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Sinus node dysfunction
Anatomy and physiology of the sinus node
Anatomy
The sinus node is a crescent-shaped, subepicardial specialized muscular structure located posterolaterally in the right atrial (RA) free wall. The sinus node lies within the epicardial groove of the sulcus terminalis, at the junction of the anterior trabeculated RA appendage with the posterior smooth-walled venous component ( Fig. 9.1 ). The endocardial aspect of the sulcus terminalis is marked by the crista terminalis. The sinus node is a tadpole-shaped structure with a head, central body, and tail with nodal extensions representing multiple limbs. The head and proximal body portion of the node usually is located subepicardially beneath the fatty tissues at the junction of the superior vena cava (SVC) and the RA appendage, whereas the remaining nodal body and tail portions penetrate inferiorly and obliquely into the musculature of crista terminalis to end subendocardially almost to the inferior vena cava. In adults, the sinus node measures 8 to 22 mm long and 2 to 3 mm wide and thick. ,
Histology
The sinus node appears to be a distributed complex of weakly coupled, heterogeneous cells, including mesh-like nests of densely packed specialized myocytes (the principal pacemaker cell) as well as nonpacemaker cells embedded in a dense supporting connective matrix ( Fig. 9.1 ).
Within the sinus node, pacemaker cells (referred to as P cells because of their relatively pale appearance on electron micrography) vary by size, shape, and electrophysiological (EP) properties and may be divided into three major classes: (1) elongated spindle-shaped cells , which are spindle shaped but with long cell dimension (extending up to 80 μm in length) and can be multinucleated; (2) spindle cells , which have a have a faintly striated spindle-shaped cell body, similar shape to that of elongated spindle cells but are shorter in length (extending up to 40 μm) and are predominantly mononucleated; and (3) spider cells , which have irregularly shaped branches with blunt ends.
The nodal margins can be discrete, with fibrous separation from the surrounding atrial myocardium, or interdigitating with the atrium through a transitional zone. Commonly, prongs of nodal and transitional cells extend from the nodal central area toward the perinodal region and atrial myocardium. The transitional zone at the node periphery exhibits mosaic features with gradation of cellular structural and membrane EP properties from the primary pacemaker cells to atrial myocardium. Compared to atrial working myocytes, nodal cells are smaller and have fewer myofilaments, poorly developed sarcomeres and sarcoplasmic reticulum, lower cell-to-cell electrical coupling, and higher density of nuclei. A gradient in myofilament content is observed from center to periphery. ,
Physiology
The sinus node is the dominant pacemaker of the heart. Its pacemaker function is determined by its reduced maximum diastolic membrane potential and steep phase 4 spontaneous depolarization. The molecular mechanisms of the pacemaker function of the sinus node are discussed in detail in Chapters 2 and 4 .
Evidence suggests that the pacemaker activity is not confined to a single cell in the sinus node; rather, nodal cells function as electrically coupled oscillators that discharge synchronously because of mutual entrainment. It is possible that sinus rhythm results from impulses originating at widely separated sites, with two or three individual wavefronts merging to form a single, widely disseminated wavefront. Mapping of electrograms in and around the node has disclosed a multicentric initiation of activation with irregular propagation to the atrial myocardium.
Current models involve the concept of a “pacemaker hierarchy” within the sinus node, with cells that depolarize at a higher frequency generating faster heart rates located at the superior compartments (head) of the sinus node, whereas slower-firing cells are located at the inferior part (tail). The hierarchy mediates heart rate changes (in response to physiological stimuli) via a dynamic craniocaudal shift in the “leading pacemaker” site. Sympathetic stimulation, for example, shifts the leading pacemaker site superiorly, resulting in an increase in heart rate.
On the other hand, in vitro studies using optical mapping have found that intranodal activation was unicentric during sinus rhythm; however, atrial overdrive pacing resulted in shifts in the site of atrial breakthroughs, multifocal breakthroughs, sinus slowing, and slowing of sinus node conduction velocity. In a recent report using simultaneous intraoperative endocardial–epicardial electroanatomical mapping of the sinus node in patients with structural heart disease, all sinus origins were unicentric at baseline, with predominantly matching exit site on epicardium and endocardium; after overdrive suppression, there was a tendency to a caudal shift in exits, with multicentric endocardial–epicardial breakthroughs and asymmetrical wavefront propagation.
The sinus node is insulated electrically from the surrounding atrial myocytes, except at a limited number of preferential exit sites that allow transmission of sinus impulses to atrial myocardium. Anatomical insulation (provided by substantial interstitial tissue, fat, and blood vessels) and functional barriers (poor electrical coupling between adjacent cells due to reduced expression of connexins) are critical for protecting the small cluster of pacemaker cells in the sinus node from the hyperpolarizing influence of the surrounding atrial myocardium and enabling “source” nodal cells to overcome the source-sink mismatch and depolarize the much larger surrounding atrial tissue (“sink”). ,
Blood supply
The blood supply to the sinus node region predominantly comes from a large central artery, the sinus nodal artery, which is a branch of the right coronary artery in 55% to 60% of patients, and from the circumflex artery in 40% to 45%. The sinus nodal artery typically passes centrally through the length of the sinus body, and it is disproportionately large, which is considered physiologically important in that its perfusion pressure can affect the sinus rate. Distention of the artery slows the sinus rate, whereas collapse causes an increase in sinus rate.
Innervation
The sinus node is densely innervated with postganglionic adrenergic and cholinergic nerve terminals (threefold greater density of beta-adrenergic and muscarinic cholinergic receptors than adjacent atrial tissue). Neural and hormonal factors influence both the rate of spontaneous depolarization in pacemaker cells (likely via craniocaudal shift in the principal pacemaker site within the sinus node region), and the point of exit from the sinus node complex to the atrium. These changes often are associated with subtle changes in P wave morphology. The right vagus nerve predominantly affects sinus node function.
Enhanced vagal activity can produce sinus bradycardia, sinus arrest, and sinoatrial exit block, whereas increased sympathetic activity can increase the sinus rate and reverse sinus arrest and sinoatrial exit block. Sinus node responses to brief vagal bursts begin after a short latency and dissipate quickly. In contrast, responses to sympathetic stimulation begin and dissipate slowly. The rapid onset and offset of responses to vagal stimulation allow dynamic beat-to-beat vagal modulation of the heart rate, whereas the slow temporal response to sympathetic stimulation precludes any beat-to-beat regulation by sympathetic activity.
Periodic vagal bursting (as may occur each time a systolic pressure wave arrives at the baroreceptor regions in the aortic and carotid sinuses) induces phasic changes in the sinus cycle length (CL) and can entrain the sinus node to discharge faster or slower at periods identical to those of the vagal burst. Because the peak vagal effects on sinus rate and atrioventricular node (AVN) conduction occur at different times in the cardiac cycle, a brief vagal burst can slow the sinus rate without affecting AVN conduction or can prolong AVN conduction time and not slow the sinus rate.
Pathophysiology of sinus node dysfunction
Sinus node dysfunction (SND) refers to a wide range of abnormalities involving sinus node and atrial impulse generation and propagation, leading to the inability of the sinus node to generate heart rates that are appropriate for the physiological needs. Causes of SND can be classified as intrinsic (secondary to a pathological condition involving the sinus node proper, Table 9.1 ) or extrinsic (caused by depression of sinus node function by external factors such as drugs or autonomic influences, Table 9.2 ).
TABLE 9.1
Causes of Intrinsic Sinus Node Dysfunction
| Idiopathic degenerative disorder (most common) |
| Ischemic heart disease |
| Genetic defects: mutations in SCN5A , HCN4 , GJA5 , ANK2 , and EMD genes |
| Atrial tachyarrhythmias |
| Hypertensive heart disease |
| Cardiomyopathy |
| Congenital heart disease: sinus venosus atrial septal defect, left atrial isomerism |
| Surgical trauma: Mustard, Senning, Glenn, and Fontan procedures, valve replacement, maze procedure |
| Cardiac transplant |
| Inflammatory diseases: rheumatic fever, pericarditis, myocarditis |
| Infectious causes: Lyme disease, legionella, Q fever, typhoid, psittacosis, malaria, leptospirosis, Chagas disease |
| Collagen vascular disease: systemic lupus, scleroderma |
| Infiltrative diseases: amyloidosis, sarcoidosis, hemochromatosis, tumors |
| Neuromuscular disorders: Friedreich’s ataxia, myotonic dystrophy, Emery-Dreifuss muscular dystrophy |
TABLE 9.2
Causes of Extrinsic Sinus Node Dysfunction
|
Not only the automaticity of the individual nodal cells but also architectural factors at the tissue level are essential for normal pacemaking function. Defects in sinus node architecture can disrupt the normal source-sink balance, leading to SND. Structural changes (e.g., sinus nodal cell loss and fibrosis) and alterations in the normal gradient of EP properties in the sinus node complex likely underlie slowing of pacemaking with normal aging and cardiovascular disease (e.g., atrial fibrillation [AF], heart failure). Furthermore, autonomic modulation, adenosine, ischemia, and structural remodeling can potentially lead not only to depression of sinus pacemaker function but also to complete block of conduction through all nodal conduction pathways.
Intrinsic sinus node dysfunction
Degenerative diseases
SND is generally a disease of aging, and idiopathic degenerative disease is probably the most common cause of intrinsic SND. Aging-related progressive fibrosis with cell loss and degeneration (structural remodeling) as well as EP remodeling of the sinus node (e.g., during AF) are important factors in the pathophysiology of SND. These degenerative changes are typically more diffuse, affecting surrounding atrial tissue (atrial remodeling or “atriopathy”) as well as other parts of the conduction system. The frequent lack of an effective escape rhythm in patients with SND and the long asystolic pauses are likely a manifestation of the diffuse nature of the conduction system disease.
Ischemic heart disease
Coronary artery disease is very common among SND patients. Although this can be coincidental, since both diseases tend to occur in older individuals, ischemic heart disease is thought to be responsible for as much as one-third of chronic SND. Additionally, SND (sinus bradycardia or sinus arrest) is observed in up to 15% to 25% of patients with acute myocardial infarction, most commonly in inferior and posterior infarctions.
SND after an acute myocardial infarction is usually a transient phenomenon, most commonly related to increased vagal tone, and is generally associated with other signs of vagotonia, such as AVN conduction delay, and is responsive to atropine and catecholamine stimulation. Possible mechanisms include neurological reflexes (Bezold-Jarisch reflex), coronary chemoreflexes (vagally mediated), humoral reflexes (enzymes, adenosine, potassium [K + ]), and oxygen-conserving reflex (“diving” reflex). Pain and the use of vagotonic medications, such as morphine, can potentiate vagal tone and exacerbate SND. However, infarction or ischemia of the sinus node or the surrounding atrium (e.g., secondary to proximal occlusion of the right or the circumflex coronary artery) can also cause SND, which can be more persistent.
Atrial arrhythmias
Atrial tachyarrhythmias can precipitate SND, likely secondary to sinus node remodeling. Although early studies implicated anatomical structural abnormalities in the sinus node, which suggested a fixed SND substrate, more recent evidence has implicated a functional, and potentially reversible, component involving remodeling of sinus node ion channel expression and function. This finding is supported clinically by the observation that successful catheter ablation of AF and atrial flutter can be followed by significant improvements in sinus node function. In particular, downregulation of the funny current (If) and malfunction of the calcium (Ca 2+ ) clock (characterized by reduced sarcoplasmic reticulum Ca 2+ release and downregulated ryanodine receptors in the sinus node) seem to account largely for tachycardia-induced remodeling of sinus node. The remodeled atria are associated with more caudal activation of the sinus node complex, slower conduction time along preferential pathways, and only modest shifts within the functional pacemaker complex. Endogenous adenosine recently has been implicated in the pathophysiology of SND following the termination of atrial tachyarrhythmias.
On the other hand, SND has been associated with an increased propensity for atrial tachyarrhythmias, AF in particular. The mechanism leading to AF in patients with SND is unlikely to be bradycardia dependent because AF was found to develop despite pacing in these patients. Importantly, patients with SND appear to have more widespread atrial changes beyond the sinus node, a finding indicating atrial myopathy with fibrosis and scar formation, as evidenced by increased atrial refractoriness, prolonged P wave duration, conduction slowing, electrogram fractionation, and regions of low voltage and scar. Furthermore, abnormal atrial electromechanical properties, chronic atrial stretch, and neurohormonal activation are likely contributors to SND and its related atrial myopathy. Atrial and sinus node remodeling in heart failure, hypertension, and aging have shown a caudal shift of the pacemaker complex with loss of normal multicentric pattern of activation. Similar and often more severe atrial and sinus node remodeling has been observed in patients with intermittent atrial tachyarrhythmias. The diffuse atrial myopathy potentially underlies the increased propensity to both SND and atrial arrhythmias.
Familial sinus node dysfunction
Genetic defects in ion channels and structural proteins have been shown to contribute to SND, many of which also exhibit an increased propensity to AF. Mutations in the SCN5A gene (which encodes the alpha subunit of the cardiac sodium [Na + ] channel [INa]) have been linked to sick sinus syndrome, manifesting as sinus bradycardia, sinus arrest, sinoatrial block, or a combination of these conditions, which can progress to atrial inexcitability (atrial standstill). Loss-of-function SCN5A mutations result in reduced peak INa density, hyperpolarizing shifts in the voltage dependence of steady-state channel availability, and slow recovery from inactivation. These effects likely cause reduced automaticity, decreased excitability, and conduction slowing or block of impulses generated in the sinus node to the surrounding atrial tissue. SND can also manifest concomitantly with other phenotypes that are linked to SCN5A loss-of-function mutations such as Brugada syndrome and progressive cardiac conduction disorders (Lev-Lenègre disease). ,
Heterozygous mutations in the HCN4 gene (which encodes the protein that contributes to formation of If channels) have been identified in individuals with sinus bradycardia and chronotropic incompetence. Severe bradycardia, QT prolongation, and torsades de pointes have been described in another family. HCN mutations slow channel activation kinetics or, when located in cyclic nucleotide-binding domains, abolish sensitivity of HCN channels to cyclic adenosine monophosphate, thus reducing If and the rate of diastolic depolarization.
Several other mutations have been associated with familial forms of SND, including mutations in the ANK2 gene (which encodes for ankyrin, which links the integral membrane proteins to the underlying cytoskeleton), the MYH6 gene (which encodes for atrial myosin heavy chain), and the EMD gene (which encodes the nuclear membrane protein emerin). Mutations in the GJA5 gene (which encodes for connexin 40, a gap junction protein) have been associated with individuals with atrial standstill and AF. Additionally, mutations in the calsequestrin gene ( CASQ2 ), which is involved in Ca 2+ handling and is associated with catecholaminergic polymorphic ventricular tachycardia, have been linked to SND.
Congenital heart disease
Congenital heart disease, such as sinus venosus atrial septal defects, can be associated with SND, even though no surgery has been performed. Heterotaxy syndromes, particularly left atrial (LA) isomerism, can be associated with congenital absence of the sinus node.
A more common cause of SND in patients with congenital heart disease is sinus node injury caused by corrective cardiac surgery. Most commonly associated with this complication are the Mustard, Senning, Glenn, and Fontan operations, as well as repair of atrial septal defects, especially of the sinus venosus type. Surgical incisions, suture lines, and cannulation of the SVC can result in direct damage to the sinus node, its blood supply, or neural inputs. Additionally, SND may develop as a consequence of longstanding hemodynamic perturbations or the atrial arrhythmias frequently observed in this patient population.
Other causes
Cardiomyopathy and long-standing hypertension can result in SND. Orthotropic cardiac transplantation with atrial-atrial anastomosis is associated with a high incidence of SND in the donor heart (likely because of sinus nodal artery damage); this is far less likely with a caval-caval anastomosis. Musculoskeletal disorders such as myotonic dystrophy or Friedreich’s ataxia are rare causes of SND. Other causes of SND include a variety of infiltrative, infectious, and inflammatory disorders ( Table 9.1 ).
Extrinsic sinus node dysfunction
In the absence of structural abnormalities the predominant causes of SND are drug effects and autonomic influences ( Table 9.2 ).
Drugs
Drugs can alter sinus node function by direct pharmacological effects on nodal tissue or indirectly by neurally mediated effects. Drugs known to depress sinus node function include beta-blockers, calcium channel blockers (verapamil and diltiazem), digoxin, sympatholytic antihypertensive agents (e.g., clonidine), and antiarrhythmic agents.
Autonomic influences
SND can sometimes result from excessive vagal tone in individuals without intrinsic sinus node disease. Hypervagotonia can be seen in hypersensitive carotid sinus syndrome and neurocardiogenic syncope. Surges in vagal tone also can occur during Valsalva maneuvers, endotracheal intubation, vomiting, and coughing. Sinus slowing in this setting is characteristically paroxysmal and may be associated with evidence of atrioventricular (AV) conduction delay, secondary to effects of the enhanced vagal tone on both the sinus node and AVN ( Fig. 9.2 ).
Significant sinus bradycardia is very common in highly conditioned athletes and is usually correlated to type and intensity of training. Respiratory sinus arrhythmia, wandering pacemaker, junctional bradycardia, first-degree AV block, and Wenckebach second-degree AV block are also more common in this population. These changes, at least in the initial stages, have been attributed to increased vagal tone. However, over time, endurance training does lead to intrinsic changes in the sinus node and the cardiac conduction system potentially related to dilatation and hypertrophy of the athlete’s heart. Deconditioning of athletes can sometimes help prevent symptomatic bradyarrhythmias; however, it is not uncommon that slow heart rates persist for many years after training has stopped.
Other causes
Obstructive sleep apnea can be associated with significant sinus bradycardia and long sinus pauses during apneic episodes. Less common extrinsic causes of SND include electrolyte abnormalities such as hyperkalemia, hypothermia, increased intracranial pressure (the Cushing response), hypoxia, hypercapnia, hypothyroidism, and obstructive jaundice.
Clinical presentation
Patients with SND often are asymptomatic or have symptoms that are mild and nonspecific, and the intermittent nature of these symptoms makes documentation of the associated arrhythmia difficult at times. Additionally, because most patients with SND are elderly, symptoms of the disease can erroneously be attributed to the aging process or other comorbidities.
Symptoms of SND include paroxysmal dizziness, presyncope, or syncope, which are predominantly related to prolonged sinus pauses. Episodes of syncope are often unheralded and can manifest in older patients as repeated falls. The highest incidence of syncope associated with SND probably occurs in patients with tachycardia-bradycardia syndrome, in whom syncope typically occurs secondary to a long sinus pause following cessation of the supraventricular tachyarrhythmia (usually AF). Occasionally, a stroke can be the first manifestation of SND in patients presenting with paroxysmal AF and thromboembolism.
Patients with sinus bradycardia or chronotropic incompetence often present with decreased exercise capacity or fatigue. Chronotropic incompetence is estimated to be present in 20% to 60% of patients with SND. Other symptoms include irritability, nocturnal wakefulness, memory loss, lightheadedness, and lethargy. More subtle symptoms include mild digestive disturbances, periodic oliguria or edema, and mild intermittent dyspnea. Additionally, symptoms caused by the worsening of conditions such as congestive heart failure and angina pectoris can be precipitated by SND.
Epidemiology and natural history
SND is largely a disease of the elderly and its incidence increases exponentially with age. Most SND patients are in their seventh or eighth decade of life and have frequent comorbid diseases. SND in young patients is often related to underlying heart disease. Although the exact incidence of SND is difficult to determine, it has been estimated at 0.8 per 1000 person-years. SND likely accounts for 50% or more of permanent pacemaker placements in the United States. With the aging population, it is projected that the annual incidence of SND cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060 ( Fig. 9.3 ). The most significant risk factor for SND is advancing age. Other risk factors include greater body mass index, longer QRS duration, hypertension, right bundle branch block, and cardiovascular disease.
The natural history of SND can be variable, but slow progression (over 10–30 years) is expected. The prognosis largely depends on the type of SND and the presence and severity of the underlying heart disease. SND does not appear to affect survival whether untreated or treated with pacemaker therapy; mortality in patients with SND is primarily determined by underlying heart disease. The worst prognosis is associated with the tachycardia-bradycardia syndrome (mostly because of the risk for thromboembolic complications), whereas sinus bradycardia is much more benign.
Up to 50% of SND patients experience episodes of AF over a lifetime. The incidence of new-onset AF in patients with SND is about 5.2% per year. Atrial-based pacing (AAI or DDD) in SND patients is associated with a 20% reduction in risk of AF and stroke as compared with single-chamber ventricular pacing (VVI).
The incidence of advanced AV conduction system disease in patients with SND is relatively low (5%–10%) and, when present, its progression is slow. At the time of diagnosis of SND, approximately 17% of the patients have some degree of AV conduction system disease (PR interval longer than 240 milliseconds, bundle branch block, His-ventricular (HV) interval prolongation, AV Wenckebach rate less than 120 beats/min, or second- or third-degree AV block). New AV conduction abnormalities develop at a rate of approximately 7% per year in patients with baseline bundle branch block or bifascicular block, but much less frequently (0.6%–1.8% per year) in those without any evidence of AV or intraventricular conduction abnormalities. The incidence of advanced AV block during long-term follow-up is low (approximately 1% per year).
Diagnostic evaluation
Generally, the noninvasive methods of ECG monitoring, exercise testing, and autonomic testing are used first. However, if symptoms are infrequent and noninvasive evaluation is unrevealing, invasive EP testing can be considered.
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