Elsevier

Heart Rhythm

Volume 7, Issue 4, April 2010, Pages 438-444
Heart Rhythm

Clinical
Atrial fibrillation
Role of inflammation and oxidative stress in atrial fibrillation

https://doi.org/10.1016/j.hrthm.2009.12.009Get rights and content

Background

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. Increasing evidence indicates that inflammation and oxidative stress contribute to the pathogenesis of AF, but their role remains poorly defined. In addition, whether inflammation and oxidative stress are associated with particular types of AF is unclear.

Objective

The purpose of this study was to define the role of inflammation and oxidative stress in AF.

Methods

Using a case-control study design, 305 patients with AF were compared with 150 control patients. AF was categorized into lone and typical AF and further subcategorized as paroxysmal, persistent, or permanent AF. Serum concentrations of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), N-terminal pro–brain (B-type) natriuretic peptide (NTpBNP), and urinary F2-isoprostanes, a measure of oxidative stress, were measured.

Results

IL-6, IL-8, IL-10, TNF-α, MCP1, VEGF, and NTpBNP concentrations were independently associated with AF (all P <.05). However, F2-isoprostane excretion was not elevated (P = .50). Graded increases in TNF-α [median (interquartile range) 6.8 (3.4–11.3), 8.0 (5.6–10.9), 10.1 (5.7–12.4) pg/mL, P <.05] and NTpBNP [170.6 (67.3–481.9), 681.39 (310.3–1,439.0), 1,179.9 (653.1–2,096.0) pg/mL, P <.001] were seen among the subgroups of paroxysmal, persistent, and permanent AF, respectively.

Conclusion

Inflammatory biomarkers were significantly increased in patients with AF, supporting a strong association between inflammation and AF. Surprisingly, urinary F2-isoprostanes, a sensitive index of systemic oxidative stress in vivo, were not increased in AF overall or in different subtypes of AF.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia seen in clinical practice. It contributes to impaired patient quality of life and increased morbidity and mortality.1, 2, 3, 4 Long-term maintenance of sinus rhythm in patients with AF remains a challenge because of the adaptive changes that occur, commonly termed electrical and structural remodeling. The mechanisms underlying both the initiation and perpetuation of AF are not well established but are thought to involve inflammation and oxidative stress.5, 6, 7

Several lines of evidence support a strong association between inflammation and the pathogenesis of AF. Inflammatory infiltrates, myocyte necrosis, and interstitial fibrosis were found in atrial tissue from patients with idiopathic or “lone” AF but not in control patients.3, 8, 9, 10 Furthermore, a number of studies have shown that concentrations of inflammatory mediators or markers, such as interleukin (IL)-6 and high-sensitivity C-reactive protein (hs-CRP), are increased in patients with AF.5, 8, 11, 12, 13 One mechanism that may mediate the effects of inflammation in AF is oxidative stress.

Emerging evidence implicates oxidative stress in the initiation and maintenance of AF.14 Carnes et al15 showed that AF induced by rapid pacing in dogs decreases tissue ascorbate levels and increases protein nitration, a marker of oxidative and nitrosative stress. Biochemical evidence of oxidation by peroxynitrite and hydroxyl radicals, both downstream products of oxygen radical generation, has also been demonstrated in experimental models of AF.16 Coronary artery bypass surgery, a procedure often complicated by AF, is associated with an increase in oxidized glutathione and lipid peroxidation.17, 18, 19, 20 However, in vivo studies have been difficult to perform because of the lack of reliable methods for quantifying oxidative stress. Although a number of assays are available, they are used primarily to measure oxidation in vitro and are inaccurate when applied to the in vivo assessment of oxidative stress in humans.21 The development of methods for quantifying F2-isoprostanes, which are prostaglandin-like compounds derived from the free radical–catalyzed peroxidation of arachidonic acid, has allowed facile and accurate assessment of oxidative stress in vivo.19, 22

Although inflammation and oxidative stress both are considered to be potential initiators and mediators of AF, few studies have evaluated their role in AF generally and in different types of AF specifically. Thus, we hypothesized that measures of inflammation and oxidative stress are increased in AF. We also hypothesized that indices of inflammation and oxidative stress are lower in patients with lone AF than in those with typical AF, and in patients with paroxysmal AF than in those with persistent or permanent AF.

Section snippets

Study population

Between November 2002 and October 2006, subjects with AF were prospectively enrolled in the Vanderbilt AF Registry, which comprises clinical and genetic databases.23 At enrollment, a detailed medical and drug history was obtained. Patients with AF were recruited from the Vanderbilt Cardiology and Arrhythmia Clinics, the emergency department, and in-patient services. Individuals older than 18 years with a diagnosis of AF, confirmed by ECG, who presented because of symptoms or who were diagnosed

AF and control groups

The clinical characteristics of the control population are listed in Table 1. The control group had a median age of 49 years (interquartile range 39–56 years) and had more female subjects (72%) than did the AF group. Body mass index (30.2 vs 26.6 kg/m2) and statin use (50% vs 11%) were significantly higher in patients with AF than in subjects in the control group. The clinical characteristics of patients with AF (n = 305, including both typical and lone AF) are representative of an outpatient

Discussion

Evidence has emerged implicating inflammation and oxidative stress in the pathogenesis of AF.2, 14, 26, 27, 28 We showed not only that inflammatory markers were associated with AF but also that elevated inflammatory mediators varied according to the different subtypes of the arrhythmia. Surprisingly, in the same large cohort of patients with this common arrhythmia, levels of urinary F2-isoprostanes, a sensitive index of oxidative stress in vivo, were not increased.

In this study, we measured a

Study limitations

This study has a number of limitations. First, the study had a cross-sectional design; thus, we have inflammatory marker data only for one time point, that is, at enrollment into the AF Registry. Therefore, the effects of pharmacotherapeutic agents, such as statins, known to modulate the inflammatory response could not be assessed longitudinally. Control subjects were enrolled to provide information about baseline levels of oxidative stress and cytokines in subjects without inflammatory disease

Conclusion

This study demonstrated that concentrations of inflammatory biomarkers were significantly increased in patients with AF and supports a strong association between AF and inflammation. Elevated inflammatory markers in patients with lone AF suggest that inflammation is associated with AF independent of comorbidities such as heart failure. Urinary F2-isoprostanes, a sensitive systemic index of oxidative stress in vivo, showed no significant differences between AF and control groups or among the

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    This work was supported by National Institutes of Health GrantsHL085690, HL87254, and P60AR056116, and American Heart Association Award 0940116N.

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