Enhanced cardiac automaticity

INTRODUCTION — Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone. Enhanced normal automaticity accounts for the occurrence of sinus tachycardia, while abnormal automaticity may result in various atrial or ventricular arrhythmias, for example, an accelerated idioventricular rhythm or an ectopic atrial tachycardia.

This topic will review the physiologic principles underlying both enhanced normal automaticity and automatic automaticity. The diagnosis and treatment of arrhythmias resulting from enhanced cardiac automaticity are discussed separately. (See "Sinus tachycardia: Evaluation and management" and "Focal atrial tachycardia".)

ENHANCED NORMAL AUTOMATICITY — Enhanced normal automaticity is best understood by beginning with a brief review of the physiology and hierarchy of stimulation of normal cardiac automaticity. This will be followed by a discussion of the electrophysiologic principles underlying the normal and enhanced automaticity of the sinoatrial (SA) node, the subsidiary atrial pacemakers, the atrioventricular (AV) node, and the ventricles.

Normal automaticity — Normal automaticity involves the slow, progressive depolarization of the membrane potential (spontaneous diastolic depolarization or phase four depolarization) until a threshold potential is reached, at which point an action potential (figure 1 and figure 2) is initiated. Although automaticity is an intrinsic property of all myocardial cells, the occurrence of spontaneous activity is prevented by the natural hierarchy of pacemaker function. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

The spontaneous discharge rate of the SA nodal complex exceeds that of all other subsidiary or latent pacemakers. As a result, the impulse initiated by the SA node depresses the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, slowly depolarizing and previously suppressed pacemakers in the atrium, AV node, or ventricle can become active and assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. The emergence of subsidiary or latent pacemakers under such circumstances is an appropriate fail-safe mechanism which assures that ventricular activation is maintained. A subsidiary pacemaker may also become activated if there is sympathetic stimulation or increased catecholamines, resulting in a pacemaker discharge rate that is faster than the rate of sinus node discharge. This represents an accelerated rhythm.

SA node — The ionic mechanisms responsible for normal pacemaker activity in the SA node have not been conclusively defined, but are likely the result of a hyperpolarization-activated inward current and decay of outward potassium currents [1]. This progressive net gain of positive charge underlies the spontaneous diastolic depolarization of SA node cells which results from the following sequence of events (figure 2) [2,3]:

●During the first third of diastolic depolarization, the inward leak of sodium ions is coupled with a time-dependent decrease in the outward potassium current.

●During the latter two thirds of depolarization, a slow inward movement of calcium ions occurs. This process moves the membrane potential to the threshold potential, at which time there is a more rapid inward calcium current, generating a slow action potential.

Effects of drugs and autonomic tone on the SA node — Drugs and autonomic neurotransmitters perturb these currents, thereby altering the SA node discharge rate. As an example, agents and neurotransmitters that accelerate the sinus node discharge rate bind to the beta adrenergic receptor, leading to an increase in the inward movement of calcium due to the phosphorylation of a protein that modulates the opening of calcium channels  (figure 3) [4,5]. The ensuing influx of calcium accelerates the rate of diastolic depolarization [2].

Parasympathetic tone, on the other hand, reduces the spontaneous discharge rate of the SA node, while its withdrawal accelerates SA node automaticity. Acetylcholine, the principle neurotransmitter of the parasympathetic nervous system, inhibits spontaneous impulse generation in the SA node by increasing potassium conductance [3]. The resulting hyperpolarization of the membrane potential lengthens the time required for the membrane potential to depolarize to threshold, thereby decreasing the automaticity of the SA node.

In addition to altering ionic conductance, changes in autonomic tone can also produce changes in the rate of the SA node by shifting the primary pacemaker region within the pacemaker complex, which is described as a cylindrical crescent [6]. Intrinsic discharge frequencies vary within different regions of the SA node; the discharge rate is faster in the cranial portion of the node, while it is slower in the caudal region. As a result, autonomically-mediated shifts of pacemaker regions may be accompanied by changes in the sinus rate [7,8]. Vagal fibers are more dense in the cranial portion of the SA node and stimulation of the parasympathetic nervous system shifts the pacemaker center to a more caudal region of the SA nodal complex, resulting in slowing of the heart rate, whereas stimulation of the sympathetic nervous system or withdrawal of vagal stimulation shifts the pacemaker center cranially, resulting in an increase in heart rate (figure 4).

The following are examples of stimuli which can alter the automaticity of the SA node:

●Exercise, which augments sympathetic tone, enhances normal automaticity in the SA node and can produce sinus tachycardia (heart rates exceeding 100 beats/minute). (See "Sinus tachycardia: Evaluation and management".)

●Respiratory sinus arrhythmia (respirophasic arrhythmia that is irregularly irregular) is primarily caused by withdrawal of vagal tone during inspiration (and hence a faster heart rate) and by reinstitution of vagal tone during expiration (and hence a slower heart rate). These alterations in vagal tone are mediated by peripheral sensors linked to arterial chemoreceptors and baroreceptors, intracardiac reflexes, and pulmonary stretch receptors [9-11]. (See "Normal sinus rhythm and sinus arrhythmia".)

●Digitalis has a well-known negative chronotropic effect on the SA node, caused by enhancement of vagal (parasympathetic) tone [9,12]. Digoxin does not appear to have any direct depressant effects on the intrinsic functions of the sinus node [13].

●Beta blockers, which block the effect of sympathetic stimulation and circulating catecholamines on the SA node, result in a reduction in its normal automaticity. However, their effect at rest is less marked, as normal resting SA nodal function is not dependent upon sympathetic stimulation but is mediated more by vagal tone. However, during times of sympathetic stimulation, these agents will blunt the acceleration in heart rate.

●Calcium channel blockers, especially verapamil and diltiazem, reduce the influx of calcium ions, and therefore will reduce the rate of diastolic depolarization and hence the rate of SA nodal discharge.

●Ivabradine, which has a direct effect on SA automaticity and impulse discharge. Its action is unlike beta blockers, digoxin, or calcium channel blockers. It works by modulating the "f-current" (I_f). Ivabradine slows the sinus rate by prolonging the slow depolarization phase.

Subsidiary atrial pacemakers — Latent atrial pacemakers have been identified in the atrial myocardium (especially the crista terminalis), coronary sinus, and AV valves [14-18], while ectopic atrial pacemakers have been identified in the region around the pulmonary veins [19]. They may responsible for precipitating atrial fibrillation and their elimination or isolation with radiofrequency catheter ablation has been found to be effective for the prevention of paroxysmal atrial fibrillation [20]. (See "Atrial fibrillation: Catheter ablation".)

Latent atrial pacemakers (located in the atrial myocardium) may be expected to contribute to impulse initiation in the atrium if the discharge rate of the SA node is reduced temporarily or permanently. In contrast to the normal pacemaker tissue, these latent or ectopic pacemakers usually generate a fast action potential, mediated by sodium ion fluxes. However, when severely damaged, the atrial tissue may not be able to generate a fast action potential (which is energy-dependent) but rather generates a slow, calcium ion-mediated action potential (which is energy-independent).

Automaticity of subsidiary atrial pacemakers may also be enhanced by coronary disease and ischemia, chronic pulmonary disease, or drugs such as digitalis and alcohol, possibly overriding normal SA node activity [9,21,22].

AV node or junction — It is uncertain if the AV node itself has pacemaker cells, but it is clear that the AV junction, which is an area that includes atrial tissue, the AV node and His-Purkinje tissue, does have pacemaker cells and is capable of exhibiting automaticity. Automaticity of the AV junction appears to arise via a mechanism similar to that which occurs in the SA node [23-25]. Diastolic depolarization is caused by a gradual decrease in the outward potassium current and an increase in the inward movement of calcium ions. Acceleration of AV nodal automaticity by beta-adrenergic agonists is believed to result from activation of the calcium channel, resulting in an increased inward calcium current, similar to that induced in the SA node.

Ectopic AV nodal tachycardias due to enhanced automaticity have the following clinical features:

●Marked sinus bradycardia or SA node exit block can result in an escape ectopic AV nodal or junctional rhythm.

●The emergence of an ectopic AV junctional rhythm is usually characterized by a gradual increase in spontaneous discharge rate (a warm-up phenomenon) until a reasonably regular rate of 35 to 60 beats per minute is attained [25].

●Acceleration of the AV junctional rate to 70 to 130 beats per minute (ectopic junctional tachycardia) can occur with an inferior myocardial infarction, open heart surgery, myocarditis, digitalis intoxication (which is associated with an increase in outputs from the central sympathetic nervous system), or sympathetic activation.

●The onset and termination of accelerated junctional tachycardias are usually gradual (ie, nonparoxysmal).

●The tachycardia rate is slowed by enhanced vagal tone and is accelerated by vagolytic or sympathomimetic agents.

Ventricle — Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity [26,27]. The relatively slow spontaneous discharge rate of Purkinje fibers ensures that pacemaker activity in the His-Purkinje system will be suppressed on a beat-to-beat basis by the more rapid discharge rate of the SA node [28,29].

Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of "overdrive suppression" by more proximal pacemakers (ie, sinus and AV node) that have a faster discharge rate (figure 5). However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. In this setting, some Purkinje fibers which survive the infarction have moderately reduced maximum diastolic membrane potentials and therefore accelerated spontaneous discharge rates [30-36]. In the presence of ischemia or myocardial infarction, myocardial cells may demonstrate spontaneous automaticity. This is discussed below. (See 'Abnormal automaticity' below.)

ABNORMAL AUTOMATICITY — Enhanced automaticity of the SA node, subsidiary atrial pacemakers, or the AV node due to a mechanism other than acceleration of normal automaticity has not been demonstrated clinically. However, abnormal automaticity of Purkinje fibers and atrial and ventricular tissue can occur.

As noted above, isolated cardiac Purkinje fibers usually have relatively slow spontaneous discharge rates (phase 4 of the action potential responsible for spontaneous automaticity is relatively flat), whereas atrial and ventricular muscles are quiescent. However, depolarization of these tissues by acute myocardial ischemia can induce spontaneous activity.

●With an acute myocardial infarction and transmural ischemia, membrane integrity is lost and there is an outward leak of potassium. There is loss of the normal energy-dependent fast sodium-mediated action potential (due to inactivation of the normal sodium-potassium ATPase pump, which requires energy and O₂ to synthesize ATP). This results in an increase in intracellular potassium levels and lower extracellular potassium.

●As a result of the reduction in transmembrane potassium gradient, the resting membrane potential (which is normally -90 mV) becomes less negative and reaches the threshold potential of -60 mV. The normal rapid influx of sodium, which accounts for the fast action potential, is lost, and the fast action potential is no longer generated.

●However, the slow influx of calcium currents, which is energy independent and normally occurs during phase 2 of the action potential (which is responsible for maintaining this plateau phase of the action potential) still occurs. Hence, as a result of the loss of the fast inward sodium influx but maintenance of the slow influx of calcium ions, the fast action potential is converted to a slow action potential which has spontaneous automaticity. Thus, latent energy-independent slow action potential (mediated by calcium currents) is therefore exposed. This automaticity is not suppressed by overdrive pacing, is more easily suppressed by calcium channel blockade than by sodium channel blockade, and is accelerated by beta-adrenergic agonists [35-40]. Thus, abnormal automaticity in these tissues resembles normal automaticity in the sinus and AV nodes (ie, results from a time-dependent decay of outward potassium currents and progressive activation of inward calcium currents) [41,42].

Acceleration of Purkinje fiber automaticity can also be augmented by the elevated levels of catecholamines and increased sympathetic tone which occurs during ischemia [43]. Purkinje fibers surviving myocardial infarction appear to be more sensitive to the positive chronotropic effects of catecholamines than normal Purkinje fibers, perhaps because of denervation supersensitivity [44,45].

There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".)

Isolated myocytes obtained from hypertrophied and failing hearts have been shown to manifest spontaneous diastolic depolarization and enhanced pacemaker currents, suggesting that abnormal automaticity may contribute to the occurrence of some arrhythmias in heart failure and left ventricular hypertrophy [46,47]. It has been shown that stretch of the myocardium can increase its automaticity (ie, electromechanical feedback). This may account for arrhythmias that are seen with heart failure and acute dilation of the atrial or ventricular myocardium. (See "Left ventricular hypertrophy and arrhythmia".)

Some of the arrhythmias that occur with digoxin toxicity may be related to suppression of sinus node activity by increased vagal tone as well as enhanced automaticity (resulting from an increase in central sympathetic neural outputs occurring with elevated digoxin levels), although this is not firmly established since delayed potentials (delayed after depolarizations [DADs]) and triggered automaticity are other potential mechanisms. It is likely that both mechanisms play a role as triggered automaticity may be enhanced by sympathetic stimulation. (See "Cardiac arrhythmias due to digoxin toxicity".)

The role of abnormal automaticity in the genesis of other clinical arrhythmias has generally not been established. Although automaticity is not responsible for most clinical tachyarrhythmias, which are usually due to a reentry, it may certainly precipitate or trigger any reentrant arrhythmia.

SUMMARY

●Definition – Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). (See 'Introduction' above.)

●Normal automaticity – The spontaneous discharge rate of the sinoatrial (SA) nodal complex exceeds that of all other subsidiary or latent pacemakers, thereby depressing the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, previously suppressed pacemakers in the atrium, atrioventricular (AV) node, or ventricle can assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. (See 'Normal automaticity' above.)

●Effects of drugs and autonomic tone – Drugs and autonomic neurotransmitters alter the SA node discharge rate (see 'Effects of drugs and autonomic tone on the SA node' above):

•Increased sympathetic input or withdrawal of parasympathetic input (eg, exercise, beta agonist medications) results in higher sinus rates.

•Decreased sympathetic input or increased parasympathetic input (eg, beta blockers, digoxin) leads to lower sinus rates.

●AV node automaticity – The AV junction, an area that includes atrial tissue, the AV node, and His-Purkinje tissue, contains pacemaker cells and is capable of exhibiting automaticity, which may result in ectopic AV nodal tachycardias. (See 'AV node or junction' above.)

●Ventricular automaticity – Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity. Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of suppression by more proximal pacemakers that have a faster discharge rate. However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. (See 'Ventricle' above.)

●Abnormal automaticity – There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. (See 'Abnormal automaticity' above.)