Sinus Node Dysfunction

Practice Essentials

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.

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Background

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.

A conglomeration of electrocardiogram (ECG) abnormalities represent manifestation of SND, including^{[1, 3, 4]} :

• Sinus bradycardia
• Sinus pause
• Sinus arrest
• SA nodal exit block
• Inadequate heart rate response to physiologic demands during activity (chronotropic incompetence)
• Supraventricular tachycardia (eg, atrial fibrillation, atrial flutter, and atrial tachycardia as part of the tachycardia-bradycardia syndrome)^{[1, 5]}

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.

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Pathophysiology

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:

• Fatigue
• Dizziness
• Confusion
• Fall
• Syncope
• Angina
• 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.^[6]

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.^[7]

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.

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Etiology

Sinus node dysfunction (SND) occurs as a result of disorders in automaticity, conduction, or both of the sinoatrial (SA) node.^[8]  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:

• Beta blockers
• Non-dihydropyridine calcium channel blockers (eg, diltiazem, verapamil)
• Digoxin
• Antiarrhythmic medications
• Ivabradine
• Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) used in the treatment of Alzheimer disease
• Parasympathomimetic agents
• Sympatholytic drugs (eg, methyldopa, clonidine)
• Lithium
• 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^[13]  (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.^[14]  The causes of SND were inappropriate sinus bradycardia, sinus arrest, and SA exit block.^[14]

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.^[11]

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).^[12]

Infiltrative diseases

The SA node may be affected by infiltrative disease, such as amyloidosis, sarcoidosis, scleroderma, 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 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.^[15]

Genetic mutations

Mutations in HCN4 can produce both symptomatic and asymptomatic SND, as illustrated by numerous reports of sinus bradycardia in family members with such mutations.^[16]

Trauma

Cardiac trauma 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, Salmonella typhi infection) are associated with relative sinus bradycardia; however, these usually do not result in permanent SND.^[17]  

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.

Sinus venosus atrial septal defect (ASD), Ebstein anomaly, and heterotaxy syndromes, particularly left atrial isomerism, can also lead to SND.

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.^[18]  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
• SND may occur after repair of partial anomalous pulmonary venous return (PAPVR) or total anomalous pulmonary venous return (TAPVR)
• 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

Other

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.^[19]

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Epidemiology

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.^[20]  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.^[2] 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).^[2]

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]}

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Prognosis

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.^[21]  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.^[27]

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.^[28]

The complications of SND include the following:

• Sudden cardiac death
• Syncope
• Thromboembolic events, including stroke
• CHF
• Atrial tachyarrhythmias

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.^[21]

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Patient Education

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.

For patient education information, see the Heart Health Center, as well as Heart Rhythm Disorders.

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History and Physical Examination

History

Most patients with sinus node dysfunction (SND) present with one or more of the following nonspecific symptoms, primarily due to bradycardia, sinus pause, and sinus arrest:

• Fatigue
• Lightheadedness
• Palpitations
• Presyncope/syncope
• Dyspnea on exertion
• Chest discomfort

Symptoms are frequently intermittent with gradual progression in frequency and severity, although some patients may present with profound, persistent symptoms. Rarely, patients with SND may be asymptomatic and identified on routine electrocardiography (ECG) or ambulatory ECG monitoring.

Patients with symptomatic SND are usually older with frequent comorbid diseases; they often seek medical attention owing to symptoms of lightheadedness, presyncope, syncope and, in patients with alternating periods of bradycardia and tachycardia, palpitations and/or other symptoms associated with a rapid heart rate.

Patients with coexisting cardiac pathologies such as valvular or ischemic heart disease may notice increasing dyspnea on exertion or worsening chest discomfort related to a lower heart rate and the resulting reduction in cardiac output. Because symptoms may be variable in nature, nonspecific and, frequently, transient, it may be challenging at times to establish this symptom-rhythm relationship. Atrial arrhythmias appear to develop slowly over time, possibly the result of a progressive pathologic process that affects the sinoatrial (SA) node and the atrium.^[29]

Prior to any testing beyond an ECG, a thorough clinical evaluation should be performed for potentially reversible causes, which include medication use (eg, beta blockers, calcium channel blockers, digoxin, antiarrhythmics), myocardial ischemia, systemic illness (eg, hypothyroidism), and autonomic imbalance.

Physical examination

The physical examination essentially demonstrates findings of the underlying condition(s). The universal feature, however, is bradycardia.

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Approach Considerations

See also the Guidelines section for recommendations from the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society for the evaluation and management of bradycardia and disorders of cardiac conduction delay.

For patients in whom sinus node dysfunction (SND) is clinically suspected but not confirmed by electrocardiography (ECG) and/or exercise stress test findings, a number of different modalities may be helpful. In most patients, ambulatory ECG monitoring for an extended period of time (typically 2-4 weeks but potentially longer) has the greatest yield and allows for correlation with symptoms. In select patients in whom the diagnosis remains uncertain, other diagnostic testing options include adenosine administration, carotid sinus massage, and invasive electrophysiologic (EP) studies. 

The introduction of the implantable loop monitor has also enhanced the diagnostic yield of the clinical evaluation if symptoms are intermittent, extending over weeks to months. 

Laboratory studies

Because hypothyroidism and electrolyte imbalances can contribute to SND, thyroid function testing and serum electrolyte testing (Na⁺, K⁺, Ca²⁺) can be useful. Infiltrative cardiomyopathies (eg, amyloid, sarcoid) can present with evidence of diffuse conduction system disease, but screening is typically reserved for patients in whom specific clinical factors suggest the diagnosis.

Echocardiography

No specific imaging studies are required in the initial workup of SND. However, an echocardiogram should be considered because it can document the presence of underlying valvular or ischemic heart disease and may suggest the diagnosis of amyloid when diffuse conduction system findings are present.

Transesophageal atrial pacing

Transesophageal atrial pacing is reserved mainly for pediatric patients. It may be performed safely to determine sinus node recovery time in children who present with dizziness, syncope, or palpitations.

Exercise stress testing

Exercise stress testing helps in identifying abnormal sinus node function. A subnormal increase in heart rate after exercise (ie, chronotropic incompetence) can help identify individuals with SND who may benefit from a pacemaker implantation.

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Electrocardiography

The diagnosis of sinus node dysfunction (SND) in patients with suggestive symptoms is often made on the basis of surface electrocardiographic (ECG) features. Manifestations seen on ECG may include the following:

• Periods of inappropriate and often severe bradycardia, with heart rate of below 50 beats per minute (bpm)
• Sinus pauses, arrest, and sinoatrial (SA) exit block with, and often without, appropriate atrial and junctional escape rhythms
• Alternating bradycardia and atrial tachyarrhythmias; atrial fibrillation is the most common arrhythmia, but atrial flutter and paroxysmal supraventricular tachycardias (ie, due to atrial tachycardia) may also occur

See the images below.

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This 12-lead electrocardiogram (ECG) is from an asymptomatic girl aged 10 years, which was brought to our attention because of the irregularity of the....

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Below is an electrocardiogram (ECG) of a girl aged 2 years who was referred to the clinic by a pediatrician for evaluation of a heart murmur. This ECG....

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This is a 12-lead electrocardiogram (ECG) from a boy aged 12 years with a history of syncope. This patient was healthy until 1 month earlier, when he ....

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Ambulatory ECG (Holter) Monitoring and Event Recording

For patients with clinically suspected sinus node dysfunction (SND) in whom the initial electrocardiogram (ECG) and monitoring are not diagnostic, ambulatory ECG monitoring or long-term event monitoring (eg, 7 or 30 days) is useful in the assessment of SND^[30]  and for correlation with symptoms. 

The specificity of a direct observation of spontaneous (ie, not provoked by an electrophysiologic [EP] study) SND is 100%, and an EP study is not required. Therefore, cardiac monitoring, rather than EP study, is the method of choice to assess SND.

A 24-hour Holter study also has the advantage of revealing whether SND produces symptoms such as dizziness, presyncope, or syncope; these cannot be determined during an EP study, because the patient is heavily sedated. Therefore, a 24-hour Holter study can help decide if pacemaker therapy is required.

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Pharmacologic Stimulation Tests

This section outlines steps to allow systematic evaluation of sinus node (SN) function.

Calculating the intrinsic heart rate (IHR)

The IHR is the heart rate in the presence of complete pharmacologic denervation of the SN. This is achieved with the simultaneous use of beta blockers and atropine. The calculation of the IHR following simultaneous administration of beta blockers and atropine is largely of historical interest and is rarely performed in the modern evaluation of patients with suspected SN dysfunction (SND). The IHR in a healthy person is approximately equal to 117.2 – (0.53 × age in years).

Sinus node response to pharmacologic challenge

A number of drugs have been used in to aid in the diagnosis of SND. The pharmacologic protocols are briefly described below.

Atropine and isoproterenol

Atropine (1 or 2 mg) and isoproterenol (2-3 mcg/minute) may be useful, because both agents normally increase the sinus rate. A suggested abnormal response is an increase in the sinus rate of less than 25% above the baseline, or to a sinus rate below 90 beats per minute.^[31] Due to fact that in most cases the diagnosis of SND can be achieved by establishing a symptom-rhythm correlation with the use of ambulatory monitoring in conjunction with a comprehensive history and physical examination, testing with these agents is rarely necessary.

Adenosine

Adenosine has been proposed as an alternative to invasive electrophysiology studies, but its routine use is not yet established.

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Electrophysiologic Studies

Invasive electrophysiologic (EP) studies are rarely used for the evaluation of sinus node dysfunction (SND) because of their limited sensitivity in eliciting bradyarrhythmias as well as due to the widespread availability of diagnostic options for long-term monitoring. However, in patients with suspected SND who also describe sustained episodes of tachyarrhythmias, EP studies may be helpful in an effort to identify a tachycardia (eg, atrial tachycardia) that would be potentially curable with ablation.^[28] Nevertheless, invasive EP studies may be performed in the following situations involving symptomatic patients^[28] :

• Those without ECG findings suggestive of SND and no other evident cause for their symptoms
• Those in whom ECG events are compatible with SND but fail to correlate with symptoms
• Those with SND who have sustained episodes of tachycardia that may be amenable to ablation
• Those with syncope or near syncope who have bundle branch or bifascicular block; such patients may require invasive EP evaluation of the sinoatrial (SA) node, the atrioventricular (AV) node, and the infranodal His-bundle-Purkinje system function. EP testing that shows SA nodal dysfunction allows for the selection of appropriate therapy in up to 50% of these patients.
• Those with syncope or near syncope who have ventricular arrhythmias may require EP study to assess for inducibility of ventricular tachyarrhythmias

The salient aspects of EP studies that aid in eliciting a bradyarrhythmic abnormality include assessment of the SA node recovery time, SA conduction time (SACT), and the SN and atrial tissue refractory periods. 

Classic EP criteria for SND include the presence of 1 or more of the following:

• Corrected SN recovery time (CSNRT) greater than 275 milliseconds (ms)
• SA conduction time greater than 200 ms
• SA node arrest
• SA exit block
• SN reentry tachycardia

SN recovery time (SNRT)

EP studies can document SND when studying SN automaticity by directly recording electrical activity.

Measurement of SNRT is achieved by pacing the atrium. Pacing should be performed from a catheter placed in the high right atrium (HRA) near the SN at the junction of the superior vena cava (SVC) and the RA for 4-6 trials of 30 seconds each. Each trial should use successively shorter pacing cycle lengths (eg, 600 ms, 550 ms, 500 ms), beginning with a cycle length just shorter than the resting sinus cycle length. SNRT is the time interval between the last paced captured beat to the first spontaneous sinus beat.

Gradual return of the SN to its baseline rate occurs over 5-6 beats. Prolonged pauses (ie, secondary pauses) can occur after the initial recovery interval in SND.

If the longest interval for the recovery interval or secondary pause exceeds 1500 ms, the SNRT is prolonged.

To adjust for heart rate and before each pacing increase, the resting sinus cycle length (SCL) is measured. When the resting SCL is subtracted from the SNRT, the CSNRT is obtained. Its upper reference range limit is 525 ms; if the SNRT exceeds the SCL by more than 525 ms, the SNRT is abnormal. The same occurs if the ratio of SNRT to SCL (ie, SNRT/SCL × 100) is more than 160%.

Sinoatrial conduction time (SACT)

SACT is another parameter that can be used to assess SN function. It is defined as the time interval in milliseconds for an impulse that originates in the SN to conduct through the perinodal tissue to the adjacent RA tissue. (The tissue that surrounds the SN or perinodal tissue has characteristics that are similar to those of the AV node.)

Note the following:

• Eight premature atrial contractions (PACs) are fired in the HRA at 5-10 bpm faster than the SN rate before they are stopped abruptly.
• SACT represents the time in milliseconds that it takes for the PAC fired in the HRA to enter and reset the SN. It also represents the time for the new spontaneous SN impulse (ie, SCL) to reach the HRA. SACT is measured as the time in milliseconds from the last PAC to the first spontaneous sinus beat.
• When the time interval between the last spontaneous SN depolarization (ie, before the PAC) and the one that occurred after a PAC is less than twice the value of the 2 previous spontaneous SN depolarizations, reset of the SN by the PAC has occurred.
• SACT can be calculated as the interval from the PAC to the next spontaneous SN beat, which includes conduction through the perinodal tissue into the SN, resetting the SN, and conduction through the same perinodal tissue back into the HRA (ie, [return interval - SCL]/2). The reference range is 50-125 ms in children and 200-250 ms in adults.
• If the SN cannot produce a spontaneous impulse following PACs (ie, these have not reset the SN and, therefore, SACT cannot be calculated), SA entrance block is present. This block could be caused by a markedly prolonged SA conduction and/or an increased refractory period of the peri-SN or SN fibers, both of which indicate SND. SN entrance block alternating with reset responses also denotes SND.
• SN reentry tachycardia occurs when activation of the atrium during the supraventricular tachycardia is the same as sinus beats (ie, the P-wave axis and morphology are the same as those in the sinus rhythm). It is usually indicative of SND.

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Approach Considerations

See also the Guidelines section for recommendations from the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society for the evaluation and management of bradycardia and disorders of cardiac conduction delay.

The only effective medical care in patients with sinus node dysfunction (SND) is correction of extrinsic causes. Admit patients for testing and pacemaker placement when indicated. Transfer patients for complicated dysrhythmias and pacemaker implantation.

No treatment is required for asymptomatic patients, even if they have abnormal SN recovery times (SNRTs) or sinoatrial conduction times (SACTs). If the patient is receiving medications that can provoke sinus bradyarrhythmias (eg, beta blockers), the medications should be stopped if possible.

Acute treatment consists of atropine (0.04 mg/kg intravenously [IV] every 2-4 h) and/or isoproterenol (0.05-0.5 mcg/kg/min intravenously [IV]). A transvenous temporary pacemaker is sometimes required despite medical therapy.

In patients with bradyarrhythmias-tachyarrhythmias, the tachyarrhythmias may be controlled with digoxin, propranolol, or quinidine. However, these patients should be monitored closely with frequent Holter monitoring to ensure that the bradyarrhythmias are not exacerbated or causing symptoms (eg, dizziness, syncope, congestive heart failure); if exacerbation of arrhythmias or symptoms occur, permanent pacemaker therapy is also required.

Activity

Patients with symptomatic SND who are not on pacemaker therapy should titrate their level of activity to minimize symptoms.

Consultations

These include cardiac electrophysiology consultation.

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Pacemaker Therapy

Pacemaker therapy is the only effective surgical care for patients with chronic, symptomatic sinus node dysfunction (SND). The major goal of pacemaker therapy in patients with SND is to relieve symptoms.

Recommendations for permanent pacing in SND

On the basis of the American College of Cardiology Foundation, American Heart Association, the Heart Rhythm Society (ACCF/AHA/HRS), and the European Society of Cardiology (ESC), general recommendations for cardiac pacing therapy for SND are outlined below.^{[1, 4, 32]}

Class I recommendations (All level of evidence C)

Permanent pacemaker implantation is indicated for the following^{[1, 4, 32]} :

• SND with documented symptomatic bradycardia, including frequent sinus pauses that produce symptoms
• Symptomatic chronotropic incompetence
• Symptomatic sinus bradycardia that results from required drug therapy for medical conditions

Class IIa recommendations (All level of evidence C)

Permanent pacemaker implantation is reasonable for the following^{[1, 4, 32]} :

• SND with a heart rate below 40 bpm, when a clear association between significant symptoms consistent with bradycardia and the actual presence of bradycardia has not been documented
• Syncope of unexplained origin, when clinically significant abnormalities of SN function are discovered or provoked in electrophysiologic (EP) studies

Class IIb recommendation

Permanent pacemaker implantation may be considered in minimally symptomatic patients with a chronic heart rate below 40 bpm while awake (level of evidence: C).^{[1, 4, 32]}

Class III recommendations (All level of evidence C)

Permanent pacemaker implantation is not indicated for SND in the following individuals^{[1, 4, 32]} :

• Asymptomatic patients
• Those for whom the symptoms suggestive of bradycardia have been clearly documented to occur in the absence of bradycardia
• Those with symptomatic bradycardia due to nonessential drug therapy

Single- versus dual-chamber pacemakers

In patients with SND, the annual incidence of complete heart block is about 0.6%.^[33] In the United States, the implantation of dual-chamber pacemakers is preferred in practice because their use anticipates the possible subsequent development of conducting system dysfunction.

This practice is supported by data from the Danish Multicenter Randomized Trial on Single Lead Atrial Pacing versus Dual Chamber Pacing in Sick Sinus Syndrome (DANPACE) trial, in which 9.3% of patients with single-lead atrial pacing (AAI) required upgrade to a dual-chamber pacemaker (DDD) over 5.4 years of follow-up due to new development of significant atrioventricular (AV) conduction abnormalities.^[34] This was necessary despite the fact that these patients had no significant intraventricular conduction abnormality, had PR intervals below 260 ms, and had no Wenckebach AV block with atrial pacing at 100 bpm at baseline. In addition, the incidence of atrial fibrillation (AF) was higher in patients in AAI mode than those in DDD mode. However, no significant mortality difference was noted between the groups in AAI and DDD modes.^[34]

Arguably, a single-chamber atrial pacemaker with AAI mode is an acceptable alternative in patients with SND and normal AV and intraventricular conduction because of the added expense of, and the potential for, more lead extraction with a dual-chamber pacemaker.

In patients with SND and known AV conduction abnormality (including bundle branch block and bifascicular block), a dual-chamber pacemaker should be used due to the high risk of AV block (about 36% in a 5-year follow-up study).

In a collaborative pooled-analysis of 10 randomized trials (n = 6639) to evaluate the effect of existing pacing strategies on the risk of postimplantation AF and heart failure events in SND patients, Chen et al stratified the pooled-analysis into two subsets—AAI versus DDD, and minimal ventricular pacing (MinVP) versus DDD—and found that although composite AF and heart failure (HF) events were similar in the AAI versus DDD subset, there was a substantially reduced risk of composite AF and HF in the MinVP group receiving pacemaker as primary treatment.^[35] Over the long term, however, the rate of AF and HF was similar in the MinVP versus DDD subset of patients who were scheduled for device replacement. The investigators indicated their findings supported the use of MinVP over conventional DDD in improving clinical outcomes for SND patients who received a pacemaker as primary treatment.^[35]

Pacemaker programming features

Chronic right ventricular pacing has been shown to be associated with an increased incidence of AF, stroke, HF, and probably death.^{[21, 22, 36]} A study suggested that right ventricular (RV) pacing is detrimental to left ventricular (LV) function even in patients with a normal LV ejection fraction (LVEF).^[37] Therefore, avoiding RV pacing is advantageous in patients with SND treated with pacemaker therapy.

However, using the intrinsic AV conduction in patients with a very long intrinsic PR interval may not be beneficial clinically, as suggested by a trial in patients with an intracardiac defibrillator (ICD).^[34] Theoretically, a very long PR interval may result in pacemaker syndrome during sinus tachycardia or a fast atrial pacing rhythm.

As noted above, in the DANPACE trial, about 65% of patients with a moderate AV delay setting in DDD mode with mean RV pacing had a lower incidence of AF and no increased rate of HF, as compared with patients in AAI mode.^[34] The optimal AV delay settings in patients with SND are remain unknown, although various programming algorithms from different pacemaker companies are very effective in reducing RV pacing.

Mode switch is an important feature to monitor atrial flutter and AF events. Because more than 50% of patients with SND may develop tachy-brady syndrome over time,^[21] it is very important to identify these patients through pacemaker monitoring and to anticoagulate them to reduce their risk of stroke. However, the most appropriate anticoagulant therapy is still uncertain for patients in whom AF is detected only as an incidental finding on pacemaker or ICD diagnostics.

Rate response features have been used in patients with SND, especially in the presence of chronotropic incompetence. However, the clinical benefits of this program feature are still controversial.^[38]

• References

Funny Current Blocker Ivabradine

Spontaneous depolarization of the sinus node involves "funny" (I(f)) current in sinoatrial (SA) node myocytes. This is an inward current that is activated on hyperpolarization to the diastolic range of voltages, thereby generating repetitive activity and modulating spontaneous rate. The degree of activation of the funny current determines the steepness of phase 4 depolarization and, hence, the frequency of action potential firing.

I(f) is controlled by intracellular cyclic adenosine monophosphate (cAMP) and is thus activated and inhibited by beta-adrenergic and muscarinic M2 receptor stimulation, respectively; it represents a basic physiologic mechanism for mediating autonomic regulation of the heart rate. Typically, given their exclusive role, f-channels are ideal targets of drugs aiming for pharmacologic control of the cardiac rate. Molecules able to bind specifically to and block f-channels can therefore be used as pharmacologic tools for heart rate control with little or no adverse cardiovascular side effects. 

In addition, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known to cause rhythm disturbances (eg, inherited sinus bradycardia). Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biologic pacemakers that may eventually be able to replace electronic devices.

Current status of ivabradine

A selective f-channel inhibitor, ivabradine, is now commercially available and used in patients with heart failure (HF) and sinus tachycardia.

The 2016 American College of Cardiology, American Heart Association, and the Heart Failure Society of America (ACC/AHA/HFSA) guideline update on new pharmacologic therapy for HF gives a class IIa recommendation for the use of ivabradine to reduce HF hospitalization in patients with symptomatic (New York Heart Association [NYHA] class II-III) stable chronic HF with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤35%) receiving guideline-directed evaluation and management, including a beta blocker at the maximum tolerated dose, as well as who are in sinus rhythm with a resting heart rate of 70 bpm or more.^[39] The guideline indicates that, "given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation."^[39]

Ivabradine is contraindicated in patients with HF and SND without a permanent cardiac pacemaker.

• References

Long-Term Monitoring

Asymptomatic patients with sinus node dysfunction (SND) should be observed for symptoms. In patients with a pacemaker, carry out the following on routine pacemaker interrogations:

• Monitor leads and battery status
• Ensure adequate heart rate support at rest, during daily activities, and during exercise
• Monitor for pacemaker malfunction
• Ensure minimal right ventricular (RV) pacing.
• Monitor for atrial fibrillation and atrial flutter events

Pregnancy

Patients with SND who become pregnant and take antiarrhythmic medications should have their medication levels measured because these drug regimens frequently require adjustment. In addition, medication with teratogenic effects (eg, amiodarone, which is associated with fetal thyroid dysfunction) should be avoided.

Patients with SND who become pregnant and have a pacemaker are advised to perform frequent pacemaker checks and make the appropriate adjustments.

Patients with SND who become pregnant and have ventricular dysfunction due to cardiomyopathy or a Mustard or Fontan procedure should have regular and close medical follow-ups with their obstetrician and cardiologist. This permits appropriate adjustment and implementation of anti-congestive heart failure (CHF) medication. If the CHF progresses despite medical management and becomes intractable, the mother and fetus are at risk and early delivery may be scheduled.

• References

Future Directions

Certain genetic mutations have been linked to sinus node and conduction system disease. SCN5A, HCN4, RYR2, CASQ2, and ankyrin-B (ANKB) mutations are associated with sinus node dysfunction, whereas mutations of SN5A, SCN1B, KCNJ2, TBX5, and NKX2-5 are associated with conduction system disease. Neuromuscular genetic disorders including emerin (EMD), lamin A/C (LMNA), and myotonic dystrophy type 1 (DM1) are also associated with AV conduction disease.[7] Gene- and stem cell-based therapies are currently being investigated as therapeutic options for patients with genetic or degenerative abnormalities of the cardiac electrical conduction system.

• References

Guidelines Summary

2018 ACC/AHA/HRS guidelines

The guideline on the evaluation and management of bradycardia and cardiac conduction delay was released in November 2018, by the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Rhythm Society (HRS). ^{[40, 41]}

The guideline’s top 10 key messages for assessing and treating patients with bradycardia or other disorders of cardiac conduction delay are provided below.

Sinus node dysfunction is most often related to age-dependent progressive fibrosis of the sinus nodal tissue and surrounding atrial myocardium leading to abnormalities of sinus node and atrial impulse formation and propagation and will therefore result in various bradycardic or pause-related syndromes.

Sleep disorders of breathing and nocturnal bradycardias are relatively common. Treatment of sleep apnea reduces the frequency of these arrhythmias and also may offer cardiovascular benefits. The presence of nocturnal bradycardias should prompt consideration for screening for sleep apnea, beginning with solicitation of suspicious symptoms. However, nocturnal bradycardia is not in itself an indication for permanent pacing.

The presence of left bundle branch block on electrocardiogram markedly increases the likelihood of underlying structural heart disease and of diagnosing left ventricular (LV) systolic dysfunction. Echocardiography is usually the most appropriate initial screening test for structural heart disease, including LV systolic dysfunction.

In sinus node dysfunction, there is no established minimum heart rate or pause duration where permanent pacing is recommended. It is important to establish a temporal correlation between symptoms and bradycardia when determining whether permanent pacing is needed.

In patients with acquired second-degree Mobitz type II atrioventricular (AV) block, high-grade AV block, or third-degree AV block not caused by reversible or physiologic causes, permanent pacing is recommended regardless of symptoms. For all other types of AV block, in the absence of conditions associated with progressive AV conduction abnormalities, permanent pacing should generally be considered only in the presence of symptoms that correlate with AV block.

In patients with an LV ejection fraction between 36% and 50% and AV block, who have an indication for permanent pacing and are expected to require ventricular pacing over 40% of the time, techniques that provide more physiologic ventricular activation (eg, cardiac resynchronization therapy [CRT], His bundle pacing) are preferred to right ventricular pacing to prevent heart failure.

Because conduction system abnormalities are common after transcatheter aortic valve replacement (TAVR), recommendations on postprocedure surveillance and pacemaker implantation are made in this guideline.

In patients with bradycardia who have indications for pacemaker implantation, shared decision-making and patient-centered care are endorsed and emphasized in this guideline. Treatment decisions are based on the best available evidence and on the patient’s goals of care and preferences.

Using the principles of shared decision-making and informed consent/refusal, patients with decision-making capacity or his/her legally defined surrogate have/has the right to refuse or request withdrawal of pacemaker therapy, even if the patient is pacemaker dependent, which should be considered palliative, end-of-life care, and not physician-assisted suicide. However, any decision is complex, should involve all stakeholders, and will always be patient specific.

Identifying patient populations that will benefit the most from emerging pacing technologies (eg, His bundle pacing, transcatheter leadless pacing systems) will require further investigation as these modalities are incorporated into clinical practice.

• References

Medication Summary

Currently, no medications are routinely used to treat symptomatic sinus node dysfunction (SND). Virtually most medications are ineffective over the long term, and many demonstrate lack of efficacy from tachyphylaxis. Nonetheless, acute treatment with the anticholinergic agent atropine and/or the adrenergic agonist isoproterenol may be warranted. Oral analogues of these drugs (eg, propantheline and orciprenaline [metaproterenol], respectively) are not effective on a long-term basis.

• References

Atropine

• Dosing, Interactions, etc.

Clinical Context:  Atropine increases the heart rate through vagolytic effects, causing an increase in cardiac output.

• References

Class Summary

Atropine, by vagolytic effect, increases the heart rate. Although it may also be used for the initial treatment of chronic arrhythmias, cardiac pacing is preferred for long-term control.

• References

Isoproterenol (Isuprel)

• Dosing, Interactions, etc.

Clinical Context:  Isoproterenol has sympathomimetic effects; specifically, beta1- and beta2-adrenergic receptor agonist activity.

• References

Class Summary

When given systemically, isoproterenol stimulates beta receptors in the heart, which produces positive inotropic and chronotropic effects. This results in increased cardiac output.

• References

Quinidine

• Dosing, Interactions, etc.

Clinical Context:  Quinidine maintains normal heart rhythm following cardioversion of atrial fibrillation or flutter. It depresses myocardial excitability and conduction velocity. Control the ventricular rate and CHF (if present) with digoxin or calcium channel blockers before the administration of quinidine.

• References

Class Summary

It may be necessary to use antiarrhythmic agents for concomitant tachyarrhythmia.

• References