A case–control study to investigate association between serum uric acid levels and paroxysmal atrial fibrillation

The relationship between serum uric acid (SUA) levels and paroxysmal atrial fibrillation (AF) remains controversial. The objective of this case–control study was to investigate the association between serum SUA levels and paroxysmal AF by gender in 328 patients. This study included 328 hospitalized patients with newly diagnosed paroxysmal AF in China between January 2019 and September 2021. Controls with sinus rhythm were matched (2:1) to cases by age and gender. Baseline data were analyzed using ANOVA, T-test, and Chi-square test. Pearson correlation analyses were used to confirm the correlation between variables, and multivariate regression analyses were used to adjust for covariates. Elevated SUA levels in female patients were significantly associated with paroxysmal AF after adjusting for confounding factors (OR = 1.229, 95% CI 1.058–1.427, P = 0.007). Further results showed SUA levels were negatively correlated with high-density lipoprotein cholesterol (HDL-C) (r = − 0.182, p = 0.001) and apolipoprotein A1 (APOA1) (r = − 0.109, p = 0.049), were positively correlated with low-density lipoprotein cholesterol (LDL-C) (r = 0.169, p = 0.002) and prealbumin (PAB) (r = 0.161, p = 0.004) . Nevertheless, there was no significant complication difference between SUA levels and paroxysmal AF (P > 0.05). Increased SUA in female patients was significantly associated with paroxysmal AF in a Chinese population. This finding implies that it would be interesting to monitor and interfere with hyperuricemia in paroxysmal AF patients.


Association between SUA levels and metabolic indicators in men and women with paroxysmal AF. As shown in
, we observed higher SUA had higher Scr in men and women (P < 0.05). Additionally, the results also showed higher SUA had higher ALB, PAB, TG, and LDL-C in men (P < 0.05).

Discussion
This study performed a case-control design to investigate the association between SUA levels and paroxysmal AF by gender in 984 participants from China. We reported that elevated SUA levels in female patients were significantly associated with AF after adjusting for confounding factors. Further results showed that SUA levels were negatively correlated with HDL-C and APOA1, were positively correlated with LDL-C and PAB. However, we did not observe the association between SUA levels and metabolic indicators in women with paroxysmal AF. Meanwhile, there was no significant comorbidity difference between SUA levels and paroxysmal AF. These significant findings might help evaluate the relationship between SUA levels and paroxysmal AF, as well as better understand the pathologic mechanisms of paroxysmal AF.
In the present study, we compared comorbidities and some serum markers between paroxysmal AF patients and sinus rhythm participants. We found that patients with paroxysmal AF were more likely to have hypertension, coronary heart disease, and diabetes, which were important risk factors for paroxysmal AF. Moreover, we observed that TC, LDL-C, and HDL-C were lower in patients with paroxysmal AF. We speculated that this result may be related to lipid-lowering drugs in patients with paroxysmal AF, Wang et al. also obtained similar results with our study 15 . The current results also showed that SUA levels in women with paroxysmal AF patients were significantly higher, but not in men. We further investigated the gender-specific association between SUA levels and paroxysmal AF by multivariate logistic regression analysis. The findings indicated that SUA levels were significantly correlated with paroxysmal AF after adjusting for all confounding factors, while this independent association was only in the total population and women. Although several studies have also reported a strong association between SUA and AF 13,20,21 , few studies have reported the association between SUA levels and paroxysmal AF. A meta-analysis included 31 studies with 504,958 participants that investigated the association between SUA levels and different types of AF, the results suggested that SUA levels were significantly different among participants with new-onset, paroxysmal and persistent AF 22 . Another retrospective study showed that in patients with paroxysmal AF undergoing catheter ablation, increased SUA levels were associated with a higher incidence of AF recurrence 23 . These findings were consistent with our current results.
Evidence about the association between SUA and paroxysmal AF could help understand the multifactorial mechanisms of AF. AF was mediated by inflammation, oxidative stress, neurohormonal activation, and immune activation 13,24 . Xanthine oxidase can produce SUA, which was upregulated by inflammation and neurohormones. The activation of inflammatory and xanthine stress pathways facilitated by xanthine oxidoreductase were associated with the initiation and maintenance of AF 25,26 . On the one hand, high levels of SUA can mediate the formation of the free radical superoxide anion, and left atrial remodeling is promoted by xanthine stress 27,28 . On the other hand, elevated SUA can induce inflammation by reducing the bioavailability of nitric oxide in the vascular wall 29 . Meanwhile, activation of inflammation also facilitated the production of SUA by augmenting cell destruction 30 . Furthermore, this process may increase the risk factors of developing AF such as hypertension,  Table 1. www.nature.com/scientificreports/ diabetes, and metabolic syndrome. Therefore, we hope this study will contribute to a better understanding of these important mechanisms of AF. In addition, our findings also indicated a gender-specific association between SUA and paroxysmal AF, that was, SUA levels were independently associated with paroxysmal AF in women. There are possible mechanisms that could explain the current results. According to previous reports 31,32 , cardiomyocytes have receptors that express sex hormones, and estrogen plays an important role in the occurrence of AF by changing ion channels. Estrogen enhances AF-triggering activity by increasing ICaL and NCX activity. Liang et al. 33 also found that estrogen prolongs the APD of the atrium and promotes AF by reducing the double-pore potassium channel (TASK-1) in the atrium. Although this finding was consistent with those of previous studies 21,34,35 , some studies still reported inconsistent results. A study based on the general Japanese population found an independent association between SUA and AF in both sexes 36 , and several other studies also reported similar results 37,38 . The gender-specific association between SUA levels and paroxysmal AF remains controversial, and more evidence is needed to confirm this relationship and the underlying mechanisms in the future.
Additionally, we further explored the correlation between SUA levels and paroxysmal AF-related metabolic factors. As far as we know, this is the first study to systematically investigate the relationship between SUA levels and metabolic factors in a paroxysmal AF population. The results of Pearson correlation analysis indicated that SUA levels were negatively correlated with HDL-C and APOA1, and were positively correlated with LDL-C and PAB. There are several possible reasons for the current results. First, it has been demonstrated that ApoA1 levels of paroxysmal AF patients decreased significantly 39 ; Second, the anti-inflammatory and antioxidant properties of HDL-C and APOA1 may prevent the formation of the AF matrix and risk factors [40][41][42] ; Third, it more and more appeared that abnormal levels of LDL-C might increase the risk of incident AF 43,44 ; In addition, lower serum PAB are associated with inflammatory status, impaired cardiac function, and cardiovascular risk 45,46 , and it has been found in the AF patients 47 . Nevertheless, we did not observe the association between SUA levels and metabolic indicators in women with paroxysmal AF. Certainly, it is essential to further confirm these relationships and explore their potential mechanisms.
The current study had several obvious limitations that deserve mention. First, the retrospective case-control design couldn't determine the causality between SUA levels and paroxysmal AF pathology. Therefore, it is essential to confirm the results in prospective cohort studies. Second, smaller sample size was limited to patients visiting a single hospital in China, the results can't be extrapolated to the general population. Thus, large-sample and multi-center population studies are needed in the future. Third, we didn't investigate the age-related association between SUA levels and paroxysmal AF. Fourth, due to the limited sample size, we failed to match more relevant factors, such as comorbidities, medications, etc. Additionally, several potential confounding factors such as inflammation and oxidative stress state should also be considered. Nevertheless, this study did provide a new perspective to better understand the pathologic mechanisms of paroxysmal AF. Further prospective studies are needed to confirm the current results and age-specific association between SUA levels and paroxysmal AF.

Conclusion
In conclusion, we reported herein that elevated SUA in female patients was significantly associated with paroxysmal AF. Current findings proposed the hypothesis that elevated SUA might be a significant serum marker involved in the pathologic progression of paroxysmal AF along with several metabolic factors. Further rigorous investigations were needed to confirm these findings and explore the potential mechanisms.

Data availability
The datasets are not publicly available due to them containing information that could compromise research participant privacy, but the minimal data are available from the corresponding author on reasonable request.