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INTRODUCTION
Uric acid (UA) is a breakdown product from xanthine and hypoxanthine through xanthine oxidase (XO) in purine metabolism and has long been recognized as an antioxidant [1]. However, studies have shown that it can also generate oxygen free radicals in different types of cells, including cardiac myocytes and endothelium, leading to oxidative stress [2]. Increased UA promotes pro-oxidative and inflammatory state [3] by intensifying XO activity and interfering with renin-angiotensin system, which induces vascular endothelial injury [4,5], resulting in a variety of cardiovascular diseases, such as atherosclerosis and hypertension. Hyperuricemia is an independent unfavorable risk factor for cardiovascular diseases and mortality [6,7].
According to recent studies, hyperuricemia is linked to a higher prevalence of atrial and ventricular arrhythmias [8,9]. Urate-lowering therapy (ULT) may also have cardioprotective benefits through lowering UA levels and the direct effects of the medication [10-12]. However, little is known about their effects on arrythmia risk. We aim to investigate the link between ULT and incident arrhythmias through a systematic review and meta-analysis.
MATERIALS AND METHODS
Design
This systematic review has been carried out following the recommendations of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement and guidelines for systematic reviews.
Search strategy
Potentially eligible studies were identified by two investigators (TL, PW) through independent searches of PubMed and Embase databases, from inception to May 2023. The search terms used were derived from those related to “Arrhythmias” and “Urate-lowering therapy”, as described in the Supplementary Material 1. No restrictions were applied on study design or language in the search strategy. If necessary, relevant articles in languages other than English were translated using Google Translate or other appropriate methods. Furthermore, additional relevant studies were searched manually by examining the references of the retrieved articles.
Study selection criteria
The study being sought must be cohort study, which compares patients who use ULT and the other group of patients who do not use ULT (comparator). The main objective of the study is to compare the prevalence of cardiac arrhythmias in each group and determine the size of the effect with a 95% confidence interval (CI). Two investigators (TL and PW) independently reviewed the articles to determine if they met the criteria for inclusion in the study. If there were any disagreements, a third investigator, JK, helped to resolve them through discussion. The quality of each study was assessed by three investigators (PW, MT, and TK), using the Newcastle-Ottawa quality assessment scale (NOS) [13] for cohorts and the Revised Cochrane Risk-of-Bias tool (RoB2) for randomized controlled trials (RCTs) [14]. If two studies used the same database, only the study with the greatest number of participants would be taken into consideration for inclusion.
Data extraction
We utilized a standardized form to collect data, which included the last name of the first author, country where the study was conducted, study design, publication year, population of participants, recruitment of participants, diagnosis of cardiac arrhythmias (Arrhythmias of interest include supraventricular tachycardia, ventricular tachycardia and atrial fibrillation/flutter), ULT (Xanthine oxidase inhibitors (XOIs): allopurinol and febuxostat, uricosuric agents: probenecid and benzbromarone, and uricase agents: pegloticase) use, mean age of participants, percentage of female participants, and variable adjusted in multivariate analysis. This extraction process was independently carried out by three investigators (PW, MT, and CA). Any inconsistencies in the data were resolved by referring back to the original articles.
Quality of included studies
For the cohort studies, the researchers used the NOS to assess the quality of the included studies. This scale uses a star grading system, with a range of 0 to 9, to assess the studies in three areas: participant recruitment and selection, group comparability, and the determination of the outcome of interest in cohort studies. A higher grade corresponds tohigher quality. For the RCTs, we utilized the RoB2 for quality assessment, which consists of 5 domains, including biases arising from the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Each domain was evaluated and stratified into one of the three types of bias judgments: low, high, and some concerns. Three investigators (MT, CA, TK) independently evaluated the quality of each study, and any differing opinions were resolved through discussion with a fourth investigator (PW).
Statistical analysis
We conducted a meta-analysis of the studies included in our research using a random-effects model and the generic inverse-variance method of DerSimonian and Laird [15]. Our analysis focused on examining the incidence of arrhythmia and the use of ULT as reported in these studies. To assess the heterogeneity of the effect size estimates, we used forest plots to check for any non-overlapping confidence intervals and calculated the Q statistic and the I2 statistic. For the Q statistic, substantial heterogeneity was defined as p<0.10. The I2 statistic ranges from 0 to 100%, with values below 25% indicating low heterogeneity, values between 25% and 50% indicating moderate heterogeneity, and values above 50% indicating substantial heterogeneity. We performed a sensitivity analysis to examine the impact of individual studies on our overall results by removing one study at a time. We did not utilize funnel plots and Egger’s test to investigate publication bias since the number of included studies was not sufficient to reject the assumption of no funnel plot asymmetry. All statistical tests were conducted using STATA 17 software (College Station, TX, USA).
RESULTS
From the Embase and MEDLINE databases, we found a total of 1,135 articles. After eliminating duplicate articles, we were left with 1,050 articles to review. Of these, 964 articles did not meet the eligibility criteria based on title, study design, type of article, and abstract review. As a result, we identified 86 articles that were considered relevant and were thoroughly reviewed. Ultimately, 81 more articles were excluded as they did not meet the inclusion criteria or did not have comparable outcomes of interest. No additional articles were found through manual search. Thus, a total of 5 articles [11,12,16-18] met all the eligibility criteria and were included in the data analysis. Figure 1 provides an overview of the search methodology and selection process used in this study.
The 5 included articles are comprised of three RCTs and two retrospective cohorts from 1991 to 2022. These articles involved 12,420 subjects, with 7,359 subjects in the ULT group and 5,061 subjects in the non-ULT group. Among the 5 articles, 3 focused on allopurinol, 1 on febuxostat, and 1 used combined ULTs without specifying a specific drug. Four articles specifically examined the relationship with atrial fibrillation (AF). Additional characteristics of the included studies can be found in Table 1. Both retrospective cohort studies [11,18] were of high quality, as indicated by the high Newcastle-Ottawa score (Table 1). The risk of bias assessment for RCTs [12,16-17] shown in Figures 2 and 3 demonstrated some concerns arising from the randomization process and the deviations from the intervention but there were no apparent factors that affect the results and outcome evaluations.
Subgroup analysis
1) ULT and the risk of AF
Subgroup analysis did not show that ULT users had a significant reduced risk of AF (pooled RR 0.76, 95% CI: 0.54~1.05, p=0.096 with I2=15.4%) compared to non-ULT users as shown in Figure 5.
Subgroup analysis for the retrospective cohorts showed the significant reduction in the risk of arrhythmias (pooled RR 0.83, 95% CI: 0.74~0.93, p=0.001, I2=0.0%) (Supplementary Figure 1) but the subgroup analysis for three RCTs showed no significant reduced risk of arrythmia (pooled RR 0.53, 95% CI: 0.27~1.03, p=0.062, I2=0.0%) (Supplementary Figure 2). There were insufficient data to perform additional analysis for supraventricular tachycardia and ventricular arrythmia (VA).
Publication bias
As there were only five studies in the primary analysis, the number was insufficient to reject the assumption of no funnel plot asymmetry. Therefore, neither Egger’s test nor a funnel plot was performed.
Sensitivity analysis
A sensitivity analysis was performed to assess the influence of the individual studies on the overall results by omitting one study at a time as shown in Figure 6.
DISCUSSION
To our knowledge, this is the first comprehensive review and analysis that explores the connection between ULT and arrhythmias. The use of ULT has been linked to a decreased risk of arrhythmias. However, the specific reasons behind this association are not yet fully understood. We propose several potential explanations.
One of the main reasons for the reduced risk of arrhythmias with ULT is likely the direct effect it has on lowering levels of serum UA as hyperuricemia is associated with an increased risk of both AF and VA. Various mechanisms contribute to the higher AF risk in patients with elevated UA levels, particularly when the levels exceed 7.0 mg/dL in men and 5.7 mg/dL in women [19]. It is believed that UA contributes to the structural and electrophysiological remodeling of the atrium, which disrupts signaling pathways and molecules involved in AF onset and perpetuation [8]. Additionally, UA can enter atrial myocytes and produce reactive oxygen species, which are a key stimulus for AF development [20]. Limited data exist on the relationship between hyperuricemia and VA. However, in patients with ST-elevation myocardial infarction, high UA levels have been found to reduce the susceptibility of the ventricular myocardium and impair coronary artery reperfusion, leading to VAs [21]. Yamada et al. [9] demonstrated that patients with left ventricular (LV) hypertrophy have increased risk of VA when UA is elevated and hypothesized that LV myocardium damage may be provoked by increased UA.
Additionally, inhibiting XO enzyme activity has been shown to weaken sympathetic innervation and reduce arrhythmias in an independent manner from its direct effect of reducing UA levels. Lee et al. [10] conducted a study using rats and found that inhibiting XO decreased the production of ROS, which are known to cause inflammation and disrupt cardiac electrical and structural remodeling, promoting AF [22]. XO is one of the major sources of ROS in the heart [23]. By suppressing XO, the CaMKII oxidation and RyR2 hyperphosphorylation were restored, resulting in a decrease in intracellular ROS and a reduced vulnerability to AF [24]. These effects on oxidative stress and sympathetic innervation were XOI dependent and not yet demonstrated on the use of uricosuric or uricase agents [10]. The majority of ULT included in our study are XOI, allopurinol and febuxostat.
Apart from reduced serum urate, antioxidant action, and decreased sympathetic activity, allopurinol may prevent VAs by anti-ischemic effect [25], lowering blood pressure [26] and reducing LV mass [27]. In a study using a canine model, allopurinol suppressed AF by attenuating the interstitial fibrosis of the atrium, which is a pathological substrate for AF induction [28]. This effect might be the unique feature of allopurinol to mitigate arrythmia. Although it is believed that the anti-ischemic effect results from XO inhibition [25], none of the studies have investigated this effect on febuxostat, which appears to be a more potent XOI [29]. Future studies should explore whether this is a class effect or exclusive to allopurinol.
The main strengths of this study are that we included a large number of participants, and the results remain robust even after we performed the sensitivity analysis as there is only little change in the overall outcome estimate. The statistical heterogeneity of the meta-analysis was insignificant to low (I2 0.0%~15.4%), most likely because of variations in participant characteristics and study design. However, there are a few limitations in our study. The majority of the included studies focused on allopurinol and AF, with only one study specifically examining the effects of febuxostat. Furthermore, none of the studies specifically investigated VA. The studies related to allopurinol and VA were all related to myocardial infarction, which may not be applicable to other types of VA.
CONCLUSION
According to our findings, ULT may be able to prevent arrhythmias in addition to decreasing UA levels. More research is required to fully understand our findings and investigate the intricacies behind the mechanisms.
SUPPLEMENTARY DATA
Supplementary data can be found with this article online at https://doi.org/10.4078/jrd.2023.0059
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