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Cardioversion for Atrial Fibrillation: Does Inflammation Matter?

Timothy Watson, MRCP, Puneet Kakar, MRCP, and Gregory Y.H. Lip, MD*

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The long-term maintenance of sinus rhythm after cardio-ersion for atrial fibrillation (AF) has long been acknowledgeds problematic. Even after initial successful restoration of sinushythm, some 53% patients will return to AF over the follow-ng months, whereas only approximately 25% remain in sinushythm at 5 years.1,2 This is despite an aggressive rhythmontrol strategy, using serial attempts at cardioversion andoncomitant antiarrhythmic drug prescription. More recently,he advent of catheter-based (and surgical-based) technologiesas offered the potential of a cure for AF, with some promisingesults,3 but even after these procedures, recurrence, oftensymptomatic, is common, further highlighting the difficultiesncountered in maintaining sinus rhythm.4,5

What contributes to the poor results of cardioversion andong-term maintenance of sinus rhythm? Structural andlectrical remodeling within the atria may perpetuate AF—hat is, “AF begets AF”—admittedly in an experimentaloat model.6 These remodeling changes include progressiveeft atrial dilatation and increasing atrial fibrosis,7 the loss ofate adaptation, and the prolongation of atrial conductivity.8alcium may also accumulate within atrial myocytes,

hereby shortening the atrial refractory period, and hence,romoting the propagation of multiple wavelet reentry cir-uits.7 The net result is that the biophysical properties oftrial tissue are altered at microscopic and macroscopicevels in AF,9 thereby serving to perpetuate the arrhythmia.

Does inflammation have a role in this, contributing to theerpetuation and maintenance of AF? Although the precisetimulus for the initiation of these atrial changes remainsoorly understood, an increasing body of evidence suggestshat inflammation may be central to this pathogenic pro-ess.10 The histology of atrial biopsies taken from patientsith AF has demonstrated evidence of inflammatory infil-

rates and oxidative damage within the atrial tissue.11,12 Ofourse, these changes may clearly be a consequence of thearious underlying co-morbidities that commonly associateith AF (e.g., ischemic heart disease, hypertension, diabe-

es mellitus). However, this observation holds true even forhose with lone AF, thereby raising the possibility thatnflammation may still play some role in the initiation ofF, at least in this patient group.12

Systemic indexes of inflammation are also reported inF.10 For example, C-reactive protein (CRP) is a circulating

cute-phase reactant and is considered the prototypic down-tream marker of inflammation.13,14 CRP is synthesized byhe liver in response primarily to interleukin-6 (IL-6) but alsoo interleukin-1. Many markers of inflammation exist, but

University Department of Medicine, City Hospital, Birmingham,nited Kingdom. Manuscript received December 28, 2006; revised manu-

cript revised and accepted December 28, 2006.*Corresponding author: Tel: 44-0-121-507-5080; fax: 44-0-121-554-

083.

aE-mail address: g.y.h.lip@bham.ac.uk (G.Y.H. Lip).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2006.12.089

igh-sensitivity CRP (hs-CRP) is probably the most robust andeproducible.14 Indeed, there is a consistent, significant asso-iation between baseline hs-CRP levels and cardiovascularisk, an association that holds true across many popula-ions.14,15 hs-CRP also appears to correlate with an increasingF burden and is associated with the persistence of AF.16,17

urthermore, hs-CRP levels appear to correlate with increasinguration of AF and left atrial size, effectively supporting linksmong inflammation, AF burden, and structural remodeling.18

n addition to being predictive for the future development ofF, hs-CRP is as a consistent predictor of early relapse after

uccessful cardioversion for AF, even after adjustment foronfounding factors, such as hypertension and ischemic heartisease.10

Although many studies have demonstrated the potentialmportance of CRP, the role of IL-6 remains questionable.lthough Roldan et al19 reported increased levels of IL-6 inatients with AF, this would appear to be related to underlyingo-morbidities such as hypertension and coronary artery dis-ase rather than directly related to AF per se. This has fueledpeculation that abnormalities of inflammation in AF mayimply reflect the various co-morbidities that often coexist.

Given the prognostic value of inflammatory indexes inardiovascular disease, what is the prognostic value in AF?he relation between AF and excess morbidity and mortal-

ty is irrefutable. Specifically, there is a high risk for strokend thromboembolism, for which there is evolving evidencehat AF may contribute to a hypercoagulable state.20 Al-hough the precise mechanisms that “drive” this process re-ain poorly understood, it is plausible that inflammation may

erald an important avenue of investigation. Indeed, Conwayt al21 were able to establish that elevated IL-6 levels were anndependent predictor of the composite of stroke or death in aohort of high-risk patients with AF. More recently, Lip et al22

nvestigated the associations among CRP, CD40 ligand (aarker of platelet activation with links to inflammation), and

troke risk in patients with AF. This study revealed a signifi-ant positive association between elevated CRP levels, but notD40 ligand, and stroke risk, as well as prognosis (mortality,ascular events).

Given the consistent association between AF and inflam-ation, are the abnormalities noted simply a consequence of

he various confounding factors that commonly coexist withF and that may also contribute to an inflammatory re-

ponse in their own right? The link would appear to remainomewhat tenuous with questions remaining on “cause andffect.” Despite this, there remains a great deal of interest inharmacologic agents that may modify the inflammatoryrocess, in particular drugs that modulate the renin-angio-ensin-aldosterone system (RAAS).10 Of note, angiotensinI has been shown to possess a number of proinflammatoryroperties. In particular, this hormone increases the produc-ion of proinflammatory cytokines (e.g., IL-6 and tumorecrosis factor-�), adhesion molecules (e.g., vascular cell

dhesion molecule-1), monocyte chemoattractant protein-1,

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1618 The American Journal of Cardiology (www.AJConline.org)

nd selectins (e.g., P-selectin).23,24 Similarly, through theelease of various chemokines (e.g. cytokine-induced neu-rophil chemoattractant), angiotensin II is able to initiateeutrophil recruitment.24 Importantly, atrial tissue expressesngiotensin-converting enzyme and angiotensin II recep-ors25 and thereby holds the capacity for the local produc-ion and utilization of angiotensin II. There is also histologicvidence to support the upregulation of these receptors inF,26 with the expression of angiotensin II receptors being

inked with increased atrial cell death and leukocyte infil-ration. All these would support a potential (complex) rela-ion among the RAAS, inflammation, and AF.

In this issue of the American Journal of Cardiology,veit et al27 report on the effect of candesartan and various

nflammatory markers on the maintenance of sinus rhythmfter cardioversion for AF. Unsurprisingly, their studyhowed that low levels of hs-CRP and E-selectin at baselineere consistent with a greater probability of cardioversion

uccess at 6 months; however, this did not hold true forther inflammatory markers, notably IL-6, CD40 ligand,nd tumor necrosis factor-�. Rather curiously, despite firminks among AF, inflammation, and the RAAS, the investi-ators found no evidence that candesartan affected the var-ous markers of inflammation at baseline. Interestingly,veit et al27 demonstrated that the restoration and mainte-ance of sinus rhythm for 6 months had little impact oneducing hs-CRP levels.

Although these data may well be tainted by the complex-ties of investigating any group of patients with numerouso-morbidities, this must surely strengthen the argument thatnflammation in AF is simply a reflection of underlying vas-ular disease. Perhaps a holistic approach to AF is needed, withcomprehensive clinical assessment and management of all

o-morbid risk factors and appropriate “upstream” therapieshat address various aspects of cardiovascular risk reduction,ncluding RAAS blockade, good blood pressure control,mega-3 fatty acids, and statins. Central to AF managementust also be appropriate risk stratification and antithrombotic

herapy. Only then can our management of this common ar-hythmia—AF is being described as the “new epidemic”—ruly improve.

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2. Bertaglia E, D’Este D, Zerbo F, Zoppo F, Delise P, Pascotto P. Success ofserial external electrical cardioversion of persistent atrial fibrillation in main-taining rhythm; a randomized study. Eur Heart J 2002;23:1522–1528.

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