Elsevier

Heart Rhythm

Volume 11, Issue 7, July 2014, Pages 1102-1108
Heart Rhythm

Association between serum uric acid and atrial fibrillation: A systematic review and meta-analysis

https://doi.org/10.1016/j.hrthm.2014.04.003Get rights and content

Background

Atrial fibrillation (AF) is mediated by oxidative stress, neurohormonal activation, and inflammatory activation. Serum uric acid (SUA) is a surrogate marker of oxidative stress. Xanthine oxidase produces SUA and is upregulated by inflammation and neurohormones.

Objective

To perform a meta-analysis to evaluate the evidence supporting an association between AF and SUA.

Methods

We searched the MEDLINE database (1966 to 2013) supplemented by manual searches of bibliographies of key relevant articles. We selected all cross-sectional and cohort studies in which SUA was measured and AF was reported. In cross-sectional studies, we calculated the pooled standardized mean difference of SUA between those with AF and those without AF. In cohort studies, we calculated the pooled relative risk with the corresponding 95% confidence interval (CI) for incident AF by using the random effects method.

Results

The search strategy yielded 40 studies, of which only 9 met our eligibility criteria. The 6 cross-sectional studies comprised 7930 evaluable patients with a median prevalence of heart failure of 4% (IQR 0%–100%). The standardized mean difference of SUA for those with AF was 0.42 (95% CI 0.27–0.58) compared with those without AF. The 3 cohort studies evaluated 138,306 individuals without AF. The relative risk of having AF for those with high SUA was 1.67 (95% CI 1.23–2.27) compared with those with normal SUA.

Conclusion

High SUA is associated with AF in both cross-sectional and cohort studies. It is unclear whether SUA represents a disease marker or a treatment target.

Introduction

Atrial fibrillation (AF) is an important cause of morbidity and mortality. Along with the increased risk of death, AF can lead to stroke and decreased quality of life.1 The pathogenesis of AF remains incompletely understood.

Uric acid is produced by xanthine oxidase (XO), is the terminal breakdown product of purine nucleotides, and is a surrogate marker of oxidative stress. Recent studies have demonstrated that there is a strong association between serum uric acid (SUA) levels with an important AF mediator (such as heart failure mortality)2 and incident coronary artery disease.3

The key pathways implicated in the development of AF are neurohormonal activation,4 oxidative stress/nitroso–redox imbalance,5 and immune activation.6 There seems to be a common mechanism linking all 3 pathways since mechanical stretch mediated by neurohormones leads to oxidative stress and inflammation upregulates XO7, 8, 9; therefore, SUA may play a role in the etiology and persistence of AF. Identifying new associations and mechanisms of AF could lead to therapeutic targets in the future. Therefore, the purpose of this meta-analysis was to help define the relationship between SUA and AF in an effort to better understand the pathophysiology of the disease.

Section snippets

Search strategy

A search was conducted through the MEDLINE database by using PubMed, which contained articles from 1966 to July 2013. This search was conducted by filtering all articles except those containing key terms such as uric acid and AF. More specifically, the search was performed by entering the following: (“uric acid”[MeSH Terms] OR (“uric”[All Fields] AND “acid”[All Fields]) OR “uric acid”[All Fields]) AND (“atrial fibrillation”[MeSH Terms] OR (“atrial”[All Fields] AND “fibrillation”[All Fields]) OR

Literature search

Our search yielded 40 abstracts (Figure 1). We excluded 21 at the abstract level because they did not met our inclusion criteria and selected 19 for full-text review; of the19 selected for full-text review, we included 9 studies and excluded 10 for the following reasons: studies did not include data that could be abstracted for mathematical pooling (n = 4); editorials or review articles (n = 4); and studies included uric acid measurements that could not be replicated (n = 1).11 Interrater

Discussion

Our study reports that high SUA is associated with AF. This association was consistently seen in both cross-sectional and cohort studies, and it was also seen with different types of analyses that included univariate, multivariate, random effects mathematical pooling, and subgroup analyses. It was also seen consistently in multiple and diverse populations. The strengths that lend weight to this conclusion include the stratified analysis of the different study designs and the large sample size.

Conclusion

Despite its limitations, this study finds a clear and strong association between AF and elevated SUA. Future studies should focus on evaluating the mechanistic relationship between SUA and AF and determining whether modifying SUA on patients at risk for AF can decrease its incidence.

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