experimental evidence suggests that ROS may be implicated not only in promoting AF but also in maintaining atrial arrhythmia. The administration of antioxidants such as vitamin C or statins (which are known to have pleiotropic antioxidant effects) decreased AF inducibility in canine models of tachypacing-induced AF [96,97]. Antioxidants such as vitamin C and n-acetylcysteine have been administered to patients undergoing cardiac surgery and have been shown to decrease postoperative AF [98,99]. These early results are encouraging and warrant further investigation of inflammation and oxidative stress as viable therapeutic targets in patients with AF. Reentrant mechanism Maps of AF in animals and humans suggest that this arrhythmia is caused by multiple wandering wavelets ( figure 4), and these may be due to heterogeneity of atrial refractoriness and conduction. In addition, the response of atrial activity to adenosine infusion suggests a reentrant rather than a focal mechanism [100]. Adenosine increases the inward potassium rectifier current, which shortens refractory periods and would accelerate reentrant circuits. In contrast, this effect would slow an automatic or triggered focus. In a series of 33 patients with AF undergoing electrophysiology study, adenosine increased the dominant frequencies, supporting reentrant rather than focal sources for the perpetuation of AF. It has been suggested that at least four to six independent wavelets are required to maintain AF [101]. These wavelets rarely reenter themselves but can re-excite portions of the myocardium recently activated by another wavefront, a process called random reentry [7,102-104]. As a result, there are multiple wavefronts of activation that may collide with each other, extinguishing themselves or creating new wavelets and wavefronts, thereby perpetuating the arrhythmia ( figure 5). The reentrant circuits are therefore unstable; some disappear, while others reform. These circuits have variable but short cycle lengths, resulting in multiple circuits to which atrial tissue cannot respond in a 1:1 fashion. As a result, functional block, slow conduction, and multiple wave fronts develop [104]. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 12/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Patients with AF may have increased dispersion of refractoriness. This correlates with enhanced inducibility of AF and spontaneous episodes [105] likely related to unstable reentry circuits. Some patients have site-specific dispersion of atrial refractoriness and intraatrial conduction delays resulting from nonuniform atrial anisotropy [106]. This appears to be a common property of normal atrial tissue, but there are further conduction delays to and within area surrounding the AV node in patients with induced AF, suggesting an important role for the low right atrium in the genesis of AF. Abnormalities in restitution as well as the spatial distribution of such abnormalities can be related to the persistence of AF. In one study, monophasic action potential recordings were evaluated in patients with AF [107]. The action potential duration was plotted as a function of the preceding diastolic interval, and the slope of the action potential duration versus the diastolic interval (the restitution curve) was determined. If the slope was greater than one, oscillations occurred that may cause localized conduction delay or block resulting in a wave break giving rise to atrial fibrillation. These different patterns of conduction are reflected in the morphology of electrograms recorded with mapping during induced AF. Single potentials were indicative of rapid uniform conduction, short double potentials indicated collision, long double potentials were indicative of conduction block, while fragmented potentials were markers for pivoting points or slow conduction ( figure 6) [108,109]. Sites of fragmented potentials or complex fractionated atrial electrograms are potential targets for radiofrequency ablation to terminate AF as they may represent critical areas from which AF originates and perpetuates. (See "Atrial fibrillation: Catheter ablation".) This phenomenon has been termed microreentry to distinguish it from classic reentry in which the same reentrant pathway is repetitively traversed. The impulse may circulate around a central line of functional block, so-called leading circle reentry; this type of reentry tends not to be stable but rather to drift through the atria until it is extinguished. The perpetuation of AF may also depend importantly upon macroreentry around natural orifices and structures in the atrium, which provides a rationale and anatomic landmarks for ablative treatment. The collision of wavefronts cancels many atrial depolarizations that might otherwise reach the AV node, resulting in a slower heart rate than might otherwise have occurred ( figure 7A-B). Although multiple wandering wavelets probably account for the majority of AF, one study reported nine patients in whom a single, rapidly firing focus was identified with electrophysiologic mapping [110]. Organized and rapid atrial activity with a centrifugal and consistent pattern of atrial activation resulted from this focus, but it fired irregularly with striking https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 13/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate and abrupt changes in atrial cycle lengths. In most of the patients, the focus was near the ostia of great vessels and was amenable to radiofrequency ablation ( figure 8 and figure 9). Small reentrant sources, called rotors, may drive or maintain AF in some cases. These rotors result in a hierarchical distribution of frequencies throughout the atria that may be identified with spectral analysis of intracardiac recordings. Ablation of such sites has terminated paroxysmal AF, suggesting that they may play an important role [111], but it is not clear that the rotors are responsible for AF or are fixed in most instances. AF may be chaotic and have wavelets and rotors that are secondary rather than the predominant cause of AF [112]. However, antral pulmonary venous reentrant and focal drivers may be responsible for AF [54]. The complexity of such drivers increase with prolonged AF. These sites are often localized near the PV orifices in patients with paroxysmal AF, and are more often localized to the left or right atria in patients with chronic AF [100]. The fibrillating atrium cannot be captured by pacing when the atrial electrograms are disorganized. This observation supports the presence of microreentry, since there is no excitable gap (or it is very small) to permit capture. However, when type I ( figure 9) AF (which has organized atrial electrograms) is induced by rapid atrial pacing, the fibrillating atrium can be captured with rapid atrial pacing, suggesting the presence of an excitable gap [113]. ROLE OF THE ATRIOVENTRICULAR NODE The atrioventricular (AV) node regulates the number of atrial impulses that reach the ventricle. The ventricular rate in atrial fibrillation (AF) is typically irregularly irregular, with a ventricular rate that may be slow, moderate, or rapid depending on the capacity of the AV node to conduct impulses. The rate of AV nodal conduction is dependent upon multiple factors, including electrical properties of the node and the influence of the autonomic nervous system [114]. In addition, the use drugs such as digoxin, calcium channel blockers, or beta blockers may influence AV nodal function. There also may be a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [115]. AV nodal tissue consists of so-called "slow response" fibers, which depend on a mixed calcium/sodium current. This current is often called the inward calcium current, since in a normal physiologic environment, the ions are almost exclusively calcium. The mixed current uses a kinetically slow channel and is responsible for phase 0 depolarization. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 14/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate These characteristics lead to properties that are quite different from "fast-response" tissue in the atria, which as noted above, depend on an inward sodium current that uses a kinetically fast channel for phase 0 depolarization [8,116]: Partial and complete reactivation returns only 100 ms or more after return to the diastolic potential (versus 10 to 50 ms in the atria). The refractory period changes little as a function of rate. Conduction velocity is relatively slow, ranging from 0.01 to 0.1 m/s. Unlike tissue generating a fast action potential that has an all-or-none response (ie, the velocity of impulse conduction is similar at all stimulation rates until block occurs), tissue that generates a slow action potential exhibits a graded or decremental response, in which the velocity of impulse conduction slows as the stimulation rate increases. As noted above, the ventricular rate usually ranges 90 and 170 beats/min. Ventricular rates below 60 beats/min are seen with AV nodal disease, drugs that affect conduction, and high vagal tone as can occur in a well-conditioned athlete. Ventricular rates above 200 beats/min suggest catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the last setting and must be distinguished from a rate-related or underlying bundle branch block. In the classical view, the AV node is bombarded by impulses from the fibrillating atria. Some impulses traverse the AV node and reach the specialized infranodal conduction system and then the ventricles. However, most atrial impulses penetrate the AV node from varying distances and then are extinguished when they encounter the refractoriness of an earlier wavefront; this phenomenon of concealed conduction in turn creates a refractory wave that affects succeeding impulses. The failure of the refractory period to shorten with increasing rate (as occurs in the atria) further decreases the likelihood of an impulse traversing the AV node. Anatomically distinct AV nodal inputs, called the slow and fast pathways, are involved in the ventricular response to AF. The importance of these pathways has been demonstrated in radiofrequency ablation studies in which ablation reduced the number of beats that successfully reached the infranodal conduction system and the ventricles [117-120]. (See "Atrioventricular nodal reentrant tachycardia".) In addition to its intrinsic properties, the AV node is richly supplied and affected by both components of the autonomic nervous system. AV conduction is enhanced and refractoriness https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 15/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate reduced by the sympathetic fibers, and conduction reduced and refractoriness prolonged by the parasympathetic fibers. The net effect of the electrophysiologic properties of the AV node is that the rate of conduction into the specialized infranodal conduction system is (fortunately) much slower than the rate of the fibrillating atria. In some cases, the high degree of refractoriness in the AV node with AF results in high-grade or third-degree block. In this setting, the pacemaker that controls the ventricles is below the AV node. (See "The electrocardiogram in atrial fibrillation".) In patients with the preexcitation syndrome, the AV node is bypassed by "fast-response" tracts, which activate and reactivate much faster than the AV node and are therefore capable of rapid conduction. The development of AF in such a patient can result in very rapid transmission of atrial impulses to the ventricles [120] and can rarely cause ventricular fibrillation [15]. (See "The electrocardiogram in atrial fibrillation".) It is also important to recognize that the presence of an accessory pathway can increase the propensity for development of AF. In patients with AF who have Wolff-Parkinson-White (WPW) syndrome, catheter ablation of the accessory pathway is indicated to lower the sudden death risk but also to decrease the probability of recurrent AF. Unexpected ventricular rates The ventricular response to AF characteristically is irregularly irregular although it may appear regular in the presence of complete AV block. The usual ventricular rate in AF is between 90 and 170 beats per minute in the absence of AV node disease, drugs that affect conduction, or enhanced vagal inputs. Ventricular rates that are clearly outside this range suggest some concurrent problem: A ventricular rate below 60 beats per minute, in the absence of AV nodal blocking agents, suggests AV nodal disease that may be associated with the sinus node dysfunction. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) A ventricular rate above 170 beats per minute suggests thyrotoxicosis, catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract in the preexcitation syndrome. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) SPECIFIC CLINICAL SITUATIONS Late recurrent AF after catheter ablation The etiology of late recurrent atrial fibrillation (AF) following pulmonary vein isolation (PVI) has been debated. In some cases, triggering foci outside of the PVs may initiate AF [121-124]. Alternatively, persistence of the substrate for https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 16/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate maintaining AF (abnormal electrical properties of the atria themselves) may be more important than the triggering foci, especially in chronic AF. However, there is increasing evidence that when AF does recur late after PVI, it often represents incomplete electrical isolation of the PVs, either due to resumption of conduction across the ablation scar or to residual conduction in PVs that were not successfully ablated. Most [125-128], but not all [129], studies of the former mechanism support the hypothesis that resumption of PV-left atrial (LA) conduction is associated with an increased risk of recurrent AF. However, recurrent conduction across ablated lesions is more common than clinically evident recurrent AF [127,130]. Pre-existing LA scarring may predispose patients to late recurrence. In a series of 700 consecutive patients undergoing first-time PVI, scarring was detected in 6 percent [131]. These patients had a much higher rate of recurrence than those without scarring (57 versus 19 percent). Possible causes of scarring include atrial remodeling and inflammation. The patients with scarring had significant elevations in serum C-reactive protein (CRP) compared to those without scarring (5.9 versus 0.31 mg/L). This is consistent with other studies showing a relationship between serum CRP and AF [132]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'.) After cardiac surgery AF occurs frequently (approximately one of four patients) after cardiac surgery. Nonuniform atrial conduction is greatest on days two and three in this setting, and the longest atrial conduction time is greatest on day three after open heart surgery; these abnormalities coincide with the time of greatest risk for AF [133]. The degree of atrial inflammation after surgery in dogs was associated with a proportional increase in the inhomogeneity of atrial conduction and in the duration of AF; antiinflammatory therapy decreased the inhomogeneity [134]. Nevertheless, the mechanism of AF in the postoperative period is likely multifactorial. It is important to note that in most of the patients, especially those without a prior history of AF, that the AF is self-limited, and antiarrhythmic drug therapy can usually be stopped two to three months following surgery when the inflammation has subsided. (See "Atrial fibrillation and flutter after cardiac surgery".) Hyperthyroidism It is well established that hyperthyroidism can increase susceptibility to development of AF. As a consequence, all patients with new onset AF should have some measure of thyroid function tested. Successful treatment of the hyperthyroidism often results in elimination of the AF. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 17/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Obesity Obesity has been associated with AF and it is possible that both are related mechanistically [135]. In a sheep model, weight gain was associated with increased left atrial volume, fibrosis, inflammatory infiltrates, and lipidosis. There was reduced conduction velocity in atrial tissue and increased inducible and spontaneous AF with obesity. Atrial endothelin-A and -B receptors, endothelin-1, atrial interstitial and cytoplasmic transforming growth factor beta1, and platelet-derived growth factor were higher with obesity. In a clinical study of 110 patients undergoing AF ablation versus 20 reference patients without AF, pericardial fat volumes were associated with AF, its chronicity, and its symptom burden. Pericardial fat predicted AF recurrence post-ablation [136]. Associations persisted after adjusting for body weight but body mass index was not associated with these outcomes in multivariate-adjusted models. In another report [137], weight management with subsequent weight loss was associated with improved AF symptom burden scores, symptom severity scores, number of episodes, and cumulative duration of AF. This preliminary information does not yet prove that obesity causes AF by any specific mechanism. In a study of atrial sheep myocytes, acute, short-term incubation in free fatty acids resulted in no differences in passive or active properties of isolated left atrial myocytes but stearic acid reduced membrane capacitance and abbreviated the action potential duration, likely due to a reduction of the L-type calcium and of the transient outward potassium currents [138]. GENETICS OF AF Over the last decade, a preponderance of evidence suggests a large genetic contribution to atrial fibrillation (AF) [139,140]. Having a family member with AF is associated with a 40 percent increased risk for the arrhythmia [141]. Initially, traditional genetic techniques such as linkage analysis led to the discovery of rare, monogenic causes of AF. The first such study identified a genetic locus for AF using a series of related families with early onset AF [142]. A later study identified the first gene for familial AF [143]. Using a large Chinese kindred with autosomal dominant AF, they found a gain-of-function mutation in KCNQ1 (the gene encoding the subunit of the potassium channel current, I ). Since then, several additional gain-of-function variants Ks have been identified in KCNQ1 [144,145]. In addition to KCNQ1, mutations have been identified in other potassium channels genes, including KCNA5 [146], KCND3 [147], and KCNJ2 [148], and accessory subunits KCNE1 [149], KCNE2 [150], KCNE3 [151], and KCNE5 [152,153]. The majority of these functionally validated, AF-associated potassium channel variants have a gain-of-function channel, with an expected shortening of the atrial action potential duration and atrial refractory period. Variation in sodium channel subunits has also been identified as an important factor in the development of familial AF, with AF-causing variants observed in both the https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 18/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate major cardiac sodium channel alpha subunit SCN5A [154] and its associated beta subunits [155,156]. Several variants have also been identified in genes that do not directly alter the atrial action potential, but instead would be expected to cause AF through alternative mechanisms, eg, somatic mutations in GJA5, which encodes the gap junctional protein; connexin 40, a frameshift mutation that resulted in early truncation of NPPA [157], which encodes for the precursor for atrial natriuretic peptide; and genetic variation in several developmentally related cardiac transcription factors, ie, NKX2.5, PITX2, GATA4, GATA5, and GATA6 [156,158,159]. Genome-wide association studies (GWAS) have been used to identify genetic loci associated with AF. GWAS rely on the unbiased comparison of common single-nucleotide polymorphisms (SNPs) throughout the genome, with SNPs occurring with different frequency in individuals with a disease versus controls being used to localize disease-related genetic loci. The first GWAS performed for AF identified a region on chromosome 4q25, which was associated with AF in those of European and Asian descent [160]. Subsequently, these findings were broadly replicated in individuals of European, Asian, and African descent [161,162]. Genetic variants on chromosome 4q25 that are most significantly associated with AF reside about 150 kilobases upstream of the nearest gene PITX2. PITX2 encodes the paired-like homeodomain transcription factor 2, which helps determine cardiac laterality, suppresses the default expression of a sinoatrial nodal gene programme in the left atrium, and encodes the pulmonary venous myocardium [163]. In addition, PITX2 is associated with formation of the pulmonary veins. These findings are particularly interesting in light of the fact that AF triggers frequently arise in the pulmonary veins. In addition to the role of PITX2 in development, studies demonstrate a role for the PitX2c transcript in expression of gene-encoding ion channels, calcium cycling proteins, and gap junctions; these direct electrophysiological influences likely lead to formation of substrate for triggered activity as well as reentry [164]. Related analysis identified the same genomic region as being associated with an increased risk of cardioembolic stroke [156,165] and a prolonged PR interval [166]. To date, GWAS have identified 14 genomic regions of susceptibility for AF, with 17 independent signals at these loci [167]. These include the ZFHX3 gene that encodes a zinc finger homeobox transcription factor [168], the KCNN3 gene that encodes the SK3 potassium channel [169], and the PRRX1 gene that encodes a member of the paired-related homeobox gene family [168]. Whole exome and genome sequencing has been increasingly used to identify rare variants associated with AF [156]. For example, Oleson et al reported a much higher prevalence of rare variants in genes associated with AF (KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5) in early onset, lone AF patients than in the background population [170]. This approach is beginning to identify rare candidate variants in genes not previously linked to other types of https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 19/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Mendelian disease and thus may offer new insights into AF pathogenesis and disease pathways that could ultimately provide novel therapeutic targets for this common condition. A 2018 meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than 500,000 individuals, sought to identify AF-associated genes at the GWAS loci by performing RNA sequencing and expression quantitative trait locus analyses in 101 left atrial samples (which is the most relevant tissue for AF) [171]. A transcriptome-wide analysis was also performed; this analysis identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci-implicated genes enriched within cardiac developmental, electrophysiological, contractile, and structural pathways. SUMMARY The precise mechanisms by which age and other risk factors such as hypertension, coronary artery or valvular heart disease, or heart failure increase the propensity for development of atrial fibrillation (AF) are poorly understood ( figure 1). These conditions may affect the triggers of or the substrate for the maintenance of AF. (See 'Introduction' above.) These mechanisms are complex and involve a dynamic interplay between the triggers and substrate abnormalities. It is likely that short-lived episodes are due to specific triggers, including autonomic perturbations, focal discharges, specific reentry circuits in the pulmonary veins (PVs), and effects of stretch, whereas inflammation, dilatation, fibrosis, repolarization abnormalities, and conduction disturbances allow for perpetuation of episodes of AF. (See 'Mechanisms of atrial fibrillation: triggers and substrates' above.) AF is most often initiated (triggered) by rapid firing from the PV. (See 'Triggers of AF' above.) Paroxysmal AF commonly precedes chronic AF. This suggests that, in addition to other predisposing factors, AF may play a role in its own natural history. (See 'Electrical remodeling' above.) The autonomic nervous system likely influences the initiation and perpetuation of AF. (See 'Role of the autonomic nervous system' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 20/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate 1. Wasmer K, Eckardt L, Breithardt G. Predisposing factors for atrial fibrillation in the elderly. J Geriatr Cardiol 2017; 14:179. 2. Goudis CA, Korantzopoulos P, Ntalas IV, et al. Obesity and atrial fibrillation: A comprehensive review of the pathophysiological mechanisms and links. 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