DOENÇA DO NÓ SINUSAL

NTRODUCTION — Sick sinus syndrome (SSS) is characterized by dysfunction of the sinoatrial (SA) node that is often secondary to senescence of the SA node and surrounding atrial myocardium. The term "sick sinus syndrome" was first used in 1967 to describe the sluggish return of SA nodal activity in some patients following electrical electroversion and was later applied to a clinical syndrome characterized by chronic SA node dysfunction, a sluggish or absent SA nodal pacemaker after electrical electroversion, frequently depressed escape pacemakers, and/or atrioventricular (AV) nodal conduction disturbances [1-3]. These abnormalities can result in profound sinus bradycardia, sinus pauses, sinus arrest, SA nodal exit block, and inappropriate responses to physiological demands during exercise or stress. SSS can also be accompanied by AV nodal conduction disturbances and by paroxysmal supraventricular tachycardia as part of the tachycardia-bradycardia syndrome. (See 'Tachycardia-bradycardia syndrome' below.)

The initial clues to the diagnosis of SSS are often clinical, as patients may present with symptoms of lightheadedness, presyncope, syncope, dyspnea on exertion, angina, and/or palpitations. A routine electrocardiogram (ECG) may provide further information in such patients. However, the symptoms are nonspecific and the ECG changes may not be diagnostic, thereby necessitating either noninvasive or electrophysiologic studies to confirm the diagnosis. The diagnostic evaluation should also include a search for remediable causes of SA nodal depression, such as drugs (eg, beta blockers, calcium channel blockers, digoxin), ischemia, and autonomic imbalance, prior to initiation of treatment. (See "Diagnosis and evaluation of the sick sinus syndrome".)

Treatment of SSS is directed at symptoms. Control of symptomatic SSS usually involves the implantation of a pacemaker. Medications may be helpful in select cases, but are not as effective as permanent pacing. (See "Treatment of the sick sinus syndrome".)

The clinical manifestations, causes, and natural history of sick sinus syndrome will be reviewed here. The noninvasive and electrophysiologic evaluation of SSS, the treatment of SSS, and the appropriate timing of referral to a specialist are discussed in detail separately. (See "Diagnosis and evaluation of the sick sinus syndrome" and "Treatment of the sick sinus syndrome" and "Arrhythmia management for the primary care clinician", section on 'Referral to a specialist'.)

CLINICAL CHARACTERISTICS — Patients with symptomatic SSS are primarily older, with frequent comorbid diseases and a high mortality rate. In three major trials of pacing in this disorder, the median or mean age was 73 to 76 years [4-6]. Although less common, SSS also occurs in younger adults and children. (See 'Childhood and familial disease' below.)

The sick sinus syndrome is defined by electrocardiographic criteria, since clinical signs and symptoms may be absent or quite varied. Importantly, sinus bradycardia may not always denote the presence of sick sinus syndrome. As an example, highly conditioned athletes often have a pronounced increase in vagal tone at rest with heart rates well below 60 beats per minute. Symptoms of lightheadedness, presyncope, or syncope are often the reason that the patient seeks medical attention. Other manifestations include increasing dyspnea on exertion, worsening angina, and, in patients with alternating bradycardia and tachycardia, palpitations and other symptoms associated with a rapid heart rate. (See 'Tachycardia-bradycardia syndrome' below.)

The characteristics of the sick sinus syndrome include:

Chronic, inappropriate, and often severe bradycardia [1,3].
Sinus pauses, arrest, and sinoatrial exit block with, and often without, appropriate atrial and junctional escape rhythms. The failure of escape pacemakers may lead to symptomatic bradycardia [1,3]. (See "Sinoatrial nodal pause, arrest, and exit block".)
Alternating bradycardia and atrial tachyarrhythmias in over 50 percent of cases [1,4,7-11]. AF is most common, but atrial flutter and paroxysmal supraventricular tachycardias may also occur.
In the absence of drugs that slow AV conduction, AF with a slow ventricular response reflects associated dysfunction of the AV node. Spontaneous reversion or DC cardioversion will typically produce a slow and often unstable sinus rhythm [1-3].
Atrial arrhythmias seem to develop slowly over time [12,13], possibly the result of a progressive pathological process that affects the SA node and the atrium [14].
The electrocardiographic manifestations may occur with or without symptoms.
An example of the ECG findings that may be seen is shown in the accompanying figure (waveform 1). The patient initially has coarse atrial fibrillation with a slow ventricular response in the absence of drugs that slow AV nodal conduction. When atrial fibrillation spontaneously terminates, there is a delay before normal sinus activity resumes. The patient was symptomatic during these changes in rhythm.

Evaluation — The diagnosis of the sick sinus syndrome is made from the ECG and the history. There are, however, a variety of noninvasive and invasive tests that permit more complete evaluation of SA nodal function. (See "Diagnosis and evaluation of the sick sinus syndrome".)

ETIOLOGY

Tachycardia-bradycardia syndrome — Alternating bradycardia and atrial tachyarrhythmias occur in over 50 percent of cases of SSS [1,4,7-11]. AF is the most common atrial tachyarrhythmia and prolonged symptomatic pauses can occur after termination of AF that may result from tachycardia-mediated remodeling of the sinus node [15]; such remodeling has also been demonstrated with atrial flutter [16]. In at least some patients with tachy-brady syndrome associated with paroxysmal AF, radiofrequency ablation to prevent recurrence of AF can reverse sinus node remodeling as evidenced by a reduction in sinus node recovery time, increases in the mean and maximal heart rates, and no symptoms attributable to bradycardia or sinus pauses on ambulatory monitoring, thereby avoiding the need for pacemaker implantation [17].

Sinus node fibrosis — The most common cause of sick sinus syndrome 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 including the AV node [10,14,18]. The transitional junction between the sinus node and atrial tissue may also be involved, and there may be degeneration of nerve ganglia.

Disease of the SA nodal artery — The SA nodal artery may be narrowed by atherosclerosis, inflammatory processes, or even emboli [18-21]. Some investigators suggest that coronary artery disease is a major cause [19], while others have found the SA artery to be patent in the sick sinus syndrome [22-24]. As an example, approximately 5 percent of patients with myocardial infarction, usually inferior, show sinus node dysfunction that tends to be reversible [25-27]. Furthermore, a correlative study of coronary artery anatomy and electrophysiologic testing found a correlation between the frequency of an abnormal intrinsic heart rate and the degree of narrowing of the SA nodal artery in patients with an acute myocardial infarction: the intrinsic heart rate was abnormal in almost all patients with more than a 75 percent narrowing, but only about 33 percent with less than 50 percent narrowing [28].

Other — The sick sinus syndrome is less often due to a variety of other disorders:

Infiltrative diseases – The SA node may be affected by infiltrative disease, such as amyloidosis, scleroderma [19], hemochromatosis, and rarely tumor.
Epicardial and pericardial disease – The SA node is located near the epicardium. As a result, diseases that involved the epicardium or pericardium (such as pericarditis and tumors) may affect the SA nodal function [18,19,22,29,30].
Inflammatory diseases – Rheumatic fever, pericarditis, diphtheria, Chagas disease, Lyme disease, and other disorders may depress SA nodal function.
Primary SA node dysfunction – The sinus node disease may be intrinsic, induced by autonomic abnormalities, or both [31-34] (see below).
Drugs and toxins – A number of drugs and toxins can depress sinus node function. Drugs associated with sinus node dysfunction include parasympathomimetic agents, sympatholytic drugs (reserpine, guanethidine, methyldopa, clonidine, beta blockers), cimetidine, digitalis, calcium channel blockers, amiodarone and other antiarrhythmic drugs, and lithium [35-42]. 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 [43].
Trauma – Cardiac trauma during surgery may affect either the SA node directly or its blood supply.
Miscellaneous – Other disorders that can induce the sick sinus syndrome include hypothyroidism, hypothermia, hypoxia, and muscular dystrophies. Some infections (eg, leptospirosis, trichinosis, and Salmonella typhosa) are associated with relative sinus bradycardia, but permanent sick sinus syndrome has not followed these [44-47].
Intrinsic versus extrinsic dysfunction — Sinus node dysfunction is due with roughly equal frequency to intrinsic disease of the sinus node and to extrinsic autonomic influences [31-34]. The extrinsic type is more commonly seen in younger patients, often without evident organic heart disease. Both increased vagal tone and perhaps a deficiency in atrial cholinesterase, which leads to an abundance of acetylcholine for release in tissues, may be important in this setting.

Another potential cause, particularly in patients with primary or Chagasic sinus node dysfunction, is circulating anti-M2-cholinergic receptor antibodies [48]. These antibodies stimulate cholinergic receptors, decreasing chronotropism.

Childhood and familial disease — The sick sinus syndrome in children is seen with congenital and acquired heart disease, particularly after corrective cardiac surgery [49-52]. In a series of 30 children and young adults, 22 had significant cardiac disease, and sinus node dysfunction developed after cardiac surgery in 13 [49]. The causes of sinus node dysfunction were inappropriate sinus bradycardia, sinus arrest, and sinoatrial exit block.

SCN5A mutations — Familial sick sinus syndrome is rare [53-59]. Mutations in the cardiac sodium channel gene SCN5A may be responsible for some familial cases:

In a study of 10 children from seven families with familial sick sinus syndrome, genomic DNA encoding the alpha subunit of the cardiac sodium channel was screened for mutations [53]. 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 [56]. Three of these patients had SSS with multiple affected family members.
Mutations in SCN5A are not pathognomonic for sinus node disease. In fact, 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. (See "Brugada syndrome" and "Genetics of congenital and acquired long QT syndrome" and "Etiology of atrioventricular block" and "Genetics of dilated cardiomyopathy".)

HCN4 mutations — The HCN4 gene codes for the alpha subunit of a hyperpolarization-activated cyclic nucleotide-gated cation channel, thought to contribute to the pacemaker current in the sinus node.

Mutations in HCN4 can produce both symptomatic and asymptomatic sinus node dysfunction, as illustrated by the following:

Two patients with idiopathic sinus node dysfunction have been reported with a heterozygous mutation of the HCN4 gene [57,58].
A mutation of the HCN4 gene was identified in 15 members of a single family with asymptomatic sinus bradycardia [59]. Compared to 12 unaffected family members, those with the HCN4 mutation had a lower resting heart rate (52 versus 73 beats/min).
Eight members of a family with asymptomatic sinus bradycardia shared a missense mutation in the HCN4 gene [60].
Although two of these families had asymptomatic bradycardia, HCN4 is one of a family of pacemaker ion channel genes, and these findings provide targets for future investigations in this area.

SUMMARY

The sick sinus syndrome (SSS) is defined by electrocardiographic criteria since clinical signs and symptoms may only manifest occasionally and may be quite varied. The electrocardiographic characteristics of the sick sinus syndrome include (see 'Clinical characteristics' above):
Chronic, inappropriate, and often severe bradycardia.
Sinus pauses, arrest, and sinoatrial exit block with, and often without, appropriate atrial and junctional escape rhythms.
Alternating bradycardia and atrial tachyarrhythmias in over 50 percent of cases, with atrial fibrillation (AF) being the most common atrial tachyarrhythmia.
In the absence of drugs that slow atrioventricular (AV) conduction, AF with a slow ventricular response reflects associated dysfunction of the AV node.
Symptoms of lightheadedness, presyncope, or syncope are often the reason that the patient seeks medical attention. Other manifestations include increasing dyspnea on exertion, worsening angina, and, in patients with alternating bradycardia and tachycardia, palpitations and other symptoms associated with a rapid heart rate. (See 'Clinical characteristics' above.)
The most common cause of SSS 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 including the AV node. In addition, blood supply to the SA may be compromised (eg, by atherosclerosis, an inflammatory processes, or embolic disease) or the SA node may be involved in other systemic illnesses (eg, infiltrative disease, malignancy, Lyme disease). (See 'Etiology' above.)
A number of drugs can depress sinus node function, including parasympathomimetic agents, sympatholytic drugs (eg, reserpine, guanethidine, methyldopa, clonidine, beta blockers), cimetidine, digitalis, calcium channel blockers, lithium, amiodarone and other antiarrhythmic drugs. (See 'Other' above.)
While SSS is more often seen in adults, it has been described in children with congenital and acquired heart disease, particularly after corrective cardiac surgery. In addition, rare familial cases of SSS associated with specific gene mutations have been reported. (See 'Childhood and familial disease' above.)
There are variable and often long periods of normal sinus node function. However, sinus node dysfunction eventually progresses in most patients, with the majority ultimately requiring implantation of a permanent pacemaker. (See 'Natural history' above.)