7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Sinus node dysfunction: Epidemiology, etiology, and natural history : Munther K Homoud, MD : Samuel L vy, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 08, 2022. INTRODUCTION The sinoatrial (SA) node is normally the dominant pacemaker in the human heart. Originally described in 1907 as a subepicardial structure located at the junction of the right atrium and superior vena cava, the SA node represents the integrated activity of pacemaker cells in a compact region of the right atrium that depolarize and produce action potentials almost synchronously [1-3]. While the location of the primary pacemaker may move among groups of cells within the region of the SA node, only about 1 percent of the cells in the SA node act as the leading pacemaker [4]. Sinus node dysfunction (SND), also historically referred to as sick sinus syndrome, is the term used to describe the inability of the SA node to generate a heart rate that meets the physiologic needs of an individual. The initial clues to the diagnosis of SND are often derived from taking the history and obtaining a routine electrocardiogram (ECG), though the symptoms and ECG findings are frequently vague and nonspecific. The diagnostic evaluation should initially include a search for remediable causes of SA nodal depression such as drugs (eg, beta blockers, calcium channel blockers, digoxin) and metabolic diseases (eg, hypothyroidism). Treatment of SND is directed at symptoms and typically involves the implantation of a permanent pacemaker. The epidemiology, potential etiologies, and the natural history of SND will be reviewed here. The clinical manifestations, approach to diagnosis, and the treatment of SND are discussed in detail https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 1/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate separately. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation" and "Sinus node dysfunction: Treatment".) NORMAL PHYSIOLOGY OF THE SA NODE Cellular physiology Pacemaking activity that originates from the sinoatrial (SA) node is incompletely understood. There are two predominant mechanisms that are thought to serve as the initiation of sinus activity: The funny current (I ) f Spontaneous intracellular calcium release by sarcoplasmic reticulum The I current is the result of sodium and potassium ionic currents that allow for a steady f increase in the resting membrane potential of the cell ( figure 1). Once the resting membrane reaches the depolarization threshold of the cell, an action potential is generated, and electrical activity ensues. The rate of the steady increase of the resting membrane potential can be modulated by other ionic currents as well as beta-adrenergic activity. As the slope of the increase in resting membrane potential steepens, the rate of spontaneous sinus node activity increases. The second mechanism thought to be critical in SA node activity initiation is spontaneous sarcoplasmic reticulum calcium release within the SA nodal cells [5]. The release of calcium into the intracellular space results in activation of the sodium-calcium exchange current, eventually leading to phase 4 depolarization. These two mechanisms are not mutually exclusive, and evidence suggests that they may be complementary in their pacemaking actions. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Action potential in slow response tissues'.) While the calcium and potassium currents are the predominant determinants of SA nodal automaticity, there is evidence to suggest that the sodium channel may also play a role. Mutations in the human cardiac sodium channel (SCN5A) cause one type of long-QT syndrome (LQT3), and these individuals may also have sinus pauses and sinus bradycardia in addition to the characteristic prolongation of the QT interval. Studies in cells expressing either wild type or LQT3 channels showed that an increase in a persistent inward current in the mutated channels reduced the sinus rate directly and could also result in the failure to repolarize completely [6]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 3 LQTS (LQT3)'.) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 2/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate As mentioned above, pacemaking can originate from different areas within the sinus node. Mapping of sinus node activation indicates that at faster rates, the SA impulse originates in the superior portion of the SA node, or extranodally, while at slower rates, it arises from the inferior portion of the node or, once again, extranodally [7]. The SA node may be insulated from the surrounding atrial myocytes except at a limited number of preferential exit sites. Shifting pacemaker sites may select different exit pathways to the atria. Autonomic nervous system and the SA node The SA node is innervated by the parasympathetic and the sympathetic nervous systems, and the balance between these systems controls the pacemaker rate. The classic concept has been that of a reciprocally balanced relationship between sympathetic and parasympathetic inputs. More recent investigations, however, stress dynamic, demand-oriented interactions and the anatomic distribution of fibers that allows both autonomic systems to act quite selectively [8]. Muscarinic cholinergic and beta-1 adrenergic receptors are nonuniformly distributed in the SA node and modulate both the rate of depolarization and propagation [7]. Parasympathetic activity Parasympathetic input via the vagus nerves decreases the SA nodal pacemaker and is the dominant input at rest. The mediator of parasympathetic activity is acetylcholine (ACh) which, as a ligand gating agent, acts through the G-protein, G , to activate a i certain group of membrane channels called I channels ( figure 1) in tissues of the SA and KACh atrioventricular (AV) nodes as well as of the atria, Purkinje fibers, and ventricles [9]. Acetylcholine increases the outward potassium current, thereby slowing the SA nodal pacemaker, by at least two important mechanisms: The resting potential and the maximum diastolic potential become more negative; as a result, more current is required to reach threshold. The outward potassium current opposes the inward currents responsible for depolarizing the cell, resulting in a decrease in phase 4 depolarization. Acetylcholine also reduces the inward calcium current, I through the G-protein system. Ca Sympathetic activity Sympathetic nerve input, as well as the adrenal medullary release of catecholamines, increases the sinus rate during exercise and stress. The manner in which beta- receptor stimulation by catecholamines affects automaticity is complex and involves interactions of the beta-receptor/adenylate cyclase/G-protein systems. Catecholamines enhance the L-type of inward calcium current by increasing cyclic adenosine monophosphate (AMP) and activating the protein kinase A system; the increment in inward calcium current would be expected to increase the rate of phase 4 diastolic depolarization. The redistribution of calcium may also increase the completeness and the rate of I deactivation. Catecholamines may also enhance I . f K https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 3/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate SA nodal remodeling Atrial tachyarrhythmias can cause persistent changes in atrial electrophysiology that result in increased vulnerability to further dysrhythmia. This phenomenon is called "atrial remodeling." (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) The SA node may also undergo electrophysiologic changes in response to atrial arrhythmias or other stimuli (see bullets below); these changes result in SA node dysfunction and are referred to as "SA nodal remodeling" [10,11]. Remodeling of the SA node may also occur in the setting of heart failure, even in the absence of a history of atrial fibrillation [12]. In a study of 18 patients with symptomatic heart failure and 18 age-matched controls, those with heart failure had significant prolongation of the intrinsic sinus cycle length, corrected sinus node recovery time, and sinoatrial conduction time, as well as caudal displacement of sinus activity and an increase in the number and duration of fractionated atrial electrograms [13]. After ablation for atrial fibrillation, reverse remodeling of the SA node may occur with elimination of the SA node depression and the prolonged sinus pauses [14]. Reverse remodeling of SA nodal function also occurs after the termination of atrial flutter [15] and after the catheter ablation of right atrial flutter [16]. As little as 10 to 15 minutes of atrial pacing causes SA nodal remodeling in humans [17]. Interestingly, asynchronous ventricular pacing has also been associated with SA nodal remodeling [18]. DEFINITION Sinus node dysfunction (SND) is characterized by dysfunction of the sinoatrial (SA) node that is often secondary to senescence of the node and surrounding atrial myocardium. The term "sinus node dysfunction" was first used in 1967 to describe the sluggish return of SA nodal activity in some patients following electrical cardioversion and is now commonly used to describe the inability of the SA node to generate a heart rate that meets the physiologic needs of an individual [19-21]. SND can present with numerous ECG abnormalities including: Sinus bradycardia Sinus pauses Sinus arrest SA nodal exit block Inadequate heart rate response to physiological demands during activity (chronotropic incompetence) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 4/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate SND can also be accompanied by supraventricular tachycardias (atrial fibrillation, atrial flutter, and atrial tachycardia) as part of the tachycardia-bradycardia syndrome. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation", section on 'ECG findings'.) EPIDEMIOLOGY The epidemiology of SND is difficult to study, given the nature of SND and its varying manifestations, including nonspecific symptoms and ECG findings. However, patients with symptomatic SND are generally older (ie, seventh or eighth decade of life) with frequent comorbid diseases. In a pooled analysis of 20,572 patients from two large epidemiology studies (Atherosclerosis Risk in Communities [ARIC] and Cardiovascular Health Study [CHS]) who were followed for an average of 17 years, 291 incident cases of SND were noted, yielding in an incidence rate of 0.8 cases per 1000 person-years [22]. While several variables were associated with development of SND (eg, higher body mass index, hypertension, prior cardiovascular event), advancing age was the most significant risk factor for SND (hazard ratio 1.73 for each additional five years of age; 95% CI 1.47-2.05). In three major trials of pacing in this disorder, the median or mean age was 73 to 76 years [23-25]. Males and females appear equally affected, and although less common, SND can occur in younger adults and children. (See 'Childhood and familial disease' below.) ETIOLOGY Sinoatrial (SA) node dysfunction occurs as a result of disorders in automaticity, conduction, or both. Local cardiac pathology, systemic diseases that involve the heart, and medications/toxins can all be responsible for abnormal SA node function and result in SND. Most cases of sinus node dysfunction entail extrinsic and intrinsic components. Identification of an extrinsic component is important because it is often modifiable. Drug-induced SND (suppression) is transient and modifiable, whereas SND due to an infiltrative cardiomyopathy, surgical intervention, or a mutation in a number of genes identified to be associated with SND is not. Thus, it is important to identify and eliminate any aggravating (reversible) factors causing SND, given the absence of treatment of intrinsic SND other than pacemaker therapy with its associated limitations. (See "Sinus node dysfunction: Treatment".) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 5/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Abnormal automaticity, or sinus arrest, refers to a failure of sinus impulse generation. Abnormal conduction, or sinoatrial delay or block, is a failure of impulse transmission. In such cases, the sinus impulse is generated normally, but it is abnormally conducted to the neighboring atrial tissue. Both abnormal automaticity and abnormal conduction may result from one of several different mechanisms including fibrosis, atherosclerosis, and inflammatory/infiltrative myocardial processes. Sinus node fibrosis The most common cause of sinus node dysfunction is the replacement of sinus node tissue by fibrous tissue, which may be accompanied by degeneration and fibrosis of other parts of the conduction system as well, including the atrioventricular (AV) node [26-28]. The transitional junction between the sinus node and atrial tissue may also be involved, and there may be degeneration of nerve ganglia. Medications and toxins A number of medications and toxins can reversibly depress sinus node function, resulting in symptoms and ECG changes consistent with SND. The most commonly used prescription medications which alter myocardial conduction and can potentially result in SND include [29-34]: Beta blockers Nondihydropyridine calcium channel blockers Digoxin Antiarrhythmic medications Acetylcholinesterase inhibitors such as donepezil (Aricept) and rivastigmine used in the treatment of Alzheimer disease Other medications associated with depression of sinus node function include parasympathomimetic agents, sympatholytic drugs (eg, methyldopa, clonidine), cimetidine, lithium, and ivabradine [35,36]. In addition, poisoning by grayanotoxin, produced by some plants (eg, Rhododendron sp.) and found in certain varieties of honey, has been associated with depressed sinus node function [37]. Childhood and familial disease SND is rare in children, but when present it is most often seen in those with congenital and acquired heart disease, particularly after corrective cardiac surgery [38-41]. Familial sinus node dysfunction is rare, with mutations in the cardiac sodium channel gene SCN5A and the HCN4 gene (thought to contribute to the pacemaker current in the sinus node) responsible for some familial cases [42-48]. In a series of 30 children and young adults (ages 3 days to 25 years) with sinus node dysfunction, 22 had significant cardiac disease, and sinus node dysfunction developed after https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 6/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate cardiac surgery in 13 [38]. The causes of sinus node dysfunction were inappropriate sinus bradycardia, sinus arrest, and sinoatrial exit block. In a study of 10 children from seven families with familial SND, genomic DNA encoding the alpha subunit of the cardiac sodium channel was screened for mutations [42]. Compound heterozygous nucleotide changes were identified in five children from three families (but in none of over 75 control subjects). In a series of 38 patients with clinical evidence of Brugada syndrome, four had SCN5A mutations [45]. Three of these patients had SND with multiple affected family members. Mutations in SCN5A are not pathognomonic for sinus node disease, however, as different SCN5A mutations are associated with other cardiac abnormalities including Brugada syndrome, congenital long QT syndrome type 3, familial AV block, and familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation (AF). (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Etiology of atrioventricular block" and "Genetics of dilated cardiomyopathy" and "Brugada syndrome: Epidemiology and pathogenesis", section on 'SCN5A'.) Mutations in HCN4 can produce both symptomatic and asymptomatic sinus node dysfunction, as illustrated by numerous reports of sinus bradycardia in family members with such mutations [46-49]. Other SND is less often due to a variety of other disorders: Infiltrative diseases The SA node may be affected by infiltrative disease, such as amyloidosis, sarcoidosis, scleroderma [50], hemochromatosis, and rarely tumor. Inflammatory diseases Rheumatic fever, pericarditis, diphtheria, Chagas disease, and other disorders may depress SA nodal function. SA nodal artery disease The sinus node is perfused by branches of the right coronary artery in 55 to 60 percent and by the left circumflex artery in the remaining 40 to 45 percent. The SA nodal artery may be narrowed by atherosclerosis, inflammatory processes, or even emboli [28,50-52]. Approximately 5 percent of patients with myocardial infarction, usually inferior, show sinus node dysfunction that tends to be reversible [53-55]. In one study of 46 patients with prior inferior myocardial infarction (23 patients with and 23 without SND), the intrinsic heart rate was abnormal in almost all patients with more than a 75 percent narrowing of the SA nodal artery, but only 30 percent with less than 50 percent narrowing [56]. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 7/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Trauma Cardiac trauma during surgery may affect either the SA node directly or its blood supply. Miscellaneous Other disorders that can cause SND include hypothyroidism, hypothermia, hypoxia, and muscular dystrophies. Some infections (eg, leptospirosis, trichinosis, and Salmonella typhosa) are associated with relative sinus bradycardia, but permanent SND has not followed these [57-60]. NATURAL HISTORY The natural history of SND typically involves intermittent but progressive cardiac rhythm disorders, which have been associated with higher rates of other cardiovascular events and higher mortality. There is a tendency for the rhythm disturbances associated with SND to evolve over time, along with a higher likelihood of thromboembolic events and other cardiovascular events. Rhythm For many patients with SND, there are variable, and often long, periods of normal sinus node function [61]. Nevertheless, once present, sinus node dysfunction eventually progresses in most patients, along with a greater likelihood of developing atrial tachyarrhythmias [62]. However, it is very difficult to predict the time course of disease progression, which is why most patients with symptomatic SND will be treated earlier in an attempt to alleviate symptoms. (See "Sinus node dysfunction: Treatment".) Sinus node dysfunction progresses over time. In one cohort of 52 patients with sinus node dysfunction who presented with sinus bradycardia associated with sinoatrial (SA) block or SA arrest, it took an average of 13 years (range 7 to 29 years) for progression to complete SA arrest and an escape rhythm [61]. Atrial arrhythmias and conduction disturbances become more common over time, possibly the result of a progressive pathological process that affects the entire atrium and other parts of the heart [27,63,64]. As an example, among 213 patients with a history of symptomatic SND who were treated with atrial pacing and followed for a median of five years, 7 percent developed atrial fibrillation and 8.5 percent developed high-grade atrioventricular block [65]. Cardiovascular events Patients with SND, particularly those with alternating tachycardia and bradycardia, are at an increased risk for thromboembolic events even after pacemaker implantation. A possible contributor to cardiovascular events after pacemaker implantation is https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 8/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate asymptomatic episodes of atrial fibrillation resulting in thromboembolic events. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) In one prospectively-followed cohort of 35 patients aged 45 years with symptomatic SND manifested by a mean sinus rate at rest 50 beats/minute and/or intermittent SA block, who did not undergo immediate treatment but were followed for an average of 17 months, a cardiovascular event requiring treatment occurred in 57 percent of patients and included syncope (23 percent), overt heart failure (17 percent), chronic atrial fibrillation (11 percent), or poorly tolerated atrial arrhythmias (6 percent) [66]. Independent predictors of a cardiovascular event were age, left ventricular end-diastolic diameter, and left ventricular ejection fraction. In a study of 225 patients with SND who were randomized to single-chamber atrial or ventricular pacing, the annual risk of thromboembolism was approximately twofold higher for patients with SND and tachycardia/bradycardia syndrome compared with patients without tachycardia/bradycardia syndrome [67]. Mortality The relationship between SND and mortality is difficult to clearly understand as many individuals with SND have pre-existing comorbidities (hypertension, diabetes mellitus, atrial fibrillation) that are known to increase all-cause mortality. In one study of 19,893 persons from two prospective cohorts without atrial fibrillation or a pacemaker at baseline who were followed for an average of 17 years, 213 persons developed SND (0.6 events per 1000 person- years) [68]. While the development of SND was associated with a significantly higher mortality, this association was attenuated following adjustment for incident cardiovascular disease during follow-up. While SND certainly contributes to patient morbidity, if or how SND increases overall mortality is unclear. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 9/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Sinus node dysfunction (The Basics)" and "Patient education: Bradycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Physiology of the SA node The sinoatrial (SA) node is innervated by the parasympathetic and the sympathetic nervous systems, and the balance between these systems controls the pacemaker rate. Parasympathetic input via the vagus nerves decreases the SA nodal pacemaker and is the dominant input at rest, while sympathetic nerve input, as well as the adrenal medullary release of catecholamines, increase the sinus rate during exercise and stress. (See 'Autonomic nervous system and the SA node' above.) Definition Sinus node dysfunction (SND) is characterized by dysfunction of the SA node that is often secondary to senescence of the SA node and surrounding atrial myocardium. Medications may also contribute and can often unmask subclinical sinoatrial dysfunction. (See 'Definition' above and "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation", section on 'Clinical presentation'.) Epidemiology The epidemiology of SND is difficult to study, given the nature of SND and its varying manifestations, but patients with symptomatic SND are generally older (ie, seventh or eighth decade of life) with frequent comorbid diseases. Causes SA node dysfunction occurs as a result of disorders in automaticity, conduction, or both. Sinus node fibrosis is the most common cause of SND, although medications and toxins as well as systemic diseases that involve the heart can also be responsible for abnormal SA node function and result in SND. (See 'Etiology' above.) Natural history The natural history of SND caused by sinus node fibrosis typically involves intermittent but progressive cardiac rhythm disorders, which have been associated with higher rates of other cardiovascular events and higher mortality. There is a tendency for the rhythm disturbances associated with SND to evolve over time, along with a higher likelihood of thromboembolic events and other cardiovascular events. (See 'Natural history' above.) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 10/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Keith A, Flack M. The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. J Anat Physiol 1907; 41:172. 2. Bleeker WK, Mackaay AJ, Masson-P vet M, et al. Functional and morphological organization of the rabbit sinus node. Circ Res 1980; 46:11. 3. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47:658. 4. Boyett MR, Dobrzynski H, Lancaster MK, et al. Sophisticated architecture is required for the sinoatrial node to perform its normal pacemaker function. 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Topic 940 Version 35.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 15/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate GRAPHICS Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 16/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Contributor Disclosures