Inflammation and the Pathogenesis of Atrial Fibrillation

NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 1

Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, National YangMing University, Number 201, Section2, Shipai Road, Beitou District, Taipei11217, Taiwan, Republic of China (Y.F.H., Y.J.L., S.A.C.). Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Number111, Section3, HsingLong Road, Taipei11696, Taiwan, Republic ofChina (Y.J.C.)

Correspondence to: S.A.C. epsachen@ ms41.hinet.net

Inflammation and the pathogenesis ofatrialfibrillationYu-Feng Hu, Yi-Jen Chen, Yenn-Jiang Lin and Shih-Ann Chen

Abstract | Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the development of preventative therapies for AF has been disappointing. The infiltration of immune cells and proteins that mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF. Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of AFand recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and catheter ablation. Mediators of the inflammatory response can alter atrial electrophysiology and structural substrates, thereby leading to increased vulnerability to AF. Inflammation also modulates calcium homeostasis and connexins, which are associated with triggers of AF and heterogeneous atrial conduction. Myolysis, cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to structural remodelling of the atria. The development of thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity. Understanding the complex pathophysiological processes and dynamic changes of AFassociated inflammation might help to identify specific antiinflammatory strategies forthe prevention of AF.

Hu, Y.F. etal. Nat. Rev. Cardiol. advance online publication 27 January 2015; doi:10.1038/nrcardio.2015.2

IntroductionAtrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with detrimental conse-quences. In addition to worsening patient quality of life, AF is associated with stroke, heart failure, and increased mortality.1 Worldwide, AF has affected >30million indi-viduals since 2010, and the incidence of AF continues to increase.2,3 Current treatments for AF include pre-venting its recurrence (via rhythm control) and conse-quences (by rate control and antithrombosis).4,5 In many patients, heart-rate control is sufficient to control a rapid rhythm and its associated symptoms, and the preven-tion of AF recurrence relies primarily on antiarrhythmic drugs. Catheter ablation is considered as an alternative to antiarrhythmic drugs because of its superiority to medical therapy for the maintenance of sinus rhythm.1,5,6 Although major progress has been made in the treatment of AF, its recurrence and subsequent treatment after medication or catheter ablation, including any associ-ated complications, problems remain.1,4,5,7 An improved understanding of the pathophysiology underlying AF and subsequent remodelling is necessary for the devel-opment of novel therapeutic approaches. Increasing evidence supports the role of inflammation in the pathophysiology of AF, which suggests that the inflam-matory process is a potential therapeutic target.8,9 The main pathophysiological mechanisms contributing to AF development and progression include both electrical

and structural remodelling of the atria. Moreover, AF itself can induce inflammation during atrial remodel-ling, which perpetuates the arrhythmiathe so-called AF begets AF phenomenon. Instead of emphasizing the clinical correlations of inflammation in different scenarios of AF,8,10 in this Review we discuss the patho-physiological role of inflammation and its interaction with the established mechanisms of AF. We also highlight p otential inflammation-based therapeutic options.

Sources of inflammation in AFInflammation in patients with AF can arise from dif-ferent sources, which might have underlying inflam-matory mechanisms and temporal changes (Figure1). Many systemic diseases (such as coronary artery disease, hypertension, and obesity) are associated with low-grade in flammationand increased levels of proinflammatory cytokines.1113

ObesityObesity is associated with new-onset AF in the general population or in patients after cardiac surgery.14,15 Obesity-induced immune cell infiltration into the adipose tissue, particularly by M1 macrophages (a pro-inflammatory phenotype),16,17 as well as inflammation of adipose tissue and secreted proinflammatory cytokines occurs in patients with obesity.1719 High levels of inflam-matory activity in the pericardial adipose tissue has been described in patients with AF.20 For example, epicardial inflammatory activity was 35% higher in 21 patients with

Competing interestsThe authors declare no competing interests.

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AF than in 21 matched controls without AF, as meas-ured by 18F-fluorodeoxyglucose PET.20 Proinflammatory cytokines from adipose tissue might reach the atrium via the circulation or paracrine factors. In a study of 34 patients, high-dominant frequencies or complex atrial fractionated electrogram sites were located adjacent to epicardial fat areas, which suggest that epicardial fat might maintain AF by releasing paracrine inflammatory mediators.21,22 Free fatty acid overload in patients with obesity induces lipid accumulation within cardiomyo-cytes and apoptosis, which might also trigger regional inflammation.23 These factors suggest that inflammation is an important pathophysiological mechanism of AF in patients with obesity.

HypertensionThe association between inflammation and AF in patients with hypertension is not yet established. In spon-taneously hypertensive rats and hypertensive sheep (who received unilateral nephrectomy followed by clamping of the remaining renal artery to 60%), leucocyte infiltration into the atria and inflammation was observed, which was

Key points

Inflammation and its associated immune response are involved in the initiation and maintenance of atrial fibrillation (AF)

AF can further promote inflammation, which contributes to the clinical phenomenon of AF begets AF

Inflammatory pathways contribute to both electrical and structural atrial remodelling and thrombogenesis in patients with AF

The mechanisms and dynamic changes that underlie the inflammatory responses in different clinical scenarios of AF should be determined to enable the development of specific, individualized antiinflammatory strategies

Therapies that target specific inflammatory cascades might be potential therapeutic strategies for the prevention of AF

followed by atrial fibrosis.24,25 In these models, vulner-ability to the development of AF increased by 62% after the development of atrial fibrosis, but not inflamma-tion alone. However, in another sheep model, in which hypertension was induced by prenatal steroids, increased vulner ability to AF was noted, but atrial inflammation not observed.26 In this model, plasma renin concentra-tion and vascular reactivity to angiotensinII were not altered, whereas in spontaneously hypertensive rats and sheep with unilateral nephrectomy-induced hyperten-sion, the reninangiotensinaldosterone system (RAAS) was activated.2426 The discrepancy between these studies might imply a pathophysiological role of RAAS in AF.

The atria of angiotensinII-treated mice are character-ized by increased neutrophil infiltration, which is depend-ent on CD11b and CD18 integrins.27 AngiotensinII increases inflammation by stimulating the production of proinflammatory cytokines (such as IL-6, IL-8, and tumour necrosis factor [TNF]) and directly activating immune cells.28 Furthermore, angiotensinII can induce the expression of adhesion molecules such as vascular cell adhesion protein1, intercellular adhesion molecule1, selectins, or CC motif chemokine2 (also known as monocyte chemotactic protein1), which promote the recruitment of immune cells.28 Blocking angiotensin-induced inflammatory cascades (such as TNF and IL-1) might prevent cardiac damage in response to angio-tensinII in a mouse model of AF.29 Several mechanistic hypotheses in addition to the role of RAAS have also been proposed. Atrial stretch, owing to elevated left ventricular diastolic pressure in patients with hypertension, might activate regional RAAS, cardiac apoptosis, and oxidative stress, which can subsequently induce regional inflamma-tion in the heart.30 Cellular stress from reactive oxidative species might be induced by hypertension in patients in AF,31 and reactive oxygen species can further stimulate signal trans duction thereby increasing production of proinflammatory cytokines, such as IL-1, IL-6, and TNF.32

Coronary artery diseaseAtrial myocardial infarction, or ischaemia that is sec-ondary to an occluded coronary artery, is expected to induce myocardial damage and atrial inflammation during the healing process, and might consequently induce AF.33 The pathophysiology of ischaemic heart disease is more complex than that of occluded arteries, in which low-grade inflammation is an important factor.13 For example, the increased expression of platelet-bound and plasma stromal cell-derived factor1 was observed in patients with AF and ischaemic heart disease com-pared with those in sinus rhythm.34 The increased level of stromal cell-derived factor1 is a risk factor for devel-oping coronary artery disease and is associated with i nflammatory cell recruitment.35,36

Surgery and ablationInflammation can also be induced by cardiac surgery or catheter ablation. In the ARMYDA-3 study,37 high postoperative C-reactive protein (CRP) levels were associated with an increased risk of AF. Surgery-induced

Systemic diseaseObesity, hypertension, coronary artery diseases

Atrial myocardial injuryAtrial ischaemia or infarction, surgical or catheter ablation

Immune diseases with autoantibodyValvular heart diseases

Modulating factorsChronic viral infection,

epicardial fat,genetic predisposition

Mediator moleculesROS, Ang II, TGF-, MPO, PDGF, HSPs, proinammatory cytokines

Inammation

Electrical remodelling Structural remodelling

Atrial brillation

Nature Reviews | CardiologyFigure 1 | Sources of inflammation in patients with atrial fibrillation. Activatedinflammatory pathways alter the electrophysiology, structure, and autonomic remodelling of the atria. Inflammation induced by atrial fibrillation canestablish an inflammatory cycle that leads to increased severity of the arrhythmia. Abbreviations: AngII, angiotensinII; HSP, heat shock protein; MPO, myeloperoxidase; PDGF, plateletderived growth factor; ROS, reactive oxygen species; TGF, transforming growth factor.

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inflammation has been modelled in canine sterile peri-carditis, an experimental model of postoperative AF in humans. AF, induced by burst atrial pacing after open chest operation in these dogs, was reduced by 60% after treatment with anti-inflammatory drugs.38,39 Radiofrequency ablation induces an inflammatory response that develops after thermal injury and is likely to contribute to the maturation of ablation lesions after the procedure.5,40 Patients undergoing radiofrequency ablation for AF have high CRP levels within 3days of the procedure, and the extent of CRP elevation predicts early AF recurrence within this 3-day period, but not late AF recurrence at 3 or 6months.41,42

Autoimmune reactions in AFWhether the inflammation in AF is associated with an autoimmune response remains unclear. Certain auto antibodies, such as those against the muscarinic acetylcholine receptorM2 and heat shock proteins (HSPs), have also been associated with AF.4345 However, whether these autoantibodies cause or are only released in response to AF is unknown. Valvular heart diseases are associated with volume or pressure overload in the atrium and also increase atrial stretch, which activates RAAS, reactive oxygen species, matrix metalloprotein-ases (MMPs), cardiac myolysis, and apoptosis, and might subsequently increase inflammation and vulnerability toAF.30

Polymorphisms in the genes encoding IL-1, IL-6, and IL-10, which are responsible for modulating expression levels of inflammatory cytokines, are independently associated with AF in humans.4649 For example, the 174G>C IL-6 polymorphism is associated with the new onset of AF after surgery.50 In two large cohort studies of patients with viral infection, such as HIV or herpes simplex virus, both latent and chronic viral infection were independently associated with the devel-opment of AF, possibly through inflammatory pro-cesses.51,52 However, the underlying mechanisms of AF in patients with a viral infection remain unclear. In indi-vidualswithHIV, several mechanisms were proposed to explain the HIV-induced dilated cardiomyopathy. For example, theendothelium in the heart can act as a reservoir of HIV particles and cytokines, such as TNF and IL-6, and reactive oxygen species, which all increase inflammation.53 Moreover, HIV-associated proteins, such as immunodeficiency virus transactivating regulatory protein (Tat), can lead to destruction of mitochondria, which results in myocardial damage.54

Inflammation leads to AFIn patients with lone AF, atrial pathology reveals infil-tration of lymphomononuclear cells and necrosis of the adjacent myocytes, which is not present in patients who are in sinus rhythm.55 In a number of case-controlled studies, higher levels of inflammatory markers (such as CRP, HSP 1 [commonly known as HSP27], IL-6, IL-8, and TNF) as well as elevated neutrophil and lymphocyte ratios have been reported in patients with AF compared with those in sinus rhythm.8,10,5659 Increased CRP levels

have been reported to predict the development of new-onset AF in several large, prospective cohorts.6062 In the Cardiovascular Health Study60 (5,806 patients followed up for a mean period of 6.9years), higher CRP levels (>3.41 mg/l) were associated with the presence of AF compared with lower levels (


Graded increases in the levels of CRP, HSP27, and TNF are also observed in patients with persistent AF compared with those with paroxysmal AF or without arrhythmias.57,68,69 The maintenance of sinus rhythm after cardioversion or catheter ablation of persistent or long-lasting AF leads to a gradual decrease in CRP levels relative to levels before the procedure (from 0.29 0.13 mg/dl to 0.10 0.06 mg/dl; P 50% (P 30% (P 200units) could be used to predict AF recur-rence after catheter ablation (HR4.2, 95%CI 1.214.6, P = 0.02).90 A higher percentage of activated Tlympho-cytes (CD3+ and HLA-DR+) was observed in the periph-eral blood of patients with paroxysmal or persistent AF compared with healthy control individuals (36% versus 27%; P


lymphocytes (3.0 in mice with AF versus 2.4 in mice without AF; P = 0.001) in the peripheral circulation has been associated with an increased incidence of new-onset AF (OR1.10 per unit increase, P = 0.04).95 An elevated neutrophil-to-lymphocyte ratio before or after catheter ablation is associated with increased AF r ecurrence after the procudure.96,97

The contributions of acute and chronic inflammation in AF, which might mediate distinct inflammatory cascades and signals, remain poorly understood. Atrial neutrophil infiltration is mediated by CD11bintegrin in patients with AF.27 Myeloperoxidase is most abundantly expressed in neutrophil granulocytes.98 In patients undergoing off-pump CABG surgery, levels of IL-6 and IL-8 (but not TNF) are elevated immediately after surgery (IL-6 from 0 to 435 pg/ml; IL-8 from 10 to 50 pg/ml).99 The increase in the level of IL-6 after surgery is associated with postopera-tive AF (OR7.63 if IL-6 >401 pg/ml, P = 0.04).99 Among patients with AF who receive catheter ablation, the levels of IL-6 and CRP both significantly increase after ablation (IL-6 from 1.1 2.5 to 12.4 15.3 pg/ml; P = 0.007; CRP from 2.4 2.9 to 20.1 9.2 mg/l, P = 0.001); however, levels of IL-8, IL-10, IL-12, stromal cell-derived factor1, and TNF remain unchanged.100

In addition to their role in allergic and immune responses, mast cells also participate in cardiovascu-lar disease-related inflammation.101 Mast cells might actively induce inflammation and atrial fibrosis in patients with AF and secrete platelet-derived growth factorA (PDGF-A) and promote cell proliferation and collagen expression in cardiac fibroblasts (Figure2).94 Cardiomyocytes, fibroblasts, and endothelial cells can also induce inflammatory responses;85 however, whether innate and adaptive immune responses lead to different infiltration patterns in AF requires additional studies.

Acute and chronic inflammation might also interact and contribute to the pathogenesis of AF. For example, preoperative and postoperative CRP levels are both pre-dictive of the development of AF after cardiac surgery.58 Cardiac injury after myocardial infarction is associated with early stimulation of inflammatory signalling.85 The timely increase of anti-inflammatory mediators can stop excessive inflammatory injury and repair cardiac tissue.85 However, the dynamic changes in inflammatory responses during different stresses before the onset or maintenance of AF have yet to be defined. Understanding the temporal changes in these inflammatory responses might be important for the selection of appropriate inflammatory pathway targets to treat AF.

Many subpopulations of Tlymphocytes and monocyte or macrophages have different proinflammatory or anti-inflammatory responses. For example, M1 macrophages are proinflammatory and recruited early during tissue damage to clear debris and dead cells.102 By contrast, M2 macrophages, which are recruited after M1 macrophages, have reparative functions and secrete proangiogenic or fibrotic mediators to promote wound healing.102 CD4+ (Thelper1 or Thelper2 cells), CD8+, natural killer, and Tregulatory cells all have different roles during chronic inflammation.103 However, little is known about

how these subpopulations of immune cells and their temporary changes affect the pathogenesis of AF.

Cytokines, chemokines, and mediatorsThe involvement of different inflammation-associated cytokines and chemokines has been proposed in the pathogenesis of AF (Figure2, Table1). Clinical data indicate an important association between CRP levels and AF. However, in the prospective Copenhagen City Heart Study,61 increases in CRP levels owing to genetic polymorphisms (CRP polymorphism: rs1205, rs1130864, rs3091244, and rs3093077) did not increase the incidence of AF, suggesting that CRP indicates the systemic or regional inflammatory state, but does not have a pathophysiological role. Substantial differences exist between the studies to investigate cytokines and chemokines in the pathogenesis of AF, including study design, patient number, enrolled populations, sample collection, treatment, and follow-up strategies. The mechanisms that underlie postoperative or postabla-tion AF recurrence might differ from those underlying AF onset in the general population and could lead to activation of different cytokines. Consequently, incon-sistent results among these studies are not unexpected. Furthermore, only CRP has been linked to new-onset AF in the generalpopulation.104

In mice, cardiac-specific expression of TNF or TGF-1 can increase the vulnerability to AF and atrial remod-elling, including fibrosis and heterogeneous conduc-tion.105108 In clinical studies, the serum or atrial tissue levels of TNF or TGF-1 increase in patients with AF, compared with individuals in sinus rhythm, which further supports a detrimental role for these proteins in AF.88,92,109111 The TGF- inhibitor tranilast can prevent atrial remodelling and development of AF in a canine model,112 but no reports exist of studies investigat-ing anti-TNF strategies in the treatment or prevention of AF in humans. However, in the ATTACH trial,113 the use of anti-TNF antibodies in the treatment of patients with heart failure was associated with a higher combined risk of death from any cause or hospitaliza-tion for heart failure than placebo (HR2.84, 95%CI 1.017.97, P = 0.043). Because heart failure is a common comorbidity in patients with AF, an anti-TNF antibody as a cytokine therapy must be used with caution. The levels of myeloperoxidase in atrial tissue are higher in patients with AF than in individuals in sinus rhythm, and increased myeloperoxidase levels in the blood have been associated with early AF recurrence after catheter ablation (HR2.12, 95%CI 1.713.27, P = 0.032).42,114,115 Increased atrial myeloperoxidase levels are also associated with AF vulnerability in canine models.39 In mice pre-treated with angiotensinII, myeloperoxidase deficiency decreases atrial fibrosis and protects mice from AF, which was reversed after restoring myeloper oxidase.114 These data suggest that TNF, TGF-1, and myeloperoxidase might be therapeutic targets for the treatment of AF.

HSPs have multifunctional cardioprotective roles.116 HSPs are a family of proteins that prevent toxic protein aggregation by binding to unfolded proteins,117 and can

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prevent AF by reversing atrial structural remodelling (by mediating apoptosis, fibrosis, and myolysis) and abnormal calcium homeostasis.118 Most studies of HSPs in patients with AF focus on HSP27, HSP60, and HSP70 (Figure3).117118 HSP27 levels progressively decrease from 7.2 0.5 ng/ml in control individuals to 6.1 0.5 ng/ml in patients with paroxysmal AF and 4.7 0.5 ng/ml in those with persistent AF (P = 0.02 for the trend).57 Moreover, HSP27 levels are correlated with increased left atrial size (left atrial diameter 4 cm versus


mitochondria and cytosol to the plasma membrane and is released to the extracellular space.129 HSP60 induces cardiomyocyte apoptosis partially via TLR4129,130 and cytokine production through the TLR4MYD88p38/NF-B pathway.131 In addition, HSP60 activates mono-cytes, macrophages, and Tlymphocytes through TLR2 or TLR4(Figure2).132,133

In a prospective study of 329 patients undergoing elective CABG surgery, increased postoperative anti-HSP65 was independently associated with post operative AF (OR1.4, P = 0.04),43 and higher anti-HSP70 levels were recorded in patients with persistent AF than in those with paroxysmal AF (median 53 g/ml versus 43 g/ml; P = 0.035).45 These findings indicate a patho-genic role of humoral immune responses in patients with AF.43,45 However, ongoing studies to address the mechanisms of a humoral immune response in AF have not yet been reported. Whether an anti-HSP60 or anti-HSP70 autoantibody functions as a trigger or inhibitor for AF-related inflammation remains unclear. HSPs that function as autoantigens might induce an adaptive immune response and activate Blymphocytes to produce antibodies that neutral-ize and promote the clearance of autoantigens.134 The HSPautoantibody complex might also induce a com-plement pathway that leads to macrophage activation and consequently promote inflammation. For example, anti-HSP60 autoantibodies can induce atherosclerosis via endothelial damage.135,136 Autoantibodies against HSP60 canmediate endothelial injury by activating complement-mediated or antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells.135,136 Conversely, the binding of autoantibodies to HSPs enables the clearance of extracellular HSPs from the tissue and prevents the continuous activation of immune systems.135,137 High serum anti-HSP70 levels (>119.6 g/ml) were also associated with a 61% reduced risk of cardio vascular complications compared with low HSP70

levels in patients with diabetes mellitus (95%CI 0.170.87).137 Ifautoantibodies against HSPs are a trigger of inflammation, induction of immune tolerance to HSP60 might decrease immune responses to DAMPs via Treg-ulatory cells and inhibit the release of proinflammatory immune cells and cytokines.138 However, if these autoan-tibodies are an inhibitor of inflammation, they might be used as a new DAMP-specific anti-inflammatory therapy to treat AF,139 in an approach similar to that of IgM antibodies against oxidised LDL, which can prevent inflammation and atherosclerosis.140

Inflammation and electrical remodellingThe detailed pathophysiological mechanisms of electri-cal and structural remodelling in AF have been exten-sively reviewed previously.141 Different inflammatory cytokines modulate the function of ion channels and calcium homeostasis (Figure4). TNF induces abnor-mal Ca2+ handling and arrhythmogenicity in pulmo-nary vein cardiomyocytes.142 TNF can also decrease the expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase2a (SERCA2a) by enhancing methylation in the promoter region.143 Mice that selectively overexpress TNF in myocardial tissue have prolonged action poten-tial and Ca2+ transient durations, and higher diastolic and lower systolic Ca2+ currents than those with normal TNF levels.105,106 Furthermore, mice with an elevated TNF level have increased vulnerability to AF and also develop spontaneous episodes of AF.105,106 These findings suggest that TNF can directly alter Ca2+ handling in cardiomyo-cytes, which is crucial for the initiation of AF and atrial el ectrical remodelling.105,106,142,143

PDGF from myofibroblasts can reduce the dura-tion of action potentials and Ca2+ transients when directly applied to cardiomyocytes, which supports a role for PDGF in electrical remodelling.144 IL-2 is pre-dominantly secreted by activated Tlymphocytes,145 and changes the amplitude of electrically-stimulated

Increase cardiac apoptosis

Innate and adaptiveimmune cells

Inhibit TLR-4 expressionAnti-inammatory cytokines

Increase proinammatorycytokines

HSP60

HSP60HSP70

HSP27

Restore L-type calcium currentPrevent action potential duration shorteningPrevent myolysisPrevent F-actin stress bre

TLR-2,TLR-4

Cardiomyocytes

Intracellular cardiomyocyte(HSP27, HSP70)

HSPs

Extracellular(HSP27, HSP60, HSP70)

Secrete anti-HSP autoantibodies

Nature Reviews | CardiologyFigure 3 | HSPs in atrial fibrillation. HSPs prevent protein aggregation and stabilize protein folding. However, HSPs can function as damageassociated molecular patterns and induce an immune response. Intracellular HSP27 and HSP70 restore abnormal calcium currents and prevent shortening of the action potential duration, myolysis, and Factin stress fibre formation, which can reverse AFrelated electrical and structural remodelling in cardiomyocytes. Extracellular HSP70 and HSP60 activate TLR2 and TLR4 on immune cells and cardiomyocytes. HSP60 can induce cardiomyocyte apoptosis. HSP60 and HSP70 also activate immune cells that secrete proinflammatory cytokines and induce humoral responses to produce antiHSP autoantibodies. HSP27 might inhibit TLR4 expression and its associated NFB pathway, and increase secretion ofIL10; these responses are considered antiinflammatory. Abbreviations: HSP, heat shock protein; TLR, Tolllike receptor.

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andcaffeine-induced Ca2+ transients in ventricular myocytes, which has a similar effect to, and might be explained by, a suppression of SERCA2a function and increase of Na+/Ca2+ exchanger activity without changing L-type calcium channels.146 However, this effect has not yet been demonstrated in atrial myocytes.

Inflammation also alters the conduction properties of the atria. Acute atrial inflammation after right atriotomy in dogs increases the heterogeneity of conduction and AF duration, which can be prevented by the systemic administration of methylprednisolone.39 The increased heterogeneity of conduction also correlates with higher atrial myeloperoxidase activity.39 Heterogeneous con-duction can be created by the local application of ara-chidonic acid (a mediator of inflammation) in the left atria of dogs and be prevented by the topical application of methylprednisolone.147 Furthermore, heterogeneous conduction might be the result of the altered expres-sion or distribution of gap junction-5 protein (com-monly known as connexin-40 [Cx40]), gap junction-1 protein (commonly known as connexin-43 [Cx43]), or atrial fibrosis.108,148 Reduced expression and transmural gradient of Cx40 and Cx43 (both of which are absent in the epicardium, decreased in the mid-myocardium, and normal in the endocardium) in the canine sterile pericarditis model is associated with markedly abnormal

atrial conduction and vulnerability to the induction and maintenance of AF.148 TNF also downregulates Cx40 andchanges the intracellular distribution of Cx43 in cardio myocytes (which is dispersed from the intercalated discs) in mice.106,149

In clinical studies, mediators of the inflammatory response are associated with atrial electrical proper-ties.57,90,150 CD36 levels are positively correlated with atrial voltage (rcoefficient=0.63, P = 0.001).90 Low levels of HSP27 (


which high CRP or IL-6 levels independently predicted stroke in patients with AF.156,157 These mechanisms might be associated with hypercoagulation, platelet activation, and endothelial dysfunction (Figure5). The vonWillebrand factor (vWF) and asymmetric dimethyl-arginine (ADMA), biomarkers of endothelial dysfunc-tion were both predictors of stroke in patients with AF in a prospective cohort.158160 In 994 patients in the SPAFIII trial,158 levels of vWF independently predicted the occurrence of stroke (relative risk1.2 per 20 IU/dl increase of vWF, 95% CI 1.01.5, P = 0.06) and vascu-lar events (RR1.2 per 20 IU/dl increase of vWF, 95% CI 1.01.4, P = 0.02). ADMA levels were also used, in a single hospital cohort, to predict adverse cardiovascu-lar events including cardiovascular death and ischae-mic stroke (HR1.36 per 0.1 mol/l increase of ADMA, 95%CI 1.071.74, P = 0.01).160 In patients with AF, atrial lymphomononuclear infiltration was concomitant with increased expression of vWF and tissue factor.161,162 High endocardial levels of vWF are also associated with addi-tional platelet adhesion and thrombus formation on the atrial endocardium.163 A lack of endothelial cells and endothelial nitric oxide synthase in the cellular region with platelet adhesion and thrombus formation sug-gests that endothelial dysfunction also contributes to t hrombogenesis in AF.163

TLR4 might also be an underlying immune mecha-nism to induce atrial endothelial dysfunction. TLR4 knock-out mice have a lower incidence of atrial throm-bosis after thoracic transverse aortic constriction compared with wild-type mice.83 TLR4-related NF-B signal pathways can activate mitogen-activated protein kinase p38, decrease phosphorylation of endothelial nitric oxide synthase, and increase vascular cell adhe-sion protein1 and plasminogen activator inhibitor1

expression in mice atria.83 Prothrombin and throm-bin receptor (protease-activated receptor1) were also highly expressed in left atrial endocardium concomitant with monocyte infiltration and tissue fibrosis.164 Tissue factor and thrombin activate intrinsic coagulation pathways and platelet aggregation, further contributing tothrombogenesis.164

Proinflammatory cytokines from immune cells and leucocyteplatelet interactions might also mediate pro-thrombotic states (Figure5).8 Proinflammatory cytokines such as IL-6 can induce platelet activation165 and are associated with spontaneous echo contrast and adverse cardiovascular outcomes in patients with AF.157,166 Acute onset of AF will induce plateletleucocyte interactions.167 Platelets can interact with neutrophils and monocytes and be activated via CD40, P-selectin, and CD36 in AF. However, in clinical studies, inconsistent results linking the levels of soluble CD40 or P-selectin to thrombo-embolism in AF have been reported.156,168,169 Whether monocyte CD36 is associated with thromboembolism is currently unclear.

Current anti-inflammatory therapiesTo date, no drug has been designed to target the inflam-matory pathway specifically in patients with AF, but most drugs used to prevent AF are arbitrarily consid-ered anti-inflammatory as part of their pleiotropic effects. Angiotensin-converting-enzyme inhibitors, a ngiotensin-receptor blockers, statins, and n-3 poly-unsaturated fatty acids have been studied in large, pro-spective, randomized trials and meta-analyses for both primary and secondary prevention of AF.4,5,170 Owing to the heterogeneity between studies and disappointing results in prospective trials, only angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers are considered reasonable approaches for the primary pre-vention of new-onset AF in patients with heart failure and reduced left ventricular ejection fraction (classIIa indication, level of evidenceB).4

These findings should not discourage the develop-ment of anti-inflammatory therapies in the prevention of AF, because most of these studies did not demonstrate a downregulation of inflammation after drug applica-tion.171 Even among positive results, the prevention of AF does not seem to be the result of reduced inflammation. For example, in the ARMYDA-3 trial,37 treatment with atorvastatin significantly reduced the incidence of post-operative AF after elective cardiac surgery with cardio-pulmonary bypass surgery (OR0.39, 95%CI 0.180.85, P = 0.017); however, CRP levels did not significantly decrease after statin use. Colchicine might prevent AF by treating pericarditis after surgery or ablation. For example, colchicine seems to reduce postoperative AF (from 22.0% to 12.0%; P = 0.02) and decreases the com-plication rate and length of hospital stay.172,173 Colchicine also prevents early AF recurrences in patients at 3months after pulmonary vein isolation (from 33.5% to 16.0%; P = 0.01).174 This effect is associated with a signifi-cant decrease in inflammatory mediators, including CRP and IL-6 (CRP: 0.46 mg/l; interquartile range: 0.78

Platelet

P-selectinCD36

CD40Thrombus

Neutrophil

Monocyte

Proinammatorycytokines: IL-6

von Willebrand factor

Damagedendothelium

Thrombin

Tissue factor

PAR-1

eNOS

Atrium

Immunecell

inltration

Plateletleucocyteinteraction Coagulation

factor

Nature Reviews | CardiologyFigure 5 | The pathophysiological link between inflammation and thrombogenesis. Immune cell infiltration induces endothelial dysfunction, which decreases eNOSexpression, but increases the expression of vonWillebrand factor, thrombin, tissue factor, and PAR1 on the atrial endocardium. Leucocytes (neutrophils andmonocytes) that are partially activated by proinflammatory cytokines might interact with and activate platelets via CD36, CD40, and Pselectin. The adhesion and activation of platelets and coagulation factors also contributes to a thromboticclot. Abbreviations: eNOS, endothelial nitric oxide synthase; PAR1, proteinaseactivated receptor1.

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to 0.08 mg/l, P


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AcknowledgementsThis authors were supported in part by the Ministry ofScience and Technology, Taiwan (NSC1022325B010005, NSC1012321B075004, and NSC1022911I008001).

Author contributionsAll authors substantially contributed to the discussionof content, researched data for thearticle,and wrote, reviewed, and edited the manuscript before submission.

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Inflammation and the pathogenesis ofatrialfibrillationYu-Feng Hu, Yi-Jen Chen, Yenn-Jiang Lin and Shih-Ann ChenIntroductionSources of inflammation in AFKey pointsFigure 1 | Sources of inflammation in patients with atrial fibrillation. Activatedinflammatory pathways alter the electrophysiology, structure, and autonomic remodelling of the atria. Inflammation induced by atrial fibrillation canestablish an inflammatAutoimmune reactions in AFInflammation leads to AFAF promotes inflammationFigure 2 | Inflammatory cell regulation in lone and postoperative AF. DAMPs can activate cells via TLR2 and TLR4, including immune cells, cardiomyocytes, fibroblasts, and endothelial cells, which induce inflammatory cascades. Innate and adaptive immune reImmune reactions in AFCytokines, chemokines, and mediatorsInflammation and electrical remodellingFigure 3 | HSPs in atrial fibrillation. HSPs prevent protein aggregation and stabilize protein folding. However, HSPs can function as damage-associated molecular patterns and induce an immune response. Intracellular HSP27 and HSP70 restore abnormal calciuFigure 4 | Inflammatory cells and mediators of inflammation modulate cardiacelectrophysiology and structural properties. Calcium homeostasis in cardiomyocytes is regulated by TNF, PDGF, and IL2, which are associated with increased triggering and shortenInflammation and structural remodellingInflammation and thrombogenicityFigure 5 | The pathophysiological link between inflammation and thrombogenesis. Immune cell infiltration induces endothelial dysfunction, which decreases eNOS expression, but increases the expression of vonWillebrand factor, thrombin, tissue factor, and Current anti-inflammatory therapiesFuture targeting of inflammation in AFConclusionsAcknowledgementsAuthor contributions

Inflammation and the Pathogenesis of Atrial Fibrillation

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