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Atrial fibrillation: Pathophysiology and epidemiology
Classification of atrial fibrillation
Atrial fibrillation (AF) has been described as lone, idiopathic, nonvalvular, valvular, paroxysmal, persistent, or permanent. Each of these classifications has implications regarding mechanisms as well as response to therapy. At the initial detection of AF, it is impossible to know the subsequent pattern of duration and frequency of recurrences. Thus, a designation of the first-detected episode of AF is made on the initial diagnosis, irrespective of the duration of the arrhythmia. When the patient has experienced two or more episodes, AF is classified as recurrent.
After termination of an episode of AF, the rhythm can be classified as paroxysmal or persistent ( Table 16.1 ). Paroxysmal AF is defined as AF that terminates spontaneously or with intervention within 7 days of onset. Persistent AF lasts longer than 7 days and often requires electrical or pharmacological cardioversion. Subcategories of persistent AF (according to arrhythmia duration) include early persistent AF (defined as AF that is sustained beyond 7 days but is less than 3 months in duration) and long-standing persistent AF (defined as AF that is sustained longer than 1 year but is being considered for ablation). Permanent AF refers to AF that is accepted by the patient and physician, and for which no further attempts to restore or maintain normal sinus rhythm (NSR) will be undertaken. Hence, the term permanent AF represents a therapeutic attitude on the part of the patient and physician rather than an inherent pathophysiological attribute of AF.
TABLE 16.1
Classifications of Atrial Fibrillation (AF)
From Kirchhof P. et al. ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893–2962.
| AF PATTERN | DEFINITION |
|---|---|
| First diagnosed AF | AF that has not been diagnosed before, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms. |
| Paroxysmal AF | Self-terminating, in most cases within 48 hours. Some AF paroxysms may continue for up to 7 days. a AF episodes that are cardioverted within 7 days should be considered paroxysmal. a |
| Persistent AF | AF that lasts longer than 7 days, including episodes that are terminated by cardioversion, either with drugs or by direct current cardioversion, after 7 days or more. |
| Long-standing persistent AF | Continuous AF lasting for ≥1 yr when it is decided to adopt a rhythm control strategy. |
| Permanent AF | AF that is accepted by the patient (and physician). Hence, rhythm control interventions are, by definition, not pursued in patients with permanent AF. Should a rhythm control strategy be adopted, the arrhythmia would be reclassified as “long-standing persistent AF.” |
a The distinction between paroxysmal and persistent AF is often not made correctly without access to long-term monitoring. Hence, this classification alone is often insufficient to select specific therapies. If both persistent and paroxysmal episode are present, the predominant pattern should guide the classification.
Although useful, this arbitrary classification does not account for all presentations of AF, and overlap occurs. Paroxysmal AF often progresses to longer, non-self-terminating episodes. Additionally, the pattern of AF can change in response to treatment. AF that has been persistent can become paroxysmal with antiarrhythmic drug therapy, and AF that had been permanent can potentially be cured or made paroxysmal by surgical or catheter-based ablation. Furthermore, the distinction between persistent and permanent AF is not only a function of the underlying arrhythmia but also a reflection of the clinical pragmatism of the patient and physician. The severity of symptoms associated with AF, anticoagulation status, and patient preference all affect the decision of whether and when cardioversion will be attempted. This decision would then affect the duration of sustained AF and could lead to a diagnosis of persistent or permanent AF. Furthermore, significant discrepancies exist between the clinical AF classification and the objective cardiac device-derived assessments of AF temporal persistence (in AF patients with pacemakers or defibrillators) ( Fig. 16.1 ). Patients within the same clinical class (“paroxysmal” or “persistent” AF) are highly heterogeneous with regard to AF temporal persistence, arrhythmia burden, and stages of disease.
AF can be classified as valvular or nonvalvular, a classification that carries certain implications for the choice of therapeutic options for stroke prevention. Valvular AF generally refers to AF in the setting of moderate-to-severe mitral stenosis (potentially requiring surgical intervention) or in the presence of an artificial (mechanical) heart valve. Nonvalvular AF does not imply the absence of valvular heart disease; rather, nonvalvular AF is AF in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve.
The terms lone and idiopathic AF have been variably defined in the literature, but they generally refer to younger AF patients who have no clinical or echocardiographic evidence of cardiopulmonary disease, hypertension, or diabetes mellitus. However, this categorization is being abandoned, since the category of lone AF no longer has mechanistic or clinical utility. Similarly, the term chronic AF has variable definitions and should not be used to describe populations of patients with AF.
Mechanism of atrial fibrillation
The pathogenesis of AF remains incompletely understood and is believed to be complex, multifactorial, and variable in different individuals. Two concepts of the underlying mechanism of AF have received considerable attention: factors that trigger AF and factors that perpetuate the arrhythmia. In general, patients with frequent, self-terminating episodes of AF are likely to have a predominance of factors that trigger AF, whereas patients with AF that does not terminate spontaneously are more likely to have a predominance of perpetuating factors. Although such gross generalization has clinical usefulness, often there is considerable overlap of these mechanisms. The typical patient with paroxysmal AF has identifiable ectopic foci initiating the arrhythmia, but these triggers cannot be recorded in all patients. Conversely, occasional patients with persistent or permanent AF can be cured of their arrhythmia by ablation of a single triggering focus, a finding suggesting that perpetual firing of the focus can potentially be the mechanism sustaining this arrhythmia in some cases.
Advanced mapping technologies, along with studies in animal models, have suggested the potential for complex pathophysiological substrates and modifiers responsible for AF ( Fig. 16.2 ), including the following: (1) continuous aging or degeneration of atrial tissue and the cardiac conduction system; (2) progression of structural heart disease (e.g., valvular heart disease and cardiomyopathy); (3) myocardial ischemia, local hypoxia, electrolyte derangement, and metabolic disorders (e.g., atherosclerotic heart disease, chronic lung disease, hypokalemia, and hyperthyroidism); (4) inflammation related to pericarditis or myocarditis, with or without cardiac surgery; (5) genetic predisposition; (6) drugs; and (7) autonomic influences.
Mechanism of initiation of atrial fibrillation
The factors responsible for the onset of AF include triggers that induce the arrhythmia and a receptive substrate that sustains it. There are two different types of arrhythmias that can potentially play a role in generating AF: PACs that initiate AF (focal triggers) and focal tachycardia that either induces fibrillation in the atria or mimics AF by creating a pattern of rapid and irregular depolarization wavefronts in the atria for as long as the focus continues to discharge.
The mechanism of initiation of AF is not certain in most cases and likely is multifactorial. The triggers are diverse yet may not cause AF in the absence of other contributors. Triggers propagating into the atrial myocardium can potentially initiate multiple reentrant wavelets and AF. In some patients with paroxysmal AF, impulses initiated by ectopic focal activity propagate into the LA and encounter heterogeneously recovered tissue. If reentry were assumed to be the mechanism of AF, initiation would require an area of conduction block and a wavelength of activation short enough to allow the reentrant circuits to persist in the myocardium.
Once triggered, AF can be self-sustained, whereby the continued firing of the initiating focus may not be required for the maintenance of the arrhythmia. In this setting, ablation of the focus may not terminate AF but can potentially prevent the reinitiation of AF. Conversely, initiation and maintenance of AF can depend on uninterrupted periodic activity of a few discrete reentrant or triggered sources localized to the LA (i.e., focal drivers), emanating from such sources to propagate through both atria and interact with anatomical or functional obstacles, thus leading to fragmentation and multiple wavelet formation. Factors such as wavefront curvature, source-sink relationships, and spatial and temporal organization are all relevant to the understanding of the initiation of AF by the interaction of the propagating wavefronts with such anatomical or functional obstacles. Indeed, all these factors, which differ from triggers, importantly influence the initiators of AF.
AF-triggering factors include sympathetic or parasympathetic stimulation, bradycardia, PACs (which likely are the most common cause; Fig. 16.3 ), atrial flutter (AFL; see Fig. 13.3 ), supraventricular tachycardias (SVTs; especially those mediated by atrioventricular [AV] bypass tracts [BTs]; Fig. 16.4 ), and acute atrial stretch. Identification of these triggers has clinical importance because treatment approaches directed at the elimination of the triggers (e.g., catheter ablation of the initiating PACs or SVT) can be curative in selected patients.
Pulmonary vein triggers
Triggering foci of rapidly firing cells within the sleeves of atrial myocytes extending into the PVs have been shown to be the underlying mechanism in most cases of paroxysmal AF. 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 PV foci. The PVs also represent the main trigger site for AF initiation in patients with recurrent persistent AF, with an overall prevalence similar to that found in patients with paroxysmal AF.
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 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.
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. 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 and induce AF. The discontinuous properties of conduction within the PV can also provide a substrate for reentry within the PV itself, although this remains to be proven.
Nonpulmonary vein triggers
Although more than 90% of AF triggering foci that are mapped during 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 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).
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. 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”). Alternatively, 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 but can also be induced by the AF itself.
The mechanisms responsible for perpetuation of human AF remain controversial. It is now well established that AF is not spatially uniform within human atria; marked differences are observed in regional spatial disorganization, rate gradients, and spectral gradients between different atrial regions. The controversy is currently centered on whether myocardial activation in AF exhibits any organization and, if it does, whether this organization is due to functional or structural properties of the tissue. The hierarchical theory of AF proposes a degree of organization in AF that is sustained by discrete electrical drivers. In contrast, the anarchical theory proposes that AF is the result of randomly propagating, self-perpetuating wavelets that wander throughout the atria without discrete drivers. Differences in reported AF mechanisms may be because AF is recorded across diverse models, investigational tools, and clinical populations, ranging from paroxysmal to permanent AF. It is also possible that several mechanisms of AF might exist, even in the same patient.
Multiple wave reentry hypothesis
For many years, the “multiple wave reentry” hypothesis was the most widely held theory on the maintenance of AF and was a key development in our understanding of the mechanism of AF. Moe et al. proposed the multiple wavelet hypothesis of AF based on observations during induced AF in the canine vagal nerve stimulation model. According to this hypothesis, AF is a disorganized anarchical atrial rhythm sustained by multiple randomly wandering wavelets in both atria that collide with each other and extinguish themselves or create new, daughter wavelets that continually reexcite the atria and perpetuate the arrhythmia. Those functional reentrant circuits are therefore unstable; some disappear, while others reform. These circuits have variable, but short, CLs to which atrial tissue cannot respond in a 1:1 fashion. As a result, functional block, slow conduction, and multiple wavefronts develop. Moe et al. developed a computational model that indicated that 23 to 40 such random wandering wavelets were necessary to sustain AF. Later, studies by Allessie et al. suggested that only four to six simultaneously circulating, random wavelets were necessary to sustain AF. These wavelets rarely reenter themselves but can reexcite portions of the myocardium recently activated by another wavefront, a process called random reentry.
In simulated cardiac tissue, multiple-wavelet fibrillation is equivalent to spiral/scroll waves that are inherently unstable and spontaneously develop wave breaks along the arm of the rotor, which then form daughter wavelets. Because multiple-wave-reentry fibrillation is purely reentrant, its initiation requires a trigger to create the original unstable spiral/scroll wave that subsequently breaks up to create daughter wavelets; however, once initiated, additional triggers are no longer required to maintain fibrillation; AF self-replenishes due to the collision between unstable spiral waves and wavebreak.
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 larger the number of wavelets present, the more likely the arrhythmia will be sustained. The number of wavelets coexisting at any moment depends on the atrial mass, excitation wavelength, refractory period, conduction velocity, and anatomical obstacles in different portions of the atria. In essence, a large atrial mass with short refractory periods and prominent conduction delay would yield increased wavelets and would present the most favorable situation for AF to be sustained.
Clinical support for this hypothesis seemed to come from the surgical maze and some substrate-based catheter ablation procedures, which were proposed to result in dividing the atrial into small electrical compartments and thus disallowing maintenance of the randomly propagating wavelets. The reentrant circuits that comprise multiple wave reentry are functional, multiple, and dynamic; thus, ablation of multiple wave reentry is not aimed at eliminating the possibility of its existence but at maximizing the probability of its spontaneous termination through collisions between circuit cores and unexcitable tissue boundaries via atrial debulking and compartmentalization.
Localized source hypothesis
In contrast to the nonhierarchical, self-sustaining disorganized electrical activity implicated in the multiple wavelet theory, recent evidence suggests the presence of the hierarchical electrical organization in which localized sources drive disorganized activity. This hypothesis suggests that AF is intermittently maintained by a small number of localized (spatially stable) high-frequency sources with periods of self-sustaining disorganization. Rotors and focal sources exhibit 1:1 activation within their spatial domain, with peripheral disorganization. Localized sources (“drivers”) can be either discrete foci with centrifugal spread of activation or small anatomical reentry circuits or functional rotors.
This concept was supported by experimental studies using high-resolution optical mapping, which demonstrated spatial and temporal organization during AF. Furthermore, recent studies that repeated the original canine studies of Moe et al. and used high-density simultaneous biatrial mapping showed that AF was perpetuated by repetitive activation patterns emanating from focal activation sources, rather than meandering multiwavelet reentry. All wavefronts emanated from focal sources, largely either colliding or merging with each other at variable sites or encountering refractory tissue. Those independent focal sources initiated wavefronts reactivating the atria after an electrically silent period, lasted several AF cycles, and controlled surrounding atrial tissue, thereby maintaining AF.
When cardiac impulses are continuously generated at a rapid rate from any source or any mechanism, they activate myocardial tissue in a 1:1 manner, up to a critical rate. Once this critical rate is exceeded, not all the tissue of the 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), and “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. 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. This is the mechanism of AF in several animal models in which the driver consists of a stable, abnormal 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.
The concept of fibrillatory conduction is relevant to the “mother rotor fibrillation” hypothesis, in which a fast stationary or meandering spiral/scroll wave in one region of the tissue develops peripheral wave breaks as the spiral/scroll arm propagates into surrounding tissue with longer refractory periods. Though some investigators suggest that these mother rotors are likely fixed, others have suggested that they may precess (i.e., wobble), albeit in small, fairly well-defined areas. In atria with extensive fibrosis, multiple stable rotors can possibly coexist in different regions, insulated by intervening tissue that cannot maintain 1:1 conduction. This variant is equivalent to mother rotor fibrillation with multiple stable mother rotors. Unlike multiple-wavelet fibrillation, in which the functional reentry is inherently unstable and nonlocalized and the spontaneous peripheral wave breaks play a causal role in both initiating and maintaining fibrillation, mother rotor fibrillation is driven by a localized source and the peripheral wave breaks are noncausal epiphenomena. However, similar to multiple-wave-reentry fibrillation, mother rotor fibrillation is purely reentrant and requires a trigger to initiate the original rotor; once initiated, no further triggers are necessary to perpetuate fibrillation.
Recently, several studies using novel mapping technologies and computational methods for advanced signal processing have provided a growing body of evidence in favor of organized drivers underlying perpetuation of human AF. AF could be acutely terminated by directly ablating sites of rotors and focal sources that could be identified using widely different types of mapping technologies and analysis algorithms, including phase mapping, activation time mapping, electrographic flow, and spectral analysis. However, the definition used for localized drivers in AF has varied in different studies, and the mechanistic role of focal and rotational activation patterns identified by current AF mapping algorithms is yet to be proven.
Substrate for atrial fibrillation
As noted, 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.
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 to maintain homeostasis (so-called atrial remodeling), including changes at the ionic channel level, cellular level, extracellular matrix level, or a combination of these, which result in electrical, functional, and structural 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. 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.
Even in the setting of the AF occurring in the absence of apparent structural heart disease, 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.
Atrial electrophysiological properties
In normal atrial cardiomyocytes, phase 0 of the action potential is mediated by the rapidly activating sodium (Na + ) current (I Na ). These potentials are called fast response potentials (see Chapter 2 ). As a result, the atrium has several properties that permit the development of very complex patterns of conduction and an extremely rapid atrial rate, as seen in AF. The action potential duration is relatively short, and reactivation can occur partially during phase 3 and usually completely within 10 to 50 milliseconds after return to the diastolic potential. The refractory period shortens with increasing rate, and very rapid conduction can occur.
Patients with AF and no apparent structural heart disease appear to have increased dispersion of atrial refractoriness, which correlates with enhanced inducibility of AF and spontaneous episodes. Some patients have site-specific dispersion of atrial refractoriness and intra-atrial conduction delays resulting from nonuniform atrial anisotropy.
Atrial fibrosis
Atrial fibrosis plays an important role in the pathophysiology of AF. Atrial fibrosis results from various cardiac insults that share common fibroproliferative signaling pathways. Fibrotic myocardium exhibits slow and inhomogeneous conduction, with spatial “non-uniform anisotropic” impulse propagation, likely secondary to reduced intercellular coupling, discontinuous branching architecture, and zigzagging circuits. When combined with inhomogeneous dispersion of refractoriness within the atria, conduction block provides milieu necessary for the development of reentry. The greater the slowing of conduction velocity in fibrotic myocardium, the shorter the anatomical circuit needed to sustain a reentrant wavelet. In fact, reentrant circuits need to be only a few millimeters in length in discontinuously conducting tissue. Thus, atrial regions with advanced fibrosis can harbor local sources for AF. Such a hypothesis would not preclude the remainder of the atria from showing fibrillatory conduction or functional reentrant waves.
Increased atrial fibrosis is a manifestation of the normal aging process as well as various pathological conditions such as hypertension, coronary artery disease, heart failure, and sleep apnea. Increased atrial fibrosis has been demonstrated even in patients with so-called lone or idiopathic AF, suggesting that AF in these patients potentially represents an arrhythmic manifestation of “fibrotic atrial myopathy.” The strong association of sinus node dysfunction and AF (the tachycardia-bradycardia syndrome) also suggests that replacement of atrial myocytes by fibrosis likely plays an important part in the pathogenesis of AF, although in some instances the bradycardia component is a functional response to the tachycardia. Recent studies using delayed-enhancement CMR imaging and electroanatomic voltage mapping demonstrated that the extent and distribution of the fibrotic atrial changes can widely vary among patients with AF. Nonetheless, a higher degree of fibrosis often is observed in patients with persistent AF versus paroxysmal AF. Additionally, atrial fibrosis defined by delayed-enhancement CMR was found to be independently associated with AF recurrence in patients undergoing catheter ablation procedures.
Importantly, AF itself seems to produce various alterations of atrial architecture that further contribute to atrial remodeling, mechanical dysfunction, and perpetuation of fibrillation. Long-standing AF results in loss of myofibrils, accumulation of glycogen granules, disruption in cell-to-cell coupling at gap junctions, and organelle aggregates.
Changes in AF characteristics during evolving fibrosis also have a direct impact on why electrical or drug treatment ultimately fails to achieve conversion to NSR. In the markedly fibrotic and discontinuous atrial tissue, characterized by discontinuous anisotropy, marked degree of gap junctional uncoupling, and fiber branching, the safety factor for propagation is higher than in normal tissue. Hence, blocking of the Na + current to the same degree as is necessary for the termination of functional reentry may not terminate reentry caused by slow and fractionated conduction in fibrotic scars of remodeled atria. Conduction in discontinuous tissue is mostly structurally determined and leads to excitable gaps behind the wavefronts. If a gap is of critical size, the effectiveness of drugs that prolong atrial refractoriness will be limited. Furthermore, scar tissue is likely to exhibit multiple entry and exit points and multiple sites at which unidirectional block occurs. This can potentially lead to activity whose appearance in local extracellular electrograms changes from beat to beat, as well as beat-to-beat CL variability. Although such regions can be expected to respond to defibrillation, AF can resume after extrasystoles or normal sinus beats immediately after conversion, with unidirectional block recurring because of scar.
Atrial stretch
Atrial stretch and dilation can play a role in the development and persistence of AF. Clinically, AF episodes occur more frequently in association with conditions known to cause elevated LA pressure and atrial stretch, such as acutely decompensated heart failure. Additionally, the echocardiographic LA volume index and restrictive transmitral Doppler flow patterns are strong predictors of the development of AF.
The structure of the dilated atria can potentially have important EP effects related to stretch of the atrial myocardium (so-called mechanoelectrical feedback). Acute atrial stretch shortens action potential duration and atrial refractory period and depresses atrial conduction velocity, potentially through a reduction of cellular excitability by the opening of stretch-activated channels or changes in cable properties (membrane resistance, capacitance, and core resistance). Regional stretch for less than 30 minutes activates the immediate early gene program, thus initiating hypertrophy and altering action potential duration in affected areas. Additionally, acutely altered stress and strain patterns augment the synthesis of angiotensin II, which induces myocyte hypertrophy. Angiotensin II can contribute to arrhythmogenic electrical dispersion by regionally increasing L-type calcium (Ca 2+ ) current (I CaL ) and decreasing the transient outward potassium (K + ) current (I to ).
Altered stretch of atrial myocytes also results in the opening of stretch-activated channels, increasing G protein–coupled pathways. This leads to increased protein kinase A and C activity, enhanced I CaL through the cell membrane, and increased release of Ca 2+ from the sarcoplasmic reticulum, leading to Ca 2+ overload and thus promoting afterdepolarizations and triggered activity. Furthermore, acute stretch can promote an increase in dispersion of refractoriness and spatial heterogeneity by causing conduction block and potentially contributing to the development of AF. These alterations occur nonuniformly because stretch is greater in areas of thin versus thick atrial myocardium.
Additionally, chronic atrial stretch, as a result of AF and several conditions associated with AF, can promote atrial fibrosis via the activation of multiple profibrotic and hypertrophic signaling pathways.
Inflammation
There is increasing evidence that implicates inflammation (and its downstream effects, including atrial fibrosis) in the pathogenesis of AF. Clinically, AF occurs frequently in the setting of inflammatory states such as cardiac surgery and acute pericarditis. Major cardiovascular risk factors and conditions associated with AF (such as hypertension, congestive heart failure, coronary artery disease, obesity, and diabetes) have also been linked to low-grade inflammation. Additionally, the levels of inflammatory biomarkers (C-reactive protein [CRP] and interleukin-6 [IL-6]) are significantly elevated in patients with AF. Several meta-analyses strongly indicate that specific circulating inflammatory markers, such as CRP and IL-6, are associated with greater AF risk in the general population and patients who underwent cardiac surgery, as well as with AF recurrence after electrical cardioversion or ablation.
Additionally, local inflammation, including locally driven immune cell and cytokine response, and the paracrine effect of epicardial adipose tissue, appears to play a key role in AF pathophysiology.
There is also evidence suggesting that inflammation is involved in electrical and structural atrial remodeling. Furthermore, inflammation appears to increase the inhomogeneity of atrial conduction directly, potentially via disruption of expression of connexin proteins, leading to impaired intercellular coupling.
It is also likely that inflammation can be a consequence of AF. CRP levels decrease following restoration of NSR. Rapid atrial activation in AF results in Ca 2+ overload in atrial myocytes that can potentially result in cell death, which induces a low-grade inflammatory response. The inflammation, in turn, can induce healing and reparative fibrosis that likely enhance remodeling and promote perpetuation of the arrhythmia.
Currently, the exact role of inflammation in AF is poorly defined, and it remains unclear whether inflammation is actually involved in the mechanisms underlying AF or is simply an epiphenomenon. Given the complexity of AF pathophysiology, the relative impact of inflammation in different stages of atrial remodeling remains to be elucidated. Although therapies directed at attenuating the inflammatory burden (e.g., glucocorticoids, statins, and angiotensin II inhibitors) appeared promising, early clinical trials do not support a significant benefit.
Atrial remodeling in atrial fibrillation
AF is a progressive arrhythmia. In 14% to 24% of patients with paroxysmal AF, persistent AF develops, 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. 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 and pharmacological therapy 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.
Changes in atrial EP characteristics 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 Ca 2+ handling, which causes contractile dysfunction (contractile remodeling), as well as atrial dilation with associated structural changes (structural remodeling). Experimentally, electrical and contractile remodeling begins shortly after the onset of AF, with a parallel decrease in both atrial refractory period and contractility over the first minutes of AF. This is followed by further abbreviation in atrial refractoriness and increase in atrial dimensions over the following days. Structural changes follow a much slower time course, likely starting after several weeks.
Electrical remodeling
Electrical remodeling results from the high rate of electrical activation. The EP changes typical of atrial myocytes during AF include shortening of the action potential duration and atrial refractory period and reduction in the amplitude of the action potential plateau. Furthermore, AF results in deficiency in the ability of the repolarization time course (i.e., action potential duration) to adapt to changes in rate (“abnormal restitution”). Consequently, the atrial refractory period fails to lengthen appropriately at slow rates (e.g., with return to NSR). These changes can contribute to the stability of a longer-lasting form 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. Tachycardia-induced changes in refractoriness are spatially heterogeneous, and there is increased variability both within and among various atrial regions, which can promote atrial vulnerability and AF maintenance and provide a substrate for reentry.
The mechanisms for electrical remodeling and shortening of the atrial refractory period are not entirely clear. Several potential explanations exist, including ion channel remodeling, angiotensin II, and atrial ischemia. The principal components of electrical remodeling include reduction in the L-type Ca 2+ current (I CaL ), rectifier background K + current (I K1 ), and constitutive acetylcholine-regulated K + current (I KACh ), and abnormal expression and distribution of the gap junctions. Recent studies demonstrated that AF persistence was associated with numerous transcriptional changes in ion channel expression.
Downregulation of I CaL seems to be responsible for the shortening of the atrial action potential, whereas a decrease in I to is considered to result in loss of physiological rate adaptation of the action potential. The fast atrial rate during AF causes accumulation of intracellular Ca 2+ , and the reduction in I CaL can be explained by a decreased expression of the L-type Ca 2+ channel α1C subunit, likely as a compensatory mechanism to minimize the potential for cytosolic Ca 2+ overload secondary to increased Ca 2+ influx during the rapidly repetitive action potentials during AF. Verapamil, an L-type Ca 2+ channel blocker, was shown to attenuate electrical remodeling and hasten complete recovery without affecting inducibility of AF, whereas intracellular Ca 2+ overload, induced by hypercalcemia or digoxin, enhances electrical remodeling. Additionally, electrical remodeling can be attenuated by the sarcoplasmic reticulum’s release of the Ca 2+ antagonist ryanodine, a finding suggesting the importance of increased intracellular Ca 2+ to the maladaptation of the atrial myocardium during AF.
Angiotensin II may also be involved in electrical remodeling, and angiotensin II inhibitors can potentially prevent the remodeling process. Angiotensin-converting enzyme inhibitors reduce the incidence of AF in patients with 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.
More recently, microRNAs (miRNAs or miRs), a group of small noncoding RNA molecules that negatively regulate gene expression, were found to have an important role in a wide range of electrical and structural atrial remodeling processes. Furthermore, experimental studies showed that the rapid rates of AF can lead to autonomic atrial remodeling, with heterogeneous increase in atrial sympathetic innervation, which can potentially promote enhanced automaticity, triggered activity, and spatially heterogenous abbreviation of refractoriness.
Furthermore, persistent AF can result in other changes within the atria, including gap junctional remodeling, 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.
Contractile and structural remodeling
Sustained AF has also been associated with structural changes such as myocyte hypertrophy, myocyte death, tissue fibrosis, impaired atrial contractility, and atrial stretch and dilation. Atrial dilation increases electrical instability by shortening the effective refractory period and slowing atrial conduction. These structural changes, many of which probably are irreversible, appear to occur over periods of weeks to months.
Cellular remodeling is caused by the apoptotic death of myocytes with myolysis. 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.
Contractile remodeling is likely caused by downregulation of I CaL (resulting in reduced release of Ca 2+ 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 likely contributes to the episodes of bradycardia seen in the tachycardia-bradycardia syndrome and may reduce sinus rhythm stability and increase the stability of AF. 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 properties 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 lead to increased PV activity. Atrial stretch can lead to increased intra-atrial 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.
Tachycardia-induced atrial 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.
If NSR is restored within a reasonable time period, 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.
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