Etiology

Bradycardia is due to sinus node dysfunction or conduction system disease, the causes of which may be intrinsic or extrinsic.

  • Intrinsic causes are the result of fibrous changes of the nodal tissue. Intrinsic causes are vast and include idiopathic degenerative processes (e.g., aging), congenital or genetic abnormalities, valvular disease, direct tissue damage (e.g., hypoxia, surgical trauma [surgical aortic and tricuspid valve repair/replacement, transcatheter aortic valve replacement]), tissue inflammation or infiltration (e.g., sarcoidosis, amyloidosis, hemochromatosis), infections (e.g., typhoid fever, diphtheria, tuberculosis, toxoplasmosis, rheumatic fever, viral myocarditis, Lyme disease), autoimmune or collagen vascular diseases (e.g., lupus erythematosus, connective tissue disease), or abnormal autonomic effects. [18]

  • Extrinsic causes include exposure to toxins (e.g., lead, black widow spider venom, xylazine poisoning, or tricyclic antidepressant overdose), drugs (e.g., digoxin, beta-blockers, calcium-channel blockers, ivabradine, or class I or III anti-arrhythmic drugs), electrolyte abnormalities (e.g., hyperkalemia, acidemia), or environmental insults (e.g., hypothermia).[3][19][20][21]​ Additionally, situations that cause high (intense) vagal tone (activation) (increased parasympathetic input to the sinus node) can result in bradycardia. These include vomiting, coughing, glottis stimulation, micturition, and defecation. Iatrogenic causes include vagal nerve stimulators. Carotid sinus hypersensitivity and neurocardiogenic syncope could also lead to bradycardia. Some causes, such as hypothyroidism, electrolyte disorders, and those that are drug-induced, are reversible. Inferior wall myocardial infarction and increased intracranial pressure can also cause various types of bradycardia (i.e., Cushing reflex).

Sleep-disordered breathing (SDB), comprising obstructive sleep apnea (OSA), central sleep apnea, and Cheyne-Stokes breathing, can be associated with various bradycardias.[22][23][24][25] Sinus bradycardia, second-degree atrioventricular (AV) block, vagotonic AV block, or complete heart block have been observed in some patients only during sleep. In SDB, the prevalence of profound sinus bradycardia is 7% to 40%, of second- or third-degree AV block is 1% to 13%, and of sinus pauses is 3% to 33%.[25] High vagal tone in an otherwise healthy young adult is a common cause of sinus bradycardia and Mobitz I (rarely Mobitz II) AV block. This may even manifest during sleep and may be exacerbated by SBD. It is proposed that hypoxia in the absence of lung inflation leads to increased vagal stimulation of the carotid body resulting in bradycardia.[25] Over time, the sustained physiological stresses associated with SDB are thought to interact with circadian mechanisms to remodel the structure and electrophysiologic function of the heart, increasing the risk of rhythm disorders.[25] In a small cohort study of patients with severe OSA and 50% prevalence of episodes of severe nocturnal bradycardia, treating OSA with continuous positive airway pressure (CPAP) decreased the median number of bradycardic events recorded by an insertable loop recorder over a 16-month follow-up period.[25]

Generalized conduction system disease related to calcification and fibrosis is called Lev's disease (or Lev-Lenegre Syndrome) and is a cause of acquired complete heart block. Lev's disease is seen most commonly in older people and is often described as senile degeneration of the conduction system.

Bradyarrhythmias can be seen in adults with congenital heart disease. In fact, arrhythmias are the most common complication seen in adults living with congenital heart disease. This is due to cardiac conduction abnormalities, or can also be sequelae of procedural intervention. The most common congenital causes of sinus node dysfunction are heterotaxy/polysplenia, left juxtaposition of atrial appendages, or surgical repairs. The most common congenital causes of AV node dysfunction are heterotaxy/polysplenia, congenitally corrected transposition of great arteries, ventricular septal defect, and tricuspid atresia. The SCN5A gene has been shown to cause inherited conduction disease. This gene encodes the cardiac sodium channel alpha subunit. Although this is the most common gene associated with conduction disease, it only accounts for 5% of cases. Therefore, genetic testing is not routinely performed or recommended.[26][27]

Of note, pathologic bradycardia during pregnancy is rare and is usually due to congenital heart block. Normally, physiologic adaptations during pregnancy lead to an increase in cardiac output and resting heart rate. Heart rate can increase by up to 10-20 bpm, reaching a maximum in the third trimester.[28][29] Symptomatic bradycardia has been associated with supine hypotensive syndrome of pregnancy. This is seen when maternal positional changes cause compression of the inferior vena cava by the gravid uterus.[29]

Rarely, bradycardia may be associated with seemingly unrelated clinical conditions. For example, bradycardia can be rarely associated with epilepsy, and should be considered in patients with unusual presentations of syncope or in patients with a history suggestive of both epilepsy and syncope. Ictal bradycardia and ictal asystole predominantly occur in association with focal seizures, with loss of awareness in people with mainly left lateralized temporal lobe seizures, and are associated with electroencephalogram signs of brain ischemia during these episodes.[30]

Pathophysiology

The cellular mechanisms are complex and interrelated. Failure of any one of these mechanisms can have an effect on heart rate. Normal cardiac electrical activation requires normal sinus node automaticity and effective atrioventricular (AV) node and His-Purkinje conduction. Anything that causes sinus node automaticity or conduction through the AV node and/or His-Purkinje system can cause bradycardia.

Classification

Clinical classification

Bradycardia is classified as asymptomatic or symptomatic. Asymptomatic patients often do not require treatment. Bradycardia, including sinus bradycardia and Mobitz type I (Wenckebach) atrioventricular (AV) block, can be completely benign in young, healthy, athletic individuals.

Bradycardia classification

Bradycardia can be classified according to the site of the conduction disturbance.[3]

Sinus node dysfunction

  • Sinus bradycardia: heart rate <50 bpm. It can be a normal finding, especially during rest or sleep, or can be abnormal and symptomatic.[4] It is common in athletes, as they often have high resting vagal tone.

  • Sinus nodal pauses/arrest: episodic, abrupt termination of sinus rhythm generally lasting >3 seconds. Episodes can last >30 seconds. There can be hemodynamic collapse, acute drop in blood pressure, and/or loss of consciousness. The term sinus arrest is used generally for long sinus node pauses (i.e., >5 seconds). Paroxysmal sinus arrest or bradycardia can be due to intense vagal discharge.[5]

  • Sinus nodal exit block: sinus node continues to activate but electrical activation is delayed and blocked either completely or incompletely between the sinus node and the atria. There can be various levels of block (e.g., complete or intermittent block).[6]

  • Tachycardia-bradycardia syndrome: occurs when there are episodic periods of tachycardia (usually atrial flutter, atrial fibrillation, or atrial tachycardia), followed by termination of the tachycardia leading to sinus arrest or long sinus pauses, followed by sinus bradycardia.[7]

  • Chronotropic incompetence: a form of bradycardia in which the sinus rate does not accelerate appropriately with exercise. Although there are no standardized criteria for diagnosing chronotropic incompetence, it is generally defined as failure to reach 85% of the age-predicted maximal heart rate (defined as 220 minus the patient's age in years), or the inability to reach 80% of the heart rate reserve (computed as the change in heart rate from rest to peak exercise divided by the difference of the resting HR and the age-predicted maximal HR), on a dynamic exercise test.[8]

  • Sinus node dysfunction (SND): historically known as sick sinus syndrome; a general term describing bradycardia presumed to be caused by sinus node disease manifesting as one of the above abnormalities. There is evidence of slowing of sinus node function. Although this is generally not due to autonomic abnormalities, they can contribute. The exact cause is unknown, but it is thought that degenerative fibrosis of the cardiac conduction fibers and surrounding atrial myocardium from factors such as long-standing hypertension, valvular disease, coronary artery disease, atrial arrhythmias, congestive heart failure, or increasing age contribute. The incidence of SND increases with age. SND accounts for nearly half of the pacemaker implantations in the United States. Some patients have marked bradycardia owing to SND only after medications that slow the sinus node are initiated. It has been associated with atrioventricular (AV) nodal conduction abnormalities and a high risk of systemic embolism.[9][10][11]​​​[12]

AV conduction disease

AV block occurs when the atrial depolarization fails to reach the ventricles or when atrial depolarization is conducted with a delay.

  • First-degree AV block: delay in AV conduction, such that the PR interval is >0.2 seconds. During first-degree AV block, there is one-to-one conduction but there is delay in AV nodal conduction.[13] It is not necessarily associated with bradycardia but it may be associated with higher degrees of AV block and subsequent bradycardia or sinus node dysfunction.

  • Second-degree AV block: periodic failure of conduction from the atria to the ventricles. This assumes that the atrial rate is regular. A blocked premature atrial beat is not second-degree AV block. There are different types:

    • Mobitz I: grouped beating with a constant PP interval, lengthening in the PR interval, and changing (usually shortening) RR intervals with the cycle ending with a P-wave and not followed by a QRS complex. As the PR interval gradually prolongs, the RR interval tends to stay the same or shorten.[14] This is also called Wenckebach AV block.

    • Mobitz II: associated with single nonconducted P-waves with a constant PP interval and constant PR intervals (no change in the PR >0.025 seconds).[15]

    • 2:1 block: only one PR interval to examine before the blocked P-wave and 2 P-waves for every QRS complex. In most cases, it will change to Mobitz I or II. If there is an associated bundle branch block along with a normal PR interval, this suggests block in the His-Purkinje system.

    • High-degree AV block: more than one sequentially blocked P-wave.[16]

  • Third-degree AV block: occurs when there are no conducted impulses from the atria to the ventricles. This is also called complete AV block. This may occur with regular atrial activity without conduction or with an atrial tachyarrhythmia.

  • Paroxysmal AV block: normal AV nodal conduction followed by sudden block of AV conduction associated with a long pause and multiple blocked P-waves, with subsequent resumption of AV conduction. This can be related to underlying AV nodal or His-Purkinje conduction anomalies or to abrupt parasympathetic activation causing block in AV nodal conduction. In the latter instance, there is often slowing in sinus activation.

  • Vagotonic AV block: slowing of the sinus node with prolongation of the PR interval followed by AV block owing to transient abrupt increase in parasympathetic tone.

  • Congenital complete heart block: usually associated with a narrow QRS complex escape rhythm arising in the AV node.

Escape rhythms

When the sinus rate slows or there is AV block, other cardiac structures can activate owing to their intrinsic automaticity. The AV nodal rate tends to be 40 to 60 bpm and the ventricular rate tends to be 20-40 bpm.

  • Ectopic atrial rhythm: originates from atrial structures other than the sinus node during sinus bradycardia or sinus arrest.

  • Junctional rhythm: escape rhythm when there is bradycardia or arrest of sinus node or atrial activation. Activation of the junction may occur with or without AV block.[17]

  • Ventricular rhythm: an escape rhythm from the ventricles when there is AV block or sinus bradycardia.

Atrioventricular dissociation

  • Atrial and ventricular activation occur from different pacemakers. Ventricular activation may be from junctional or infranodal automaticity. AV dissociation can occur in the presence of intact AV conduction, especially when rates of the pacemaker, either junctional or ventricular, exceed the atrial rate.

  • The atria and ventricles do not activate in a synchronous fashion but beat independent of each other. Usually, the ventricular rate is the same as or faster than the atrial rate. When the atrial rate is faster and the atria and ventricles are beating independently, complete heart block is present.

  • AV dissociation can be complete or incomplete. When incomplete, some P-waves conduct and capture the ventricles but, if they do not, it is complete. Complete AV dissociation mimics AV block and has to do with P-wave timing in relation to independent ventricular activation.

  • There are two types:

    • Isorhythmic: when the atrial rate is the same (or nearly the same) as the ventricular rate but the P-wave is not conducted

    • Interference: when P-waves and QRS rates are similar but, occasionally, the atria conduct to the ventricles.

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