Background: Several studies were published to assess the association between serum uric acid levels and atrial fibrillation risk, but no consistent results were reported. We performed a meta-analysis to evaluate the evidence of the association between hyperuricemia and atrial fibrillation risk. Material/Methods: Pubmed and Embase databases were searched for prospective cohort studies assessing the association between hyperuricemia and atrial fibrillation risk. Relative risks (RRs) with corresponding 95% confidence intervals (95%CIs) were pooled using random-effect of meta-analysis to assess the risk of atrial fibrillation in individuals with hyperuricemia. Results: Six cohort studies were finally included into the meta-analysis. Meta-analysis of those 6 studies showed that hyperuricemia was significantly associated with increased risk of atrial fibrillation (RR = 1.49, 95%CI 1.24-1.79, P < 0.001). Sensitivity analysis by omitting single study sequentially by turns did not have any obvious influence on the pooled risk estimates. There was no obvious risk of publication bias in the meta-analysis. Conclusions: Based on the currently available data, hyperuricemia is associated with increased risk of atrial fibrillation.

Atrial fibrillation is a common disease in the elderly, and it's also associated with increased risk of cardiovascular disease and stroke [1,2,3]. There are increased incidence and prevalence of atrial fibrillation in the world [4]. The management of atrial fibrillation has evolved greatly in the past few years, and there are many substantial advances or developments in the treatment of atrial fibrillation [5]. Multiple pieces of evidence indicate that the development of atrial fibrillation depends on the electrophysiological and structural remodeling of the atria. However, the exact pathogenesis of atrial fibrillation is still not well understood, and a better understanding of its exact pathogenesis can help us to develop new treatments or preventive methods [4,6,7]. Several risk factors have been identified for atrial fibrillation, such as obesity, and diabetes [8,9,10,11,12]. Inflammation has been demonstrated in the pathophysiological mechanism of atrial fibrillation [5,12,13,14]. The uric acid is the end-product during the purine degradation in humans, and it has emerged as risk factors of many common diseases including cardiovascular diseases. In addition, uric acid has been clearly associated with inflammation and oxidative stress, and it can promote inflammation via the activation of pro-inflammatory cytokines [15,16]. Several studies were published to assess the association between serum uric acid levels and atrial fibrillation risk, but no consistent results were reported [17,18,19,20,21,22,23,24]. We thus performed a meta-analysis to evaluate the evidence of the association between serum uric acid levels and atrial fibrillation risk.

Search strategy and study selection

Pubmed and Embase databases were searched for prospective cohort studies that were published to assess the association between hyperuricemia and atrial fibrillation risk. The last search was performed on October 16, 2015. The search strategy used in the meta-analysis was as following: (atrial fibrillation) and (urate OR uric acid OR hyperuricemia). Hand searching of selected journals and cross checking of bibliographies from other published reviews or relevant articles was also done to supplement the electronic searches. After removal of duplicate references, initial screening of article titles and abstracts was performed by two members of the review team. Full texts of potentially relevant articles were obtained and assessed independently by two members of the review team using a structured flow chart and detailed guidelines. Any disagreements were settled by discussion among all members of the review team.

The inclusion criteria were as following: (1) Prospective cohort studies; (2) Assessing the effect of hyperuricemia on risk of atrial fibrillation; (3) Reported risk estimates for atrial fibrillation, such as relative risks (RR), hazard ratios (HR), or odds ratios (OR) with 95% confidence intervals (95%CI). When more than 2 publications reported outcomes from the same study, only the one with the longest follow-up or largest dataset was included into the meta-analysis.

Data extraction and quality assessment

The following data were extracted from each study: first author, study design, country, baseline characteristics, follow-up, number of participants, number of cases, adjusted factors, and RRs and their 95%CIs. The quality of included studies was assessed using the Newcastle Ottawa scale (NOS) as recommended by the Cochrane Non-Randomized Studies Methods Working Group [25]. Quality was assigned as A or excellent with 7-9 stars, B or good with 4-6 stars, and C or suboptimal with 0-3 stars. Only studies with excellent or good quality were finally included into the analysis.

Statistical analysis

To evaluate the association between serum uric acid levels and atrial fibrillation risk, we used meta-analysis to calculate the pooled RR and 95%CI under a random-effect model [26]. The I2 statistic method was used to evaluate the between-study heterogeneity [27]. The significance of pooled RR was determined by the Z test, and a P value of less than 0.05 was considered significant. Sensitivity analysis was performed by sequentially omitted single study by turns. To assess the risk of publication bias, our meta-analysis used both funnel plot and Egger's test [28]. Statistical analyses were performed using STATA 12.0 (StataCorp, College Station, Texas, USA). P value less than 0.05 was considered significant.

Study characteristics

Through the literature search of Pubmed and Embase databases, 126 individual abstracts were found, 115 abstracts were firstly excluded after reviewing the abstracts. 11 full-text articles were reviewed for more detailed evaluation. After full-text evaluation, 5 articles were further excluded, and 6 cohort studies finally met the inclusion criteria and were included [21,29,30,31,32,33]. Table 1 showed the main baseline characteristics of those 5 cohort studies included into the meta-analysis (Table 1).Those 6 studies involved a total of 426,159 participants (Table 1). The sample size ranged from 400 to 280,060 persons (Table 1), while the time of follow-up ranged from 2 years to 16.8 years (Table 1). As to the quality assessment by NOS Scale, the scores ranged from 6 to 9 points, and all studies had excellent or good quality (Table 1).

Meta-analysis

Meta-analysis of those 6 studies showed that hyperuricemia is significantly associated with increased risk of atrial fibrillation (RR = 1.49, 95%CI 1.24-1.79, P < 0.001) (Fig. 1).

Sensitivity analysis by omitting single study sequentially by turns did not show any obvious influence on the pooled estimates, which further confirmed the findings in the direction and magnitude of the present meta-analysis (Fig. 2).

Funnel plot's shape revealed some evidence of asymmetry in the meta-analysis. In addition, and the P value of Egger's test was more than 0.022 which was less than 0.05. Thus, there was possible risk of publication bias in the meta-analysis.

We performed a meta-analysis to evaluate the evidence of the association between hyperuricemia and atrial fibrillation risk. Six cohort studies were finally included into the meta-analysis. Meta-analysis of total 6 studies showed that hyperuricemia was significantly associated with increased risk of atrial fibrillation (RR = 1.49, 95%CI 1.24-1.79, P < 0.001). Sensitivity analysis by omitting single study sequentially by turns did not show any obvious influence on the pooled estimates (Fig. 2). Thus, our meta-analysis suggests that hyperuricemia is obviously associated with increased risk of atrial fibrillation.

Hyperuricemia has been shown to be associated with risk of several cardiovascular diseases, such as coronary heart disease and stroke [34,35]. In present study, we found that hyperuricemia is obviously associated with increased risk of atrial fibrillation. Since atrial fibrillation is a common and important risk factor of coronary heart disease and stroke, the finding in the meta-analysis may explain the associations of hyperuricemia with coronary heart disease and stroke, namely atrial fibrillation caused by hyperuricemia further results in coronary heart disease and stroke [10,36].

Serum uric acid is the end product of purine degradation in humans. Uric acid can promotes inflammation via the activation of pro-inflammatory cytokines [37]. At present, serum uric acid has emerged as risk factors of cardiovascular diseases. In addition, uric acid has been clearly associated with inflammation and oxidative stress in several pathological conditions, and it can promote inflammation via the activation of pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNF-α) [15,16,38,39]. Inflammation and oxidative stress has been demonstrated in the pathophysiological mechanism of atrial fibrillation [5,12,13,14], and thus uric acid may be also have certain roles in the development of atrial fibrillation. A recent research showed that intracellular urate taken up by uric acid transporters could enhance the Kv1.5 protein expression and function in atrial myocytes, which may result from oxidative stress derived from nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase [40]. However, more studies are needed to investigate the exact mechanism underling the roles of uric acid in atrial fibrillation.

The findings from previous studies and present meta-analysis have provided strong evidence for hyperuricemia as important risks of several common cardiovascular diseases. Thus, risk of cardiovascular diseases in hyperuricemia individuals may be effectively decreased through allopurinol treatment. A recent meta-analysis suggest that treatment of hyperuricemia with allopurinol is associated with an improvement in endothelial function [41]. However, results from other literatures are still unable to provide a definite conclusion on the preventive effect of allopurinol against cardiovascular diseases [42,43]. Further studies are needed to further assess the effect of uric acid lowering therapy on atrial fibrillation risk or cardiac events and death in individuals with atrial fibrillation.

Though there was a conclusive and reliable finding in the meta-analysis, there were several limitations needing to be acknowledged. The limited number of included studies decreased the credibility of the pooled results in the meta-analysis. There were only five cohort studies in our study. More studies are needed to further validate the findings in our meta-analysis. In addition, most of those studies were from limited areas of the world, the findings in the meta-analysis might not be generalized to all populations. Studies from different countries are necessity to add further evidence. Finally, most included did not consider uric acid lowering therapy when performing multivariable logistic regression analyses. To get a more precise evaluation of hyperuricemia on atrial fibrillation, future studies of large cohorts and prospective analyses are required to confirm the role of uric acid as a risk determinant for atrial fibrillation.

In summary, our meta-analysis suggests that hyperuricemia is obviously associated with increased risk of atrial fibrillation. Further studies are needed to further assess the effect of uric acid lowering therapy on atrial fibrillation risk or cardiac events and death in individuals with atrial fibrillation.

No conflicts of interest to be noted.

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