 29.5 ± 5.8 ms to 7.9 ± 2.0 ms, P < 0.05) and restoration of isoprenaline response (increases in rates of SAN 65.5 ± 1.3%, SAP 28.4 ± 3.4% and SAP‐TBX18 103.3 ± 10.2%; P < 0.001). These changes were driven by a TBX18‐induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01 × 10−5 ± 2.2 × 10−6 to 2.8 × 10−5 ± 4.3 × 10−6 arbitrary units, P < 0.001). Biophysically detailed computer modelling incorporating isoform‐specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.

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