Sick sinus syndrome and atrial fibrillation in older persons - A view from the sinoatrial nodal myocyte.

YJMCC-08013; No. of pages: 13; 4C: 6, 7, 10 Journal of Molecular and Cellular Cardiology xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc

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Review article

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O. Monfredi ⁎, M.R. Boyett

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Institute of Cardiovascular Sciences, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK

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a b s t r a c t

Article history: Received 10 November 2014 Received in revised form 30 January 2015 Accepted 2 February 2015 Available online xxxx

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Sick sinus syndrome remains a highly relevant clinical entity, being responsible for the implantation of the majority of electronic pacemakers worldwide. It is an infinitely more complex disease than it was believed when first described in the mid part of the 20th century. It not only involves the innate leading pacemaker region of the heart, the sinoatrial node, but also the atrial myocardium, predisposing to atrial tachydysrhythmias. It remains controversial as to whether the dysfunction of the sinoatrial node directly causes the dysfunction of the atrial myocardium, or vice versa, or indeed whether these two aspects of the condition arise through some related underlying pathological mechanism, such as extracellular matrix remodeling, i.e., fibrosis. This review aims to shed new light on the myriad possible contributing factors in the development of sick sinus syndrome, with a particular focus on the sinoatrial nodal myocyte. This article is part of a Special Issue entitled CV Aging. © 2015 Published by Elsevier Ltd.

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Keywords: Sinoatrial node Pacemaking Ion channels Calcium handling Atrial fibrillation Arrhythmia

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Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . Sick sinus syndrome (SSS) — clinical aspects . . . . . . . . . . Familial SSS . . . . . . . . . . . . . . . . . . . . . . . . . Molecular and biophysical aspects of SSS . . . . . . . . . . . 4.1. INa and SSS . . . . . . . . . . . . . . . . . . . . . . 4.2. The fast Na+ channel gene, SCN5A, and familial SSS . . . 4.3. If and SSS . . . . . . . . . . . . . . . . . . . . . . 4.4. HCN channels and familial SSS . . . . . . . . . . . . . 4.5. ICa,L and SSS . . . . . . . . . . . . . . . . . . . . . 4.6. IK,ur and SSS . . . . . . . . . . . . . . . . . . . . . 4.7. The Ca2 + clock and SSS . . . . . . . . . . . . . . . . 4.8. Connexins and SSS . . . . . . . . . . . . . . . . . . 4.9. Adenosine receptors and SSS . . . . . . . . . . . . . . 4.10. The Renin–angiotensin–aldosterone (RAA) system and SSS 4.11. The Popeye domain containing genes (Popdc) and SSS . 4.12. MicroRNAs and SSS . . . . . . . . . . . . . . . . . 4.13. Other rare causes of familial SSS . . . . . . . . . . . 5. The relationship between bradycardia and AF in SSS . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Sick sinus syndrome and atrial fibrillation in older persons — A view from the sinoatrial nodal myocyte

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⁎ Corresponding author at: Institute of Cardiovascular Sciences, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester, M13 9NT, UK. Tel.: +44 161 2751194; fax: +44 161 2751183. E-mail address: [email protected] (O. Monfredi).

http://dx.doi.org/10.1016/j.yjmcc.2015.02.003 0022-2828/© 2015 Published by Elsevier Ltd.

Please cite this article as: Monfredi O, Boyett MR, Sick sinus syndrome and atrial fibrillation in older persons — A view from the sinoatrial nodal myocyte..., J Mol Cell Cardiol (2015), http://dx.doi.org/10.1016/j.yjmcc.2015.02.003

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O. Monfredi, M.R. Boyett / Journal of Molecular and Cellular Cardiology xxx (2015) xxx–xxx

1. Introduction

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Sick sinus syndrome (SSS) and atrial fibrillation (AF) are often, pathologically speaking, ‘partners in crime’ [1]. Through ill-defined mechanisms, each lays the groundwork for the development and perpetuation of the other. Both conditions increase markedly in incidence and prevalence over time, and in aged populations these conditions are common [2,3], contributed to by the gradual decrease in intrinsic

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heart rate seen over time [4] (see Fig. 1a). However, exactly how sinus node dysfunction affects the atrial myocardium to predispose to AF and vice versa is not entirely clear. It is likely to be (at least in part) caused by a combination of anatomical and electrophysiological remodeling. The latter entity involves remodeling of important membrane bound ion channels, Ca2+ handling proteins, extracellular matrix proteins, and conducting gap junction channels. Genomic control of these processes is likely to be contributed to by complex processes including

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Fig. 1. The sick sinus syndrome is contributed to by the well-recognized phenomenon of a decrease in the intrinsic heart rate (the heart rate following dual autonomic blockade) occurring with age, in both sexes. Panel a(i) demonstrates the gradual decrease in intrinsic heart rate seen in males with aging, while panel a(ii) demonstrates a similar phenomenon in females (taken from Jose et al. [4]). Panel b(i–iii) demonstrates histograms of intrinsic heart rate in gradually increasing age groups, demonstrating that there is a shift to lower intrinsic heart rate with aging (taken from Jose et al. [4]). SSS is a syndrome of the elderly, with a peak incidence at around 75 years of age. This has been recognized since the very early days of investigation into the condition — panels c(i) and c(ii) demonstrate the age dependency of SSS (taken from Rubenstein et al. [2] and Hartel et al. [3] respectively). Some authors have suggested a bimodal distribution in the incidence of SSS, and an early peak can be seen in panel c(i) but not in c(ii). This early peak presumably represents those cases of SSS arising through genetic causes, or as a consequence of congenital heart disease and cardiac surgery at an early age. Panel d demonstrates an ECG recording taken from a patient in the original description of SSS by Short [5] — long periods of P-wave asystole are apparent.


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Table 1 Causes of SAN dysfunction.

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SSS, first described in 1954 [5] but not referred to as such until 1968 [6], is relatively common in the elderly, affecting 1 in 600 patients over the age of 65 [7], with a mean age of occurrence of between 73 and 76 years [8–10] (see Figs. 1b,c). The elderly patients that it affects often have no pre-existing cardiac history or signs of heart disease [11]. Despite its elderly preponderance, it can occur at any age, including in childhood [12] (see Fig. 1c), when it is usually associated with congenital heart disease or prior corrective cardiac surgery [13–16]. It is the most frequent indication for the implantation of an electronic pacemaker [17], accounting for between 30 and 50% of implants in the USA [18]. In its most common ‘idiopathic’ form, it has no preponderance for one sex or the other [12], and it is less common in black populations than white [19]. Other associations with SSS in the large recent population study by Jensen et al. included greater body mass index, height, Nterminal pro-B type natriuretic peptide, cystatin C, longer QRS interval, lower heart rate, prevalent hypertension, right bundle branch block and any cardiovascular disease [19]. Clinically, SSS refers to the group of disorders in which the heart is unable to perform its usual pacemaking function. Given that this is primarily the role of the sinoatrial node (SAN) some have suggested that SSS is more accurately (and interchangeably) referred to as sinoatrial nodal dysfunction (SND). The SAN is made up of a group of highly specialized cells, arranged sub-epicardially in an irregular matrix in the wall of the right atrium, extending from the entrance of the superior vena cava in an inferior direction, parallel to the crista terminalis, a variable distance towards the inferior vena cava. The underlying problem in SSS may be with either the formation of electrical impulses in the SAN (leading to bradycardia, sinus pause or sinus arrest; see Fig. 1d), or their conduction away from the SAN to the atrial myocardium and thereafter to the rest of the heart (so-called SAN ‘exit block’). It is important to note that automaticity is not unique to the cells of the SAN within the heart. Indeed, instability of the resting membrane potential and diastolic depolarization (critical components of automaticity) occur in cells of the atrioventricular node, the His– Purkinje system and elsewhere in the cardiac conduction system. Despite extensive efforts to define the nature of abnormal automaticity, exit block, abnormal conduction in sinus node or atrium, or indeed abnormal excitability, SSS has remained largely an ECG-based diagnosis. Predictably, the major clinical sign of SSS is bradycardia, leading to clinical symptoms of fatigue, lethargy and pre-syncope/syncope due to cerebral hypoperfusion. However, the bradycardia of SSS is also paradoxically associated with supraventricular tachycardias, particularly

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3. Familial SSS

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SSS can be familial. Though this is relatively rare and limited to a relatively small number of kindreds worldwide, it has attracted a large amount of scientific attention because of what such families can teach us about SAN physiology, and the underlying etiology of idiopathic SSS. Our current understanding of familial SSS is that it is most usually associated with mutations in one of two genes: the fast Na+ channel gene ‘SCN5A’ [40–43], and the HCN genes responsible for the formation of f-channels and the so-called ‘funny current’, If [44–47]. This is not to say that other genes will not be implicated over time, including those important for generating the L-type Ca2 + current. Unlike with other causes of SSS, congenital SSS presents as bradycardia progressing to atrial inexcitability or standstill, which are unusual in other types of SSS [40]. Substantial further details of these familial aspects of SSS are beyond the scope of this review, which aims to focus on ‘idiopathic’ SSS in older people, but they will be discussed briefly in the sections below focusing on individual ionic currents/proteins.

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4. Molecular and biophysical aspects of SSS

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AF with fast ventricular response (suggesting no concomitant dysfunction of the atrioventricular node). Atrial flutter and other paroxysmal supraventricular tachycardias may (more rarely) predominate. Tachycardias affect around 50% of patients with SSS [2,5,8,20–23], leading some to term this ‘tachy-brady syndrome’. Diagnosis of SSS is usually straightforward, involving a combination of clinical examination, resting 12-lead ECG, telemetric ECG recording or data from an implantable loop recorder. Exercise testing can show chronotropic incompetence, but is not usually required, nor is electrophysiological testing, which in most cases would show abnormalities of corrected SAN recovery time (cSNRT). There are extrinsic and intrinsic causes of SSS – intrinsic causes are not usually reversible – but several causes of extrinsic SSS are reversible, including pharmacological SSS (caused for example by β-blockers or ivabradine), which should be alleviated simply by discontinuing the medication. Similarly, SSS caused by atherosclerosis of the coronary arteries might be alleviated by pharmacological treatments or by revascularization. A comprehensive list of causes of SSS is given in the table below. In the majority of cases, the SSS is irreversible, and if causing symptoms, the treatment of choice is the insertion of an electronic pacemaker to prevent low ventricular rates. This may be a single atrial lead device, a single ventricular lead device, or most commonly of all a dual chamber device (usually as long as the patient is not in permanent AF).

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alterations in micro-RNAs and transcription factors. This review aims to shed light upon what is known about the molecular and biophysical aspects of SSS in older people. (See Table 1.)

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Automaticity is a critical characteristic of the SAN, one which it 159 shares with other cells that comprise the cardiac conduction system of 160 the heart. The reason that the SAN is the primary pacemaker of the 161

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Sinus node fibrosis Infiltration Inflammation Atherosclerosis Ischemia

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Epicardial and pericardial disease Drugs

Aging (e.g., [24]) Amyloidosis (e.g., [25]), sarcoidosis ([26]), scleroderma (e.g., [27]), hemochromatosis (e.g., [28]), malignancy (e.g., [29]) Rheumatic fever (e.g., [30]), diphtheria (e.g., [31]), Chagas disease (e.g., [32]), Lyme disease (e.g., [33]) Atherosclerosis of the nodal artery or other major coronary vessel contributing blood supply to the sinus node (e.g., [34]) Angina, acute myocardial infarction, embolism (for example during percutaneous implantation of aortic valve prosthesis); usually transient (e.g., [35]) Pericarditis (e.g., [36])

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Toxins Trauma Endocrine Thermoregulatory Metabolic

Parasympathomimetics or sympatholytics (e.g., reserpine, guanethidine, methyldopa, clonidine, β-blockers); anti-arrhythmics (digitalis, amiodarone, Ca2+ channel blockers); cimetidine; lithium Grayanotoxin produced by some plants including Rhododendron spp.; also found in some kinds of honey (e.g., [37]) Road traffic accident causing contusion to SAN region (e.g., [38]) Hypothyroidism (e.g. [39]) Hypothermia Hypoxia


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4.2. The fast Na+ channel gene, SCN5A, and familial SSS

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As described above, the SCN5A gene is responsible for producing the pore-forming α-subunit of the cardiac Na+ channel Nav1.5. SCN5A mutations are highly heterogenous [58] and not unique to SSS — depending on the SCN5A mutation (gain- or loss-of-function), the clinical phenotype can vary widely, from SSS to AF [72], Brugada syndrome, congenital long QT syndrome type 3, familial atrioventricular nodal block [73] and familial dilated cardiomyopathy (see [72–78]). SSS is usually caused by loss-of-function mutations (for review see [79]), although it can be caused by gain-of-function mutations [80]. Most familial cases of SSS exhibit autosomal dominant inheritance, but an autosomal recessive disorder of compound heterozygous SCN5A mutations exists which are associated with severe ECG abnormalities manifesting in the first decade of life, mandating insertion of an electronic pacemaker [43,81]. A

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The fast Na+ current, INa, carried by the cardiac Na+ channel Nav1.5 is believed to be absent, or only expressed at very low levels, in central cells of the SAN (see Fig. 2a), yet it is relatively abundant in the SAN periphery [55], where it is believed to be critical for the efficient and expedient exit of impulses generated within the SAN to the surrounding atrial myocardium [7]. It has previously been demonstrated that there is a decrease in the rate of the upstroke of the action potential in the periphery of the rabbit and cat SAN with aging, which likely reflects an age-related decrease in the density of INa in this region [49] (see Fig. 2b). This decrease in INa could also explain the age-related increase in SAN conduction time (see Fig. 2c) and sinus node exit block demonstrated using computer modeling of the rabbit SAN [56]. It has also been demonstrated in wild-type mice that there is an age related decrease in mRNA abundance for Nav1.5, suggesting that INa will decrease concomitantly with aging [52]. Targeted disruption of the SCN5A gene, which codes for poreforming Nav1.5 α sub-units, recapitulates certain aspects of the SSS. Lei et al. demonstrated that SCN5A+/− mice had a depressed heart rate and demonstrated occasional SAN block in vivo [57] (see Fig. 2d). Isolated cells from these hearts had less INa, and slowed intrinsic pacing rates, while SAN preparations showed slowed SAN conduction time and

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frequent sino-atrial conduction block (see Fig. 2e). As if to underline the importance of these Na+ channels, SCN5A−/− homozygous knockout is embryonically lethal [57]. The same authors demonstrated that deficiency of Nav1.5 in mice leads to upregulation of transforming growth factor β1 (TGFβ1), causing fibrosis and consequent electrical remodeling favoring SSS [52]. The T-box transcription factor Tbx5 is essential for Nav1.5 expression in the ventricular conduction system, and its removal causes dramatic reductions in membrane expression of not only Nav1.5 but also connexin 40 (see below) in the cardiac conduction system, specifically the atrioventricular node [58,59], leading to arrhythmias involving the ventricular conduction system, including slowed conduction (with possibly similar effects in the SAN). In a similar fashion, Bmal1 encodes a core molecular clock transcription factor that is important for circadian expression of SCN5A — inducible cardiomyocyte specific deletion of Bmal1 in mice leads to slowed heart rates (see Fig. 3a), longer PR and QRS intervals, and arrhythmias (see Fig. 3b) due to loss of circadian SCN5A expression [60], with concomitantly decreased levels of Nav1.5 and INa in ventricular myocytes. The promoter region of the SCN5A gene has binding sites for several transcription factors, including nuclear factor NF-κB and forkhead box protein O1 (FOXO1) [61–63]. Upregulation of these factors, for example by oxidative stress or angiotensin II seen in heart failure, ischemia and hypertension, leads to a decrease in Nav1.5 expression and concomitantly decreased INa [63] (see Fig. 3c). TGFβ1 opposes the effect of FOXO1, increasing SCN5A mRNA and INa [62] (see Fig. 3d), and suggesting a possible therapeutic target in individuals whose SSS is related to low INa. MOG1 is a small protein that interacts with Ran, the Ras family GTPase involved in nuclear import and export [64], and in so doing interacts with and regulates the function of Nav1.5 (knockdown of MOG1 expression using siRNAs in cardiomyocytes almost completely abolished INa [65]; see Fig. 3e). Overexpression of MOG1 enhances cell surface expression of Nav1.5 and INa density [66] (see Fig. 3f). Chakrabarti et al. demonstrated that MOG1 had the potential to be used therapeutically to increase trafficking of Nav1.5 to the plasma membrane from the endoplasmic reticulum, rescuing the function of Nav1.5 and restoring INa in an animal model of SSS involving loss of INa due to defective Nav1.5 trafficking [65] (see Fig. 3g). Other Na+ channel isoforms contribute to INa, for example in the mouse heart, Nav1.5 is responsible for 92% of INa, with the other 8% being carried by the other neuronal and skeletal isoforms of voltagegated Na+ channels (Nav1.1 to 1.8) [67]. Nav1.1 and 1.6 participate in pacemaking in the SAN [68], with Nav1.6 acting as a depolarization reserve to guarantee excitation [69]. Mutations in these channels are predicted to contribute to the development of SSS. For example, Nav1.8 is known to have an important role in regulating action potential firing frequency in intracardiac neurons of mice [70], and mutations in Nav1.8 (encoded by SCN10A) are associated with prolonged cardiac conduction and heart block [71].

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heart is that the rate of its automaticity in health exceeds that of the other automatic regions of the heart. Some authors believe that in SSS there is a decrease in the numbers of functioning SAN cells (citing pathological findings of decreased numbers of cells in the SAN of patients with SSS) [48], while others believe that numbers do not decrease, rather it is the function of the normal number of cells that are present which becomes defective. It has also been suggested that SSS may simply be an exaggeration of the normal aging phenotype of the SAN — we know that SAN automaticity slows with aging, with a decrease in the ‘intrinsic’ heart rate, i.e., heart rate when the effects of the two arms of the autonomic nervous system are blocked [7,49] (see Fig. 1a). An inducible model of SSS has been developed that involves specific deletion of cells in the SAN [50]. This model recapitulates many (but not all [51]) of the human aspects of SSS, including the atrial tachyarrhythmias, and offers substantial promise for furthering understanding of the condition. Automaticity within SAN cells is brought about by a complex interplay of mechanisms grouped into one of two broadly interacting, synergistic ‘coupled clock’ mechanisms. The ‘membrane clock’ refers to the large number of voltage-gated ion channels that reside within the membrane of the cell and allow the time-dependent passage of charged species either into or out of SAN cells, a process that is dependent upon relative concentrations of the same ion on either side of the membrane. It has been shown that there are a great many changes in the expression levels of ion channels with aging — see [52,53]. The synergistic and complementary ‘calcium clock’ refers to the membrane-independent cycling of calcium that occurs into and out of the SAN cell's major intracellular store – the sarcoplasmic reticulum (SR) – in rhythmical fashion. This rhythmical release of calcium interacts with membrane bound exchangers and ion channels to bring about automaticity, most critically the Na+/Ca2+ exchanger, also known as NCX. There are several areas of crossover between the two clock mechanisms that allow high levels of tuning between the timing cycles of the individual clocks on a beatto-beat basis. The fact that there are two clocks that are mutually entrained affords a substantial degree of robustness and reliability to this most crucial of physiological processes. For a thorough review of the current state of understanding of sinoatrial nodal physiology, the reader is directed towards [54]. It follows from the above that it is likely that any substantial flaw in any of the many complex processes making up both of the clocks involved in SAN cell automaticity may contribute to the development of SSS.

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Fig. 2. The fast Na+ current and SSS. a. Immunohistochemical staining for Nav1.5 reveals its presence to be low in the center of the SAN of wild type mice (WT, black line), with increasing levels present in the periphery of the SAN, the crista terminalis (CT) and the septum (SEP). Levels of Nav1.5 immunofluorescence are low in all areas in heterozygous Nav1.5 knockout mice (Scn5a+/−, gray line). From Lei et al. [57]. b. The rate of upstroke of transmembrane potentials from primary pacemaker fibers in rabbits (b(i)) and cats (b(ii)) can be seen to slow with aging (from bottom to top). The vertical dotted line reflects the time of steepest deflection of the atrial EGM. Adapted from Alings et al. [49]. c. Isochrones of activation in the rabbit SAN, demonstrating that compared to the young animal (c(i)), older rabbits (c (ii)) demonstrated delayed activation time within the SAN, and a substantially larger area where AP upstroke velocity was slow (b5 v/s) — hatched area. * = region where impulse arose. Time for impulse to be conducted to reference atrial electrode was 28 ms in youngest rabbit vs 46 ms in oldest rabbit. VCI = inferior vena cava, VCS = superior vena cava. Adapted from Alings et al. [49]. d. Surface ECG recordings from wild type (d(i) and Scn5a+/- mice, demonstrating a complete absence of P waves at 24 weeks (d(ii)), with only intermittent P waves at 60 weeks (d(iii)). Adapted from Lei et al. [57]. e. Conduction abnormalities in SCN5A+/- heterozygous mouse SAN preparations. APs recorded from close to the center of the SAN in WT (e(i)) and SCN5A+/− mice (e(ii)), showing differences in intrinsic beating rate. e(iii) and (iv) demonstrate extracellular potential recordings in WT (e(iii)) and SCN5A+/− mice (e(iv)); the time from earliest initiation of the AP at the leading pacemaker site and the arrival of the impulse in the atrial muscle are calculated (dashed lines), and can be seen to be much longer in the SCN5A+/− animals, suggesting SAN conduction delay. e(iv) demonstrates simultaneous extracellular recordings of AP in the SAN and atrial muscle (AM) of an example SCN5A+/− mouse, demonstrating SAN conduction block, and failure to capture the AM in a 2:1 ratio. From Lei et al. [57].

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Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels) carry a mixed inward Na+/K+ cationic current during the early part of diastole, which is believed to be extremely important in the ‘membrane clock’ arm of the coupled clock paradigm of pacemaking [83]. The ‘funny current’ produced is activated in early diastole (during hyperpolarization; subsequently deactivated by depolarization) and contributes significantly to the early part of diastolic depolarization (for review see [54]). A significant number of HCN channels are open at ‘resting’ potentials in SANC [84], meaning that the maximum diastolic potential never gets as negative in these cells as it does in cells of the

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recent study of 15 families with hereditary SSS showed that (unlike SSS in general) those with SCN5A mutations had a strong male preponderance, and an early age of onset of clinical manifestations [17]. There are now a substantial number of well described SCN5A mutations that are associated with SSS in humans [77], and the features of SSS have been recapitulated in heterozygous SCN5A+/− mice [82].

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working atrial and ventricular myocardium (though If is not the only reason for this — SANC lack IK1 which contributes to the stable resting membrane potential typical of working atrial and ventricular myocytes, for example). HCN4 channels and their modification by cAMP are believed by many to be important in the autonomic regulation of heart rate [85–88], though this is controversial [89,90]. Three of the four members of the HCN channel family have been identified in SAN cells: HCN1, 2 and 4 [91–95]. HCN4 is the most important and abundant, accounting for approximately 75% of If in the SAN. Its absence (hetero- or homozygous) leads to the failure of maturation of pacemaker type cells during embryogenesis and death [86] (see Fig. 4a). Induced knockout later in life in the mouse leads to profound bradycardia and conduction system disease terminating in death within 5 days [87] (see Fig. 4b), suggesting that a more gradual loss of these channels could contribute to the development of SSS over time. The divalent-permeant channel-kinase TRPM7 has been shown to be highly expressed in human atrial myocytes, fibroblasts, embryonic myocardium and the SAN [96]. In vivo disruption of TRPM7 in zebrafish and mice has been shown to impair cardiac automaticity by slowing


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Fig. 3. Novel mechanisms for the control of INa that may be affected in SSS. The core molecular clock transcription factor Bmal1 is important for control of heart rate and arrhythmogenesis via its effect on circadian control of Scn5a and INa in mice. a. Induced knockout of Bmal1 causes mean cycle length to be significantly greater when measured in vivo. b. ECGs recorded pre- and postinduced knockout of Bmal1 demonstrate only infrequent and isolated pauses prior to induced knockout (b(i)), compared to frequent and more significant SAN arrhythmias post-induced knockout (b(ii)). From Schroder et al. [60]. The transcription factor FOXO1 suppresses Nav1.5. Its knockout (green line) leads to greater levels of INa at physiological voltages (c). From Cai et al. [61]. TGFβ1 antagonizes this effect of FOXO1 by causing its phosphorylation (pFOXO, d(i)), leading to increased levels of Scn5a (d(ii)). From Kaur et al. [62]. MOG1 protein interacts with and regulates Nav1.5. Knockdown of MOG1 expression markedly reduced INa densities in neonatal cardiomyocytes (e). Traces shown are peak INa. scrm = scrambled siRNA; siRNA = small interfering RNA used to knock down MOG1. (f) — the Nav1.5 mutation D1275N results in low levels of Nav1.5 on the plasma membrane. Levels of Nav1.5 on the plasma membrane can be rescued by MOG1 (right hand dark gray bar). (g) — raw traces of INa in cells transfected with WT (top) or mutant (bottom) SCN5A constructs with (+) and without (−) MOG. It can be seen that INa is restored in the mutant cells with MOG. From Chakrabarti et al. [65].

diastolic depolarization and inducing sinus pauses (see Fig. 4c), via a decrease in Hcn4 mRNA and If in the SAN [96]. Although the majority of If in the SAN is carried by HCN4 channels, HCN1 protein is also highly expressed in the SAN, being co-localized with HCN4 [97]. HCN1 and HCN2 (see next paragraph) mRNA have been demonstrated to be downregulated with aging in mice (in this study HCN4 mRNA was not downregulated) [52], while in rats aging was associated with a significant downregulation in both HCN2 and HCN4 mRNA [98]. Induced murine absence of HCN1 causes congenital SAN dysfunction, with bradycardia, sinus dysrhythmia, prolonged SAN recovery time, increased SAN conduction time, and recurrent pauses [97] (see Fig. 4d), reflecting many of the essential characteristics of SSS. Unlike HCN4 channels, HCN1 channels are hardly affected by cAMP [93,99].

HCN2 knockout also leads to sinus dysrhythmia and hyperpolarization of the maximum diastolic potential in SAN cells, although not to bradycardia [100]. These mice had 30% less If than their wild type litter mates [100], suggesting that HCN2 channels contribute a significant amount to If in mice behind HCN4 channels. A canine model of heart failure has demonstrated decreased expression of both HCN4 and HCN2, suggesting that they may have a role to play in the SSS seen in this condition [101].

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4.4. HCN channels and familial SSS

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Several mutations have been described in the HCN4 gene, which af- 349 fect different areas of the HCN4 protein, including the intracellular C- 350 terminal and the ion pore region, and lead to familial cases of SSS 351


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[44–47]. These mutations have varying effects on the biophysical properties of the HCN4 channel [102], including a negative shift in voltage dependency of activation, decreased current density, slower activation, faster deactivation and insensitivity to cAMP — all of these decrease the inward current in the diastolic depolarization range of SAN cells and therefore have the potential to contribute to the SSS phenotype. Some of the mutations are associated with a wide spectrum of other cardiac arrhythmias [47], including heart block and ventricular arrhythmias, whereas others seem only to give the SSS phenotype [46]. It has been shown that the complete conditional and time-dependent genetic silencing of If by expression of a dominant negative non-conductive HCN4 channel subunit can be completely rescued by the concomitant genetic deletion of cardiac muscarinic G-protein activated channels (GIRK4 channels), without impairing the regulation of the heartbeat [103]. This has the potential to be a new therapeutic strategy in the treatment of SSS caused by genetic mutations in HCN4 channels. The mice used in these studies also demonstrated heart block and ventricular arrhythmias, which the authors postulated were due to delayed afterdepolarizations in atrioventricular nodal myocytes and Purkinje fiber myocytes [103]. The delayed afterdepolarizations were said to be due to a dominant negative effect of the mutant HCN4 channels on the HCN3 channels that are proposed to regulate ventricular repolarization [103,104]. To date, it would appear that there have been no reports of mutations in HCN1 or 2 genes causing familial cases of SSS.

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Fig. 4. The funny current and SSS. a. Contraction rates of isolated embryonic hearts at embryonic day 9.5 in HCN4 wild-type (+/+), heterozygous (+/−) and homozygous (−/−) knockout mice. The number of hearts in each group is represented by n = .... * = p b 0.001 in (+/+) vs (−/−). From Stieber et al. [86]. b. The effect of tamoxifen induced knockout of HCN4 in mice on heart rate in vivo. Tamoxifen was given to control and conditional knockout mice at 08:00 h on several occasions beginning at day 0 (arrows). In control animals this had no effect on heart rate (b(i)). In conditional knockout animals, this led to significant bradycardia and death around day 4 (b(ii)). From Baruscotti et al. [87]. c. The effect of TRPM7 knockout. c(i): in vivo telemetry from wild type and TRPM7 knockout mice. Normal sinus rhythm is observed in the wild type mice (upper trace). However, in the TRPM7 knockout mice (lower trace), frequent sinus pauses are observed. c(ii): box-plot demonstrating significantly higher numbers of sinus pauses in TRPM7 knockout mice. Adapted from Sah et al. [96]. d. The effect of HCN1 knockout in mice. d(i): action potential recordings from isolated SANC showing significantly longer cycle length in the HCN1−/− knockout mice. d(ii): potential recordings from SAN preparations, showing significantly longer cycle length in the HCN1−/− knockout mice with marked sinus arrhythmia. Adapted from Fenske et al. [97].

4.5. ICa,L and SSS

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The L-type Ca2 + current is carried by L-type voltage-dependent Ca2+ channels in all regions of the heart, and is an extremely important inward current in diastole in SAN cells and during the upstroke of the action potential in (especially central) sinus node cells that lack INa, and rely on a Ca2+ dependent action potential upstroke [105]. ICa,L is activated at membrane potentials of −50 to −30 mV. In the sinus node, it is carried by both Cav1.2 (also expressed throughout the heart; activates at more positive potentials, i.e., −40 to −30 mV) and Cav1.3 (expression restricted to supraventricular tissue, especially the SAN and atrioventricular node; activates at more negative potentials, i.e., − 60 to −40 mV) α1 pore-forming sub-units, albeit with distinct characteristics [106,107]. Jones et al. demonstrated that the area of the SAN expressing Cav1.2 protein diminished with age, and that one required lower doses of Ca2 + channel blocking medications to cause SAN preparations to cease beating in older guinea-pigs [108]. Platzer et al. demonstrated that homozygous knockout of Cav1.3 in mice led to bradycardia and “arrhythmias”, the arrhythmias here being defined as high standard deviation measurements in RR intervals [109]. They also noted a prolongation of the PR interval, suggestive of atrioventricular nodal dysfunction in addition to SAN dysfunction. Mangoni et al. made similar findings in SAN cells from mice with targeted inactivation of the gene coding for the α-1 pore-forming subunit of Cav1.3 channels (Cacna1d knockout), i.e., that inactivation caused bradycardia and arrhythmia (again referring

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4.7. The Ca2+ clock and SSS

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Rhythmical Ca2+ release from the SR via ryanodine receptors, and SR refilling via the SERCA pump are critical processes central to the functioning of the Ca2+ clock [54]. In a pacing-induced model of heart failure in the dog it has been shown that there are fewer and smaller releases of Ca2+ from the sarcoplasmic reticulum compared to controls, alongside downregulation of RyR2, the major release channel of the SR [114, 115]. Such changes would be expected to have a significant effect on the incidence of SSS in heart failure. Similarly, aging has been shown to be associated with a significant decrease in RYR2 mRNA in the SAN of rats, which would likely affect SR Ca2+ release [53], while the same authors showed an age dependent increase in mRNA for the SERCA2a pump, primarily responsible for refilling the SR with Ca2+. Most recently, Liu et al. demonstrated that in SANC from aged mice, there was a decrease in beating rate responsiveness to both muscarinic and adrenergic autonomic agonists [116], along with decreased sarcoplasmic reticulum Ca2+ load, and a reduced size, number and duration of local Ca2+ releases, including under conditions of cAMP stress [116]. Furthermore, in these aged animals, there is decreased expression of SERCA, ryanodine receptors and the Na+–Ca2 + exchanger [116]. Overall, in this mouse model, these changes are believed to lead to the ageassociated decrease in intrinsic beating rate and the acceleration in heart rate with exercise. The multifunctional Ca2+/calmodulin dependent protein kinase II (CaMKII) plays a critical role in increasing SAN cell SR Ca2+ release in sympathetic nervous system driven fight-or-flight responses [117]. CAMKII is activated by NADPH oxidase-driven oxidation [118]. In hypertension and heart failure this is driven by high levels of angiotensin II, trapping CaMKII in a pathologically persistently active conformation and leading to apoptosis of ventricular myocytes, worsening myocardial dysfunction [118]. Swaminathan et al. have shown that oxidized CaMKII

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4.8. Connexins and SSS

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Connexins are responsible for the electrical connections between adjacent cells within the heart. There are several kinds of connexins that are heterogenous in their characteristics, including the speed at which they conduct the electrical impulse through the heart. The SAN expresses a unique connexin phenotype compared to the rest of the heart, and this also changes with age. Connexin 43 (Cx43) is an especially abundant type of connexin that is expressed within cells of the working myocardium, yet is sparsely expressed in SAN tissue. Despite this sparse expression, it has been demonstrated that with age there is a 14-fold decrease in Cx43 expressing cells within the SAN of guineapigs [125], which could possibly explain the witnessed increase in SAN conduction time and SAN exit block.

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4.9. Adenosine receptors and SSS

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Adenosine is an endogenous metabolite of the heart that is released in response to stress, whereupon it acts on adenosine A1 receptors in the SAN to slow heart rate and reduce energy consumption. It is accepted that SAN dysfunction is a hallmark of human heart failure – bradycardia accounts for around 43% of sudden cardiac deaths seen in heart failure [126,127], and that levels of adenosine are increased in patients with heart failure [128]. Lou et al. induced heart failure in dogs by tachy-pacing for 4 months [129]. They found that there was marked upregulation of adenosine A1 receptors in the heart failure animals, and that administration of adenosine in these heart failure animals prolonged post-pacing SAN conduction time, was more likely to cause intra-SAN conduction block, micro re-entry and post-pacing pauses, and that adenosine shortened atrial repolarization in the heart failure animals, leading to a significant increase in pacing-induced AF [129]. The SAN dysfunction and AF seen in the heart failure dogs could be abolished/prevented by adenosine A1 receptor antagonists such as theophylline, suggesting a potential therapeutic solution for the SSS seen in association with heart failure.

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Previous demonstrations of an increase in action potential duration with aging in the SAN of rabbits and cats [49] has led to the suggestion of a decrease in the ultra-rapid repolarizing potassium current, carried by Kv1.5 channels [7]. Indeed, it has been shown that mRNA for Kv1.5 is decreased with aging in wild type mice [52].

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is also bad for the SAN [119]. Levels of oxidized CaMKII are higher in humans with heart failure who required permanent pacemakers for SSS than those who did not [119]. Similarly, dogs with pacing induced heart failure had higher levels of oxidized CaMKII in the SAN than non-heart failure controls [119]. Mice treated with angiotensin II to increase levels of oxidized CamKII in the SAN demonstrated SAN cell apoptosis, fibrosis and slowed SAN conduction velocity [119]. These effects in mice could be blocked by CaMKII inhibition [119], suggesting a possible therapeutic application of CaMKII inhibition in patients with heart failure/hypertension-related SSS. The major Ca2+ binding protein of the SR is calsequestrin 2 (CASQ2) — loss of function mutations in CASQ2 genes leads to catecholaminergic polymorphic ventricular tachycardia (CPVT). One important clinical feature of CPVT patients is their sinus bradycardia [120] — this is believed to be important in triggering subsequent ventricular tachyarrhythmias. CASQ2 null mice also have a resting bradycardia [121]. This is somewhat unexpected, since CASQ2 deletion enhances spontaneous Ca2+ release from the SR [122], which theoretically should cause greater NCX current, faster diastolic depolarization and a quickening of the heart rate. Neco et al. [123] may have revealed why this could be however — they demonstrated that abnormally high diastolic Ca2+ release inactivates the Cav1.3-mediated ICa,L, thus reducing SR Ca2+ loading during pacemaking, and leading to a slowing of the heart rate despite the initial increase in INCX. Glukhov et al. investigated CASQ2 null mice in detail, demonstrating SAN fibrosis, decreased automaticity, SAN conduction slowing, and increased atrial ectopics and AF [124]. Underlying these clinical features were shown to be perturbations in intracellular Ca2+ cycling, including abnormal Ca2 + releases (with the upstroke of the Ca2+ transient lagging behind that of the action potential) and significantly elevated diastolic Ca2+ levels [124].

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to “substantial dispersion of consecutive measured cycle length intervals”), due predominantly to loss of the part of the L-type Ca2+ current carried by Cav1.3 channels [107]. These mice were also deaf. A specific mutation (CACNA1D) in the same region of the pore-forming αsubunit of the Cav1.3 gene has been found in two families to lead to a syndrome of SSS and deafness [110]. Voltage-dependent Ca2+ channels are also involved in so-called congenital heart block, a mis-leading name for a condition in which there is indeed atrioventricular nodal block, but also a previously underrecognized degree of sino-atrial node dysfunction and bradycardia [111]. There is a role in congenital heart block for maternal anti-Ro/La autoantibodies, which have been demonstrated to inhibit ICa,L and the related T-type voltage-dependent Ca2+ current, ICa,T (carried by Cav3.1 channels) [112,113]. The overexpression of Cav1.2 in mice with congenital heart block demonstrated reduced sinoatrial and atrioventricular nodal conduction abnormalities [111], suggesting that Ca2+ channel agonists might be a therapeutic option in congenital heart block. Bay K8644, an L-type Ca2+ channel agonist has been demonstrated to be useful in this regard, reversing the effect of maternal antibodies on ICa,L [113]. Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) also demonstrate sinoatrial nodal dysfunction, believed to be secondary to the combination of Ca2+-dependent decrease in ICa,L, and sarcoplasmic reticulum Ca2+ depletion during diastole. These two clinical syndromes underline the critical importance of voltage-dependent Ca2+ channel function in healthy automaticity, and the potential for dysfunction in SSS.

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4.10. The Renin–angiotensin–aldosterone (RAA) system and SSS

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The RAA system is recognized to have effects on the cardiac conduction system. Angiotensin II binding sites are highly localized in the SAN and AVN of rat hearts [130], and angiotensin II is believed to induce apoptosis in SAN cells [131] alongside cardiac fibrosis and hypertrophy through an effect on angiotensin II type I (ATI) receptors [132], possibly contributing over time to the development of SSS. Transgenic overexpression of ATI receptors in the myocardium of mice led to death that was preceded by sinus bradycardia and heart block [133]. Polymorphisms in the angiotensinogen gene promoter have been shown in humans to be linked to non-familial, age-dependent SSS [134], possibly by modulating angiotensinogen expression.

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4.11. The Popeye domain containing genes (Popdc) and SSS

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The Popdc genes encode membrane proteins that are expressed in all cardiac tissues, but most abundantly in the cardiac conduction system [135]. These Popdc proteins interact with the two-pore channel TREK1 to enhance its outward, hyperpolarizing K+ current — this interaction is modulated by cAMP for which they have a ‘popeye’ binding domain. Null mutations of the Popdc gene family in mice lead to a stress induced sinus bradycardia and sinus pauses that become more marked with age [136], recapitulating many of the essential features of the SSS.

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MicroRNAs are small, non-coding ribonucleic acids that are assuming an increasingly important role in the control of gene expression, usually by restricting translation or inducing degradation of the target mRNA. MicroRNAs are believed to contribute to a wide variety of conditions including heart failure [137], hypertrophy [138] and myocardial infarction [137], all of which would be likely to increase susceptibility to SSS. In human atrial fibrillation and ventricular arrhythmia, microRNA-1 is markedly decreased [139], leading to upregulation of the Kir2.1 potassium channel and its associated current IK1. An increase in IK1 can lead to membrane hyperpolarization, which would be expected to contribute to bradycardia and arrhythmias typical of SSS, including AF. The microRNAs miR-17-92 and miR-106b-25 are positively regulated by the transcription factor Pitx2 to directly target and inhibit the SAN genes Shox2 and Tbx3, which are crucial for promoting differentiation into SAN cells, while inhibiting differentiation into working myocardial cells. Knockout of these miRs decreased the threshold for developing pacing induced AF in mice [140]. Cardiomyocyte specific knockout of miR-17-92 combined with haplotype insufficiency of miR-106b-25 in mice led to SAN dysfunction, along with second degree atrioventricular block suggesting diffuse cardiac conduction system disease [140]. Therefore, manipulation of these miRNAs seems to recapitulate many of the clinical features of SSS. It is tantalizing to postulate that failure to suppress the SAN gene program (the responsibility of Shox2 and Tbx3) in certain areas of the heart can lead to the development of AF due to developmental ‘leaving behind’ of cells with SAN like characteristics, though substantiation of this and the relevance to humans remains to be elucidated.

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4.13. Other rare causes of familial SSS

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1. The membrane adaptor protein ankyrin-B (ANK2) Ankyrin-B is a member of the ankyrin family of proteins that are associated with the cytoplasmic surface of the plasma membrane in most metazoan cells, where they help to maintain well-defined neighborhoods in the membrane that are optimized for specific functions, including electrical signaling [141]. Ankyrin-B is highly expressed in the SAN, where its activity is essential for post-translational organization of SAN channels and transporters [142]. Loss-of-function

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5. The relationship between bradycardia and AF in SSS

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Whether bradycardia leads to AF and other atrial tachycardias in SSS, or vice versa remains an enigmatic ‘chicken or egg’ question for the cardiac electrophysiologist. SSS is increasingly recognized not simply to be a disease of the SAN, but a senescent disease of the SAN and atrial myocardium, and possibly of the cardiac conduction system beyond the SAN. Anatomically, such senescence of atrial myocardium along with fibrosis [149] gives a working substrate for the development of AF. Concomitant bradycardia further facilitates the development of AF through an increase in likelihood of atrial ectopics and a greater dispersion of refractoriness [1], both of which are recognized to be important initiators of AF. It has further been suggested that the behavior of the SAN itself can predispose an individual to the development of AF. Certainly the work by Chen et al. suggests that maintaining healthy electrical connections between the SAN, working atrial myocardium and pulmonary veins is very important for preventing arrhythmogenesis [150]. These authors electrically disconnected the SAN and pulmonary veins in some rabbits, while leaving these connections untouched in others. Animals with disrupted electrical connections between the SAN and pulmonary veins demonstrated more burst firing and early afterdepolarizations in their

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mutations of ankyrin-B in humans lead to a dominantly inherited form of SSS [143] that is associated with sudden death, and occasionally prolongation of the QT interval on the ECG [142,144]. Cellular experiments in knock-out animals (ANK2 gene knockout) suggested that deficient ankyrin-B affects Ca2+-handling in working cardiomyocytes, leading to extrasystoles and sudden death, especially in the context of catecholamine exposure [143–145]. This abnormal Ca2+-handling is believed to be due to deficiency in the complex of ankyrin-B with the Na+-K+ ATPase, the Na+–Ca2+ exchanger, and the IP3 receptor located in a specialized microdomain of the cardiomyocyte T-tubules [146]. This complex is believed to be important for transporting Ca2+ from the sarcoplasmic reticulum (via IP3 receptors) across the plasma membrane (via the Na+/Ca2+ exchanger), and is deficient in ankyrin-B+/− murine cardiomyocytes [146]. In AnkB+/− mice, Le Scournec et al. demonstrated that heterozygotes exhibited bradycardia and markedly increased heart rate variability compared to wild type littermates [142]. Similar to the findings in working cardiomyocytes, this was due to loss of membrane localization of NCX1 and Cav1.3 from SAN cells, leading to diminished INCX and ICa,L [142]. Furthermore, it was seen that heterozygosity for the ankyrin-B mutation led to a loss of SAN Ca2+ homeostasis [142], underlining the importance of ankyrin-based targeting pathways for automaticity, and demonstrating the potential of these pathways to be therapeutic targets in the treatment of ankyrin-B related SSS. 2. The gene encoding the α-myosin heavy chain (MYH6n) The work of Holm's group in Iceland identified that a mis-sense mutation in the MYH6 gene, encoding the α heavy chain subunit of cardiac myosin is associated with SSS susceptibility [147]. They demonstrated that the lifetime risk of developing SSS was 6% in people not carrying this mutation, while in carriers the lifetime risk was 50%. Other missense variants in this gene had previously been identified to be associated with heart rate and PR interval [148]. This association between the gene encoding a component of myosin and heart rhythm disturbances is unexpected — previously mutations in this gene would have been expected to have had a cardiomyopathic effect (both hypertrophic and dilated), or been associated with the development of congenital heart defects. The particular mutation associated with SSS was predicted to alter the structure of a converter domain of α-myosin heavy chain (α-MHC) [147], though how this adversely affects cardiac conduction is at present unclear. It has been suggested that the mutation could affect the levels of a highly conserved miRNA miR-208a, important for the expression of Gja5, otherwise known as connexin 40 (Cx40), an important gap junction protein required for formation and rapid conduction of impulses through the heart [147].

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SSS is a complex disorder (see Fig. 5) of the heart's primary pacemaker, its adjacent atrial myocardium and also a varying amount of the cardiac conduction system. Idiopathic SSS, by far the commonest form of the disorder, likely arises through complex alterations in a great many processes that contribute to the automaticity of the SAN. While we can learn much from studying familial cases of SSS occurring via single mutations affecting single genes, and from in vitro isolated manipulations of critical processes, the reality is that the cases of SSS that walk through the doors of physicians' offices have likely come about through complicated intertwined failures of processes contributing to automaticity rather than a major failure of a single process. As such physicians will remain stymied in their search for a ‘magic bullet’-type pharmacological or genetic therapeutic approach to ‘cure’ all cases of SSS. Only with the development of more rapid, accurate diagnostic techniques for identifying the underlying cause(s) of SSS will such therapeutic inventions find a place in the physician's armamentarium. In the meantime, we will have to satisfy ourselves and our patients with the fact that the only current way to effectively treat SSS is with an electronic pacemaker. Biological pacemakers promise much for SSS patients, but surely we should continue to look into ways of preventing ‘idiopathic’ SSS from developing in the first place? If we were successful in doing so, we would cut the number of pacemakers (electronic or biological) required by half, not to mention decrease the morbidity and mortality incurred by the associated atrial tachyarrhythmias. Future studies should undoubtedly focus on the study of the induction or failure of gene programs that lead to SSS, possibly controlled by as yet

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References

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undiscovered microRNAs. Although it is over 100 years since the SAN 694 was discovered, we still have much to learn. 695

[1] Amasyali B, Kilic A, Kilit C. Sinus node dysfunction and atrial fibrillation: which one dominates? Int J Cardiol 2014;175:379–80. [2] Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the sick sinus syndrome. Circulation 1972;46:5–13. [3] Hartel G, Talvensaari T. Treatment of sinoatrial syndrome with permanent cardiac pacing in 90 patients. Acta Med Scand 1975;198:341–7. [4] Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970;4:160–7. [5] Short DS. The syndrome of alternating bradycardia and tachycardia. Br Heart J 1954;16:208–14. [6] Ferrer MI. The sick sinus syndrome in atrial disease. JAMA 1968;206:645–6. [7] Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 2007;115:1921–32. [8] Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R, et al. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002;346: 1854–62. [9] Connolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 2000;342:1385–91. [10] Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994;344:1523–8. [11] de Marneffe M, Gregoire JM, Waterschoot P, Kestemont MP. The sinus node function: normal and pathological. Eur Heart J 1993;14:649–54. [12] Adan V, Crown LA. Diagnosis and treatment of sick sinus syndrome. Am Fam Physician 2003;67:1725–32. [13] Yabek SM, Jarmakani JM. Sinus node dysfunction in children, adolescents, and young adults. Pediatrics 1978;61:593–8. [14] Hayes CJ, Gersony WM. Arrhythmias after the Mustard operation for transposition of the great arteries: a long-term study. J Am Coll Cardiol 1986;7:133–7. [15] Beder SD, Gillette PC, Garson Jr A, Porter CB, McNamara DG. Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. Am J Cardiol 1983;51:1133–6. [16] Greenwood RD, Rosenthal A, Sloss LJ, LaCorte M, Nadas AS. Sick sinus syndrome after surgery for congenital heart disease. Circulation 1975;52:208–13. [17] Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, et al. Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ Arrhythm Electrophysiol 2014. [18] Bernstein AD, Parsonnet V. Survey of cardiac pacing and defibrillation in the United States in 1993. Am J Cardiol 1996;78:187–96. [19] Jensen PN, Gronroos NN, Chen LY, Folsom AR, deFilippi C, Heckbert SR, et al. Incidence of and risk factors for sick sinus syndrome in the general population. J Am Coll Cardiol 2014;64:531–8. [20] Semelka M, Gera J, Usman S. Sick sinus syndrome: a review. Am Fam Physician 2013;87:691–6. [21] Birchfield RI, Menefee EE, Bryant GD. Disease of the sinoatrial node associated with bradycardia, asystole, syncope, and paroxysmal atrial fibrillation. Circulation 1957; 16:20–6.

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pulmonary veins in response to Anemonia sulcata toxin II. By inference, these rabbits were more at risk of developing AF than animals with intact SAN-pulmonary vein connections. Other authors suggest the reverse view, that longstanding AF and other supraventricular tachycardias cause remodeling of the SAN leading to its dysfunction and subsequent bradycardias [7,151]. Rapid atrial pacing is recognized to cause altered Ca2+ cycling, caffeine sensitivity and RyR expression in the SAN, alongside decreases in If and IK,s currents due to downregulation of HCNs 4 and 2 and minK respectively [115]. While the bradycardia seen in patients following cardioversion back to sinus rhythm can be transient, it is often severe enough to warrant implantation of a permanent pacemaker. The reality of the etiology of the brady- and tachycardias seen in SSS is that they are not disparate processes, rather they are the result of the same process, that being fibrosis of both the SAN and working atrial myocardium [1,152–154], and that we should change our view from one being the cause of the other to the view that these conditions are the manifestation of the same process, albeit that some patients express an excess of one compared to the other.

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Fig. 5. Summary of factors contributing to SSS. Factors potentially contributing to the development of SSS are shown. Molecular and biophysical causes discussed within this paper are shown in black, while other intrinsic and extrinsic causes of SSS are shown in pink. The figure underlines the complexity of the etio-pathogenesis of SSS.


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Pathological studies in sinoatrial disorder (sick sinus syndrome).

First-degree sinoatrial heart block: sinoatrial block in the sick-sinus syndrome.

Does atrial pacing lead to atrial fibrillation in patients with sick sinus syndrome? Insights from the DANPACE trial.

A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation.

Elevated plasma norepinephrine level and sick sinus syndrome in patients with lone atrial fibrillation.

Improvement of symptoms in patients with sick sinus syndrome by spontaneous development of stable atrial fibrillation.

Isoprenaline: a potential contributor in sick sinus syndrome--insights from a mathematical model of the rabbit sinoatrial node.

A study of atrioventricular nodal function in patients with the sick sinus syndrome.

The sick sinus syndrome.

The sick sinus syndrome.

Potential candidates for pacemakers. Survey of heart block and sinoatrial disorder (sick sinus syndrome).

Familial sick sinus syndrome.

Hyperkalemia induced sinoatrial block or atrial fibrillation?

Letter: Sick sinus syndrome.

Sick sinus syndrome.

Letter: Sick sinus syndrome.

Sick sinus syndrome.

Sick sinus syndrome in children.

Syncope and the sick sinus syndrome.

Pacing for carotid sinus syndrome and sick sinus syndrome.

Donepezil-associated sick sinus syndrome.

Interdependent Relationship Between Atrial Fibrillation and Sinus Rhythm at the Hypothetical Interface of Atrial Fibrillation, Autonomic Tone, Sinoatrial Node and Inflammation : Analytical Review, Reconsiderations, Speculations and New Insights.

Sick sinus syndrome. Symptomatic cases in children.

Persistent Sick Sinus Syndrome in Scrub Typhus.