The sinoatrial (SA) node is innervated by the parasympathetic and the sympathetic nervous systems; 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, wheras sympathetic nerve input, as well as the adrenal medullary release of catecholamines, increases the sinus rate during exercise and stress.
Sinus node dysfunction (SND) is often secondary to senescence of the SA node and surrounding atrial myocardium. Medications may also contribute to, and can often unmask, subclinical SA dysfunction.
The epidemiology of SND is difficult to study, but patients with symptomatic SND are generally older (in the seventh or eighth decade of life) with frequent comorbid diseases.SND occurs as a result of disorders in automaticity, conduction, or both. SN fibrosis is the most common cause of SND.
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.
The treatment of sinus bradycardia and pauses starts with investigating/identifying any reversible causes, of which the most common are medications. Permanent pacemakers are often implanted in symptomatic patients with SND.
Sinus node dysfunction (SND) is characterized by dysfunction of the sinoatrial (SA) node that is often associated with senescence of the node and surrounding atrial myocardium. [1, 2] Although the term "sick sinus syndrome" (SSS) was first used to describe the sluggish return of SA nodal activity following electrical cardioversion, it is now commonly used to describe the inability of the SA node to generate a heart rate commensurate with the physiologic needs of an individual.
SA nodal exit block
Inadequate heart rate response to physiologic demands during activity (chronotropic incompetence)
When SND is associated with symptoms such as dizziness or syncope, SSS is a more clinically representative term. However, SND and SSS are often used interchangeably.
The sinus node (SN) is a subepicardial structure normally located in the right atrial wall near the superior vena cava entrance on the upper end of the sulcus terminalis. It is formed by a cluster of cells capable of spontaneous depolarization. Normally, these pacemaker cells depolarize at faster rates than any other latent cardiac pacemaker cell inside the heart. Therefore, a healthy SN directs the rate at which the heart beats. Electrical impulses generated in the SN must then be conducted outside the SN in order to depolarize the rest of the heart.
SN activity is regulated by the autonomic nervous system. For example, parasympathetic stimulation causes sinus bradycardia, sinus pauses, or sinoatrial exit block. These actions decrease SN automaticity, thereby decreasing the heart rate.
Sympathetic stimulation, however, increases the slope of phase 4 spontaneous depolarizations. This increases the automaticity of the SN, thereby increasing the heart rate. Blood supply to the SN is provided by the right coronary artery in most cases.
Sinus node dysfunction (SND) involves abnormalities in SN impulse formation and propagation, which are often accompanied by similar abnormalities in the atrium and in the conduction system of the heart. Together, these abnormalities may result in inappropriately slow ventricular rates and long pauses at rest or during various stresses. When SND is mild, patients are usually asymptomatic. As SND becomes more severe, patients may develop symptoms due to organ hypoperfusion and pulse irregularity. Such symptoms include the following:
Heart failure symptoms and palpitations
Natural history of SND
The natural history of SND typically involves intermittent and/or 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.
For many patients with SND, there are variable, and often long, periods of normal SN function. However, once present, in due course, SND progresses in most patients, accompanied by a greater likelihood of developing atrial tachyarrhythmias. However, the time course of disease progression is difficult to predict; hence, most patients with symptomatic SND are treated earlier in an attempt to alleviate symptoms.
As noted, SND usually progresses over time. In a study of 52 patients with SND and sinus bradycardia associated with sinoatrial (SA) block or sinus arrest, it took an average of 13 years (range, 7-29 years) for progression to total sinus arrest and an escape rhythm. 
The incidence of atrial arrhythmias and conduction disturbances occurs more frequently over time, which may be due in part to a progressive pathologic process that affects the entire atrium and other parts of the heart. In a study comprising 213 patients with a history of symptomatic SND who were treated with atrial pacing and followed for a median of 5 years, 7% developed atrial fibrillation and 8.5% developed high-grade atrioventricular block. 
Patients with SND, especially those with tachycardia-bradycardia, are at higher risk for thromboembolic events—even after pacemaker implantation. Asymptomatic episodes of atrial fibrillation resulting in thromboembolic events may contribute to cardiovascular events following pacemaker implantation.
Sinus node dysfunction (SND) occurs as a result of disorders in automaticity, conduction, or both of the sinoatrial (SA) node.  Local cardiac pathology, systemic diseases that involve the heart, and medications or toxins can all be responsible for abnormal SA node function and may result in SND. [8, 9, 10]
Abnormal automaticity (sinus arrest)
Abnormal automaticity, or sinus arrest, refers to a failure of sinus impulse generation. Abnormal conduction, or SA 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 or infiltrative myocardial processes.
Sinus node degeneration resulting in fibrosis, calcification, or amyloidosis
The most common cause of SND/sick sinus syndrome (SSS) is the replacement of sinus node (SN) 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. The transitional junction between the SN and atrial tissue may also be involved, and there may be degeneration of the nerve ganglia.
Medications and toxins
A number of medications and toxins can depress sinus node function, resulting in symptoms and electrocardiographic (ECG) changes consistent with SND. The most commonly used prescription medications that alter myocardial conduction and may potentially result in SND include:
Non-dihydropyridine calcium channel blockers (eg, diltiazem, verapamil)
Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) used in the treatment of Alzheimer disease
Sympatholytic drugs (eg, methyldopa, clonidine)
Poisoning by grayanotoxin, which is produced by some plants (eg, Rhododendron species) and found in certain varieties of honey, has been associated with depressed SN function
Childhood and familial diseases
Although rare in children, when SND presents in this population, it is most often seen in those with congenital and acquired heart disease, particularly after corrective cardiac surgery. Familial SSS is rare, with mutations in the cardiac sodium channel gene SCN5A [11, 12] and the HCN4 gene  (thought to contribute to the SN pacemaker current) responsible for some familial cases.
In a series of 30 children and young adults (age range: 3 days to 25 years) with SND, 22 had significant cardiac disease, and 13 developed SND after cardiac surgery.  The causes of SND were inappropriate sinus bradycardia, sinus arrest, and SA exit block. 
In a study of 10 children from 7 families with familial SSS, in which genomic DNA encoding the alpha subunit of the cardiac sodium channel was screened for mutations, compound heterozygous nucleotide changes were identified in 5 children from 3 families, but not in any of over 75 control subjects. 
In a series of 38 patients with clinical evidence of Brugada syndrome, 4 had SCN5A mutations. Of these 4 patients, 3 had SND with multiple affected family members. However, mutations in SCN5A are not pathognomonic for SND, 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). 
The SA node may be affected by infiltrative disease, such as amyloidosis, sarcoidosis, scleroderma, hemochromatosis, and rarely tumor.
Rheumatic fever, pericarditis, diphtheria, Chagas disease, and other disorders may depress SA nodal function.
SA nodal artery disease
The SN is perfused by branches of the right coronary artery in 55-60% of cases, and by the left circumflex artery in the remaining 40-45%. Stenosis of the SA nodal artery may occur due to atherosclerosis or inflammatory processes, resulting in ischemia; the latter may also occur with embolic events. Approximately 5% of patients with myocardial infarction (MI) (usually inferior wall MI) show SND that tends to be reversible. 
Mutations in HCN4 can produce both symptomatic and asymptomatic SND, as illustrated by numerous reports of sinus bradycardia in family members with such mutations. 
Cardiac trauma may affect either the SA node directly or its blood supply.
Other disorders that can cause SND include hypothyroidism, hypothermia, hypoxia, and muscular dystrophies. Some infections (eg, leptospirosis, trichinosis, Salmonella typhi infection) are associated with relative sinus bradycardia; however, these usually do not result in permanent SND. 
In addition, SND is seen in children with congenital and acquired heart disease, particularly after corrective surgery. The cause of SND in these children is likely related to the underlying structural heart disease and surgical trauma to the SN and/or SN artery.
Emery-Dreifuss muscular dystrophy is an X-linked muscle disorder associated with SND and AV conduction defects. If AV conduction defects are present, sudden cardiac death may result unless the condition is treated with permanent pacing. Males and females may be affected with equal frequency.
Surgical causes, especially from operations involving the right atrium
Gradual loss of sinus rhythm occurs after the Mustard, Senning, and all varieties of the Fontan operation. This is thought to be secondary to direct injury to the SN during surgery and also due to later, chronic hemodynamic abnormalities. Paroxysmal atrial tachycardias are frequently associated with SND, and loss of sinus rhythm appears to increase the risk of sudden death. Patients with transposition of the great arteries now undergo the arterial switch operation, which avoids the extensive atrial suture lines that lead to SN damage.
SND was described in 15% of patients who had undergone the Ross operation for aortic valve disease or complex left-sided heart disease, 2.6 to 11 years earlier.  Other arrhythmias, such as complete AV block and ventricular tachycardia, were present as well after the Ross operation.
When repairing ASDs, especially sinus venosus ASDs, SND frequently occurs because of the proximity of the defect with SN tissue.
Other surgically related causes of SND include the following:
Patients who have undergone surgery for endocardial cushion defects (ECDs) may later develop SND
SND may be caused by a Blalock-Hanlon atrial septectomy
Cannulation of the superior vena cava (SVC), usually performed for cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO), may damage SN tissue
Ischemic cardiac arrest may cause SND
Rheumatic fever is another cause of SND. Such dysfunction may also result from central nervous system (CNS) disease, which is usually secondary to increased intracranial pressure with a subsequent increase in the parasympathetic tone.
Endocrine-metabolic diseases (hypothyroidism and hypothermia) and electrolyte imbalances (hypokalemia and hypocalcemia) are other conditions that can contribute to SND.
A study by Sunaga et al involving 202 subjects indicated that in patients with persistent AF, those with low-amplitude fibrillatory waves and a large left atrial volume index are at an increased risk for the appearance of concealed SND after catheter ablation has restored sinus rhythm. 
The epidemiology of sinus node dysfunction (SND) is difficult to study, given its nature and varying manifestations, including nonspecific symptoms and electrocardiographic (ECG) findings. It is estimated that the incidence of SND in the United States is approximately 1 in 600 cardiac patients older than 65 years.  Due to its relationship with advanced age, SND is more prevalent in countries where citizens have a longer life expectancy.
Symptomatic patients are generally older, in seventh or eighth decade of life, with frequent comorbidities. Only a few epidemiologic studies have been published.
A pooled analysis of 20,572 patients from 2 large epidemiology studies (the Atherosclerosis Risk in Communities [ARIC] and Cardiovascular Health Study [CHS] trials) who were followed for an average of 17 years, 291 incident cases of sick sinus syndrome (SSS) were noted, yielding an incidence rate of 0.8 cases per 1000 person-years.  Although several variables were associated with the development of SSS (eg, higher body mass index, hypertension, prior cardiovascular event), advancing age was the most significant risk factor for SSS (hazard ratio 1.73 for each additional 5 years of age (95% confidence interval: 1.47-2.05). 
In major trials of pacing in this disorder, the median or mean age of the patients with SND was 73 to 76 years. Men and women appear equally affected and, although less common, SND/SSS can also occur in younger adults and children. [21, 22, 23]
The prognosis of patients with sinus node dysfunction (SND) is dependent on the underlying associated condition. The incidence of sudden cardiac death in patients with SND is low.  Pacemaker therapy does not appear to affect survival in patients with SND. [24, 25, 26]
Patients with tachy-brady syndrome have a worse prognosis than do patients with isolated SND. The overall prognosis in patients with SND and additional systemic ventricular dysfunction (eg, numerous postoperative Mustard and Fontan patients) depends on their underlying ventricular dysfunction or degree of congestive heart failure (CHF).
In patients who have undergone a Fontan surgery and developed SND, endocardial atrial leads can be implanted relatively safely and can permit low-energy thresholds for as long as 5 years after implantation. 
Morbidity and mortality
The relationship between SND and mortality is difficult to clearly understand, as many individuals with SND have preexisting comorbidities (eg, hypertension, diabetes mellitus, atrial fibrillation) that are known to increase all-cause mortality. 
The complications of SND include the following:
Sudden cardiac death
Thromboembolic events, including stroke
About 50% of patients with SND develop tachy-brady syndrome over a lifetime; such patients have a higher risk of stroke and death. However, the incidence of sudden death owing directly to SND is extremely low. 
Given the complex nature of many underlying associated conditions with sinus node dysfunction (SND), especially in the pediatric population, patients and family members need to be duly educated on the relevant issues, such as recognition of sudden cardiac death (SCD) and learning cardiopulmonary resuscitation (CPR) techniques, scheduling and attending pacemaker and intracardiac defibrillator (ICD) follow-ups, etc.
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