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12 May 2022: Clinical Research  

Retrospective Study from a Single Center to Evaluate the Association Between Sex and Serum Uric Acid Levels in 950 Patients with Atrial Fibrillation

Xia Zhong1ABCE, Huachen Jiao2BDFG*, Dongsheng Zhao1BCD, Jing Teng1ADF

DOI: 10.12659/MSM.935273

Med Sci Monit 2022; 28:e935273

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Abstract

BACKGROUND: The association between patients’ serum uric acid (SUA) levels and sex in atrial fibrillation (AF) remains controversial. This retrospective study from a single center in China aimed to evaluate the association between sex and SUA levels in 950 patients with AF.

MATERIAL AND METHODS: We retrospectively analyzed clinical information of 1913 consecutive hospitalized patients (male/female: 949/964, 68.26±11.02 years). The sample of 950 patients with AF served as the AF group and 963 age- and sex-matched patients without AF with sinus rhythm served as controls. The uricase method was used to determine SUA levels. The analysis of variance, t test, and chi-squared test were performed to analyze clinical baseline data. Pearson correlation analysis was performed to identify interrelationships and multivariate regression analysis was performed to determine the independent risk factor for AF.

RESULTS: SUA levels in the AF group were significantly higher in both sexes (P<0.05), especially for permanent AF. In patients with AF, SUA levels were positively correlated with serum creatinine (r=0.235, P<0.05) and prealbumin (r=0.129, P<0.05) and were negatively correlated with high-density lipoprotein cholesterol (r=-0.207, P<0.05) and apolipoprotein A1 (r=-0.167, P<0.05). SUA was independently associated with AF after adjusting for confounding factors (OR=1.244, 95% CI: 1.133-1.365, P<0.05).

CONCLUSIONS: In both sexes, increased SUA was significantly associated with AF. These findings supported the importance of monitoring SUA levels in patients with AF and other cardiac diseases.

Keywords: Accident Prevention, Atrial Fibrillation, Risk Factors, Sex Characteristics

Background

Atrial fibrillation (AF) is an increasingly common sustained arrhythmia, which currently affects 33 million people worldwide [1]. The prevalence and incidence of AF are increasing and are expected to increase further [2]. It is estimated that by 2050, the overall prevalence of AF will be triple the prevalence in 2006 [3]. AF significantly impacts patients’ cardiac performance and quality of life, leading to increased risk of heart failure, ischemic stroke, systemic embolism, and mortality [4–7]. Rate control, rhythm control, anti-arrhythmia drugs, electrical cardioversion, and catheter ablation are recommended as treatment strategies for clinical practice [8], but even with these treatments, there are still many AF hospitalizations. With the advent of the prevention era of AF, risk factor management has become a new paradigm in the treatment of AF [9]. Therefore, it is essential to investigate potential risk factors and establish prevention strategies.

Serum uric acid (SUA) is a surrogate marker of oxidative stress and also a byproduct of purine catabolism catalyzed by xanthine oxidoreductase [10,11]. There is growing evidence that inflammation and oxidative stress may contribute to the onset and progression of AF [12–14]. Meanwhile, previous findings have shown that an elevated SUA level is associated with the risk of AF [15–17], and the activation of inflammatory and oxidative stress pathways facilitated by xanthine oxidoreductase is an important factor in this process [18,19]. Nevertheless, from the clinical point of view, the relationship between SUA levels and AF may be influenced by clinical multiple confounding factors; in particular, stratification by sex can be an inconclusive measurement [10,20]. To clarify the complex association between SUA and AF, it is essential to conduct stratified studies of sex and AF type; however, few such studies have been done. Although several previous studies have reported that a sex-specific mechanism exists between SUA and AF [21,22], the results were not consistent. In our previous study with a small sample [23], we observed that elevated SUA levels in female patients were associated with AF, but the results need to be confirmed further.

Therefore, this retrospective study from a single center in China aimed to evaluate the association between SUA levels and AF by sex in 950 patients. We analyzed clinical information of 950 patients with AF and 963 age- and sex-matched patients without AF by appropriate statistical methods and investigated their SUA levels by the uricase method. In addition, we investigated the correlation between SUA levels and some related metabolic factors in patients with AF. We hypothesized that there was an association between sex and SUA levels in patients with AF.

Material and Methods

STUDY DESIGN:

The study was performed according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee on Medical Research of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine prior to data collection. Patient informed consent was waived. This study used a retrospective design to assess 1913 consecutive hospitalized patients (male/female: 949/964, 68.26±11.02 years) from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine between January 2019 and September 2021.

Considering the significant influence of age and sex on the study population, we matched the AF group and the control group by age and sex. A total of 950 patients with AF aged 28 to 85 years, and 963 age- and sex-matched patients without AF with sinus rhythm served as controls. AF was diagnosed in patients by skilled hospital physicians. Patients with self-described AF were not included. We included patients with both paroxysmal AF and permanent AF who had complete clinical information. In addition, we excluded patients with heart failure, valvular disease, cardiac surgery, hyperthyroidism, liver and kidney dysfunction, malignancy, use of uric acid-lowering drugs, diuretics, and allopurinol, and pregnant women. We collected and analyzed baseline characteristics of participants, including age, sex, laboratory data, subtypes of AF, and complications of AF, such as hypertension, coronary heart disease (CHD), and diabetes, from an electronic medical record review. Meanwhile, all the patients with AF were stratified by sex and SUA levels.

DEFINITION OF AF:

According to guidelines [24], AF was defined as an arrhythmia lasting long enough for a 12-lead electrocardiogram to be recorded, or lasting for at least 30 s. Specifically, paroxysmal AF was considered to be AF that terminated spontaneously or with intervention within 7 days of initiation. Permanent AF was specifically defined as AF with a sinus rhythm that could not be further restored or maintained.

MEASUREMENT OF SUA LEVELS AND DEFINITION OF HYPERURICEMIA:

Hematological and biochemical analyses were performed in the Shandong University of Traditional Chinese Medicine Hospital, where we have a group of examination physicians and standard inspection equipment that produce accurate and reliable examination data. The uricase method was used to determine SUA levels [25]. The conversion standard of SUA levels was as follows: 1 mg/dL=59.48 μmol/L. Hyperuricemia was identified if SUA levels >7.0 mg/dL in men and 5.0 mg/dL in women [26].

SCREENED INDICATORS:

We screened the following basic indicators of all participants: sex, age, AF subtypes, and AF complications, including hypertension, CHD, and diabetes; and the following biochemical indicators: serum creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum apolipoprotein A1 (APOA1), APOB (serum apolipoprotein B), albumin (ALB), prealbumin (PAB), lipoprotein (a) (Lp [a]), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C).

STATISTICAL ANALYSIS:

SPSS software (version 26.0; IBM Corp, Armonk, NY, USA) and GraphPad Prism software (version 9.0.0) were used for statistical analyses. Continuous variables were expressed as mean±standard deviation and compared by analysis of variance (ANOVA) or the t test. Categorical variables were presented as percentages and compared using chi-squared analysis. Pearson correlation analysis was performed to identify interrelationships between SUA and metabolic factors. In addition, multivariate regression analysis was performed to determine the independent risk factors for AF, and subgroup analysis was performed to determine the relationship between different levels of SUA and metabolic factors in patients with paroxysmal AF and permanent AF. The statistical tests were 2-sided and a P value <0.05 was considered significant.

Results

BASELINE AND CLINICAL CHARACTERISTICS:

Table 1 shows the baseline and clinical characteristics of the AF group and control group. A total of 1913 patients were enrolled into the 2 groups: AF group (n=950) and control group (n=963). Compared with controls, patients with AF were more likely to have hypertension, CHD, diabetes, and hyperuricemia (P<0.05); significantly higher levels of serum creatinine, AST, ALT, and SUA; and significantly lower levels of APOA1, APOB, ALB, PAB, TG, TC, LDL-C, and HDL-C. Figure 1 shows the comparison of SUA levels between the AF group and the control group by sex. Overall, SUA levels of AF patients were significantly higher in men and women (P<0.05). Furthermore, the SUA levels of patients with permanent AF were significantly higher than the SUA levels of patients with paroxysmal AF (P<0.05).

ASSOCIATED FACTORS OF SUA LEVELS IN PATIENTS WITH AF:

Figure 2 shows the correlation between SUA levels and AF influencing factors. In patients with AF, the results indicated that SUA levels were positively correlated with serum creatinine (r=0.235, P<0.05, Figure 2C) and PAB (r=0.129, P<0.05; Figure 2D) and were negatively correlated with HDL-C (r=−0.207, P<0.05; Figure 2A) and APOA1 (r=−0.167, P<0.05; Figure 2B).

ASSOCIATION BETWEEN SUA AND AF:

The above results showed that elevated lipid profiles (TG, TC, LDL-C, HDL-C, APOA1, APOB) and lower serum creatinine, AST, and ALT were noted in the control group, and after being analyzed for these contributions, separate models were created. Table 2 shows the relationship between SUA and AF by logistic regression analysis. We adjusted for all factors and found that SUA remained an important relevant indicator of AF (OR=1.244, 95% CI: 1.133–1.365, P<0.05). Furthermore, the independent association was significant in both men and women (P<0.05).

ASSOCIATION BETWEEN LEVELS OF SUA AND AF BY SUBTYPE AND COMPLICATIONS:

As shown in Table 3, compared with the SUA levels of the paroxysmal AF group, the levels of the permanent AF group were significantly elevated (5.52±1.98 vs 5.81±1.86, P<0.05). However, no significant differences in SUA levels between AF complications, including hypertension, CHD, and diabetes, were observed (P>0.05).

ASSOCIATION BETWEEN LEVELS OF SUA AND METABOLIC FACTORS IN PATIENTS WITH PAROXYSMAL AF:

As shown in Table 4, higher SUA levels were associated with higher serum creatinine in male and female patients with paroxysmal AF (P<0.05). Meanwhile, higher SUA levels were associated with higher ALB, PAB, TG, TC, and LDL-C in male patients with paroxysmal AF (P<0.05).

ASSOCIATION BETWEEN LEVELS OF SUA AND METABOLIC FACTORS IN PATIENTS WITH PERMANENT AF:

As shown in Table 5, higher SUA levels were associated with lower APOA1 and HDL-C and higher PAB in male and female patients with permanent AF (P<0.05). Meanwhile, higher SUA levels were associated with lower APOB, TC, and LDL-C in male patients with permanent AF (P<0.05). In addition, higher SUA levels were associated with higher serum creatinine and TG in female patients with permanent AF (P<0.05).

Discussion

This retrospective study evaluated the association between sex and SUA levels in 950 patients with AF from China. The findings showed that elevated SUA levels were significantly associated with AF in both sexes. Elevated SUA was positively correlated with serum creatinine and PAB and negatively correlated with HDL-C and APOA1. In addition, it showed a different relationship between SUA levels and metabolic factors in patients with paroxysmal AF and permanent AF.

The present results suggested that elevated SUA levels were associated with AF, and the SUA levels of patients with permanent AF were significantly elevated compared with those in patients with paroxysmal AF. To the best of our knowledge, few studies have reported the relationship between SUA levels and subtypes of AF. An earlier study based on 45 patients with paroxysmal AF, 41 patients with permanent AF, and 48 control participants reported that increased SUA was associated with permanent AF [27]. Another meta-analysis suggested that SUA levels were significantly different among participants with new-onset, paroxysmal, and persistent AF [28]. These findings were not in disagreement with the results of the present study. The correlation between hyperuricemia and risk of AF has been well established. In fact, the association between SUA and AF is complex and can be confused by causality. Moreover, the specific mechanism of SUA in the occurrence and maintenance of AF remains unclear. Conceptually, this underlying mechanism may be responsible for the activation of inflammatory and xanthine stress pathways facilitated by xanthine oxidoreductase [29–31]. Left atrial remodeling due to hyperuricemia may also be an important risk factor for AF [32]. Studies have shown that elevated SUA levels mediate the formation of free radical superoxide anion and xanthine stress promotes left atrial remodeling [33,34]. There is evidence suggesting that SUA may also be involved in the release of pro-inflammatory cytokines and the activation of the renin-angiotensin system [35,36]. Additionally, intracellular UA can increase the protein levels and channel currents of atrial Kv1.5, which can shorten the atrial refractory period to promote the development of a reentry circuit that promotes AF [37]. Certainly, further studies are needed to confirm this relationship and the potential mechanisms.

In general, women’s SUA levels are lower than men’s for life because of the effects of estrogen [38,39]. Although the sex-specific mechanism between SUA and AF has been confirmed, the findings remain controversial. Several previous studies showed that increased SUA levels are significantly associated with a greater risk of AF only in women [40–44]. Nevertheless, other previous studies indicated that elevated SUA was significantly associated with the increased risk of AF in both sexes [11,41,45,46]. In the present study, our results showed that increased SUA levels were independently associated with AF in both sexes, after adjusting for confounding factors. This is consistent with previous studies. Interestingly, to the best of our knowledge, there is no evidence to support that elevated SUA levels are associated with AF in men. Obviously, further studies are needed to investigate the potential influence and specific mechanism of sex on the association between SUA and AF.

Additionally, several studies have shown that complications such as hypertension, heart failure, coronary heart disease, diabetes, and chronic obstructive pulmonary disease are closely related to AF [47]. Aging, obesity, alcohol consumption, hypertension, diabetes, heart failure, myocardial infarction, valvular heart disease, obstructive sleep apnea, and hyperthyroidism are currently known risk factors for AF [48–52]. As expected, these factors are likely to influence our observations as confounding factors. In the current study, we tried to adjust for possible confounding factors, including sex, hypertension, CHD, diabetes, serum creatinine, AST, ALT, ALB, APOA1, APOB, ALB, and PAB, as well as for TG, TC, LDL-C, and HDL-C. We observed that SUA levels remained independently associated with AF in both men and women. Meanwhile, we observed no significant difference in SUA levels among the comorbidities of patients with AF. This result may be related to the characteristics of the included population, and further studies are needed to confirm our conclusions.

Importantly, some confounding factors associated with SUA deserve attention. Previous studies have suggested that SUA levels may be susceptible to age, sex, race, cardiovascular disease comorbidities, medications, body mass index, creatinine, cholesterol level, alcohol use, and diet [53–57]. Moreover, elevated SUA levels are associated with multiple cardiovascular diseases, diabetes, and all-cause mortality [58–60]. It is well established that SUA as a metabolic indicator is also closely associated with other metabolic factors. In our study, we mainly investigated the relationship between metabolic factors and SUA in patients with AF. Our results indicated that elevated SUA was positively correlated with serum creatinine and PAB and negatively correlated with HDL-C and APOA1. Creatinine has been reported as a major predictor of AF [61]. Low PAB has been shown to be an important risk factor for cardiovascular risk, associated with inflammatory states and impaired cardiac function [62,63]. ApoA1 and HDL-C play an important role in anti-atherosclerotic, anti-inflammatory, and anti-oxidative aspects [64–66]. In addition, we investigated the relationship between SUA and metabolic factors in men and women with paroxysmal AF and permanent AF. Specifically, we observed a different relationship between SUA levels and metabolic factors in paroxysmal AF and permanent AF. Both men and women with paroxysmal AF and elevated SUA levels had higher serum creatinine, and we observed that men had higher levels of ALB, PAB, TG, TC, and LDL-C. In addition, patients with permanent AF and elevated SUA levels had lower levels of APOA1 and HDL-C and higher levels of PAB in both men and women. Meanwhile, lower levels of APOB, TC, and LDL-C were observed in men, and higher levels of serum creatinine and TG were observed in women. Further studies are needed to confirm this result.

Here, we conducted a retrospective case-control study to mainly investigate the potential association between SUA levels and AF by sex. Importantly, we also investigated the relationship between SUA levels and other clinical parameters in patients with AF. To the best of our knowledge, limited research has been conducted in this regard. Compared to our previous study [23], the current study had a larger study population, and we divided AF patients into subtypes, including paroxysmal AF and permanent AF to explore the association between levels of SUA and metabolic factors. Both studies implied a relationship between elevated SUA and AF; however, the association in previous studies was found only in women. The heterogeneous population caused by the different proportion of patients with paroxysmal AF and permanent AF was a possible reason. Therefore, it would be interesting to investigate the association between SUA levels and AF by subtypes in the future.

This study had several potential limitations. First, the study was limited by its single-center and retrospective nature. All patient information came from the electronic medical record system of a tertiary hospital. Therefore, the study cannot support the causalities between SUA and AF. Second, the smaller sample sizes should be considered. Third, we did not involve patients with all types of AF; patients with persistent AF and asymptomatic AF were excluded. Fourth, some potential confounding factors should still be considered, such as body mass index and markers of inflammation and oxidative stress, which may have interfered with the results. Finally, there was design bias with the study having been based on limited matching factors. Here, our results were supported by those of a previous study reporting that SUA was associated with AF, but differed from earlier studies evaluating sex relationships. We hypothesized that this difference may be related to demographic characteristics, research methods, and potential confounding factors. However, it did provide us a new perspective to find the pathological mechanism of AF. It is essential to conduct relevant prospective studies in the future.

Conclusions

In conclusion, we performed a retrospective study from a single center to evaluate the association between sex and SUA levels in 950 patients with AF. We observed that in both sexes, increased SUA was significantly associated with AF. These findings support the importance of monitoring SUA levels in patients with AF and other cardiovascular diseases.

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750