1064

Clinical Review

Update on the Association of Inflammationand Atrial Fibrillation

PARAG PATEL, M.D.,∗ HISHAM DOKAINISH, M.D.,‡ PETER TSAI, M.D.,†and NASSER LAKKIS, M.D.∗

From the ∗Section of Cardiology, Baylor College of Medicine, Houston, Texas, USA; †Section of Cardiothoracic Surgery, Baylor Collegeof Medicine, Houston, Texas, USA; and ‡Section of Cardiology, McMaster University, Hamilton, Canada

Update on the Association of Inflammation and Atrial Fibrillation. Atrial fibrillation (AF)is a common arrhythmia and is associated with significant morbidity and mortality. The pathogenesisof AF remains incompletely understood and management remains a difficult task. Over the past decadethere has been accumulating evidence implicating inflammation in the pathogenesis of AF. Inflammationappears to play a significant role in the initiation and perpetuation of AF as well as the prothrombotic stateassociated with AF. Inflammatory biomarkers (C-reactive protein and interleukin-6) have been shown tobe associated with the future development, recurrence and burden of AF, and the likelihood of successfulcardioversion. Therapies directed at attenuating the inflammatory burden appear promising. Animal andclinical studies have evaluated statins, angiotensin-converting enzyme inhibitors/angiotensin-II receptorblockers, and corticosteroids for the treatment or prevention of AF. The purpose of this review is to providecurrent evidence on the relationship between inflammation and AF and potential therapies available tomodulate the inflammatory state in AF. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1064-1070, September 2010)

atrial fibrillation, inflammation, C-reactive protein, IL-6

Introduction

Atrial fibrillation (AF) is a common arrhythmia encoun-tered in clinical practice with an estimated prevalence ofapproximately 1% in the general population, and as high as9% in individuals by the age of 80 years.1 Moreover, theprevalence of AF is increasing along with the age of thepopulation. It is associated with a 2-fold increase in totalmortality, and substantial morbidity including stroke, con-gestive heart failure, tachycardia-induced cardiomyopathy,and an impaired quality of life.2 Consequently, it places ahuge burden on our health care system and is a costly publichealth problem.3

The pathogenesis of AF remains incompletely understoodand management remains a complex and difficult task. Ra-diofrequency catheter ablation has evolved into an effectiveand safe procedure, but the success of ablation is often offsetby the recurrence of AF.4 Therefore, there is still substantialinterest in advancing our understanding of the pathophysiol-ogy underlying this arrhythmia, which hopefully will guidethe development of novel therapeutic strategies.

No disclosures.

Author for correspondence: Nasser Lakkis, M.D., Professor of Medicine,Baylor College of Medicine, Houston, Texas, USA. Fax: +713-873-4903;E-mail: nlakkis@bcm.edu

Manuscript received 17 February 2010; Revised manuscript received 1March 2010; Accepted for publication 2 March 2010.

doi: 10.1111/j.1540-8167.2010.01774.x

Pathophysiology

Although there have been remarkable advances in ourunderstanding of AF, many aspects of this highly complexarrhythmia remain unclear. The pathogenesis of AF is be-lieved to be multifactorial. It involves triggers that initiatethe arrhythmia, as well as a susceptible tissue and elec-trophysiological substrate that perpetuates it (dual substrateparadigm). It is now understood that most AF is initiatedby rapidly firing ectopic foci often located in the muscularsleeves of the pulmonary veins5 or, less frequently, from theproximal superior vena cava, ligament of Marshall, or otherparts of the left and right atria. The maintenance of AF is fa-cilitated by the presence or development of abnormal tissuesubstrate that permits multiple reentrant wavelets of excita-tion to propagate within the atrial myocardium. AF tends tobecome more permanent with time, illustrated by the fact thatit becomes more difficult to restore sinus rhythm when AFhas been present for a long time (i.e., AF begets AF). Electri-cal remodeling, which develops within hours of the onset ofAF, entails electrophysiological alterations including short-ening of the atrial effective refractory period (AERP) andaction potential duration (APD). Structural remodeling is aslower process involving myocyte degeneration, myocardialfibrosis, left atrial enlargement, and results in heterogeneityof conduction. These changes create a susceptible substratethat has been implicated in the perpetuation of AF.

Inflammation has been implicated in the pathogenesis ofseveral cardiovascular diseases, most notably atherosclerosis.There is now also substantial evidence linking inflammationto the initiation and perpetuation of AF.6 The role of inflam-mation in the initiation of AF was initially suspected by the

Patel et al. Update on the Association of Inflammation and Atrial Fibrillation 1065

observation that inflammatory states, such as myocarditis,pericarditis, and cardiac surgeries are frequently associatedwith AF. Cardiac surgery and cardiopulmonary bypass in-duce a systemic inflammatory response that may contributeto the high incidence of postoperative AF (20–40%). Thistheory is supported by the observation that a rise in inflam-matory markers such as serum C-reactive protein (CRP) istemporally related to the occurrence of postoperative AF.7

The first piece of evidence directly linking inflammation tonon-postoperative AF was the histological findings of atrialmyocarditis in patients with lone AF, but not in subjectsin sinus rhythm.8 These findings were later confirmed incontrolled animal studies.9 The greatest volume of evidencesupporting a link between inflammation and AF has beenderived from studies relating inflammatory biomarkers tothe arrhythmia (discussed in the following section).

Despite the evidence linking inflammation to AF, it re-mains controversial whether inflammation is an initiatingevent in the development of AF or, conversely, if it occursas a consequence to the onset of AF. Evidence implicatinginflammation in the initiation of AF include the increasedincidence of AF in the setting of inflammatory states suchas cardiac surgery, and the observation that baseline CRPlevels predict future occurrence of AF.10 On the other hand,the observation of decreasing CRP levels following restora-tion of sinus rhythm11 has led some to believe inflammationis a consequence rather than a cause of AF. It is likely thatboth mechanisms are interrelated whereby preexisting in-flammation is involved in its initiation, and the arrhythmiasubsequently generates an inflammatory response that en-hances remodeling, thus promoting persistence of AF. Rapidatrial activation in AF results in calcium overload in atrialmyocytes often leading to cell death.12 This damage inducesa low-grade inflammatory response, including healing and re-pair that likely leads to adverse structural and electrical atrialremodeling. Inflammation-induced structural alterations aresupported by atrial biopsies with inflammatory infiltrates,myocyte necrosis, and fibrosis.8 The observation that CRPrelates to left atrial size and dysfunction lends further supportof an association between inflammation and structural re-modeling.13 Inflammation also appears to directly alter atrialconduction properties.14 In an animal model, atrial inflamma-tion was associated with an increase in the inhomogeneity ofatrial conduction and increase in the incidence and durationof AF.15 Inflammation is associated with altered distributionof atrial connexins 40 and 43.16 Abnormal expression of con-nexin proteins lead to impaired intercellular communicationand reduced conductance between neighboring cells that hasbeen linked to AF.17

Inflammatory Biomarkers

CRP

CRP, an acute-phase protein, is produced in the liverin response to IL-1, IL-6, and TNF-α. Epidemiologi-cal studies have shown that IL-6 and CRP are sensitivebiomarkers of systemic inflammation in several cardio-vascular diseases.18,19 Elevated CRP levels are associatedwith an increased risk of cardiovascular events.20 In ad-dition to being a marker of systemic inflammation, CRPmay have a direct role in mediating local inflammation by

binding to damaged cells and activating the complementpathway.

Chung et al. were the first to report an association betweenAF and elevated CRP in non-postoperative AF.21 In this case-control study, CRP levels were more than 2-fold higher inpatients with AF compared with controls. Subgroup analysisrevealed that permanent AF was associated with higher levelsof CRP than paroxysmal AF, implying that CRP levels maybe related to the burden of AF. The association betweenelevated CRP and presence of AF was further supported withthe findings from a large population-based cohort study of5,806 elderly individuals followed for a mean of 6.9 years.10

CRP was not only associated with the presence of AF, butin patients without AF at baseline elevated CRP levels weresignificantly and independently associated with the futuredevelopment of AF. In one study, every 1 mg/dL increase inserum CRP was associated with a 7-fold increased risk ofrecurrent AF and a 12-fold increased risk of permanent AFcompared with controls.22

In addition to providing insight on the relationship be-tween inflammation and AF, measurement of CRP mightbe useful clinically. Relapse into AF after cardioversion iscommon and represents a challenging therapeutic problem.Measurement of CRP prior to cardioversion may help inrisk stratification of patients at increased risk of recurrence.A meta-analysis of 7 prospective observational studies in-dicated that increased baseline CRP levels are associatedwith greater risk of AF recurrence after successful cardiover-sion.23 However, this conclusion should not be viewed asdefinitive since there was significant heterogeneity acrossthe studies. There is also evidence suggesting higher base-line CRP is associated with higher likelihood of immediatefailure of electrical cardioversion (EC) in patients with per-sistent AF.24 A more recent study reports that low baselineCRP is associated with longer-term (1 year) maintenance ofsinus rhythm after cardioversion.25 Together this evidencesuggests that measurement of baseline CRP might provideprognostic information regarding the immediate and long-term success of EC.

The exact mechanism for increased serum CRP in AF isuncertain. It may play a direct contributing role in the devel-opment or maintenance of AF, or might just be a marker ofsystemic inflammation. Increased circulating and local CRPmay localize in atrial tissue, activating the complement sys-tem and inducing inflammation. In the presence of Ca2+ ions,CRP binds to phosphatidylcholine leading to the generationof long-chain acylcarnitines and lysophosphatidlycholines.These can contribute to cellular membrane dysfunction byaffecting transmembrane ion transport.26 On the other hand,elevations in CRP may reflect underlying disease processesassociated with AF rather than something unique to the ar-rhythmia itself. A recent analysis suggests that CRP maynot be a causal factor for coronary artery disease (CAD) butrather is linked to conventional risk factors, which in them-selves are associated with inflammation.20 Similar argumentshave been made for the role of CRP in the development ofAF. Indeed, one study showed that adjusting for potentialconfounding variables obscures the difference in CRP levelsbetween subjects with AF and controls.27 In an attempt toeliminate these confounding conditions, investigators haveexamined CRP levels in patients with lone AF. Ellinor et al.found no significant difference in CRP levels between sub-jects with lone AF compared with healthy controls.28 To

1066 Journal of Cardiovascular Electrophysiology Vol. 21, No. 9, September 2010

complicate matters, a subsequent study demonstrated thatpatients with lone AF had higher CRP levels than controls,even after adjusting for other variables.29 Whether or notCRP is “causal” in AF, it is still useful for identifying indi-viduals who are more likely to develop or have recurrenceof AF.

IL-6 and IL-8

IL-6 is pro-inflammatory cytokine that is involved in thesynthesis of acute phase proteins such as CRP. Like CRP,high plasma IL-6 levels have been correlated with the pres-ence and duration of AF and increased left atrial diameter.30

In patients undergoing cardiac surgery the development ofpostoperative AF was related to increased levels of IL-6, andlinked to polymorphisms in the promoter region of the IL-6gene.31 Furthermore, in a cohort of subjects with CAD, AFwas independently associated with IL-6 levels and the CCgenotype of -174G/C IL-6 polymorphism.32 These findingsraise the possibility of a genetic susceptibility to an enhancedinflammatory response with subsequent development of AF.Another cytokine, IL-8, is a powerful chemoattractant forneutrophils and was found to be elevated in patients with AFin a small study.33

Inflammation and Thrombosis

The risk of thromboembolism in individuals with AF is ofparamount concern. The pathogenesis of thrombus formationin AF is incompletely understood and is likely multifactorial.Not only is it related to stasis in a poorly contracting leftatrium, but there is also increasing evidence supporting thepresence of a prothrombotic state34 in which inflammationplays a contributory role.

Inflammatory mechanisms likely play a role in arterialthrombogenesis, and both IL-6 and CRP are predictors ofcoronary athero-thrombotic events.18 The possible role ofinflammation in the prothrombotic state of AF is less wellstudied. Proposed mechanisms whereby inflammation mightinfluence the prothrombotic state include production of tissuefactor (TF) from monocytes, increased platelet activation,stimulation of transcription of fibrinogen, and endothelialactivation/damage.34

Inflammatory biomarkers have been shown to correlatewith prothrombotic indices (CRP to fibrinogen, IL-6 to TF)in patients with AF providing support for a potential rolefor inflammation in the prothrombotic state.27 Conversely,another study found no relationship between IL-6 levels andendothelial activation (E-selectin levels) or abnormal throm-bogenesis (prothrombin fragments) in subjects with chronicAF.35 In a small study, Conway et al.36 found an associationbetween elevated CRP and the presence of dense sponta-neous echo contrast in the left atrium or left atrial appendageby transesophageal echocardiography, which is a well recog-nized independent predictor for thromboembolism in AF.

Among patients with AF, CRP has been shown to posi-tively correlate with established clinical stroke risk stratifi-cation schema (CHADS2, SPAF) with the highest CRP lev-els seen among those at moderate to high risk for stroke.37

Likewise, another study found IL-6 levels to be significantlyhigher in AF patients with traditional risk factors for stroke.27

Whether CRP or IL-6 provides additional risk information

independent of the classic stroke risk factors is not clear andrequires further study.

In a retrospective study of 77 patients with 6-year follow-up, high IL-6 levels were found to be an independent predic-tor of stroke and the composite end-point of stroke or death.38

There was a trend toward increased risk of stroke associatedwith high CRP that did not reach statistical significance. Is-sues of statistical power may be partly responsible for theseresults, or it might be that IL-6 has a stronger associationwith the prothrombotic state in AF than CRP.

Inflammation in AF and Pharmacotherapy

Statins

Statins (3-hydroxy-3-methylglutaryl-coezyme A reduc-tase inhibitors) may exert pleiotropic actions in additionto their lipid-lowering properties. The capacity of statinsto reduce inflammation and CRP is relatively well estab-lished.39,40 However, the exact mechanism of how they exertthis anti-inflammatory effect is not well understood. Partof the pleiotropic effect of statins involves the stabilizationof endothelial cells. Leukocyte and monocyte adhesion toendothelial cells is mediated by cytokine-induced expres-sion of adhesion molecules such as P-selectin and ICAM-1.Statins reduce the expression and function of inflammatorymediators such as CRP39 and also downregulate endothe-lial cell adhesion molecules.41 These effects are importantin protecting against atherosclerosis but might also play arole in inhibiting inflammation of the atrial myocardium. Inaddition to their anti-inflammatory properties, statins mayalso protect against AF by their effects on autonomic func-tion, by exerting a direct affect on the electrophysiologicalproperties of atrial myocardium and downregulation of therenin–angiotensin system.42-44 In an animal model of sterilepericarditis, treatment with high-dose atorvastatin resulted inlower CRP and less inflammatory infiltration and atrial fibro-sis compared with the control group.45 Furthermore, therapywith atorvastatin was associated with decreased inducibilityand sustainability of AF.

Data from observational studies and retrospective anal-yses have provided the majority of the clinical evidence forstatins in preventing AF. Data from large cohorts of patientswith coronary artery disease and/or heart failure have shownthat patients taking statins had a significant reduction (31–43%) in the primary occurrence of AF.46,47 A post-hoc anal-ysis of sudden cardiac death in Heart Failure Trial (SCD-HeFT) mirrored these findings and showed statin use wasas good a predictor of reduced AF incidence as amiodaroneuse.48 A substudy of the GISSI-HF trial found that comparedwith placebo, rosuvastatin reduced the adjusted incidenceof AF in patients with chronic HF.49 A meta-analysis of10 prospective cohort studies demonstrated that statin usesignificantly reduced the relative risk of developing AF, pre-dominantly in the postoperative setting.50

Randomized controlled trials (RCT) on this topic remainlimited by small sample size. In a study of patients with a his-tory of paroxysmal AF, those randomized to atorvastatin hadlower CRP levels and a reduction in the number of AF eventscompared with the placebo group at 4–6 months follow-up.51

A meta-analysis of 6 RCTs showed statin use was signifi-cantly associated with a decreased incidence or recurrenceof AF. These studies included patients with paroxysmal AF,

Patel et al. Update on the Association of Inflammation and Atrial Fibrillation 1067

those undergoing cardiac surgery, or after acute coronarysyndrome.52 Currently, there is insufficient evidence for thewidespread use of statins solely for the prevention of AF, andlarge-scale well designed RCTs are still needed.

A few small RCTs have evaluated the protective roleof statins following cardioversion, producing conflicting re-sults. One trial showed less recurrence of AF in patientstreated with low-dose atorvastatin during the 3 monthsfollowing EC.53 Another large prospective cohort studyshowed a 25% relative risk reduction in AF recurrence at1 year after cardioversion in patients taking statins.54 Con-versely, 2 subsequent small RCTs failed to demonstrate anysignificant difference in AF recurrence after EC.55,56 Thesedisparate results might partly be explained by differences inpatient characteristics, types of statins/doses, and follow-upperiods. At this time there is insufficient evidence for theroutine use of statins before or after cardioversion to preventrecurrent AF.

AF following cardiac surgery provides an excellent modelto study the potential anti-inflammatory effects of statinssince surgery in particular has strong mechanistic links toinflammation and arrhythmogenesis. Several observationalstudies suggest statin use considerably decreases the risk ofAF after cardiac surgery,57-59 and noncardiac surgery.60 OneRCT of 200 patients showed pre-treatment with 40 mg ofatorvastatin beginning 1 week prior to cardiac surgery sig-nificantly reduced the incidence of in-hospital AF (35% inatorvastatin group vs 57% in placebo group).61 It must benoted, however, that the AF incidence rates in the placebogroup were higher than is normally expected after cardiacsurgery. In addition, fewer patients in the placebo arm re-ceived β-blockers and more underwent valve surgery, whichmay have biased the results in favor of atorvastatin. A re-cent meta-analysis of trials in the setting of cardiac surgeryprovides further support that preoperative statin therapy isassociated with a reduction in the incidence of AF (5.5% ab-solute risk reduction and 22% unadjusted odds reduction).62

Corticosteroids

Due to their potent anti-inflammatory effect, it has beensuggested that corticosteroids may reduce the incidence ofAF. In a canine model of AF induced by tachypacing, pred-nisone but not ibuprofen or cyclosporine reduced CRP, du-ration of AF and the AERP.63 In another sterile pericarditismodel, perioperative administration of prednisone attenuatedthe inflammatory response, reduced atrial thresholds and sup-pressed postoperative atrial flutter.64 Intrapericardial deliveryof corticosteroids has also been effective in reducing pericar-dial inflammation following percutaneous epicardial ablationin animals.65

Due to the unfavorable effects of long-term corticosteroiduse, most research has focused on the potential role for short-term steroids in protecting against postoperative AF. Cor-ticosteroids attenuate the systemic inflammatory responseafter cardiopulmonary bypass through reduction in comple-ment activation, cytokine release, and expression of endothe-lial adhesion molecules.66 Prophylaxis with corticosteroidsprior to cardiac surgery is associated with a postoperative re-duction in the concentrations of several inflammatory mark-ers, such as CRP, IL-6, and IL-8.67 A few RCTs have studiedperioperative steroids with AF as a primary endpoint. Halo-nen et al. showed in a prospective double-blind RCT that

patients given hydrocortisone perioperatively were signifi-cantly less likely to have AF during the first 84 hours aftercardiac surgery compared with those receiving placebo (30%vs 48%, P = 0.004).68 Prasongsukarn et al. demonstrated asimilar significant reduction in the incidence of postopera-tive AF.69 Another study did not show a significant benefitin preventing AF after CABG, but this may have been dueto the administration of fewer doses and different prepara-tions of corticosteroid compared with the other trials.70 Ameta-analysis of RCTs demonstrates that the use of periop-erative corticosteroids reduces the risk of postoperative AFby >50%.71 These results suggest that moderate doses ofcorticosteroids be used since both very high and low dosagesappear ineffective. However, a dose–response meta-analysisshowed that the benefit was not significantly different be-tween low-dose and high-dose corticosteroids.67 Overall itappears corticosteroids may be considered for AF prophy-laxis in high-risk patients undergoing cardiac surgery. Veryhigh doses should probably be avoided due to potential ad-verse effects, but further studies are needed to determine theoptimal duration and dosing strategy.

The use of corticosteroids has also been studied in am-bulatory patients after pharmacological or EC.51 Patientswere randomized to receive low-dose methylprednisoloneand propafenone or placebo and propafenone for 4 months.The recurrence rate of AF was 9.6% in the corticosteroidgroup versus 50% in the placebo group (P < 0.001). Pa-tients treated with steroids had significantly lower CRP lev-els, and high CRP levels in both groups were predictive ofrecurrence.

ACEI/ARB

As discussed earlier, inflammation likely contributes to theunfavorable structural and electrical remodeling that occursin AF. The renin–angiotensin–aldosterone system (RAS)plays a role in atrial remodeling and angiotensin-II (AT-II)mediates inflammatory responses that may be involved inthe pathogenesis of AF.72 Thus, ACE-inhibitors (ACEIs) andangiotensin II receptor blockers (ARBs) may have an antiar-rhythmic affect by attenuating changes in cardiac structureand function.

Stimulation of AT-II receptors promotes myocyte apop-tosis, inflammatory-cell infiltration, TGF-β1 synthesis, andmyocardial fibrosis.73 In experimental models, treatmentwith ACEIs inhibits atrial fibrosis, prevents left atrial di-latation, shortens AERP, and reduces AF duration.74,75 AT-IIreceptor blockade significantly reduces markers of inflam-mation (CRP, IL-6) in hypertensive patients.76 There is alsosuggestion that the RAS might affect ion-channels, conduc-tion velocity, APD, and impulse propagation.77

Retrospective analysis of large ACEI and ARB trials sug-gest that angiotensin inhibition may protect against the devel-opment of new onset AF (primary prevention) or recurrenceof AF in patients with left ventricular (LV) dysfunction,78,79

left ventricular hypertrophy,80 or following myocardial in-farction with LV dysfunction.81 A meta-analysis of random-ized trial data indicate that both ACEIs and ARBs are effec-tive at preventing the development of AF with a relative riskreduction of 28%.82 However, it must be noted that the ma-jority of these trials were post-hoc reports from randomizedtrials designed to assess outcomes other than AF. This re-duction in AF was most clearly seen in patients with systolic

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heart failure suggesting that part of the benefit may be relatedto improvement in cardiac hemodynamics and reduction inleft atrial wall stress.

A few small trials examining recurrence of AF as the mainendpoint have suggested that ACEIs and ARBs may be ben-eficial in the secondary prevention of AF.83,84 However, ina large well-designed RCT of patients with a history of AF,the addition of valsartan to standard therapy did not reducethe risk of recurrent AF compared with placebo.85 Moreover,data from the ACTIVE-I trial showed that irbersartan didnot suppress the recurrence of AF in patients with paroxys-mal AF. It may be that in these trials treatment with ARBswas started too late after the occurrence of irreversible atrialremodeling to demonstrate any discernable benefit. It is pos-sible that the greatest benefits of RAS inhibition may be inthe primary prevention of AF, as these drugs may preventbut not substantially reverse atrial structural and electricalchanges.

There has also been some investigation on the effects ofACEIs/ARBs on recurrence of AF following cardioversion.Analysis from the rhythm control arm of AFFIRM demon-strates fewer AF relapses in patients treated with ACEIs.86

Small RCTs have shown that ACEI or ARB added to amio-darone improve maintenance of sinus rhythm after EC withshort-term follow-up.83,87 There is scant evidence on the po-tential role of RAS inhibition in reducing AF recurrencefollowing catheter ablation. Retrospective analysis from anonrandomized study suggests no improvement in catheterablation outcome in patients treated with an ACEI or ARB.88

Conclusion

Over the past decade there have been accumulating dataimplicating inflammation in the pathogenesis of AF. There isevidence suggesting inflammation is involved in electrophys-iological and structural atrial remodeling, processes integralto the development and perpetuation of AF. Furthermore,inflammation likely contributes to the prothrombotic stateassociated with AF. Inflammatory biomarkers (CRP, IL-6)have been shown to be associated with future development,recurrence and burden of AF, as well as the likelihood ofsuccessful cardioversion. Therapies directed at attenuatingthe inflammatory burden appear promising, but more studiesare needed. Current evidence does not support the routineuse of statins or ACEI/ARBs for the sole purpose of pre-venting or treating AF. Corticosteroids and possibly statinsmay be considered in high-risk patients undergoing cardiacsurgery, although optimal dosing and duration remain un-clear. While the advancements in our understanding of therole inflammation plays in AF are encouraging, well designedRCTs are needed to clarify the impact of anti-inflammatoryinterventions.

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