Atrial fibrillation: A progressive atrial myopathy or a distinct disease?

International Journal of Cardiology 171 (2014) 126–133

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Atrial fibrillation: A progressive atrial myopathy or a distinct disease? Eleftherios M. Kallergis ⁎, Christos A. Goudis, Panos E. Vardas Department of Cardiology, University Hospital of Heraklion, Crete, Greece

a r t i c l e

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Article history: Received 7 May 2013 Received in revised form 9 October 2013 Accepted 10 December 2013 Available online 18 December 2013 Keywords: Atrial fibrillation Myopathy Cardiomyopathy Remodeling Atrial fibrosis

a b s t r a c t Atrial fibrillation is a complex arrhythmia with multiple possible mechanisms. A lot of experimental and clinical studies have shed light on the pathophysiological mechanisms of arrhythmia, especially on molecular basis. Electrical, contractile and structural remodeling, calcium handling abnormalities, autonomic imbalance and genetic factors seem to play a crucial role in atrial fibrillation initiation and maintenance. However, the exact pathophysiological mechanisms of atrial fibrillation are not completely understood and whether atrial fibrillation is an unclassified cardiomyopathy or a distinct disease still remains to be answered. This review highlights proarrhythmic and pathophysiological mechanisms of atrial fibrillation and approaches the molecular basis underlying atrial fibrillation susceptibility. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction In 1909, Lewis in England and Rothberger and Winterberg in Vienna, taking advantage of Einthoven's newly developed galvanometer, were the first to establish electrocardiographically that auricular fibrillation was the cause of pulsus irregularis perpetuus [1]. Rothberger, Engelmann and Winterberg proposed the idea of tachysystole or hyperectopia, which attributed atrial fibrillation to the extremely rapid discharge rate of an ectopic focus, whereas Lewis showed that the basic perpetuating mechanism of the arrhythmia is circus movement [2]. Almost 50 years had to pass before the controversy of the ectopic focus was put to rest. The insightful and ground-breaking demonstration in atrial fibrillation patients by Haissaguerre et al. provided a definite proof that pulmonary veins were an important source of ectopic beats capable of initiating frequent paroxysms of atrial fibrillation that could be eliminated by treatment with radiofrequency ablation [3]. This discovery led to a revolution in the clinical treatment of atrial fibrillation, and the procedure of pulmonary vein isolation became the gold standard of management in the EP lab. According to Coumel's triangle of arrhythmogenesis, three cornerstones are required in the onset of clinical arrhythmia: the trigger factor, the arrhythmogenic substrate and modulating factors [4] (Fig. 1). The interplay between triggers, substrate and modulating factors determines the clinical picture of the arrhythmia (Fig. 1). Our understanding of atrial fibrillation pathophysiology has advanced significantly over the last years (Fig. 1), however, no marked progress in the pharmaceutical cure of atrial fibrillation has been achieved. Ablation procedures are efficient and relatively safe, ⁎ Corresponding author at: Department of Cardiology, Heraklion University Hospital 71100, Heraklion, Crete, Greece. Tel.: +30 2810392877; fax: +30 2810542055. E-mail address: [email protected] (E.M. Kallergis). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.009

but the very large size of the patient population allows ablation treatment in only a small number of patients. Much remains to be elucidated at molecular and channel levels, in order to identify new therapeutic targets. 2. Basic arrhythmia mechanisms 2.1. Ectopic firing Resting atrial potential is maintained by high resting K + permeability through the inward rectifier K+ current IK1. Although normal human atrial cells manifest pacemaker current If, it is overwhelmed by much larger IK1, and no automaticity occurs [5]. Enhanced automaticity is caused by changes in this balance, resulting from decreased IK1 and/ or enhanced If [5]. Most common causes of ectopic firing, however, are afterdepolarizations. Early afterdepolarizations (EADs) are membrane oscillations occurring during phase 2 or 3 of the action potential. The main factor causing early afterdepolarization is action potential prolongation, allowing ICaL to recover from inactivation, leading to depolarizing inward movement of Ca++ ions. Delayed afterdepolarizations (DADs) are membrane oscillations occurring after full repolarization of the action potential that are caused by abnormal diastolic release of Ca++ from sarcoplasmic reticulum stores. Ryanodine receptors (RyRs) are sarcoplasmic reticulum Ca++ channels that release Ca++ in response to transmembrane Ca++ entry. RyRs are normally closed during diastole but can open if they are functionally defective or if the sarcoplasmic reticulum is Ca++ overloaded. As RyR2 function is modulated by phosphorylation, hyperphosphorylation favors Ca++ release and arrhythmogenicity [6]. Ca++/calmodulin-dependent protein kinase type II (CaMKII) is activated by cell Ca++ loading, which enhances Ca++ calmodulin binding [7]. Ca++/calmodulin-dependent protein kinase type-II activation, along

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Fig. 1. Atrial fibrillation pathophysiology. Modified from Ref. [159].

with atrial fibrillation-related activation of protein kinase A (PKA), phosphorylates RyRs [7]. Experimentally, vulnerability to pacing-induced atrial fibrillation due to a gain-of-function RyR2 mutation is reversed by pharmacological or genetic inhibition of CaMKII or its specific RyR2 phosphorylation site, emphasizing the potential importance of CaMKII phosphorylation in atrial fibrillation [8]. Goats with atrial dilatation also exhibit increased CaMKII activity and RyR2 hyperphosphorylation at Ser2815 [9], pointing to the possibility that structural atrial diseases may predispose to atrial fibrillation by changes in cellular Ca++ signaling. The Ca++ sensitivity and closed state stability of RyR2 are also modulated by accessory binding proteins such as FK506-binding protein (FKBP12.6). Prevention of CaMKII phosphorylation suppresses sarcoplasmic reticulum Ca++ leak, DADs, and atrial fibrillation in FKBP12.6 knock-out mice, suggesting that CaMKII phosphorylation is central to DADassociated atrial fibrillation [10]. RyR2 phosphorylation is also controlled by dephosphorylation via type 1 (PP1) and type 2A (PP2A) protein phosphatases. Inhibitor 1 protein (which specifically suppresses PP1 activity in the sarcoplasmic reticulum) is activated by PKA hyperphosphorylation in atrial fibrillation patients [11]. Inhibitor 1 activation reduces PP1mediated dephosphorylation, thus increasing phosphorylation of sarcoplasmic reticulum-located proteins. Potentially arrhythmogenic diastolic RyR2 Ca++ leak can also result from sarcoplasmic reticulum Ca++ overload. Heart failure, a frequent cause of atrial fibrillation, induces atrial cardiomyocyte sarcoplasmic reticulum Ca++ overload and DADs [12]. DADs that are large enough to reach threshold cause ectopic firing. Repetitive DADs can cause atrial fibrillation. 2.2. Reentry mechanisms Reentry can maintain atrial fibrillation by producing a rapidly firing driver with fibrillatory propagation or by producing multiple irregular

reentry circuits. The proposed theories for reentry are circus movement reentry, leading circle, spiral wave reentry and multiple wavelets. Circus movement reentry is characterized by an activation that can travel along a preformed anatomical structure and reactivate previously excited tissue [13]. Initiation of circus movement reentry requires unidirectional conduction block. A prerequisite for circus movement reentry is recovery of excitability after the previous activation, before the next activation reaches the tissue again. As a consequence of this, a short refractory period and a low conduction velocity make circus movement reentry more likely. In the leading-circle model, as no anatomic obstacle exists [14], the reentry path adopts the minimal possible path length equal to the wavelength—WL. Wavelength is the distance the impulse travels in one refractory period given by the following equation: WL = RP × CV (RP is the refractory period and CV the conduction velocity) [15]. The central region is rendered unexcitable by electrotonic depolarization by the circulating fibrillation wave. The spiral wave theory suggests that spiral waves rotate around an excitable core. The maintenance of activity depends on tissue excitability, conduction velocity and the angle of the propagation wavefront. Reduced refractory period promotes spiral-wave reentry by accelerating and stabilizing spiral-wave rotors [15]. The leading circle and spiral wave theory can explain atrial fibrillation occurrence with action potential duration shortening. Decreased INa and/or connexin changes, including decreased numbers, increased heterogeneity and lateralization of connexins [16] promote conduction velocity slowing, thus explaining susceptibility to atrial fibrillation more easily with leading circle concept. Class I antiarrhythmic agents, e.g. flecainide, even though they slow conduction velocity by blocking INa channels, they also prolong the ERP by blocking IK channels thereby contributing to suppression of leading circle [17]. Multiple wavelet hypothesis, introduced by Moe et al., supports that reentrant wavelets might wander through an excitable medium in a seemingly

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chaotic pattern [18]. The number of the wavelets depends on refractory period, tissue mass and conduction velocity. As long as the number of wavefronts does not decline below a critical level, multiple wavelets will be capable to sustain the arrhythmia [19,20]. Ectopic firing contributes to reentry by providing triggers for reentry induction, but provision is also provided for a trigger to lead directly to atrial fibrillation. It has been suggested that the multiple wavelet hypothesis would actually not exclude the coexistence of local sources of atrial fibrillation [21].The consequences of the interaction between triggers and substrate are dependent in part on the milieu created by multiple modulating factors. 2.3. Modulating factors A number of modulating factors contribute to initiation and perpetuation of atrial fibrillation. Increasing age is a significant risk factor for developing atrial fibrillation. Animal studies have demonstrated an increase in interstitial fibrosis within the atrium with advancing age [22–24]. Seminal studies by Spach and Dolber described microscopic evidence of fibrosis between groups of fibers in association with electrical uncoupling of side–side connections in the aging human atrium. These structural changes were associated with conduction anisotropy, providing the necessary substrate for reentry [25]. Several years later, Spach et al. concluded that after atrial microstructure remodeling with aging, variable arrhythmogenic conduction and sodium current disturbances are very sensitive to small changes in the location, as well as in the timing of premature stimuli within aging atrial bundles [26]. Kistler et al. described global and regional reductions in atrial voltage, increased voltage heterogeneity and significant impairment in conduction in the right atrium with increasing age [27]. Stiles et al. demonstrated bi-atrial voltage reduction in patients with paroxysmal atrial fibrillation and no recent atrial fibrillation episodes compared with controls [28]. In a recent study, Teh et al. concluded that increasing age is associated with pulmonary vein electroanatomic remodeling characterized by reduction in pulmonary vein voltage, conduction slowing and increasing proportion of complex signals without significant changes in refractoriness, thereby providing new insights into the potential mechanisms responsible for the increased prevalence of atrial fibrillation with advancing age [29]. Autonomic nervous system (ANS) contributes to the initiation, perpetuation, ventricular response rate and termination of atrial fibrillation. Autonomic changes have been shown to precede the onset of paroxysmal atrial fibrillation [30]. Vagal discharge enhances acetylcholinedependent K+ current IKACh, thereby reducing action potential duration and stabilizing reentrant rotors [31]. β-Adrenoceptor activation increases diastolic Ca++ leak and promotes DAD-related ectopic firing by hyperphosphorylating RyR2s [7]. Besides autonomic innervation to the heart from the brain and the spinal cord (extrinsic system), ganglionated plexi situated at pulmonary vein–atrial entrances, comprise the local autonomic system of the heart (intrinsic system) [32,33]. Stimulation of ganglionated plexi induces focal firing arising from pulmonary vein and non-pulmonary vein sites [34], while ablation of the major ganglionated plexi at the pulmonary vein-atrial entrances eliminates or diminishes atrial fibrillation inducibility [35]. Several experimental studies have shown that low level vagus nerve stimulation can prevent atrial fibrillation inducibility by inhibiting major ganglionated plexi [36–38] or stellate ganglion nerve activity [39]. Low level vagus nerve stimulation therefore, may constitute a safe nonpharmacological approach to control paroxysmal atrial fibrillation in the near future in humans, when suppression of cardiac sympathetic outflow is desired. Genetic advances over the last decade have facilitated the identification of mutations and common polymorphisms associated with atrial fibrillation. Mendelian families with atrial fibrillation genes having large effect size but rare frequency have been identified. The risk of atrial fibrillation approaches nearly 2-fold in first-degree relatives of those with atrial fibrillation and increases even further with an earlier age of

atrial fibrillation onset [40]. However, unlike other familial monogenic cardiac disorders, such as hypertrophic cardiomyopathy and long-QT syndrome, atrial fibrillation is more genetically heterogeneous [41,42]. Genome-wide association studies (GWAS) enriched our knowledge in molecular mechanisms underlying the arrhythmia. GWAS use singlenucleotide polymorphisms as markers of genetic variation between affected and unaffected individuals, and to date, atrial fibrillation GWAS have been successful in identifying three novel genetic loci [43–45]. GWAS and candidate gene studies have identified variants and loci with low to modest effect sizes. Ηοwever, low-frequency variants with moderate effect sizes, remain to be identified for the substantive genomic gap to be filled. To fill the gap between genetic variants and development of atrial fibrillation, new advances are being made in the field of epigenomics, transcriptomics, proteomics, and metabolomics. Regulatory loops involving microRNAs are intermediate regulators and modifiers of genes. There is increasing evidence of a key role of microRNA in atrial fibrillation, as they have been linked to fibrotic and apoptotic pathways that may contribute to atrial fibrillation susceptibility via electric or structural remodeling [46]. Several microRNAs have been targeted for their involvement in atrial fibrillation on the basis of their regulation or association with genes encoding cardiac ion channels [47] or Ca++-handling proteins. Furthermore, biological systems comprise circuitries of interacting components such as proteins, nucleic acids, and other small molecules that operate in concert to create complicated molecular networks [48,49]. Systems biology models the complex interactions among the multiple epidemiological, genomic, and omic arenas, combining and distilling hierarchies to generate nonlinear understanding of pathogenesis of the arrhythmia [50,51]. Atrial stretch appears to be one of the most prominent trigger mechanisms for signaling changes involved in the pathogenesis of atrial fibrillation. The electrical consequences of atrial stretch (mechanoelectrical feedback) contribute to both initiation and maintenance of atrial fibrillation. Altered calcium handling and stretch-activated channel activity can explain the experimental findings of stretch-induced depolarisation, shortened refractoriness, slowed conduction and increased heterogeneity of refractoriness and conduction [52]. In a model of acute atrial dilation, heterogeneous activation of stretch-activated channel Isac increases dispersion of effective refractory period, conduction slowing, and local conduction block, thereby enhancing initiation and perpetuation of atrial fibrillation [53]. Increased intra-atrial pressure and stretch have been shown to increase spontaneous electrical activity from pulmonary veins [54]. Atrial stretch is a main contributor to structural remodeling as well. Induction of heart failure by rapid ventricular pacing induces apoptosis and increased collagen synthesis in the atria within a couple of days [55]. At the molecular level, the development of atrial fibrosis due to pressure and/or volume overload is mediated by both angiotensin II-dependent and angiotensin II independent mechanisms [56,57]. Mitogen-activated protein kinases are important potential mediators of AngII effects on tissue structure [58–60]. Left ventricular failure increases atrial synthesis of angiotensin II and thereby, atrial fibrosis is induced via activation of mitogen-activated protein kinases [61]. As for tissue AngII, rapid increases in atrial expression of activated transforming growth factor-β1 (TGF-β1) occur in ventricular tachypacing congestive heart failure [62]. TGF-β1 acts through the SMAD signaling pathway to stimulate collagen production [63,64]. Atrial stretch has also been associated with altered expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMPs) [65,66]. Stretch of atrial cardiomyocytes increased MMP-2 and MMP-9 protein expressions and activities [67]. Furthermore, in patients with mitral valve disease, MMP-1 protein expression and MMP-9 activity were decreased in left atrial samples compared with biopsies from patients undergoing coronary artery bypass surgery, without a difference between mitral valve disease with and without atrial fibrillation, suggesting changes in MMPs upon increased atrial stretch [68]. The role of inflammation in the initiation of atrial fibrillation was supported on the basis that inflammatory states, such as myocarditis,

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pericarditis and cardiac surgeries, were frequently associated with the arrhythmia. Histological findings of atrial myocarditis were identified in patients with lone atrial fibrillation [69]. Several prospective epidemiological studies confirmed that inflammation may confer an increased risk of atrial fibrillation [70]. In a large cohort involving middle-aged women, inflammatory biomarkers including CRP, soluble intercellular adhesion molecule-1 and fibrinogen were independently associated with increased incidence of atrial fibrillation [71]. Moreover, CRP levels of patients with newly diagnosed nonvalvular atrial fibrillation who remained in atrial fibrillation were elevated compared to those of patients who were converted to sinus rhythm, providing evidence that inflammation is further implicated in the perpetuation of atrial fibrillation [72]. Obesity is associated with increased incidence of atrial fibrillation. There is a 3–8% higher risk of new onset atrial fibrillation with each unit increase in body mass index (BMI) [73,74], independently of other cardiovascular risk factors such as lipid levels, blood pressure, and diabetes. The mechanisms by which obesity may lead to atrial fibrillation are currently unknown. Increased left atrial size correlates to BMI, and is a possible explanation for atrial fibrillation initiation in these patients. It is attributed to diastolic dysfunction as a result of thickening of the myocardium [75], elevated plasma volume [76], and increased neurohormonal activation [77]. Sleep apnea is also a strong predictor of incident atrial fibrillation [78]. Pathophysiologically, obstructive sleep apnea induces intermittent hypoxemia and hypercapnia, sympathetic activation, and changes in blood pressure. The elevated intrathoracic pressure caused by inspiration against an obstructed airway causes increased transmural pressure gradient which in turn may lead to atrial stretch. Moreover, sleep apnea is associated with diastolic dysfunction [79]. These pathophysiological mechanisms may lead to enhanced vulnerability to atrial fibrillation. It has been demonstrated that patients with obstructive sleep apnea have a higher recurrence rate of atrial fibrillation after successful cardioversion than patients without obstructive sleep apnea, and treatment with continuous positive airway pressure reduces the recurrences [80].

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that enhances the ability of the disorder to sustain itself and create an increasing vulnerability to relapse. Electrical remodeling, initially, was thought to play a crucial role in the perpetuation of the arrhythmia (¨atrial fibrillation begets atrial fibrillation¨) [96,97]. In most cases of paroxysmal atrial fibrillation, the time spent in sinus rhythm between two episodes of the arrhythmia is usually long enough to completely reverse electrical remodeling. Complete reversal of electrical remodeling usually takes place within several days of sinus rhythm [98–100]. However, studies have showed that increased vulnerability to atrial fibrillation after cardioversion still exists two to four weeks after reversal of electrical remodeling [101,102], thus indicating that other processes occurring more slowly than electrical remodeling contribute to the initiation of the arrhythmia. 3.2. Contractile remodeling Atrial contractile dysfunction correlates with the duration of the arrhythmia and usually takes months for atrial contraction to fully recover [103,104]. Loss of atrial contractility promotes thrombus formation and increases the compliance of the fibrillating atria, thus enhancing progressive dilatation and contributing to further stabilization of the arrhythmia [105]. On the contrary, restoration of sinus rhythm reduces atrial size [106,107]. Downregulation of ICaL [108,109], upregulation of INCX [110], and defective release of Ca++ from the sarcoplasmic reticulum [111,112] are the main mechanisms of atrial contractile dysfunction, while alterations of sarcoplasmic reticulum Ca++ load or myofilament function seem to play a minor role. Oxidative injury [113] as well as reduced phosphorylation of myofibrillar proteins [11] have also been suggested to reduce the performance of the contractile apparatus in patients with atrial fibrillation. Atrial dilatation without atrial fibrillation can also cause atrial contractile dysfunction. In animal models of heart failure, atrial emptying function is reduced [114], and in patients loss of atrioventricular synchrony due to VVI pacing increases left atrial diameter and decreases atrial contractility [115]. 3.3. Structural remodeling

3. Atrial remodeling The fundamental mechanisms underlying atrial fibrillation have long been debated, but electrical, contractile, and structural remodeling are each important synergistic contributors to atrial fibrillation substrate. 3.1. Electrical remodeling Rapid atrial fibrillation alters the electrophysiological properties of atrial myocardium by causing shortening [81] and loss of rate adaptation [82] of the effective refractory period, and increased dispersion of refractoriness [83,84]. The principal component is reduced atrial action potential duration that decreases the atrial refractory period and consequently the wavelength, favoring reentry [16]. Action potential duration is modulated by ICaL [85,86], INa [87], IK1 [88] and IKACh [89,90] channels, and Na+/K+ pump [87]. Under normal conditions, Ca++ moves into the cell during each action potential and contributes to cellular repolarization. Atrial fibrillation results in intracellular Ca++ overload, engaging a series of molecular changes that diminish Ca++ entry and attenuate Ca++ loading [91]. Ca++ binds to ICaL channel and causes partial Ca++ dependent ICaL inactivation and reduction of action potential within minutes [92]. Alterations in Na+/K+ pump current result in important changes in action potential duration, action potential duration restitution, and refractory period [87]. INa also modulates atrial rotor dynamics through alteration of conduction velocity and, to a minor extent, refractory period [87]. Of the repolarizing potassium currents, Ito is significantly reduced in permanent atrial fibrillation [93,94], while inward rectifier potassium current IK1 is increased [88,93]. The increase in IK1 probably has a significant contribution in action potential shortening [95]. These electrophysiological changes promote a vicious cycle of arrhythmia

Atrial fibrosis is a hallmark feature of arrhythmogenic structural remodeling in atrial fibrillation [55]. Atrial fibrosis seems to be a convergent pathological end point in a variety of settings, such as senescence [22,116], heart failure [117] and mitral valve disease [118]. It results from accumulation of fibrillar collagen deposits, occurring most commonly as a reparative process to replace degenerating myocardial parenchyma, or as reactive fibrosis that causes interstitial expansion [119,120]. Angiotensin II (AngII) [121], transforming growth factor-β1 (TGF-β1) [122], connective tissue growth factor (CTGF) [123], and platelet-derived growth factor (PDGF) [124] play a critical role in atrial structural remodeling. Heart failure increases atrial synthesis of AngII, resulting in promotion of atrial fibrosis [61]. Increased AngII production in transgenic mice with cardiac restricted angiotensin-converting enzyme (ACE) overexpression causes marked atrial dilation with focal fibrosis and atrial fibrillation [125]. In addition, increased expression of Ang-II type I receptors have been found in the left atrium of atrial fibrillation patients, demonstrating a clear relationship between AT1 upregulation and atrial fibrillation [126]. TGF-β1 also stimulates collagen production from fibroblasts [64]. Targeted cardiac overexpression of constitutively active TGF-β1 causes selective atrial fibrosis, conduction heterogeneity and atrial fibrillation propensity [122,127]. Connective tissue growth factor (CTGF) is also implicated in fibroblast proliferation, cellular adhesion, angiogenesis and extracellular matrix synthesis [128,129]. CTGF expression is elevated in experimental models of atrial fibrillation and Ang II infusion induces CTGF expression in atria but not ventricles [123]. CTGF up-regulation has also been found in the failing heart [130] and the right atrium of patients with atrial fibrillation [123]. Platelet-derived growth factor (PDGF) stimulates proliferation, migration, differentiation, and physiological function of mesenchymal

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cells [131]. Pressure overload induces mast cell infiltration and fibrosis in the atrium of experimental model through PDGF-A, favoring enhanced atrial fibrillation susceptibility after atrial burst stimulation [124]. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability [132,133]. Cardiomyocyte–fibroblast coupling depolarizes cardiomyocyte resting membrane potential, slows conduction by drawing off excitatory current flow during phase 0, and can increase or decrease action potential duration depending on fibroblast resting potential and cardiomyocyte–fibroblast coupling properties. Both abnormal automaticity and reentry have been shown to occur in cocultures of cardiomyocytes and fibroblasts [134,135]. Fibroblasts can also promote arrhythmogenesis by producing large quantities of extracellular matrix proteins, particularly collagen, that alter cardiomyocyte architecture and disturb electrical continuity. Extracellular matrix alterations in fibrotic tissue can lead to conduction abnormalities and atrial fibrillation promotion in a variety of ways. Loss of side-toside cardiomyocyte connections due to insulating collagen within cardiomyocyte bundles has been suggested to produce zigzag conduction patterns and promote atrial microreentry [25]. In addition, reparative fibrosis separates cardiomyocytes in the longitudinal direction and interferes with longitudinal conduction. These longitudinal conduction abnormalities provide the basis for unidirectional conduction block and macroreentry. The fundamental role of atrial fibrosis has been demonstrated in experimental models and humans. In dogs, extended atrial interstitial fibrosis after pacing-induced heart failure induced atrial fibrillation without an altered atrial refractory, refractoriness heterogeneity, or conduction velocity [55]. Increased collagen deposition has been documented in lone atrial fibrillation patients compared with sinus rhythm control subjects [69,136], as well as in atrial fibrillation with mitral valve disease patients compared with sinus rhythm [136]. Atrial extracellular matrix remodeling manifested by the elective downregulation of TIMP-2 along with upregulation of MMP-2 and collagen type I in the atrium is associated with the development of sustained atrial fibrillation in patients with cardiomyopathy and heart failure [137]. Similar results were reported in another study, where longer atrial fibrillation duration was associated with elevated atrial interstitial MMP activity, decreased plasminogen activator inhibitor and TIMP expression, and enhanced collagen deposition [138]. Moreover, atrial fibrillation is associated with chamber-specific alterations in myocardial collagen content and MMP and TIMP levels, indicative of differential remodeling and altered collagen metabolism. Patients with heart failure and concomitant atrial fibrillation have shown increased atrial collagen deposition and increased activity of MMPs and TIMPs, compared with patients with heart failure alone [139]. Increased MMP-9 activity has also been reported in patients with atrial fibrillation versus sinus rhythm [140]. On the other hand, atrial fibrillation itself may promote structural remodeling, creating a long term positive feedback that contributes to the development of permanent forms. In experimental models, lone atrial fibrillation induces cellular changes resembling those seen in hibernating ventricular myocardium, characterized by cardiomyocyte volume increase, myolysis, glycogen accumulation, mitochondrial changes and chromatin redistribution [141,142]. Besides ultrastructural changes, experimental lone atrial fibrillation results in extracellular matrix accumulation [143–146]. Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased extracellular matrix-gene expression in vivo [147]. Despite the undoubtful progress in experimental and clinical studies and the extra knowledge they offered into the pathophysiological mechanisms of the arrhythmia, several key issues remain to be resolved, to better understand the role of atrial fibrosis in the development of atrial fibrillation substrate. The quantitative relationship between fibrosis and atrial fibrillation needs to be assessed. Questions regarding the

possibility of a threshold of atrial fibrosis for atrial fibrillation promotion, and the nonlinear relationship between atrial fibrosis and atrial fibrillation, await for answers. The potential interactions between fibrosis and other mechanistic determinants of atrial fibrillation occurrence, such as electrophysiological properties and atrial ectopic activity, need to be appreciated. The most crucial issue to be resolved is the identification of specific causative role of fibrosis in atrial fibrillation promotion. Another aspect of atrial fibrillation pathophysiology that has elicited great interest has been changes in gap junction/connexin physiology. Connexons (containing 6 connexin molecules each) in the gap junctions of adjacent cardiomyocytes line up and attach, transferring ions or molecules b1 kDa freely between cells, coupling them electrically [148]. In the working myocardium, conduction velocity is higher in the longitudinal than in the transverse direction. In the transverse direction, a propagating wavefront has to cross more cell-to-cell boundaries within a given distance. In addition, the smaller and sparser gap junctional plaques at side-to-side connections represent a higher resistance than the larger intercalated disks at end-to-end connections [149]. The most important connexins in atrial tissue are Cx40 and Cx43. A lot of studies have investigated changes in connexin expression and distribution in clinical and experimental atrial fibrillation models, with controversial results. In chronic atrial fibrillation patients, both higher [150] and lower levels [151,152] of Cx40 were reported. Takeuchi et al. reported that the levels of Cx40 and Cx43 were not altered in patients with atrial fibrillation or atrial dilatation [153]. Another study reported lateralization of connexins, with an increased heterogeneity in Cx40 distribution and a reduction of Cx43 [154]. Two recent experimental studies [155,156] demonstrated that connexin gene therapy preserves atrial conduction and prevents atrial fibrillation, providing important advance with respect to both pathophysiology and therapeutics of the arrhythmia. However, much more work is needed to determine the relevance of their findings to various clinical forms of atrial fibrillation. 4. Conclusion Cardiomyopathy is mainly defined by various degrees of impairment of cardiac function due to alterations of cardiac cellular phenotype, in response to a variety of agents acting on cardiomyocytes. The expert consensus panel of American Heart Association proposes the following definition: “Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability” [157]. Within this broad definition, cardiomyopathies are usually associated with failure of myocardial performance, that may be mechanical or a primary electrical disease. Atrial fibrillation may be a clinical manifestation of cardiomyopathy in the atria. Dong et al. have proposed a new classification of cardiomyopathy, atrial cardiomyopathy, that relates not to the etiology of cardiomyopathy, but exclusively to the sites of cardiomyopathy. They furthermore merged atrial cardiomyopathy into one word, atriocardiomyopathy, which is concretely composed of primary atriocardiomyopathy, such as lone atrial fibrillation with no obvious clinical cause, and secondary atriocardiomyopathy caused by organic heart diseases. Primary atriocardiomyopathy is then divided in genetic, mixed or acquired [158]. So far, no classification of atrial fibrillation in the area of cardiomyopathies exists. Atrial fibrillation is a complex, multifactorial progressive disorder, with an underlying etiology different in different patient subpopulations. Taking into account that a variety of processes affecting the electrical, contractile and structural properties of the atria are rather necessary for the initiation and perpetuation of the arrhythmia, the hypothesis of atrial fibrillation being a cardiomyopathy seems quite

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