Cardiovascular Pathology 23 (2014) 71–84

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Cardiovascular Pathology

Review Article

Atrial fibrillation from the pathologist’s perspective Domenico Corradi ⁎ Department of Biomedical, Biotechnological, and Translational Sciences (S.Bi.Bi.T.), Unit of Pathology, University of Parma, Parma, Italy

a r t i c l e

i n f o

Article history: Received 13 November 2013 Received in revised form 3 December 2013 Accepted 7 December 2013 Keywords: Atrial fibrillation Structural remodeling Fibrosis Cardiomyocyte Genetics Upstream therapy

a b s t r a c t Atrial fibrillation (AF), the most common sustained cardiac arrhythmia encountered in clinical practice, is associated with increased morbidity and mortality. Electrophysiologically, it is characterized by a high rate of asynchronous atrial cell depolarization causing a loss of atrial contractile function and irregular ventricular rates. For a long time, AF was considered as a pure functional disorder without any structural background. Only in recent years, have new mapping and imaging techniques identified atrial locations, which are very often involved in the initiation and maintenance of this supraventricular arrhythmia (i.e. the distal portion of the pulmonary veins and the surrounding atrial myocardium). Morphological analysis of these myocardial sites has demonstrated significant structural remodeling as well as paved the way for further knowledge of AF natural history, pathogenesis, and treatment. This architectural myocardial disarrangement is induced by the arrhythmia itself and the very frequently associated cardiovascular disorders. At the same time, the structural remodeling is also capable of sustaining AF, thereby creating a sort of pathogenetic vicious circle. This review focuses on current understanding about the structural and genetic bases of AF with reference to their classification, pathogenesis, and clinical implications. © 2014 Elsevier Inc. All rights reserved.

1. Background and aims Atrial fibrillation (AF) is the most common sustained arrhythmia with undisputed individual and social sequelae. Electrophysiologically, it is characterized by a high rate (400–600 beats/minute) of asynchronous atrial cell depolarization causing a loss of atrial contractile function and irregular ventricular rates [1]. Its prevalence in the developed world is approximately 1.5–2% of the general population, with the average age of patients with this arrhythmia being 75 to 85 years. In both genders, lifetime risks for the development of AF are about one in four people aged 40 and older, this magnitude being similar to that for congestive heart failure (one in five people, for the same interval) [2]. Recent evidence suggests a trend of increased incidence and prevalence over time for AF which cannot merely be explained by an aging population. In fact, in addition to wellknown conditions capable of favoring this arrhythmic disorder (i.e., valvular disease, congestive heart failure, lung disease, coronary artery disease, hypertension, diabetes mellitus, and thyroid disease) [3] new risk factors are emerging, such as obesity and obstructive sleep apnea, which might significantly predispose to AF [4]. However, in approximately 12–13% of cases, AF occurs without any clinically detectable abnormalities (“lone” or “idiopathic” AF) [5]. In turn, AF is associated with a 5-fold increased risk of ischemic stroke as a consequence of a thrombus formation in the left atrial appendage [6]. The nature of this manuscript does not imply a specific financial support. ⁎ Department of Biomedical, Biotechnological, and Translational Sciences (S.Bi.Bi.T.), Unit of Pathology, University of Parma, Via Gramsci 14, 43126 Parma, Italy. Tel.: +39 0521 702390; fax: +39 0521 292710. E-mail address: [email protected]. 1054-8807/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.12.001

AF was long thought to represent a purely functional disorder without any distinctive anatomical characterization. However, in recent years, new mapping and imaging techniques have identified atrial sites which are predominantly involved in AF initiation and maintenance, i.e., the pulmonary veins (PVs) and the surrounding left atrial posterior wall (Fig. 1) [7,8]. Ablation procedures performed in these specific left atrial sites has very often proved efficient in restoring sinus rhythm in patients suffering from AF [9]. This increased understanding of AF pathogenesis has also generated great curiosity about its underlying histopathologic substrate and, as a consequence, its electrophysiologic implications [10]. Therefore, AF has been seen in a new light according to which it is not a purely functional disease but rather the result of diverse histological changes capable of sustaining this arrhythmic disorder [11]. This review article will focus on current understanding about the structural and genetic bases of AF as seen from the perspective of a morphologist. Their clinical implications will also be discussed. A complete PubMed search was performed in order to identify original manuscripts focusing on structural remodeling in AF and published between 1973 and 2014. Selected study papers, recently published review articles, editorials from peer-reviewed journals, book sections). In addition, the reference lists of each searched publication were reviewed. All of these were full-text English-language manuscripts. 2. Classification and natural history of atrial fibrillation Currently, AF is classified by the American College of Cardiology/ American Heart Association/European Society of Cardiology (ACC/ AHA/ESC) as “paroxysmal”, “persistent”, “long-standing persistent”, or

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Fig. 1. Trigger points for atrial fibrillation. Postero-inferior view of the heart showing the most (red abbreviations) and the less (black abbreviations) common atrial trigger points for atrial fibrillation. Abbreviations: CS, coronary sinus; CVs, caval veins; LAPW, left atrial posterior wall; LM, ligament of Marshall; PVs, pulmonary veins.

“permanent” merely on the basis of its (often presumed) duration. Paroxysmal AF is defined as recurrent AF (≥2 episodes) that terminates spontaneously within 7 days. Persistent AF is defined as AF, which is sustained beyond 7 days, or lasts less than 7 days but necessitates pharmacologic or electrical cardioversion. Long-standing persistent AF is defined as continuous AF of greater than 1-year duration. Permanent AF refers to a group of patients where a decision has been made not to pursue restoration of sinus rhythm by any means, including catheter or surgical ablation [12]. Although widely used, this classification has been questioned by some groups particularly on the basis of its simplistic approach which fails in expounding on the real underlying atrial substrate. On this basis, in order to improve the use of both ablation and medical treatment strategies, patients suffering from AF should additionally be categorized in terms of underlying etiology (and potential substrate), risk factors, and mechanisms [13]. Seen from a morphologic standpoint, a further weak point of the present classification is that, in the “real world”, there is a definite clinicopathologic continuum from paroxysmal to permanent AF, while a subdivision based on arrhythmia duration with specific cutoffs forces patients into rigid and heterogeneous categories. A structural remodeling affecting the atrial myocardial architecture seems to play a crucial role in the initiation and maintenance of AF. Aging itself and several non-arrhythmic diseases such as hypertension, heart failure, valve disorders, diabetes, and thyroid dysfunctions may induce both important histological and ultrastructural changes in the atrial myocardium [11]. Clinically, the first signs of AF usually arise after months/years of remodeling and are very often preceded by asymptomatic arrhythmic episodes. In addition, once AF has taken place, also the cardiomyocyte electrophysiology are modified (socalled “electrophysiological remodeling”, see below) [14]. When established, AF behaves as a progressive disease where the arrhythmia itself may induce both further structural changes and deterioration of the underlying above-mentioned diseases, thereby creating a kind of vicious circle that does nothing but make the myocardial architecture distortion worse [15]. In this scenario, paroxysmal AF may progress to persistent or even permanent AF, whereas structural remodeling

seems to be reversible only during the first phases of the arrhythmic disorder. In any event, the degree of structural remodeling appears to be crucial because it may reach a point of no return beyond which sinus rhythm cannot be restored [14]. Interestingly, the atrial distribution of structural remodeling seems to modify over the natural history of AF. Haïssaguerre et al. observed that PVs are a major source of ectopic beats and can frequently initiate paroxysms of AF (triggered AF episodes). In this situation, the anatomical and electrical isolation of PVs has become a foundation of ablation techniques [16–18]. However, the success of this PV isolation is limited in some patients with paroxysmal AF and, especially, in the great majority of those subjects with persistent/ permanent AF, very likely because of more extensive atrial remodeling additionally involving extra-PV locations [19,20]. The most frequent sites of non-PV atrial triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, the ligament of Marshall, and the region adjacent to the atrioventricular valve annuli (Fig. 1). Furthermore, the atrial ganglionated plexi may play a significant role in the pathogenesis of AF [21]. The high rate of recurrences after PV isolation alone in patients with persistent and long-standing persistent AF, has led to the identification of further strategies aimed at improving outcomes [18]. The logic for these procedures is the fact that persistent AF seems to become pathogenetically less dependent on the PV [22] since its triggers and re-entry sites are commonly found in the left atrial myocardium around the PVs, probably as a result of greater structural remodeling which, in chronic conditions, involves the surrounding atrial myocardium [23]. Consequently, although targeting the triggers located in PVs may often be sufficient in patients with paroxysmal AF, further ablation specifically targeting the altered anatomical substrate responsible for maintaining AF may be required in chronic conditions [18]. 3. Morphologic findings of atrial structural remodeling in atrial fibrillation Large population-based investigations have associated left atrial size to the risk of developing AF. The Framingham study, which prospectively followed up adults after routine surveillance M-mode echocardiograms, showed that left atrial size is an independent risk factor for the subsequent development of AF with a hazard ratio of 1.39 for every 5-mm incremental increase in left atrial size [24]. The Cardiovascular Health Study Left atrial revealed that a diameter N5 cm was associated with a relative risk of 4.05 (1.95–8.35) for the development of AF [25]. At the same time, evidence from echocardiographic prospective studies also supports the fact that AF itself can lead to atrial dilatation. AF occurring in patients with lone AF induces a slow and progressive increase in left atrial size which is independent of left ventricular changes [26]. With the passing of time, this dilation further worsens, also because of the frequent superimposition of additional structural heart diseases, such as mitral valve dysfunctions [12]. There are contradictory data regarding right atrial enlargement in AF even though in the RACE study, performed in a patient population suffering from lone AF, both atria were enlarged with the left more that the right one [26–29]. On this basis, AF and atrial dilatation may take part in a vicious cycle which would lead to the maintenance of this arrhythmia [30]. From the histopathologic standpoint, the enlarged atrial walls are the site of profound morphologic changes affecting both the cardiomyocyte component and the myocardial interstitium (Fig. 2A and B). These modifications have been documented by both experimental and clinical studies [11]. The most evident modification in atrial cardiomyocytes is a progressive loss of sarcomeres starting from the perinuclear area and extending eccentrically towards the sarcoplasm (so-called “myocytolysis”) (Fig. 2C). Sometimes this empty perinuclear area is filled with abundant glycogen granules

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Fig. 2. The histopathology of atrial structural remodeling in atrial fibrillation. (A, B) Medium-power view of an autopsy normal (A) and atrial fibrillation remodeled (B) left atrium. This latter shows moderate-to severe architectural disarray in terms of both cardiomyocyte and interstitial changes. (C, D) A variable amount of cardiomyocytes display perinuclear loss of myofibrils (so-called “myocytolysis”, arrows) with (C) or without (D) glycogen granules accumulation (deeper red color). (E, F, G) Increasing degrees of interstitial fibrosis (red color, arrows) as collagen fibers that surround single or small groups of cardiomyocytes. (H) Sometimes the adventitial/periadventitial spaces are expanded as a consequence of collagen tissue deposition (so-called “perivascular fibrosis”, red color, arrows). Stainings: A, B, and D: hematoxylin–eosin, C: periodic acid-Schiff, E through H: Van Gieson staining for collagen fibers. Original magnifications: A, B, and E through H, ×20 (bar is 200 μm); C and D, ×40 (bar is 50 μm).

(Fig. 2D). A lower cardiomyocyte oxygen supply/demand ratio in AF would induce a metabolic shift from the use of fatty acids to the use of glucose. This intra-cardiomyocyte pathologic accumulation of glycogen could represent the result of metabolic excess of glucose or of altered glycogen catabolism with varying degrees of glycogen accumulation (Fig. 3) [31]. Interestingly, experimental studies have shown that a quantitatively different number of cardiomyocytes partially regain their fetal phenotype by means of an active process of re-expressing some embryonic-type structural proteins (such as smooth muscle actin) and the simultaneous decrease in proteins

distinctive of the adult cardiomyocyte (e.g., titin and cardiotin) [31–33]. Re-expression of smooth-muscle actin has immunohistochemically been confirmed in human left atrial biopsies from patients suffering from AF and mitral valve disease [34]. Ultrastructurally, in addition to confirming all of the changes observed histologically, transmission electron microscopy may document elongated mitochondria with characteristic longitudinally oriented cristae as well as the homogeneous distribution of nuclear heterochromatin (Fig. 4) [31]. Within certain limits, atrial cardiomyocytes in AF do not display patent histopathological degenerative findings (e.g. cytoplasmic

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Fig. 3. The spectrum of glycogen granule accumulation in atrial fibrillation cardiomyocytes. (A) Myocytolytic cardiomyocytes with no or very mild glycogen perinuclear filling (arrow). (B) High-power view of a group of cardiomyocytes with increased sarcoplasmic glycogen (arrow)—but still without any sign of myocytolysis—or with early deposition of glycogen granules into the perinuclear myocytolytic area (arrowheads). (C) Myocytolytic cardiomyocyte with moderate perinuclear glycogen. (D) Large-size cardiomyocyte with severe glycogen accumulation (arrow) into a sarcoplasm with only few peripheral myofibrils. Some myocytolytic fibers with no significant perinuclear glycogen are also detectable (arrowhead). Staining: A through D, periodic acid Schiff. Original magnifications: A through D, ×40 (bar is 50μm).

vacuoles, secondary lysosomes and lipid droplets) therefore the above-mentioned muscle cell changes have not been considered to be strictly degenerative. On this basis, Ausma et al. have hypothesized that they may simply exemplify an adaptive “dedifferentiation” toward an incomplete fetal phenotype that, within bounds, may act as a survival state [31]. The dedifferentiated cardiomyocytes in AF share several resemblances with those in the adaptive response to inadequate coronary blood flow “hibernating myocardium”, which strongly suggests that these modifications are part of a non-specific cardiomyocyte protective mechanism [35]. In AF, the myocardial interstitium is usually occupied by varying amounts of collagen I fibers which organize around single or small groups of cardiomyocytes, thereby generating a spiderweb-like network (Fig. 3E–G). Some degrees of perivascular fibrosis may also be detected in peripheral coronary artery branches (Fig. 3H) [36]. In patients with mitral disease and AF, we found that this marked interstitial collagen deposition was accompanied by decreased atrial myocardial capillary density [36]. In a goat AF model, Ausma et al. investigated the time course of the atrial structural remodeling and found that it takes place progressively over time, with full changes being reached approximately 16 weeks after atrial burst stimulation [37]. The same group found that partial reverse structural remodeling is a partially possible slow process. About 4 months after stopping AF: (i) most of the cardiomyocytes with severe myocytolysis had almost normalized (even though a large proportion of them still showed mild sarcomere loss), (ii) the adult-type expression of cell proteins had only partially recovered, iii) interestingly, the degree of fibrosis was almost superimposable on that seen during AF [38]. These data rank interstitial fibrosis first among the most urgent histopathologic modifications to be prevented. In patients with mitral disease and AF, we showed a gradient in the distribution of structural remodeling in terms of both cardiomyocyte and interstitial changes. Although qualitatively similar, the abovedescribed changes were not homogeneously distributed throughout

the left atrial myocardium but were greater in the left atrial posterior wall than in the corresponding left atrial appendage [34,36]. This asymmetric myocardial injury could be justified by two main explanations: (i) the close anatomical position of the left atrial posterior wall to the PV orifices, an area subjected to an intense stress (ii) according to Laplace’s law, the atrial free wall is characterized by a higher tension, as compared to the left atrial appendage (since the internal diameter of the left atrium is greater than its appendage diameter while the internal left atrial and appendage pressures are similar) [36]. Over the past few years, we have quantified structural remodeling of the left atrial posterior wall in patient populations affected by persistent AF associated with structural heart disease (mitral-valve dysfunction) [34,36,39,40] and, more recently, in persistent idiopathic AF (unpublished data). We found that these changes were milder in the latter than in the former category of patients. These data further strengthen the idea that the degree of structural remodeling is related both to the natural history of AF and the presence of potential associated disorders themselves capable of haemodynamically overloading the left atrial chamber. Unlike the key study by Frustaci et al. on the pathology of lone AF [41], we could not find any significant sign of inflammation in our atrial endomyocardial biopsies from idiopathic AF patients (unpublished data). However, the two AF populations were not fully comparable in terms of AF time course, therefore we cannot rule out the possibility that the interstitial fibrosis that we documented could have potentially been caused by previous myocarditis (at least in a fraction of cases). Our prior morphometric quantifications of left atrial (posterior wall, Fig. 1) structural remodeling in AF patients are summarized in Table 1 [34,36,39,40]. As already stated, PVs are involved in the initiation and maintenance of AF. Clinical investigations have shown that up to 94% of the triggers initiating AF originate within one or more PVs and may interact with the surrounding left atrial substrate through discrete or wide fascicles [42]. In fact, irregular atrial sleeves of cardiomyocytes—with potential spontaneous electrical activity - extend over the veno-atrial junction

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Fig. 4. Ultrastructure of atrial structural remodeling in atrial fibrillation. (A) Medium-power view of a myocytolytic cardiomyocyte whose perinuclear space (asterisk) is essentially empty with some mitochondria (arrowhead). The remaining myofibrils (arrow) surround the periphery of the myocytolytic area. (B) The perinuclear space in myocytolytic cardiomyocytes is sometimes filled by abundant glycogen granules (arrowhead) and a variable number of mitochondria (arrow). (C) Detail of a myocytolytic cardiomyocyte with copious glycogen (asterisk), mitochondria (arrowhead), and, peripherally, some altered myofibrils (arrow). (D) The mitochondria are very often altered with the more frequent change being an elongated shape with longitudinally oriented cristae (arrow). Glycogen granules (arrowhead) are located between the mitochondria. (E) The interstitium between cardiomyocytes (asterisks) is variably occupied by collagen fibers (arrows). (F) High-power detail of the collagen fibers shown in E; they appear longitudinally (arrow) or transversally (arrowhead) cut. Ultrastructurally, in view of their shape, pattern of distribution, and typical cross striation, these fibers are in keeping with collagen type I. Original magnifications: A and B, ×2800 (bar is 5,000 nm); C, ×11,000 (bar is 1000 nm); D and F, ×44,000 (bar is 200 nm); E, ×5600 (bar is 2000 nm). Abbreviations: N, nucleus; L, lipofuscins; M, mitochondrion.

into the PV wall and have electrical activity [43]. The sleeves (whose size is up to 25 mm in length) mainly consist of circularly or spirally oriented bundles of cardiomyocytes that interconnect with each other in a continuous pattern with some gaps throughout [44]. Even though no node-like cells have been found in human hearts, PVs are capable of sustaining automaticity. Several mechanisms have been associated with PV arrythmogenicity. Experimentally, triggered activity and irregular high-frequency rhythms have been observed following ryanodyne infusion, atrial stretching, rapid atrial pacing and congestive heart failure, but, seemingly, not in normal PV cardiomyocytes. It cannot be ruled out that re-entry mechanisms are involved in the genesis of spontaneous PV activity [45–47]. Some studies have indicated that amyloidosis is a possible group of disorders capable of bringing about atrial structural remodeling and thus providing a substrate for AF. A peculiar atrial-limited variant known as isolated atrial amyloidosis (IAA), whose fibril proteins are found in the atrial interstitium and consist of atrial natriuretic peptide (ANP) [48,49]. Röcken et al. investigated IAA in right atrial appendages taken from subjects undergoing heart surgery, and

found that amyloid was more common in patients suffering from AF than in those in sinus rhythm (especially in women with mitral valve disease) and increased with age. In addition, the amount of the material that was immuno-reactive to ANP correlated inversely with the amount of interstitial fibrosis [48]. However, further focused investigations need to be performed in order to confirm the role of amyloidosis as a substrate for AF. Finally, in this scenario of intense tissue remodelling, several experimental and clinical investigations have explored whether in AF there was any sign of cardiomyocyte death, in particular apoptosis. Unfortunately, they have reached the most varied conclusions. It should be noted that this heterogeneity in conclusions might be imputable to diverse factors including exceedingly dissimilar patient populations (or experimental designs) and different methods (with many limitations) to detect apoptotic cardiomyocytes. However, despite these disparate results, it seems that the event marking a watershed between the absence and presence of apoptosis might be the development of such a severe left ventricular failure capable of provoking further atrial hemodynamic overload [11,50–52].

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Table 1 Morphometric quantification of the left atrial structural remodeling in atrial fibrillation based on previous studies References

Patient population

Interstitial fibrosis, %

Perivascular fibrosis, %

[36] [34] [39] [40] [34,36,39,40]

PAF-MVD PAF-MVD PAF-MVD PAF-MVD Controls

7.16±3.23* (2.33-14.69) 7.49±3.34* (2.33-14.69) 8.2±2.2# (4.5-12.0) 10.4±5.1† (3.8-24.7) 0-2.75

0.32±0.25 (0-0.97) 0.34±0.31 (0-1.60)

0.07-2.03

Cardiomyocyte transverse diameter, μm

Myocytolytic cardiomyocytes, %

19.0±1.5§ (16.3-21.2) 18.6±2.1 (15.6-26.4) 18.6±1.5¶ (15.6-21.2) 10.2-14.8

19.9±7.7* (6.9-33.8) 15.1±3.1# (7.9-20.1) 20.8±5.6† (11.1-32.9) 0-2.8

Capillary density, No/mm2 830±106* (670-1020)

923±107† (732-1144) 1,276-1,514

Data from patients are expressed as average value ± its standard deviation, with range values in brackets. Control data are expressed as the overall min/max range obtained from the four studies. Abbreviations: PAF-MVD, persistent atrial fibrillation and mitral valve disease. *: statistically different from controls and the corresponding left atrial appendage; §: statistically different from controls; #: statistically different from the corresponding left atrial appendage (no control group in this study); †: statistically different from controls and mitral valve regurgitation in sinus rhythm patients (no left atrial appendage samples in this study); ¶: statistically different from controls (no left atrial appendage samples in this study).

4. Connexins and atrial fibrillation Five of the 21 connexin (Cx) isoforms in the human genome are found in the heart (Cx37, Cx40, Cx43, Cx45, and Cx50) [53]. The atria have Cx40, Cx43, and Cx45, with Cx40 being the most expressed (and two to three times more expressed in the right atrium than in the left atrium) [53,54]. Under normal conditions, Cx40 is heterogeneously distributed throughout the atrial myocardium. Cx43 is distributed homogeneously in the left atrium and right atrium, and its expression in the right atrium is similar to that of Cx40 [54]. The sinoatrial node and atrioventricular node cardiomyocytes are equipped with small dispersed gap junctions mainly constituted of Cx45. These peculiar gap junctions probably imply poor inter-cardiomyocyte coupling and are the cause of the slower impulse speed within the nodes, and the sequential contraction of the atria and the ventricles [55]. Unitary conductance is relatively high in Cx40 gap junctions (200 pS), lowest in Cx45 junctions (30 pS), and intermediate in Cx43 channels (120 pS) [53]. The difficulty in detecting Cx45 has hampered efforts to determine its levels in normal or pathological atria; however, they do seem to be lower than those of either of the other two Cxs [53,54,56]. Unlike the ventricles, which in essence have a single Cx isoform (Cx43), the presence of multiple connexon isoforms leads to many different types of gap junction channel combinations, each of which has its own electrical characteristics [57]. Unfortunately, atrial quantification of Cx in AF, each time, has reported the expression of Cx40 and Cx43 as increased, decreased or unaltered [58–64]. This inconsistency is probably the consequence of the large number of Cx combinations in the atrial myocardium and, as a result, their different electrical properties. The single investigation of Cx expression (e.g., by immunohistochemistry, Western blotting, etc.) does not take into consideration the real spatial combination of the multiple Cxs involved in gap junction structure, thereby being a too superficial method of evaluating the real functional contribution of these proteins to this cell-to-cell formation [53]. Nevertheless, the assessment of Cx43 distribution pattern throughout the myocardium may provide precious information on possible gap junction myocardial remodeling [65]. 5. Pathogenetic links between atrial fibrillation and development of atrial morphologic changes The pathogenesis of the myocardial damage in AF is dependent on multiple factors and, very likely, multifactorial with different mechanisms superimposing one on another. These factors contribute differently depending on the main underlying cause of AF. Two main key factors capable of modifying myocardial structure and function in AF would seem to be atrial tachycardia, with a high rate of cell depolarization, and volume/pressure overload leading to increasing atrial wall stretch [66]. In addition to being the cause of most of the early electrophysiological changes [11], cardiomyocyte Ca 2+ overload may also activate

the proteolytic activity of Ca 2+-activated neutral proteases, first of all calpain, which seems to be one of the main players in provoking the myocytolysis found in AF cardiomyocytes [67]. Interestingly, this protein localizes in the nuclear area as well as in the intercalated discs and, after appropriate stimuli, can cleave both cardiomyocyte cytoplasmic and membrane-associated proteins [68]. It may also degrade L-type Ca 2+ channels and factors involved in excitationcontraction coupling and may trigger particular mechanisms leading to cell death [69]. Atrial interstitial fibrosis may be the result of non-specific scar-like reparative mechanisms following cardiomyocyte necrosis or, more interestingly, be secondary to reactive fibro-proliferative signaling pathways [70,71]. Angiotensin II (AngII), through its AngII type 1 receptors (AT1) has the potential of inducing, each time, cardiomyocyte hypertrophy [72], endothelial changes [73], vasoconstriction [74], apoptotic cardiomyocyte death [75], and myocardial fibrosis [66,76]. Transforming growth factor-β1 (TGF-β1) is one of the major downstream mediators of AngII, both of which quickly increase after ventricular tachypacing-induced chronic heart failure [77]. Interestingly, in constitutively active TGF-β1 transgenic mice, TGF-β1 activity in itself does not seem to promote significant amounts of fibrosis in the ventricular myocardium. On the contrary, a selective interstitial fibrosis is stimulated in the atrial myocardium, thus suggesting a particular susceptibility of atrial cells to this cytokine [78]. Mechanical stretch can itself induce in fibroblast AngII and TGF-β1 expression, therefore greatly influencing the atrial structural remodelling and its propensity to arrhythmic disorders [79]. Cardiac fibroblasts are highly receptive in sensing, integrating and reacting to mechanical stimuli, being capable of coupling mechanical input to functional responses. This mechanically induced up-regulation of extracellular matrix production may be induced through the autocrine or paracrine action of profibrotic factors [80]. Cardiomyocytes themselves can interact and influence the myocardial fibroblast. Three further potential mediators of structural remodeling still under consideration are the platelet-derived growth factor, the ANP, and the highly promising galectin-3 [11,81]. Several inflammatory markers—such as C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin 2, interleukin 6 (IL-6), interleukin 8 (IL-8), and monocyte chemoattractant protein 1 (MCP1)—have been found as linked with AF (e.g. in post-operative AF) and its outcome [82]. However, many unsolved points remain in the knowledge of the relationship between AF and inflammation. First, there are no univocal results regarding inflammatory marker levels and natural history of atrial fibrillation. In fact, the great majority of them seem not to increase with the transition from paroxysmal to persistent or permanent AF. TNFα is the only molecule that may show a graded increase from paroxysmal to persistent/permanent AF [83,84]. Second, wondering whether inflammation is the cause or consequence of AF is probably the “chicken and egg” conundrum. Based on the available literature, very likely, both hypotheses are true. Inflammation would represent a significant trigger for the

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arrhythmia and, at the same time, AF would create an inflammatory environment [84]. Third, it is unclear whether inflammation in AF reflects a local or systemic process. Only very limited data are available on this subject, yet. Liuba et al. found higher IL-8 plasma levels in femoral vein, right atrial, and coronary sinus blood, but not in PV blood samples, this finding being in keeping with a systemic source of inflammation [85]. Marcus et al. found higher CRP levels in the left atrium than in the corresponding coronary sinus and concluded that trans-cardiac cytokine gradients in AF would arise by sequestration of inflammatory cytokines in the heart [86]. Forth, there are contrasting results as to whether inflammation reflects AF or the potential underlying disease [84,87]. Lastly, there is much convincing evidence that inflammation plays an important role in the pro-thrombotic state associated with AF. The mechanism linking these two phenomena would involve activated inflammatory cells (i.e., monocytes, macrophages, and lymphocytes) which trigger endothelial dysfunction, platelet activation, and increase fibrinogen production (for details see reference [84]). Several lines of evidence support an association between oxidative stress and AF induction and maintenance [11,88,89]. In the myocardium, increased levels of ROS such as superoxide and H2O2 have been found to be associated with AF [90–93]. The oxidized GSSG/reduced glutathione and oxidized cysteine/reduced cysteine ratios have been found increased in the blood of patients with AF [94]. Increased ROS levels result in damage to proteins, lipids, and DNA, and potentiate inflammation. In addition, ROS are also implicated in cardiac structural and electrical remodeling. In fact, it has been shown that hydroxyl radical (OH−) and peroxynitrate (ONOO−) mediate oxidative damage of myofibrils in AF [95,96]. With regard to atrial electrical remodeling, this has been found to be associated with intracellular calcium overload [97,98]. Carnes et al., in a dog model, showed that AF induced by rapid pacing decreased myocardial tissue ascorbate levels and increased protein nitration [99]. Coronary artery bypass surgery, which is often complicated by post-operative AF, is associated with an increase in oxidized glutathione and lipid peroxidation [94,100,101]. In patients with persistent AF and mitral valve disease, our group documented higher myocardial tissue levels of the inducible oxidative stress marker heme oxygenase 1 (HO-1), compared to controls. Interestingly, HO-1 was more expressed where the structural remodeling peaked (left atrial posterior wall vs left atrial appendage) [39,40]. Very recently, in comparison with controls, we have also found both HO-1 overexpression and greater 3-nitrotyrosine levels in the left and right atrial free walls of individuals with idiopathic persistent AF (unpublished data). However, despite the correlative link between oxidative stress and AF, systemic anti-oxidant therapy in patients with AF has not met with much achievement in clinical trials [102,103]. Possible explanations are that oxidative stress is either not part of the pathogenic cascade of arrhythmogenesis, or our available antioxidant treatments are not targeting the specific pathogenic source of oxidative stress in arrhythmia [102,104]. In addition, as already said for inflammation, it is still largely unclear whether oxidative stress is the cause, consequence or both in AF [11]. Further investigations are necessary to elucidate detailed mechanisms involving oxidative stress in the pathogenesis of AF. As already stated, in addition to the cardiovascular diseases that are traditionally accepted as being related to AF, other conditions may also act as risk factors for this supraventricular arrhythmia as well as being players in its pathogenesis [105]. The Veterans Health Administration Hospitals study reported that the incidence of AF in patients with diabetes mellitus was 14.9%, this being significantly higher than that of hypertension. Diabetes mellitus is a strong and independent risk factor for the occurrence of AF, with an odds ratio of 2.13 (Pb.0001) [106,107]. The precise pathogenetic mechanisms that cause AF in diabetes mellitus patients are still

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unknown. The supposed mechanisms linking diabetes mellitus and AF include autonomic remodeling, structural remodeling, electrical remodeling, and insulin resistance. With regard to structural remodeling, in a diabetes mellitus rat model Kato et al. showed fibrosis in the atria with formation of anchoring points for reentry circuits and changes in the forward propagation of fibrillatory wavelets, thereby causing atrial fractionated potentials and conduction delay [108]. A study in which atrial tissue was collected from diabetes mellitus patients, atrial samples biopsied during coronary artery bypass graft surgery displayed mitochondrial dysfunction causing oxidative stress which could also be involved in the formation of hyperglycemia-associated AF substrates, leading to atrial interstitial fibrosis [109]. It has been demonstrated that the advanced glycation end products (AGEs) and AGE receptors (RAGEs) (both constituting the AGERAGE system) facilitate the interstitial collagen deposition in atrial myocardium of diabetes mellitus rats by inducing up-regulation of the expression of connective tissue growth factors, and, as a consequence, cause myocardial structural remodeling [110]. Interestingly, in the atrial myocardium of rats with induced diabetes mellitus, the expression of Cx43 was elevated and its phosphorylation was decreased, this leading to disorders of intercellular electrical coupling and consequent atrial arrhythmia [111]. AF is one of the most frequent rhythm disturbance in the setting of hyperthyroidism with its prevalence ranging from 2% to 20% [112]. If compared with a population with normal thyroid function and a 2.3% prevalence of AF, the prevalence of AF in overt hyperthyroidism is 13.8% [113,114]. Shimizu et al. showed that in a cohort of patients with hyperthyroidism analyzed for age distribution, AF prevalence increased stepwise in each decade, peaking at about 15% in patients N70 years, therefore demonstrating that hyperthyroidism-related AF is more common with advancing age [113]. A number of potential mechanisms of AF in hyperthyroidism have been suggested including elevation of left atrial pressure as a result of increased left ventricular mass and impaired ventricular relaxation, increased atrial ectopic activity, and ischemia secondary to raised resting heart rate [115– 117]. Interestingly, it has recently been shown that both hypothyroidism and hyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. In fact, hypothyroidism and hyperthyroidism, while inducing opposite electrophysiological changes in heart rates and atrial effective refractory period, both significantly increase AF susceptibility [118]. The association of episodic heavy alcohol (ethanol) use with the onset of AF has long been designated as “holiday heart syndrome” [119]. However, more recently, it has been suggested that even habitual heavy alcohol consumption could be associated with a risk of AF [120]. Kodama et al. conducted a meta-analysis of studies related to alcohol consumption and AF to summarize the estimated risk of AF related to alcohol. In a recent meta-analysis performed by Kodama et al. on 14 previous studies, the pooled estimate for AF for highest vs. lowest alcohol intake in individual investigations was 1.51 (Pb.05) and a positive relationship between AF risk and heavy alcohol intake was consistently found in all stratified analyses. In addition, in a linear regression model, the pooled estimated for an increment of 10g per day of alcohol consumption was 1.08 (Pb.001) [121]. Over the last few years, a number of mechanisms by which alcohol consumption would relate to the development of AF have been proposed: a direct toxic effect on cardiac myocytes, a hyperadrenergic state which is reached during both drinking and withdrawal of alcohol, an impaired vagal tone, an increase in intra-atrial conduction time (which is also testified by a P-wave prolongation) [122–125]. 6. Architectural atrial structural remodeling and its propensity to develop atrial fibrillation There are no conduction system fibers between the two nodes and through the remaining atrial myocardium. This is why, because of this

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D. Corradi / Cardiovascular Pathology 23 (2014) 71–84

peculiar architecture of the atria, a cardiac impulse is first generated in the sinoatrial node and is subsequently conducted throughout the working atrial myocardium to the atrioventricular node following well-defined routes in a non-uniform anisotropic way, that is to say, strictly dependent on the anatomic orientation of the myocardial fibers. Among these routes, the terminal crest and anterior limbus of the oval fossa are the main paths for this favored anisotropic conduction which is a consequence of the cylindrical-like shape of adult cardiomyocytes, the heterogeneous distribution of gap junctions, and the muscle bundle orientation along the major axis of atrial cardiomyocytes [126]. In epicardial maps of acute AF and persistent AF, Allessie et al. found that the main feature of the substrate of longstanding AF was a significant increase in longitudinal dissociation, in terms of lines of block running parallel to the atrial musculature [17]. The term “longitudinal dissociation” originally referred to any kind of asynchronous or non-uniform propagation along the longitudinal axis of a portion of the A-V conducting system [127]. In patients with longstanding AF they found electrical longitudinal dissociation of neighboring muscle bundles and the amount of this phenomenon was more than six times higher than in acute AF. On the contrary they failed to find any rotors or foci that could explain the persistence of AF. As a whole, these findings provide evidence that in persistent AF, the route of the fibrillating waves is largely influenced by the underlying architecture of the atrial myocardium (e.g., interstitial fibrosis) [17]. In addition to longitudinal dissociation of atrial muscle bundles, “endocardial-epicardial dissociation” may be considered a further determinant for the establishment of a substrate capable of favoring persistent AF. Electric dissociation between the endocardial and epicardial myocardial layers during AF is a vital condition for transmural conduction of the fibrillation waves. In fact, only in the presence of this dissociation, electric activity in one single layer of the atrial wall can meet excitable muscle in the opposite layer [128]. Since during persistent AF, waves with a focal spread of activation are frequently observed, De Groot et al. have recently investigated whether these waves originate from focal activity (ectopic impulse formation or microreentry) or may be considered as an epicardial breakthrough of waves directly propagating in deeper layers of the atrial myocardial wall. Compared to acute AF, they found a fourfold greater incidence of epicardial breakthroughs in patients with longstanding AF, thereby implying the presence of a three-dimensional substrate where the fibrillation waves frequently cross over from the endocardial to the epicardial layers [129]. On the basis of the above observations, in recent times, Eckstein et al. have proposed a new pathogenetic hypothesis according to which structural heart disease, and AF itself, would induce structural remodeling by disrupting side-to-side cardiomyocyte connections not only between muscle bundles (longitudinal dissociation) but also between the epicardial and endocardial layers (endocardial-epicardial dissociation). As already stated, this progressive loss of endoepicardial electric connections would result in a significant increase in endocardial-epicardial dissociation, produce a three-dimensional structural substrate for AF, and increase the functional surface available for fibrillation waves [128].

that the relative risk of AF among relative pairs declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives, respectively, (Pb.001) [133]. In a patient population of 1,137 same-sex twin pairs (monozygotic and dizygotic) in which one or both members had AF, Christophersen et al. demonstrated that, compared to dizygotic, monozygotic twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3–3.0) and estimated that the heritability of AF due to additive genetics was 62% (55–68%) [134]. Ellinor et al. explored the extent of familial aggregation in patients with lone AF and found that family members had an increased relative risk of AF, compared to the general population: sons (risk ratio 8.1; 95% confidence interval 2.0–32), daughters (9.5; 1.3–67), brothers (70; 47–102), sisters (34; 14–80), mothers (4.0; 2.5–6.5) and fathers (2.0; 1.2–3.6) [135]. Darbar et al. at the Mayo Clinic found that at least 5% of all patients with AF and 15% with lone AF had a positive family history (in first- or second-degree relatives) [136]. Three main methods have been applied in investigating the genetics of AF. The “genetic linkage analysis” is a powerful tool to detect the chromosomal location of disease genes and is based on the fact that genes that are physically located close on a chromosome remaining linked during meiosis. Therefore, AF may be studied as a monogenic disease in which different members of a family have AF as a primary electrical disease. This method is appropriate when dealing with a family of two or three generations in which AF segregates across generations and exhibits a Mendelian-like pattern of inheritance [137]. The main monogenic mutations and rare variants associated with AF are listed in Table 2 [137–161]. “Gene association studies” explore the correlation between a particular disease status and a genetic variation in order to identify candidate genes (or genome regions) that may potentially be linked to a specific disease. In this scenario, a higher frequency of a single-nucleotide polymorphism (SNP) allele or genotype in a series of individuals affected with a disease can be interpreted as potentially increasing the risk of that given specific disease [162]. The main results from gene association studies in AF are shown in Table 3 [163–176]. In addition to testing for association in candidate genes, “genome-wide association studies” also identify several SNPs and loci for complex phenotypes in intergenic regions [177]. The AF susceptibility loci assessed by genomewide association studies are listed in Table 4 [178–185]. As shown in Tables 2, 3, and 4, in recent years, several monogenic mutations have been described by candidate gene tests. Even though efficient in understanding the pathogenesis of some forms of AF, they are limited in explaining the heritability of this supraventricular arrhythmia since they only refer to sporadic or familial cases of AF. On the contrary, genome-wide association studies are more efficient in recognize genetic loci associated with an increased risk of for AF [186]. Additional identification of AF susceptibility loci as well as biological pathways linking the disease with its genetic background will very likely allow us to propose AF risk scores on the basis of the genetic variants. For a more extensive treatment of AF genetics, some comprehensive articles on this subject have recently been published in the English-language literature [131,137,186–190].

7. The genetics of atrial fibrillation

8. Structural remodeling in atrial fibrillation and its implications for clinical practice

The idea that AF could be a heritable disease dates back to the mid20th century, even though only over the last decade has the underlying transmissible component been extensively explored and partially described [130,131]. Several genetic data and epidemiologic observations are strongly in keeping with the concept of AF as a disorder with genetic basis. Data from the Framingham study reported that there was an increased risk of AF in offsprings with at least 1 parent affected by AF, compared to those without parental disease [132]. Arnar et al. found

It is well known that traditional anti-arrhythmic agents classes I (i.e., flecainide, propafenone) and III (i.e., amiodarone, dofetilide, sotalol), which were initially developed to treat ventricular arrhythmias, may also be effective in restoring sinus rhythm when the onset of AF is recent. However, the overall risk of relapse is considerable and depends particularly on the duration of the arrhythmia and structural remodeling establishment [191]. In addition, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study showed that the rhythm-control

D. Corradi / Cardiovascular Pathology 23 (2014) 71–84

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Table 2 Main monogenic mutations and rare variants associated with atrial fibrillation Gene/ Locus

Gene name

Chromosomes Functional consequences

Atrial fibrillation pathogenetic mechanism

References

ABCC9

12p12.1

Defective responses to adrenergic stress

[137,138]

Decreased conduction velocity

[137,139]

Decreased conduction velocity

[140]

12p13

Retention of adenosine-triphosphateinduced inhibition of K+ current Dominant negative effect on gap junctions Dominant negative effect on gap junctions Loss-of-function effect on IKur currents

Delayed atrial action potential repolarization

[141]

21q22.12

Gain-of-function effect on IKr currents

Enhanced atrial action potential repolarization

[142]

11q13.4

Increased activity of Kv4.3/KCNE3 and Kv11.1/KCNE3 generated currents

Faster cardiac action potential repolarization and thus vulnerability to re-entrant wavelets

[143]

Xq22.3 7q36.1

Gain-of-function effect on IKs Gain-of-function effect on IKr currents

17q24.3

Gain-of-function effect on IK1 currents

Enhanced atrial action potential repolarization [144] Increase of the repolarizing currents active during the [145] early phases of the action potential leading to its shorter duration Enhanced atrial action potential repolarization [146]

11p15.5

Gain-of-function effect on IKs currents

Enhanced atrial action potential repolarization

[147–149]

LMNA NPPA

ATP-binding cassette, sub-family C (CFTR/MRP), member 9 gap junction protein, alpha 1, 43kDa gap junction protein, alpha 5, 40kDa potassium voltage-gated channel, shaker-related subfamily, member 5 potassium voltage-gated channel, Isk-related family, member 2 potassium voltage-gated channel, Isk-related family, member 3 KCNE1-like potassium voltage-gated channel, subfamily H (eagrelated), member 2 potassium inwardly-rectifying channel, subfamily J, member 2 potassium voltage-gated channel, KQT-like subfamily, member 1 lamin A/C natriuretic peptide A

Enhanced atrial action potential repolarization

[150,151] [152]

NUP155

nucleoporin 155kDa

5p13

Reduced atrial action potential duration

[137,153]

RYR2 SCN1B

ryanodine receptor 2 (cardiac) sodium channel, voltage-gated, type I, beta subunit sodium channel, voltage-gated, type II, beta subunit sodium channel, voltage-gated, type V, alpha subunit T-box 5

1q43 19q13.1

Shortened action potential duration and effective refractory period Inhibitation of the export of Hsp70 messenger RNA and nuclear import of Hsp70 protein Gain-of-function defect in RyR2 Loss-of-function effect on INa currents

[137,154] [137,154]

11q23

Loss-of-function effect on INa currents

3p21

Gain-of-function effect on INa currents

Defects in calcium ion handling Reduced SCN5A-mediated current and altered channel gating Reduced SCN5A-mediated current and altered channel gating Delayed atrial action potential repolarization

12q24.1

Enhanced DNA binding and activation of both the NPPA (ANP) and Cx40 promoter Unknown Unknown Unknown

GJA1 GJA5 KCNA5

KCNE2

KCNE3

KCNE5 KCNH2

KCNJ2 KCNQ1

SCN2B SCN5A TBX5

Unknown Unknown Unknown Unknown Unknown Unknown

6q22.31 1q21.1

1q22 1p36.21

6q14-q16 10q22-q24 10p11-q21

strategy offers no gain in survival over the rate-control strategy (with beta-blockers, calcium-channel blockers) [192]. Interestingly, a subsequent AFFIRM sub-study examining the relationships between sinus rhythm, treatment and survival demonstrated that, although sinus rhythm is associated with a significant reduction in the risk of death, the anti-arrhythmic pharmacologic strategy was associated with increased mortality, and the investigators therefore supposed that the beneficial anti-arrhythmic effects on survival may

[137,155] [156] [157,158] [159] [160] [161]

be annulled by the significant adverse effects (e.g., proarrhythmic and negative inotropic effects) [193]. Over the last few years, new pharmacologic targets have emerged from our current knowledge concerning AF-related structural remodeling and its pathophysiology. Among the various morphologic changes that take place throughout the natural history of AF, interstitial fibrosis seems to be the most lasting tissue injury as it is virtually unaltered by sinus rhythm restoration and, as it is capable of

Table 3 Main results from gene association studies in atrial fibrillation Gene

Gene name

Locus

References

ACE AGT eNOS GJA5 GNB3 IL10 IL6 KCNE1 minK KCNH2 KNCE5 MMP2 SCN5A SLN

Angiotensin I converting enzyme Angiotensinogen (serpin peptidase inhibitor, clade A, member 8) Nitric oxide synthase 3 (endothelial cell) Gap junction protein, alpha 5, 40kDa Guanine nucleotide binding protein (G protein), beta polypeptide 3 Interleukin 10 Interleukin 6 Potassium voltage-gated channel, Isk-related family, member 1 Potassium voltage-gated channel, subfamily H (eag-related), member 2 KCNE1-like Matrix metallopeptidase 2 Sodium channel, voltage-gated, type V, alpha subunit Sarcolipin

D/D M235T, G-6A, G-217A, T174M, 20C/C 2786C, G894T -44AA/+71GG C825T A-592C G-174C 38G K897T 97T C1306T H558R C-65G

[163,164] [163–166] [163–167] [168] [169] [170] [171] [167,172] [173] [174] [170] [175] [176]

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Table 4 Atrial fibrillation susceptibility loci assessed by genome-wide association studies Locus

Top SNP

Nearest gene

Nearest gene name

References

9q22 7q31 15q24 1q21 4q25 1q24 14q23 10q22 16q22

rs10821415 rs3807989 rs7164883 rs13376333 rs2200733 rs3903239 rs1152591 rs10824026 rs2106261

C9orf3 CAV1 HCN4 KCNN3 PITX2 PRRX1 SYNE2 SYNPO2L ZFHX3

Chromosome 9 open reading frame 3 Caveolin 1, caveolae protein, 22 kDa Hyperpolarization activated cyclic nucleotide-gated potassium channel 4 Potassium intermediate/small Conductance calcium-activated channel, subfamily N, member 3 Paired-like homeodomain 2 Paired related homeobox 1 Spectrin repeat containing, nuclear envelope 2 Synaptopodin 2-like Zinc finger homeobox 3

[178] [178] [178] [178,179] [178,180–184] [178] [178] [178] [178,181,185]

interfering with atrial electrical conduction [38,194], it is extremely important to prevent inter-cardiomyocyte collagen deposition by reducing atrial stretching (e.g. by means of early mitral valve surgery) and pharmacologically interfere with the molecular mechanisms leading to fibrosis [71]. Inflammation and oxidative stress may be two additional factors involved in the cascade of events leading to permanent tissue injury, and are therefore to be considered potential pharmacologic targets [195]. New non-ionic drugs that can potentially inhibit atrial fibrosis and cell hypertrophy, and modulate the specific inflammatory/oxidative status, have therefore been proposed as therapeutic options in AF that could potentially attenuate and delay atrial structural modifications (so-called “upstream therapy”, Table 5) [71,99,103,196–217]. Over the last few years, a number of clinical trials have been developed in order to assess the real effect of these classes of drugs on AF. Upstream treatment with inhibitors of the renin–angiotensin– aldosterone system, statins, and n-3 (ϖ-3) polyunsaturated fatty acids may vary the arrhythmia substrate responsible for AF in virtue of its prevention (or possibly reversal) of structural remodeling and treatment of the potential underlying cardiovascular disease associated with AF. Data from clinical investigations suggest that these therapies could be valuable for primary prevention of AF. Nevertheless, if renin angiotensin aldosterone system inhibitors or statins are warranted for proven therapy (e.g., chronic heart failure, hypertension, coronary artery disease, coronary artery bypass graft, etc.), there is a bonus that these agents may also prevent AF. Recommendations for inhibitors of the renin–angiotensin–aldosterone system and statins use in primary prevention and levels of evidence have been inserted in the 2010 ESC guidelines on AF management [196,218]. On the contrary, upstream therapy seems not to be significantly efficient in preventing recurrences of AF (secondary prevention) [197]. This different behavior may be justified by the fact that, in a patient with clinically evident AF, structural remodeling (i.e., interstitial fibrosis) has already set in and, very likely, upstream therapy cannot only prevent (or retard)

further collagen accumulation without significantly reversing previous tissue changes [197]. Given the regional distribution of AF structural remodeling (which in chronic conditions peaks in the left atrium), catheter ablation may be an effective non-pharmacological approach to AF and structural heart disease (Fig. 1). By causing ablation lines of myocardial destruction, it aims to reduce the remodeled myocardial mass to a size too small to maintain re-entrant arrhythmogenic circuits [8,9]. As already stated, the ablation of PVs is very frequently effective in treating most patients with paroxysmal AF. However, the success of this ablative procedure is limited in some patients with paroxysmal AF and, especially, in the great majority of those suffering from persistent/permanent AF, very likely because of more extensive atrial remodelling behind the PV-atrial junction [21,82,174,219]. Very recently, Pump et al. found that in patients with AF and extremely enlarged left atrium, ablation was effective in non-paroxysmal AF cases and especially associated with left atrial reverse remodeling and improved left ventricular ejection fraction [220]. For a more extensive treatment on ablation of atrial sites in AF, see the two very recent review articles [21,219]. 9. Conclusions AF is an arrhythmic disorder with significant structural bases which, at the same time, are both the result and a condition favoring the perpetuation of the disease. Due to its extreme structural stability and negligible regression after restoration of sinus rhythm, collagen deposition around cardiomyocytes (interstitial fibrosis) is the most threatening change in the setting of AF atrial structural remodeling. AF itself and the often associated cardiovascular disorders are capable of inducing in the atrial myocardium various degrees of remodeling at the histologic and ultrastructural level. The extent of structural remodeling goes hand in hand with the clinical history of AF, with the first changes being in the distal PVs and the surrounding myocardium. As the disease evolves from paroxysmal to chronic, this remodeling

Table 5 "Upstream therapy" for prevention of structural remodelling in atrial fibrillation (based on animal and human studies) Pharmacological class

Action mechanism

Main effects on structural remodelling

References

Angiotensin-converting enzyme (ACE) inhibitors

Inhibition of Angiotensin II production

Improvement of left ventricular diastolic function. Fibrosis production inhibition. Beneficial effects on inflammation, atrial stretch, myocyte metabolism, connexin distribution and electrical remodelling. Inhibition of myocyte hypertrophy. Improvement of left ventricular diastolic function. Fibrosis production inhibition. Inhibition of myocyte hypertrophy.

[198–203]

Angiotensin II type 1 (AT1) AT1 receptor antagonist receptor blockers (“sartans”) Spironolactone Aldosterone antagonist Statins 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Ascorbate Anti-oxidant activity Omega-3 poly-unsaturated Constituent of fish oil with antifatty acids inflammatory and anti-oxidative activity Corticosteroids Anti-inflammatory activity

[198,199,204,205]

Fibrosis production inhibition. Prevention of underlying heart disease by interfering with lipid metabolism. Strong anti-inflammatory and anti-oxidant activity. Protection of atrial myocardium during ischemia. Beneficial effects on interstitial fibrosis. Contradictory results on its prevention of AF after cardiac surgery. Anti-inflammatory and anti-oxidative effect. Inhibitory effect on metalloproteinase 9 activity. Attenuation the development of atrial fibrosis and inducibility of AF.

[206,207] [71,208–211]

[99,205,211] [103,210,212– 215]

Suggested in the prevention of atrial fibrillation post-cardiac surgery.

[216,217]

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spreads to larger portions of the atrial wall often making both classic antiarrhythmic dugs and ablation of the sole PV outlets ineffective. On this basis, the most urgent strategy is preventing the structural remodeling—with special regard to interstitial fibrosis—by early treatment of the arrhythmia as well as its underlying cardiovascular diseases. The association of drugs belonging to the “upstream therapy” might potentially be helpful in counteracting and delaying the myocardial collagen deposition in AF. Finally, a thorough knowledge of the AF genetic background could break new ground for future personalized treatments of AF. Acknowledgments The author is greatly indebted to Dr. Giorgio Bordin, Hospital Piccole Figlie, Parma, Italy, for drawing Fig. 1. In addition, the author would like to thank heartily Ms Gabriella Becchi and Ms Emilia Corradini, Department of Biomedical, Biotechnological, and Translational Sciences (S.Bi.Bi.T.), Unit of Pathology, University of Parma, for their invaluable technical assistance. References [1] Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954–68. [2] Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042–6. [3] Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N–9N. [4] Chen LY, Shen WK. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007;4:S1–6. [5] Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257–354. [6] Syed TM, Halperin JL. Left atrial appendage closure for stroke prevention in atrial fibrillation: state of the art and current challenges. Nat Clin Pract Cardiovasc Med 2007;4:428–35. [7] Haïssaguerre M, Sanders P, Jaïs P, Hocini M, Shah D, Clémenty J. Catheter ablation of atrial fibrillation: triggers and substrate. In: Zipes D, Jeds Jalife, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia: W.B. Saunders Company; 2004. p. 1028–38. [8] Pappone C, Rosanio S. Pulmonary vein isolation for atrial fibrillation. In: Zipes D, Jeds Jalife, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia: W.B. Saunders Company; 2004. p. 1039–52. [9] Benussi S, Pappone C, Nascimbene S, Oreto G, Caldarola A, Stefano PL, et al. A simple way to treat chronic atrial fibrillation during mitral valve surgery: the epicardial radiofrequency approach. Eur J Cardiothorac Surg 2000;17:524–9. [10] Allessie MA, Boyden PA, Camm AJ, Kleber AG, Lab MJ, Legato MJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation 2001;103:769–77. [11] Corradi D, Callegari S, Maestri R, Benussi S, Alfieri O. Structural remodeling in atrial fibrillation. Nat Clin Pract Cardiovasc Med 2008;5:782–96. [12] Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007;4:816–61. [13] Singh JP, Morady F. Patient selection and classification for atrial fibrillation ablation: thinking beyond duration. Heart Rhythm 2009;6:1522–5. [14] Smit MD, Van Gelder IC. New treatment options for atrial fibrillation: towards patient tailored therapy. Heart 2011;97:1796–802. [15] Saffitz JE, Schuessler RB. Altered atrial structure begets atrial fibrillation, but how? J Cardiovasc Electrophysiol 2004;15:1175–6. [16] Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. [17] Allessie MA, de Groot NM, Houben RP, Schotten U, Boersma E, Smeets JL, et al. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ Arrhythm Electrophysiol 2010;3:606–15. [18] Verma A. The techniques for catheter ablation of paroxysmal and persistent atrial fibrillation: a systematic review. Curr Opin Cardiol 2011;26:17–24.

81

[19] Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100:1879–86. [20] Oral H, Knight BP, Tada H, Ozaydin M, Chugh A, Hassan S, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002;105: 1077–81. [21] Corradi D, Callegari S, Gelsomino S, Lorusso R, Macchi E. Morphology and pathophysiology of target anatomical sites for ablation procedures in patients with atrial fibrillation: Part II: Pulmonary veins, caval veins, ganglionated plexi, and ligament of Marshall. Int J Cardiol 2013;168:1769–78. [22] Smelley MP, Knight BP. Approaches to catheter ablation of persistent atrial fibrillation. Heart Rhythm 2009;6:S33–8. [23] Eckstein J, Verheule S, de Groot NM, Allessie M, Schotten U. Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria. Prog Biophys Mol Biol 2008;97:435–51. [24] Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89:724–30. [25] Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, Fried LP, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455–61. [26] Suarez GS, Lampert S, Ravid S, Lown B. Changes in left atrial size in patients with lone atrial fibrillation. Clin Cardiol 1991;14:652–6. [27] Phang RS, Isserman SM, Karia D, Pandian NG, Homoud MK, Link MS, et al. Echocardiographic evidence of left atrial abnormality in young patients with lone paroxysmal atrial fibrillation. Am J Cardiol 2004;94:511–3. [28] Falk RH. Etiology and complications of atrial fibrillation: insights from pathology studies. Am J Cardiol 1998;82:10N–7N. [29] Rienstra M, Hagens VE, Van Veldhuisen DJ, Bosker HA, Tijssen JG, Kamp O, et al. Clinical characteristics of persistent lone atrial fibrillation in the RACE study. Am J Cardiol 2004;94:1486–90. [30] Thamilarasan M, Klein AL. Factors relating to left atrial enlargement in atrial fibrillation: "chicken or the egg" hypothesis. Am Heart J 1999;137:381–3. [31] Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997;96:3157–63. [32] Woodcock-Mitchell J, Mitchell JJ, Low RB, Kieny M, Sengel P, Rubbia L, et al. Alpha-smooth muscle actin is transiently expressed in embryonic rat cardiac and skeletal muscles. Differentiation 1988;39:161–6. [33] Ausma J, Wijffels M, van Eys G, Koide M, Ramaekers F, Allessie M, et al. Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation. Am J Pathol 1997;151:985–97. [34] Corradi D, Callegari S, Benussi S, Maestri R, Pastori P, Nascimbene S, et al. Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease. Hum Pathol 2005;36:1080–9. [35] Ausma J, Thone F, Dispersyn GD, Flameng W, Vanoverschelde JL, Ramaekers FC, et al. Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant. Mol Cell Biochem 1998;186:159–68. [36] Corradi D, Callegari S, Benussi S, Nascimbene S, Pastori P, Calvi S, et al. Regional left atrial interstitial remodeling in patients with chronic atrial fibrillation undergoing mitral-valve surgery. Virchows Arch 2004;445:498–505. [37] Ausma J, Litjens N, Lenders MH, Duimel H, Mast F, Wouters L, et al. Time course of atrial fibrillation-induced cellular structural remodeling in atria of the goat. J Mol Cell Cardiol 2001;33:2083–94. [38] Ausma J, van der Velden HM, Lenders MH, van Ankeren EP, Jongsma HJ, Ramaekers FC, et al. Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation 2003;107:2051–8. [39] Corradi D, Callegari S, Maestri R, Benussi S, Bosio S, De Palma G, et al. Heme oxygenase-1 expression in the left atrial myocardium of patients with chronic atrial fibrillation related to mitral valve disease: its regional relationship with structural remodeling. Hum Pathol 2008;39:1162–71. [40] Corradi D, Callegari S, Maestri R, Ferrara D, Mangieri D, Alinovi R, et al. Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study. J Cardiovasc Electrophysiol 2012;23:271–9. [41] Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997;96:1180–4. [42] Jellis C, Martin J, Narula J, Marwick TH. Assessment of nonischemic myocardial fibrosis. J Am Coll Cardiol 2010;56:89–97. [43] Zipes DP, Knope RF. Electrical properties of the thoracic veins. Am J Cardiol 1972;29:372–6. [44] Ho SY, Cabrera JA, Tran VH, Farre J, Anderson RH, Sanchez-Quintana D. Architecture of the pulmonary veins: relevance to radiofrequency ablation. Heart 2001;86:265–70. [45] Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, et al. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation 2001;104: 2849–54. [46] Wu TJ, Ong JJ, Chang CM, Doshi RN, Yashima M, Huang HL, et al. Pulmonary veins and ligament of Marshall as sources of rapid activations in a canine model of sustained atrial fibrillation. Circulation 2001;103:1157–63. [47] Honjo H, Boyett MR, Niwa R, Inada S, Yamamoto M, Mitsui K, et al. Pacinginduced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine. Circulation 2003;107:1937–43.

82

D. Corradi / Cardiovascular Pathology 23 (2014) 71–84

[48] Rocken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C, et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002;106:2091–7. [49] Feng D, Edwards WD, Oh JK, Chandrasekaran K, Grogan M, Martinez MW, et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation 2007;116:2420–6. [50] Bauer A, McDonald AD, Donahue JK. Pathophysiological findings in a model of persistent atrial fibrillation and severe congestive heart failure. Cardiovasc Res 2004;61:764–70. [51] Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensindependent and -independent pathways. Cardiovasc Res 2003;60:315–25. [52] Aime-Sempe C, Folliguet T, Rucker-Martin C, Krajewska M, Krajewska S, Heimburger M, et al. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol 1999;34:1577–86. [53] Duffy HS, Wit AL. Is there a role for remodeled connexins in AF? No simple answers. J Mol Cell Cardiol 2008;44:4–13. [54] Vozzi C, Dupont E, Coppen SR, Yeh HI, Severs NJ. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 1999;31:991–1003. [55] Severs NJ. The cardiac gap junction and intercalated disc. Int J Cardiol 1990;26: 137–73. [56] Saffitz JE. Connexins, conduction, and atrial fibrillation. N Engl J Med 2006;354: 2712–4. [57] Harris AL. Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys 2001;34:325–472. [58] Dupont E, Ko Y, Rothery S, Coppen SR, Baghai M, Haw M, et al. The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation 2001;103:842–9. [59] Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 2002;54:361–79. [60] Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, et al. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 2005;91:166–70. [61] van der Velden HM, van Kempen MJ, Wijffels MC, van Zijverden M, Groenewegen WA, Allessie MA, et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 1998;9:596–607. [62] Polontchouk L, Haefliger JA, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, et al. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol 2001;38:883–91. [63] Nao T, Ohkusa T, Hisamatsu Y, Inoue N, Matsumoto T, Yamada J, et al. Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol 2003;91:678–83. [64] Kanagaratnam P, Cherian A, Stanbridge RD, Glenville B, Severs NJ, Peters NS. Relationship between connexins and atrial activation during human atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:206–16. [65] Saffitz JE, Green KG, Kraft WJ, Schechtman KB, Yamada KA. Effects of diminished expression of connexin43 on gap junction number and size in ventricular myocardium. Am J Physiol Heart Circ Physiol 2000;278:H1662–70. [66] Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 2008;51:1–11. [67] Schoonderwoerd BA, Ausma J, Crijns HJ, Van Veldhuisen DJ, Blaauw EH, Van Gelder IC. Atrial ultrastructural changes during experimental atrial tachycardia depend on high ventricular rate. J Cardiovasc Electrophysiol 2004;15:1167–74. [68] Suzuki K, Imajoh S, Emori Y, Kawasaki H, Minami Y, Ohno S. Calcium-activated neutral protease and its endogenous inhibitor. Activation at the cell membrane and biological function. FEBS Lett 1987;220:271–7. [69] Brundel BJ, Henning RH, Kampinga HH, Van Gelder IC, Crijns HJ. Molecular mechanisms of remodeling in human atrial fibrillation. Cardiovasc Res 2002;54: 315–24. [70] Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, et al. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131–41. [71] Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802–9. [72] Sadoshima J, Izumo S. Autocrine secretion of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Contrib Nephrol 1996;118:214–21. [73] Usui M, Egashira K, Tomita H, Koyanagi M, Katoh M, Shimokawa H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation 2000;101:305–10. [74] Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin. Adv Intern Med 2000;45:419–29. [75] Schroder D, Heger J, Piper HM, Euler G. Angiotensin II stimulates apoptosis via TGF-beta1 signaling in ventricular cardiomyocytes of rat. J Mol Med 2006;84: 975–83. [76] Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol 1994;26:809–20. [77] Hanna N, Cardin S, Leung TK, Nattel S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure. Cardiovasc Res 2004;63:236–44. [78] Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res 2000;86:571–9. [79] Schotten U, Neuberger HR, Allessie MA. The role of atrial dilatation in the domestication of atrial fibrillation. Prog Biophys Mol Biol 2003;82:151–62.

[80] MacKenna D, Summerour SR, Villarreal FJ. Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res 2000;46:257–63. [81] Jalife J. Mechanisms of persistent atrial fibrillation. Curr Opin Cardiol 2014;29: 20–7. [82] Patel P, Dokainish H, Tsai P, Lakkis N. Update on the association of inflammation and atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:1064–70. [83] Hak L, Mysliwska J, Wieckiewicz J, Szyndler K, Siebert J, Rogowski J. Interleukin-2 as a predictor of early postoperative atrial fibrillation after cardiopulmonary bypass graft (CABG). J Interferon Cytokine Res 2009;29:327–32. [84] Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012;60:2263–70. [85] Liuba I, Ahlmroth H, Jonasson L, Englund A, Jonsson A, Safstrom K, et al. Source of inflammatory markers in patients with atrial fibrillation. Europace 2008;10: 848–53. [86] Marcus GM, Smith LM, Ordovas K, Scheinman MM, Kim AM, Badhwar N, et al. Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm 2010;7:149–54. [87] Pellegrino PL, Brunetti ND, De Gennaro L, Ziccardi L, Grimaldi M, Biase MD. Inflammatory activation in an unselected population of subjects with atrial fibrillation: links with structural heart disease, atrial remodeling and recent onset. Intern Emerg Med 2013;8:123–8. [88] Li J, Solus J, Chen Q, Rho YH, Milne G, Stein CM, et al. Role of inflammation and oxidative stress in atrial fibrillation. Heart Rhythm 2010;7:438–44. [89] Youn JY, Zhang J, Zhang Y, Chen H, Liu D, Ping P, et al. Oxidative stress in atrial fibrillation: An emerging role of NADPH oxidase. J Mol Cell Cardiol 2013;62:72–9. [90] Chang JP, Chen MC, Liu WH, Yang CH, Chen CJ, Chen YL, et al. Atrial myocardial nox2 containing NADPH oxidase activity contribution to oxidative stress in mitral regurgitation: potential mechanism for atrial remodeling. Cardiovasc Pathol 2011;20:99–106. [91] Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, et al. A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 2005;97:629–36. [92] Kim YM, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B. Association of atrial nicotinamide adenine dinucleotide phosphate oxidase activity with the development of atrial fibrillation after cardiac surgery. J Am Coll Cardiol 2008;51: 68–74. [93] Zhang J, Youn JY, Kim AY, Ramirez RJ, Gao L, Ngo D, et al. NOX4-dependent hydrogen peroxide overproduction in human atrial fibrillation and HL-1 atrial cells: relationship to hypertension. Front Physiol 2012;3:140. [94] Neuman RB, Bloom HL, Shukrullah I, Darrow LA, Kleinbaum D, Jones DP, et al. Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem 2007;53:1652–7. [95] Babusikova E, Kaplan P, Lehotsky J, Jesenak M, Dobrota D. Oxidative modification of rat cardiac mitochondrial membranes and myofibrils by hydroxyl radicals. Gen Physiol Biophys 2004;23:327–35. [96] Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001;104:174–80. [97] Lai LP, Su MJ, Lin JL, Lin FY, Tsai CH, Chen YS, et al. Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca(2+)-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: an insight into the mechanism of atrial electrical remodeling. J Am Coll Cardiol 1999;33:1231–7. [98] Li GR, Nattel S. Properties of human atrial ICa at physiological temperatures and relevance to action potential. Am J Physiol 1997;272:H227–35. [99] Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89:E32–8. [100] Wolin MS, Gupte SA. Novel roles for nox oxidases in cardiac arrhythmia and oxidized glutathione export in endothelial function. Circ Res 2005;97:612–4. [101] Basu S, Nozari A, Liu XL, Rubertsson S, Wiklund L. Development of a novel biomarker of free radical damage in reperfusion injury after cardiac arrest. FEBS Lett 2000;470:1–6. [102] Yang KC, Dudley SC. Oxidative stress and atrial fibrillation: finding a missing piece to the puzzle. Circulation 2013;128:1724–6. [103] Mozaffarian D, Wu JH, de Oliveira Otto MC, Sandesara CM, Metcalf RG, Latini R, et al. Fish oil and post-operative atrial fibrillation: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2013;61:2194–6. [104] Sovari AA, Rutledge CA, Jeong EM, Dolmatova E, Arasu D, Liu H, et al. Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ Arrhythm Electrophysiol 2013;6:623–31. [105] Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: causes of 'not-so-lone atrial fibrillation'. Europace 2008;10: 668–73. [106] Lin Y, Li H, Lan X, Chen X, Zhang A, Li Z. Mechanism of and therapeutic strategy for atrial fibrillation associated with diabetes mellitus. ScientificWorldJournal 2013;2013:209428. [107] Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in addition to other cardiovascular disease. Int J Cardiol 2005;105:315–8. [108] Kato T, Yamashita T, Sekiguchi A, Sagara K, Takamura M, Takata S, et al. What are arrhythmogenic substrates in diabetic rat atria? J Cardiovasc Electrophysiol 2006;17:890–4.

D. Corradi / Cardiovascular Pathology 23 (2014) 71–84 [109] Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substratespecific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 2009;54:1891–8. [110] Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura M, et al. AGEsRAGE system mediates atrial structural remodeling in the diabetic rat. J Cardiovasc Electrophysiol 2008;19:415–20. [111] Mitasikova M, Lin H, Soukup T, Imanaga I, Tribulova N. Diabetes and thyroid hormones affect connexin-43 and PKC-epsilon expression in rat heart atria. Physiol Res 2009;58:211–7. [112] Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116:1725–35. [113] Shimizu T, Koide S, Noh JY, Sugino K, Ito K, Nakazawa H. Hyperthyroidism and the management of atrial fibrillation. Thyroid 2002;12:489–93. [114] Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B. Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J 2001;142:838–42. [115] Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 2004;59:31–50. [116] Sgarbi JA, Villaca FG, Garbeline B, Villar HE, Romaldini JH. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab 2003;88:1672–7. [117] Bielecka-Dabrowa A, Mikhailidis DP, Rysz J, Banach M. The mechanisms of atrial fibrillation in hyperthyroidism. Thyroid Res 2009;2:4. [118] Zhang Y, Dedkov EI, Teplitsky D, Weltman NY, Pol CJ, Rajagopalan V, et al. Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. Circ Arrhythm Electrophysiol 2013;6:952–9. [119] Ettinger PO, Wu CF, De La Cruz C, Jr., Weisse AB, Ahmed SS, Regan TJ.. Arrhythmias and the "Holiday Heart": alcohol-associated cardiac rhythm disorders. Am Heart J 1978;95:555–62. [120] Balbao CE, de Paola AA, Fenelon G. Effects of alcohol on atrial fibrillation: myths and truths. Ther Adv Cardiovasc Dis 2009;3:53–63. [121] Kodama S, Saito K, Tanaka S, Horikawa C, Saito A, Heianza Y, et al. Alcohol consumption and risk of atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2011;57:427–36. [122] Piano MR, Rosenblum C, Solaro RJ, Schwertz D. Calcium sensitivity and the effect of the calcium sensitizing drug pimobendan in the alcoholic isolated rat atrium. J Cardiovasc Pharmacol 1999;33:237–42. [123] Denison H, Jern S, Jagenburg R, Wendestam C, Wallerstedt S. Influence of increased adrenergic activity and magnesium depletion on cardiac rhythm in alcohol withdrawal. Br Heart J 1994;72:554–60. [124] Gould L, Reddy CV, Becker W, Oh KC, Kim SG. Electrophysiologic properties of alcohol in man. J Electrocardiol 1978;11:219–26. [125] Steinbigler P, Haberl R, Konig B, Steinbeck G. P-wave signal averaging identifies patients prone to alcohol-induced paroxysmal atrial fibrillation. Am J Cardiol 2003;91:491–4. [126] Spach MS, Kootsey JM. The nature of electrical propagation in cardiac muscle. Am J Physiol 1983;244:H3-22. [127] Myerburg RJ, Nilsson K, Befeler B, Castellanos A, Gelband H. Transverse spread and longitudinal dissociation in the distal A-V conducting system. J Clin Invest 1973;52:885–95. [128] Eckstein J, Zeemering S, Linz D, Maesen B, Verheule S, van Hunnik A, et al. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping. Circ Arrhythm Electrophysiol 2013;6:334–41. [129] de Groot NM, Houben RP, Smeets JL, Boersma E, Schotten U, Schalij MJ, et al. Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough. Circulation 2010;122:1674–82. [130] Wolf L. Familial auricular fibrillation. N Engl J Med 1943;229:396–8. [131] Lubitz SA, Ozcan C, Magnani JW, Kaab S, Benjamin EJ, Ellinor PT. Genetics of atrial fibrillation: implications for future research directions and personalized medicine. Circ Arrhythm Electrophysiol 2010;3:291–9. [132] Fox CS, Parise H, D'Agostino RB, Lloyd-Jones DM, Vasan RS, Wang TJ, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA 2004;291:2851–5. [133] Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, et al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J 2006;27:708–12. [134] Christophersen IE, Ravn LS, Budtz-Joergensen E, Skytthe A, Haunsoe S, Svendsen JH, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol 2009;2:378–83. [135] Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet 2005;118:179–84. [136] Darbar D, Herron KJ, Ballew JD, Jahangir A, Gersh BJ, Shen WK, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol 2003;41: 2185–92. [137] Xiao J, Liang D, Chen YH. The genetics of atrial fibrillation: from the bench to the bedside. Annu Rev Genomics Hum Genet 2011;12:73–96. [138] Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, et al. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med 2007;4:110–6. [139] Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, et al. Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation 2010;122:236–44. [140] Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 2006;354:2677–88.

83

[141] Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 2006;15:2185–91. [142] Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet 2004;75:899–905. [143] Lundby A, Ravn LS, Svendsen JH, Hauns S, Olesen SP, Schmitt N. KCNE3 mutation V17M identified in a patient with lone atrial fibrillation. Cell Physiol Biochem 2008;21:47–54. [144] Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, Cordeiro JM, Dixen U, et al. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm 2008;5:427–35. [145] Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol 2005;16: 394–6. [146] Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, et al. A Kir2.1 gain-offunction mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun 2005;332:1012–9. [147] Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, et al. KCNQ1 gain-offunction mutation in familial atrial fibrillation. Science 2003;299:251–4. [148] Otway R, Vandenberg JI, Guo G, Varghese A, Castro ML, Liu J, et al. Stretchsensitive KCNQ1 mutation A link between genetic and environmental factors in the pathogenesis of atrial fibrillation? J Am Coll Cardiol 2007;49:578–86. [149] Das S, Makino S, Melman YF, Shea MA, Goyal SB, Rosenzweig A, et al. Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation. Heart Rhythm 2009;6:1146–53. [150] Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715–24. [151] Sebillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, et al. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet 2003;40:560–7. [152] Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med 2008;359:158–65. [153] Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, Ke T, et al. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 2008;135:1017–27. [154] Bhuiyan ZA, van den Berg MP, van Tintelen JP, Bink-Boelkens MT, Wiesfeld AC, Alders M, et al. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation 2007;116: 1569–76. [155] Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, et al. Mutations in sodium channel beta1- and beta2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2:268–75. [156] Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005;293:447–54. [157] Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE. T-box genes in vertebrate development. Annu Rev Genet 2005;39:219–39. [158] Boogerd CJ, Dooijes D, Ilgun A, Mathijssen IB, Hordijk R, van de Laar IM, et al. Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. Cardiovasc Res 2010;88:130–9. [159] Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRae CA. Locus for atrial fibrillation maps to chromosome 6q14-16. Circulation 2003;107:2880–3. [160] Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med 1997;336:905–11. [161] Volders PG, Zhu Q, Timmermans C, Eurlings PM, Su X, Arens YH, et al. Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21. Heart Rhythm 2007;4:469–75. [162] Lewis CM, Knight J. Introduction to genetic association studies. Cold Spring Harb Protoc 2012;2012:297–306. [163] Bedi M, McNamara D, London B, Schwartzman D. Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm 2006;3: 808–12. [164] Fatini C, Sticchi E, Gensini F, Gori AM, Marcucci R, Lenti M, et al. Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility. Int J Cardiol 2007;120:59–65. [165] Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, et al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 2004;109:1640–6. [166] Ravn LS, Benn M, Nordestgaard BG, Sethi AA, Agerholm-Larsen B, Jensen GB, et al. Angiotensinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population. Pharmacogenet Genomics 2008;18:525–33. [167] Fatini C, Sticchi E, Genuardi M, Sofi F, Gensini F, Gori AM, et al. Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J 2006;27:1712–8. [168] Juang JM, Chern YR, Tsai CT, Chiang FT, Lin JL, Hwang JJ, et al. The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol 2007;116:107–12. [169] Schreieck J, Dostal S, von Beckerath N, Wacker A, Flory M, Weyerbrock S, et al. C825T polymorphism of the G-protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. Am Heart J 2004;148:545–50. [170] Kato K, Oguri M, Hibino T, Yajima K, Matsuo H, Segawa T, et al. Genetic factors for lone atrial fibrillation. Int J Mol Med 2007;19:933–9.

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D. Corradi / Cardiovascular Pathology 23 (2014) 71–84

[171] Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation 2003;108(Suppl 1):II195–9. [172] Lai LP, Su MJ, Yeh HM, Lin JL, Chiang FT, Hwang JJ, et al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J 2002;144:485–90. [173] Sinner MF, Pfeufer A, Akyol M, Beckmann BM, Hinterseer M, Wacker A, et al. The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). Eur Heart J 2008;29:907–14. [174] Ravn LS, Hofman-Bang J, Dixen U, Larsen SO, Jensen G, Haunso S, et al. Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. Am J Cardiol 2005;96: 405–7. [175] Chen LY, Ballew JD, Herron KJ, Rodeheffer RJ, Olson TM. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther 2007;81:35–41. [176] Nyberg MT, Stoevring B, Behr ER, Ravn LS, McKenna WJ, Christiansen M. The variation of the sarcolipin gene (SLN) in atrial fibrillation, long QT syndrome and sudden arrhythmic death syndrome. Clin Chim Acta 2007;375:87–91. [177] Bush WS, Moore JH. Chapter 11: Genome-wide association studies. PLoS Comput Biol 2012;8:e1002822. [178] Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, et al. Metaanalysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670–5. [179] Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010;42: 240–4. [180] Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007;448:353–7. [181] Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009;41:879–81. [182] Kaab S, Darbar D, van Noord C, Dupuis J, Pfeufer A, Newton-Cheh C, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J 2009;30:813–9. [183] Viviani Anselmi C, Novelli V, Roncarati R, Malovini A, Bellazzi R, Bronzini R, et al. Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population. Heart 2008;94:1394–6. [184] Shi L, Li C, Wang C, Xia Y, Wu G, Wang F, et al. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 2009;126:843–9. [185] Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009;41:876–8. [186] Olesen MS, Nielsen MW, Haunso S, Svendsen JH. Atrial fibrillation: the role of common and rare genetic variants. Eur J Hum Genet 2013 [Epub ahead of print]. http://dx.doi.org/10.1038/ejhg.2013.139. [187] NapolitanoC. The contradictory genetics of atrial fibrillation:the growing gap between knowledge and clinical implications. J Cardiovasc Electrophysiol 2013;24:570–2. [188] Delaney JT, Jeff JM, Brown NJ, Pretorius M, Okafor HE, Darbar D, et al. Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans. PLoS One 2012;7:e32338. [189] Mahida S, Ellinor PT. New advances in the genetic basis of atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:1400–6. [190] Mahida S, Lubitz SA, Rienstra M, Milan DJ, Ellinor PT. Monogenic atrial fibrillation as pathophysiological paradigms. Cardiovasc Res 2011;89:692–700. [191] Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385–484. [192] Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. [193] Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004;109:1509–13. [194] Assayag P, Carre F, Chevalier B, Delcayre C, Mansier P, Swynghedauw B. Compensated cardiac hypertrophy: arrhythmogenicity and the new myocardial phenotype. I. Fibrosis. Cardiovasc Res 1997;34:439–44. [195] Corradi D, Callegari S, Maestri R, Benussi S, Bosio S, De Palma G, et al. Heme oxygenase-1 expression in the left atrial myocardium of patients with chronic atrial fibrillation related to mitral valve disease: its regional relationship with structural remodelling. Hum Pathol 2008;39:1162–71. [196] Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for

[197]

[198]

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209] [210]

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

European Society of Cardiology guidelines. Part I: primary prevention. Europace 2011;13:308–28. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace 2011;13:610–25. Huang G, Xu JB, Liu JX, He Y, Nie XL, Li Q, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis. Eur J Clin Invest 2011;41:719–33. Bhuriya R, Singh M, Sethi A, Molnar J, Bahekar A, Singh PP, et al. Prevention of recurrent atrial fibrillation with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers: a systematic review and meta-analysis of randomized trials. J Cardiovasc Pharmacol Ther 2011;16:178–84. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001;104:2608–14. Li Y, Li W, Yang B, Han W, Dong D, Xue J, et al. Effects of Cilazapril on atrial electrical, structural and functional remodeling in atrial fibrillation dogs. J Electrocardiol 2007;40:e1–6. Sakabe M, Fujiki A, Nishida K, Sugao M, Nagasawa H, Tsuneda T, et al. Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and overexpression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Pharmacol 2004;43:851–9. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res 2002;54: 456–61. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197–204. Goette A, Bukowska A, Lendeckel U. Non-ion channel blockers as antiarrhythmic drugs (reversal of structural remodeling). Curr Opin Pharmacol 2007;7:219–24. Williams RS, deLemos JA, Dimas V, Reisch J, Hill JA, Naseem RH. Effect of spironolactone on patients with atrial fibrillation and structural heart disease. Clin Cardiol 2011;34:415–9. Milliez P, Deangelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, et al. Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 2005;26:2193–9. Fauchier L, Clementy N, Babuty D. Statin therapy and atrial fibrillation: systematic review and updated meta-analysis of published randomized controlled trials. Curr Opin Cardiol 2013;28:7–18. Savelieva I, Camm J. Statins and polyunsaturated fatty acids for treatment of atrial fibrillation. Nat Clin Pract Cardiovasc Med 2008;5:30–41. Savelieva I, Kourliouros A, Camm J. Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch Pharmacol 2010;381:1–13. Shiroshita-Takeshita A, Brundel BJ, Burstein B, Leung TK, Mitamura H, Ogawa S, et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res 2007;74:75–84. Mariani J, Doval HC, Nul D, Varini S, Grancelli H, Ferrante D, et al. N-3 polyunsaturated fatty acids to prevent atrial fibrillation: updated systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2013;2:e005033. Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, et al. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA 2012;308:2001–11. Laurent G, Moe G, Hu X, Holub B, Leong-Poi H, Trogadis J, et al. Long chain n-3 polyunsaturated fatty acids reduce atrial vulnerability in a novel canine pacing model. Cardiovasc Res 2008;77:89–97. Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003;107:2646–52. Koyama T, Tada H, Sekiguchi Y, Arimoto T, Yamasaki H, Kuroki K, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010;56:1463–72. Halonen J, Halonen P, Jarvinen O, Taskinen P, Auvinen T, Tarkka M, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA 2007;297:1562–7. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12: 1360–420. Corradi D, Callegari S, Gelsomino S, Lorusso R, Macchi E. Morphology and pathophysiology of target anatomical sites for ablation procedures in patients with atrial fibrillation. Part I: Atrial structures (atrial myocardium and coronary sinus). Int J Cardiol 2013;168:1758–68. Pump A, Di Biase L, Price J, Mohanty P, Bai R, Santangeli P, et al. Efficacy of catheter ablation in nonparoxysmal atrial fibrillation patients with severe enlarged left atrium and its impact on left atrial structural remodeling. J Cardiovasc Electrophysiol 2013;24:1224–31.

Atrial fibrillation from the pathologist's perspective.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia encountered in clinical practice, is associated with increased morbidity and mo...
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