The Role of Inflammation in Atrial Fibrillation

Christopher J. Boss; Gregory Y.H. Lip

Disclosures

Int J Clin Pract. 2005;59(8):870-872. 

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, affecting approximately 1% of persons aged ≤65 years and 5% of individuals older than 65 years.[1] The presence of AF significantly increases mortality and morbidity, as well as adversely affects quality of life.[2,3,4] In view of the great burden of AF on health care resources, interest has been directed towards greater understanding of the associated pathophysiology underlying this common arrhythmia, in an effort to explore new therapeutic options. Indeed, the development of AF leads to many structural and functional changes within the atria that perpetuates the arrhythmia, a process known as electrical remodelling.[5] AF also confers a prothrombotic or hypercoagulable state, which may contribute to the risk of thromboembolism.[6] Furthermore, despite many new drugs and devices, AF remains common and frequently recurs despite rhythm control strategies.

Recent interest has been directed to the stimulus or 'drive' that increases the risk of development and recurrence of AF and its complications, especially thromboembolism. Inflammatory cytokines have been postulated as possible candidate stimuli. Some evidence to support an association between AF and inflammation can be extracted from the frequent association of AF with inflammatory conditions of the heart, such as myocarditis and pericarditis.[7,8] Indeed, Bruins et al.[9] were the first to propose a direct link between inflammation and AF by observing an increased frequency of AF after coronary artery bypass surgery, where the peak incidence of AF occurred on the second and third postoperative day, coinciding with the peak elevation of C-reactive protein (CRP). Atrial biopsies taken from patients in AF have also demonstrated evidence of inflammatory infiltrates within the atrial tissue with evidence of oxidative damage or occult myocarditis, even among persons who were thought to have had lone AF.[10,11]

Genetic studies have revealed that a common polymorphism Val34Leu in the clotting factor XIII-A was independently associated with interleukin (IL)-6 levels.[12] This leads to more rapid activation of factor XIII and consequently, greater cross-linking of fibrin monomers and increased clot resistance. These observations are intriguing in suggesting that genes may potentially modulate the prothrombotic state in affected patients by influencing the inflammatory state. Consistent with this, a 174G/C polymorphism of the promoter of the IL-6 gene appears to influence the development of postoperative (coronary artery bypass surgery) AF supporting the role of inflammation in the development of postoperative AF.[13]

CRP is an acute phase protein, which is directly related to inflammation. Raised levels of CRP have been noted to be higher among patients with AF when compared with matched controls in sinus rhythm.[14,15,16,17,18,19,20] Of note, persistent AF patients have a higher CRP than paroxysmal AF patients, and both groups have a higher CRP than controls.[14] In both cross-sectional and longitudinal studies, CRP has remained a robust and significant predictor of early AF relapse after successful cardioversion, even after adjustment for multiple risk factors, such as hypertension and coronary artery disease.[15,16] Importantly, the combination of microalbuminuria and an elevated CRP raises the risk of subsequent AF development by fourfold.[18]

In this issue of the International Journal of Clinical Practice, Korantzopoulos et al.[21] present data from a small study of 30 AF patients undergoing cardioversion. They were able to demonstrate an increase in fibrinogen levels amongst patients who relapsed back into AF when compared with those that did not; also, there was a trend to reduced CRP levels among those patients who were successfully cardioverted vs. those who relapsed. Whilst interesting and additive to the AF-inflammation debate, the small size and study power remain a problem, as many potential biases and confounders from comorbidities and concomitant therapies remain.

Whilst clinical data continue to be debated, cogitated and (maybe) regurgitated, perhaps attention should be drawn to the mechanism(s) leading to abnormal inflammation in AF. The precise mechanisms are uncertain, but the possibility remains that cytokines and CRP might reflect active participation of CRP in the local inflammatory response within the atrial myocardium. In human coronary disease models (where inflammation has been clearly linked to thrombosis), deposits of CRP have clearly been demonstrated, on immunohistochemical staining, in the vascular wall of active atherosclerotic plaques, where it is co-localised with the terminal complement complex.[22] Consistent with this, Roldan et al.[23] reported high levels of IL-6 in AF, but this appears to be more related to clinical variables of the patients rather than to the presence of AF per se. Thus, the inflammatory state in AF may simply reflect associated vascular disease in AF.

The association between AF and inflammation has raised potential therapeutic implications. For example, Dernellis and Panaretou[24] were able to demonstrate that the use of low dose glucocorticoids not only improved the efficacy of sinus rhythm maintenance postcardioversion but was reflected by a fall in CRP levels. Also, statins possess additional anti-inflammatory, antihypertrophic, antifibrotic and antioxidant properties, and these agents appear useful for the primary and secondary prevention of AF.[25,26,27]

Recent attention has also been focused on the potential anti-inflammatory, antioxidant and antiarrhythmic properties of oily fish, containing a high content of omega-3 fatty acids. In a prospective, population-based cohort of 4815 older (≥65 years) Mozaffarian et al.[28] showed that consumption of high levels of fish containing omega-3 fatty acids was associated with a lower incidence of subsequent AF development. Unfortunately, an even larger prospective study of 47,949 participants (mean age 56 years) found that consumption of omega-3 fatty acids from fish was not associated with a reduction in risk of AF.[29]

As inflammation is closely related to oxidative stress, perhaps some lateral thought is needed. Indeed, ascorbic acid (Vitamin C) is a water-soluble antioxidant that has been shown to attenuate atrial electrophysiological remodelling and reduce the incidence of postcoronary artery bypass surgery, possibly through scavenging peroxynitrite and other reactive oxygen species.[30,31]

Does abnormal inflammation in AF increase the risk of thromboembolism? In the study by Roldan et al.,[23] there was no association of inflammation with endothelial activation or the presence of abnormal thrombogenesis (high F1 + 2 levels) in AF. However, Conway et al.[32] were able to demonstrate that elevated IL-6 levels were an independent predictor of the composite of stroke or death among a cohort of 77 high risk AF patients. Similarly, Thambidorai et al.[33] were able to demonstrate in 104 patients with AF that clinical and transoesophageal risk factors for stroke were greater for patients with elevated CRP compared with those with normal levels.

An association between inflammation and AF is undoubtedly present, but unfortunately, association does not equate to causation. Further studies are clearly needed to better understand highly complex interaction. We have commenced a new and exciting chapter in the understanding of the pathophysiology of AF in which therapeutic options involving anti-inflammatory agents may potentially play a major role.


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