AF triggering factors include sympathetic or parasympathetic stimulation, bradycardia, PACs (which are the most common cause; Fig. 15-1), atrial flutter (AFL), supraventricular tachycardias (SVTs; especially those mediated by atrioventricular [AV] bypass tracts [BTs]; Fig. 15-2), and acute atrial stretch. Identification of these triggers has clinical importance because treatment approaches directed at elimination of the triggers (e.g., radiofrequency [RF] ablation of the initiating PACs or SVT) can be curative in selected patients.

FIGURE 15-1 Atrial fibrillation (AF) induction by premature atrial complexes (PACs) originating from the right superior pulmonary vein (PV). Two monomorphic PACs (arrows) occur at short coupling intervals and are inscribed within the T wave. The second PAC (red arrows) triggers AF.

FIGURE 15-2 Atrial fibrillation (AF) induction by orthodromic atrioventricular reentrant tachycardia (AVRT). CS_dist = distal coronary sinus; CS_prox = proximal coronary sinus; HRA = high right atrium; RVA = right ventricular apex.

Pulmonary Vein Triggers

Triggering foci of rapidly firing cells within the sleeves of atrial myocytes extending into the pulmonary veins (PVs) have been clearly shown to be the underlying mechanism in most cases of paroxysmal AF.⁴ Supporting this idea are clinical studies of impulses generated by single foci propagating from individual PVs or other atrial regions to the remainder of the atria as fibrillatory waves and abolition of AF by RF ablation to eliminate or isolate the venous foci.

Based on several features, the thoracic veins are highly arrhythmogenic. The PV-LA junction has discontinuous myocardial fibers separated by fibrotic tissues and hence is highly anisotropic. Insulated muscle fibers can promote reentrant excitation, automaticity, and triggered activity. These regions likely resemble the juxtaposed islets of atrial myocardium and vascular smooth muscle in the coronary sinus (CS) and AV valves that, under normal circumstances, manifest synchronous electrical activity but develop delayed afterdepolarizations and triggered activity in response to catecholamine stimulation, rapid atrial pacing, or acute stretch.⁵

Furthermore, the PVs of patients with paroxysmal AF demonstrate abnormal properties of conduction so that there can be markedly reduced refractoriness within the PVs, progressive conduction delay within the PV in response to rapid pacing or programmed stimulation, and often conduction block between the PV and the LA. Such findings are much more common in patients with paroxysmal AF than in normal subjects.^2,⁶ Rapidly firing foci can often be recorded within the PVs with conduction block to the LA. Administration of catecholamines such as isoproterenol can lead to shortening of the LA refractory period, thereby allowing these foci to propagate to the LA with the induction of AF.⁶ These discontinuous properties of conduction within the PV can also provide a substrate for reentry within the PV itself, although this remains to be proven.⁵

Non–Pulmonary Vein Triggers

Although more than 90% of triggering foci that are mapped during electrophysiological (EP) studies in patients with paroxysmal AF occur in the PVs, foci within the superior vena cava (SVC), small muscle bundles in the ligament of Marshall, and the musculature of the CS have been identified. Although these latter locations of triggering foci are uncommon in patients with paroxysmal AF, the common factor is that the site of origin is often within a venous structure that connects to the atrium. Other sites of initiating foci can be recorded in the LA wall or along the crista terminalis in the right atrium (RA).⁵

Mechanism of Maintenance of Atrial Fibrillation

Having been initiated, AF can be brief; however, various factors can act as perpetuators, thus ensuring the maintenance of AF.² One factor is the persistence of the triggers and initiators that induced the AF, which then act as an engine driving the continuation of AF. In this setting, maintenance of AF is dependent on the continued firing of the focus (the so-called focal driver). However, AF can persist even in the absence of the focal drivers. Without focal drivers, persistence of AF results from a combination of electrical and structural remodeling processes characterized by atrial dilation and shortening of atrial refractoriness (see later). These factors can be present at baseline or, alternatively, induced by the AF itself.

Several theories have been proposed to explain the EP mechanisms underlying AF, including the multiple wavelet theory, the single circuit reentry theory, and rapidly discharging atrial focus with fibrillatory conduction.

Multiple Wavelet Theory

For many years, the most widely held theory on the maintenance of AF was the multiple wavelet hypothesis, which was a key development in our understanding of the mechanism of AF. Moe and associates noted that, “The grossly irregular wavefront becomes fractionated as it divides about islets or strands of refractory tissue, and each of the daughter wavelets may now be considered as independent offspring. Such a wavelet may accelerate or decelerate as it encounters tissue in a more or less advanced state of recovery.”⁷ Moe and associates subsequently hypothesized that AF is sustained by multiple randomly wandering wavelets that collided with each other and were extinguished, or divided into daughter wavelets that continually reexcited the atria.⁷ Those functional reentrant circuits are therefore unstable; some disappear, whereas others reform. These circuits have variable, but short, cycle lengths (CLs), resulting in multiple circuits to which atrial tissue cannot respond in a 1:1 fashion. As a result, functional block, slow conduction, and multiple wavefronts develop. It has been suggested that at least four to six independent wavelets are required to maintain AF. These wavelets rarely reenter themselves but can reexcite portions of the myocardium recently activated by another wavefront, a process called random reentry. As a result, there are multiple wavefronts of activation that can collide with each other and extinguish themselves or create new wavelets and wavefronts, thereby perpetuating the arrhythmia.

The persistence of multiple-circuit reentry depends on the ability of a tissue to maintain enough simultaneously reentering wavefronts so that electrical activity is unlikely to extinguish simultaneously in all parts of the atria. Therefore, the more wavelets are present, the more likely it is that the arrhythmia will be sustained. The number of wavelets on the heart at any moment depends on the atrial mass, refractory period, conduction velocity, and anatomical obstacles in different portions of the atria. In essence, a large atrial mass with short refractory periods and conduction delay would yield increased wavelets and would present the most favorable situation for AF to be sustained.^2,⁸

Single Circuit Reentry Theory

Studies in isolated human atrial preparations questioned the randomness of atrial activity and suggested the presence of a single source of stable reentrant activity (“mother rotor”) that serves as a periodic background focus, with break-up of emanating waves in atrial tissue of variable electrical properties and anatomical obstacles into multiple wavelets spreading in various directions. Although well represented in animal studies, rotors have not been observed in whole human atria studied at the time of thoracic surgery. More recent data using different techniques have shown that functional reentry (or anatomical reentry with a functional component), in the form of spiral waves rotating around microreentrant circuits approximately 1 cm in diameter, was suggested to be the most likely cause of AF. Other studies have shown that these dominant rotors that drive AF invariably originate and anchor in the LA, with the RA activated passively.^8,⁹

Focal Drivers with Fibrillatory Conduction

Although multiple wandering wavelets probably account for most cases of AF, occasionally a single, rapidly firing focus can be identified with EP mapping. Impulses initiated by ectopic focal activity propagate into the atria to encounter heterogeneously recovered tissue. When cardiac impulses are continuously generated at a rapid rate from any source or any mechanism, they activate the tissue of that cardiac chamber in a 1:1 manner, up to a critical rate. However, when this critical rate is exceeded, so that not all the tissue of that cardiac chamber can respond in a 1:1 fashion (e.g., because the CL of the driver is shorter than the refractory periods of those tissues), fibrillatory conduction develops. Fibrillatory conduction can be caused by spatially varying refractory periods or by the structural properties of atrial tissue, with source-sink mismatches providing spatial gradients in the response.² Thus, fibrillatory conduction is characterized by activation of tissues at variable CLs, all longer than the CL of the driver, because of variable conduction block. In that manner, activation is fragmented.² This is the mechanism of AF in several animal models in which the driver consists of a stable, abnormally automatic focus of a very short CL, a stable reentrant circuit with a very short CL, or an unstable reentrant circuit with a very short CL. It also appears to be the mechanism of AF in patients in whom activation of the atria at very short CLs originates in one or more PVs. The impulses from the PVs seem to precipitate and maintain AF. Autonomic influences (parasympathetic or sympathetic) can cause some of these rapid discharges. Of note, it has also been suggested that fibrillatory conduction caused by a reentrant driver can potentially be the cause of ventricular fibrillation (VF).

Substrate for Atrial Fibrillation

AF results from the interplay between a trigger for initiation and a vulnerable EP substrate for maintenance. The fact that most potential triggers do not initiate AF suggests some role for functional and structural substrates in most patients. However, the relative contribution of triggers versus substrate can vary with the clinical context, and the exact nature of the interaction between triggers and substrate remains to be elucidated.⁸

AF commonly occurs in the context of other cardiac or noncardiac pathological conditions, such as valvular disease, hypertension, ischemic heart disease, heart failure, or hyperthyroidism. Depending on the type, extent, and duration of such external stressors, a cascade of time-dependent adaptive, as well as maladaptive, atrial responses develops in order to maintain homeostasis (so-called atrial remodeling), including changes at the ionic channel level, cellular level, or extracellular matrix level, or a combination of these, thus resulting in structural, functional, and electrical consequences. A hallmark of atrial structural remodeling is atrial dilation, often accompanied by a progressive increase in interstitial fibrosis. Atrial arrhythmias, especially AF, are the most common manifestations of electrical remodeling.¹⁰

Increased dispersion in atrial refractoriness and inhomogeneous dispersion of conduction abnormalities, including block, slow conduction, and dissociation of neighboring atrial muscle bundles, are key elements in the development of the substrate of AF. Importantly, different pathological conditions can be associated with a different set of remodeling responses in the atria.¹¹

Even in the setting of lone AF, whereby no structural heart disease is apparent, there is accumulating evidence that occult abnormalities (e.g., patchy fibrosis, inflammatory infiltrates, loss of myocardial voltage, conduction slowing, altered sinus node function, and vascular dysfunction) can be observed and likely represent an early stage of atrial remodeling contributing to the substrate of AF.¹²

Atrial Remodeling in Atrial Fibrillation

It is well known from clinical practice that AF is a progressive arrhythmia. Eventually, in 14% to 24% of patients with paroxysmal AF, persistent AF will develop, even in the absence of progressive underlying heart disease. Furthermore, conversion of AF to NSR, electrically or pharmacologically, becomes more difficult when the arrhythmia has been present for a longer period. In fact, the arrhythmia itself results in a cascade of electrical and structural changes in the atria that are themselves conducive to the perpetuation of the arrhythmia (“AF begets AF”), a process known as remodeling.²⁰ Recurrent AF can potentially lead to irreversible atrial remodeling and eventually permanent structural changes that account for the progression of paroxysmal to persistent and finally to permanent AF, characterized by the failure of electrical cardioversion or pharmacological therapy, or both, to restore and maintain NSR. Even after cessation of AF, these abnormalities persist for periods that vary in proportion to the duration of the arrhythmia.^17,²¹

Changes in atrial EP features that are induced by AF can occur through alterations in ion channel activities that cause partial depolarization and abbreviation of atrial refractoriness. These changes promote the initiation and perpetuation of AF (electrical remodeling) and the modification of cellular Ca²⁺ handling, which causes contractile dysfunction (contractile remodeling), as well as atrial dilation with associated structural changes (structural remodeling). Electrical remodeling can potentially begin within a few hours after the onset of AF, whereas the structural changes are slower, likely starting after several weeks.¹⁷

Electrical remodeling results from the high rate of electrical activation. The EP changes typical of atrial myocytes during AF are shortening of the atrial refractory period and action potential duration, reduction in the amplitude of the action potential plateau, and loss of response of action potential duration to changes in rate (abnormal restitution). Whereas the normal atrial action potential duration shortens in response to pacing at shorter CLs, AF results in loss of this rate dependence of atrial action potential duration, and the atrial refractory period fails to lengthen appropriately at slow rates (e.g., with return to NSR). These changes can explain the increased duration of AF because, according to the multiple wavelet theory, a short wavelength results in smaller wavelets, which increase the maximum number of wavelets, given a certain atrial mass.^2,²⁰ Tachycardia-induced changes in refractoriness are spatially heterogeneous, and there is increased variability both within and among various atrial regions that may promote atrial vulnerability and AF maintenance and provide a substrate for reentry.

The mechanism for electrical remodeling and shortening of the atrial refractory period is not entirely clear. Several potential explanations exist, including ion channel remodeling, angiotensin II, and atrial ischemia. Shortening of the atrial action potential can be caused by a net decrease of inward ionic currents (Na⁺ or Ca²⁺), a net increase of outward currents (K⁺), or a combination of both. The decrease of I_CaL seems to be responsible for shortening of the atrial action potential, whereas the decrease of I_to is considered to result in loss of physiological rate adaptation of the action potential. The reduction in I_CaL can be explained by a decreased expression of the L-type Ca²⁺ channel α_1C subunit, likely as a compensatory mechanism to minimize the potential for cytosolic Ca²⁺ overload secondary to increased Ca²⁺ influx during the rapidly repetitive action potentials during AF. Verapamil, an L-type Ca²⁺ channel blocker, was shown to prevent electrical remodeling and hasten complete recovery without affecting inducibility of AF, whereas intracellular Ca²⁺ overload, induced by hypercalcemia or digoxin, enhances electrical remodeling. Electrical remodeling can be attenuated by the sarcoplasmic reticulum’s release of the Ca²⁺ antagonist ryanodine, a finding suggesting the importance of increased intracellular Ca²⁺ to the maladaptation of the atrial myocardium during AF. Angiotensin II may also be involved in electrical and atrial myocardial remodeling, and angiotensin II inhibitors may prevent atrial electrical remodeling. Angiotensin-converting enzyme inhibitors reduce the incidence of AF in patients with left ventricular (LV) dysfunction after myocardial infarction and in patients with chronic ischemic cardiomyopathy. Atrial ischemia is another possible contributor to electrical remodeling and shortening of the atrial refractory period via activation of the Na⁺-H⁺ exchanger.^10,¹¹

Furthermore, persistent AF can result in other changes within the atria, including gap junctional remodeling, cellular remodeling, and sinus node remodeling. Gap junctional remodeling is manifest as an increase in the expression and distribution of connexin 43 and heterogeneity in the distribution of connexin 40, both of which are intercellular gap junction proteins.²⁰ Cellular remodeling is caused by the apoptotic death of myocytes with myolysis, which may not be entirely reversible. AF results in marked changes in atrial cellular substructures, including loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin.²⁰

Sustained AF has also been associated with structural changes, such as myocyte hypertrophy, myocyte death, impaired atrial contractility, and atrial stretch and dilation, which act to reduce conduction velocity.²⁰ Atrial dilation increases electrical instability by shortening the effective refractory period and slowing atrial conduction.¹⁰ These structural changes, many of which probably are irreversible, appear to occur more slowly, over periods of weeks to months.

Contractile remodeling is likely caused by downregulation of I_CaL (resulting in reduced release of Ca²⁺ during systole), as well as myolysis (loss of sarcomeres). Contractile remodeling can potentially cause thrombus formation and atrial dilation. Contractile remodeling starts early after onset of AF, and its recovery generally takes longer than reversal of electrical remodeling, likely because of the time it takes for the atria to replace lost sarcomeres.

In addition to remodeling of the atria, the sinus node can undergo remodeling, resulting in sinus node dysfunction and bradyarrhythmias caused by reduced sinus node automaticity or prolonged sinoatrial conduction. The phenomenon of sinus node remodeling may contribute to the episodes of bradycardia seen in the tachycardia-bradycardia syndrome and may reduce sinus rhythm stability and increase the stability of AF.²⁰ As mentioned earlier, elements of the sinus bradycardia appear to be functionally reversible if the tachycardia is prevented.

Studies suggest that the PVs are more susceptible to electrical alterations resulting from AF than the atria. Although the PVs display significantly longer refractory periods at baseline than the atria, they exhibit more prominent shortening of refractoriness after a brief episode of pacing-induced AF. Moreover, the short-term presence of AF does influence PV EP features by slowing the conduction velocity without affecting the conduction times of the atria. Structural changes in the atria after remodeling, such as stretch, can also result in increased PV activity. Atrial stretch can lead to increased intraatrial pressure, causing a rise in the rate and spatiotemporal organization of electrical waves originating in the PVs. These changes imply that electrical and structural remodeling increases the likelihood of ectopic PV automaticity and AF maintenance. Therefore, rather than AF begets AF, one can vary that theme: “PV-induced paroxysmal AF begets PV-induced chronic AF.”²²

Atrial tachycardia (AT)–induced remodeling can potentially underlie various clinically important phenomena, such as the tendency of patients with other forms of supraventricular arrhythmias to develop AF, the tendency of AF to recur early after electrical cardioversion, the resistance of longer duration AF to antiarrhythmic medications, and the tendency of paroxysmal AF to become persistent.²

If NSR is restored within a reasonable period of time, EP changes and atrial electrical remodeling appear to normalize gradually, atrial size decreases, and atrial mechanical function is restored. These observations lend support to the idea that the negative downhill spiral in which AF begets AF can be arrested with NSR that perpetuates NSR, and restoration of NSR may forestall progressive remodeling and the increase in duration and frequency of arrhythmic episodes by reverse remodeling.

Role of Autonomic Nervous System in Atrial Fibrillation

Cardiac function is modulated by both the extrinsic and the intrinsic cardiac autonomic nervous systems. The extrinsic (central) system is composed of the vagosympathetic system from the brain and spinal cord to the heart. The intrinsic system is composed of a large network of autonomic cardiac ganglia buried throughout the epicardial fat within the pericardial space. Groups of several cardiac ganglia comprise plexuses that coalesce in specific locations, and different groups of ganglia have different sites of innervation throughout the heart. Atrial ganglia contain afferent neurons from the atrial myocardium and from the central autonomic nervous system, and efferent cholinergic and adrenergic neurons, with heavy innervation of the PV myocardium and the atrial myocardium surrounding the ganglionic plexuses. Additionally, an extensive array of interconnecting neurons creates a communication network among the different ganglionic plexuses, as well as between the ganglionic plexuses and the atrium and PV myocardium. The intrinsic system receives input from the extrinsic system but acts independently to modulate numerous cardiac functions, including automaticity, contractility, and conduction.^23,²⁴

Several studies have suggested that both divisions of the autonomic nervous system are involved in the initiation, maintenance, and termination of AF, with a predominant role of the parasympathetic system. Electrical stimulation of autonomic nerves on the heart itself can facilitate the induction of AF. Increased vagal tone is frequently involved in the onset of AF in patients with structurally normal hearts. Parasympathetic stimulation shortens the atrial refractory period, increases the dispersion of refractoriness, and decreases the wavelength of reentrant circuits that facilitate initiation and perpetuation of AF. Long-term vagal denervation of the atria renders AF less easily inducible in animal experiments, presumably because of increased EP homogeneity. On the other hand, vagal stimulation results in maintenance of AF, and catheter ablation of the parasympathetic autonomic nerves entering the RA from the SVC prevents vagally induced AF in animal models. Sympathetic stimuli also shorten the atrial refractory period and increase the vulnerability to AF.^23,²⁵

Spatial heterogeneity of refractoriness can also be produced by the heterogeneity of autonomic innervation. It has been well established that vagal innervation of the atria is heterogeneous and vagal stimulation can precipitate AF as a result of heterogeneity of atrial refractoriness. Heterogeneity of sympathetic neural inputs also plays a role in AF. In animal models, sympathetic atrial denervation facilitates sustained AF, and AF induced by rapid RA pacing is associated with nerve sprouting and a heterogeneous increase in sympathetic innervation. Enhanced sympathetic activity can promote automaticity, delayed afterdepolarization–related AT, and focal AF. Sympathetic stimulation also shortens atrial refractoriness and may facilitate the induction of AF in patients with structural heart disease, in whom possible heterogeneous sympathetic denervation leads to increased refractoriness heterogeneity.

Experimental evidence suggests that the electrical properties of the PVs are also modulated by changes in autonomic tone.⁶ Anatomical studies revealed that the LA and PVs are innervated by adrenergic and cholinergic nerve fibers. A collection of ganglia is localized on the posterior wall of the LA between the superior PVs. Subsequent studies found that ganglionated plexuses clustered at the PV entrances (within fat pads) could be stimulated without atrial excitation. For patients with PV foci, a primary increase in adrenergic tone followed by a marked vagal predominance was reported just prior to the onset of paroxysmal AF. A similar pattern of autonomic tone was reported in an unselected group of patients with paroxysmal AF and various cardiac conditions.²⁵ Activation of the ganglionic plexuses at the PV-LA junction can potentially result in conversion of PV ectopy to AF. Furthermore, ablation of the ganglionated plexuses located at the atrial entrances or antra of the PVs can potentially abolish or reduce AF inducibility.