Correlation Between Carotid Intima Media Thickness and Serum Uric Acid, Results From 15843 Subjects in 2016-2020

Objective: Uric acid is thought to be associated with the occurrence of atherosclerosis, which is closely related to cardio-cerebrovascular disease. However, the present study examined serum uric acid (SUA) and its correlation with carotid intima-media thickness (CIMT), which is a major issue. The purpose of this paper is to examine serum uric acid concentration and its correlation with carotid artery atherosclerosis according to age and sex groups. Methods: Individuals who underwent physical examinations at the First Aliated Hospital of Chongqing Medical University from 2016 to 2020 were selected. The physical examination information of the subjects was recorded, and biochemical indexes such as blood uric acid levels were collected. The intima media thickness of the carotid artery was measured by ultrasound. Using traditional atherosclerosis risk factors as adjustment variables, the association between blood uric acid levels and atherosclerosis was assessed by logistic regression analysis. Results: A total of 15,843 subjects (73.90% male) were included, with an average age of 52±12 (20-92) years. The prevalence of CIMT thickened was 9.51%, and the plaque prevalence was 28.59%. Univariate analysis results showed that there were signicant differences in CIMT thickening and plaque occurrence among different SUA level groups in both men and women (P<0.0001). After adjustment for conventional cardiovascular risk factors, increased SUA levels were signicantly associated with an increased risk of CIMT thickening (male: ≤ 220 μmol/L as the reference group, 220-290 μmol/L: OR=1.591, 95% CI: 1.069-2.367; 290-360 μmol/L: OR=1.65, 95% CI: 1.127-2.415;360-430 μmol/L: OR=1.634, 95% CI: 1.116-2.393; >430 μmol/L: OR=1.857, 95% CI: 1.264-2.73;P < 0.05. female: ≤ 210 μmol/L as the reference group, 260-310 μmol/L: OR=1.419, 95% CI: 1.059-1.901; 310-360 μmol/L: OR=1.432, 95% CI: 1.048-1.957; >360 μmol/L: OR=1.557, 95% CI: 1.113-2.177; P < 0.05). Correlation analysis in each age subgroup showed that CIMT was signicantly associated with SUA in men ≥ 60 years old and women 45-60 years old and ≥ 60 years old (male: ≤ 220 μmol/L as the reference group, >430 μmol/L: OR=1.972, 95% CI: [1.2,3.238]. female: ≤ 210 μmol/L as the reference group, >360 μmol/L (45-60 years old): OR=1.77, 95% CI:[1.107,2.832]; > 360 μmol/L ( ≥ 60 years old), OR = 1.65, 95% CI: [1.067, 2.551]. P < 0.05). Conclusions: In both men and women, increased SUA levels are closely associated with thickened CIMT, which is associated with a higher risk of cardio-cerebrovascular disease. The age at which this association was observed in women was lower than in men, and whether this result is due to changes in hormone levels before and after menopause remains to be prospectively studied. of cardiovascular events. This relationship may be strengthened with increasing age, and the degree of association in the female population is greater than that in the male population.


Introduction
In recent years, with the improvement of people's living standards and changes in the diet, the incidence of atherosclerosis has shown an increasing trend each year and has begun to occur in increasingly younger individuals, resulting in higher mortality worldwide [1]. Atherosclerosis is a result of lipid metabolic disorders when fat lesions form on the arterial wall lining, and thickening and hardening of the arterial wall and narrowing of the vascular lumen are the main causes of cardio-cerebrovascular disease [2,3]. Carotid intima thickness has been suggested to be a marker of atherosclerosis sensitivity and has been increasingly used as a proxy indicator for atherosclerosis [4,5]. Several studies have shown that increased carotid intima thickness is closely associated with plaque occurrence and an increased risk of future cardio-cerebrovascular disease (including stroke and coronary heart disease) [6,7]. was de ned as waist circumference ≥ 90 cm in men and ≥ 85 cm in women [20]. The systolic blood pressure and diastolic blood pressure (SBP and DBP, respectively) were measured by two highly trained nurses at 8 to 10 a.m., and the average of the six measurements was taken as the nal value. Adult hypertension was de ned as SBP/DBP ≥ 140/90 mm Hg or use of antihypertensive drugs [21]. Creatinine, fasting blood glucose, HDL-C, LDL-C, hemoglobin, mean platelet volume, globulin, total cholesterol, triglycerides, alanine transaminase, glutamic-oxalacetic transaminase, glutamyltransferase, urea and urine pH indexes were measured in strict accordance with the standard procedures by the automatic biochemical instrument laboratory of the First A liated Hospital of Chongqing Medical University. The laboratory has obtained ISO15189 standard certi cation. Blood uric acid was measured by the Roche C701 uricase colorimetric method. The source of the SUA reference interval was obtained from the reagent manufacturer's instructions and approved by clinical veri cation.

Ultrasound examination of carotid intima media thickness
The intima media thickness of the common carotid artery was measured by Toshiba Aplio 500 color Doppler ultrasonography. The vertical distance between the upper endometrial margin and the upper endometrial margin was measured at the distal common carotid artery (1.0-1.5 cm below the level of bifurcation) and the carotid bulb (where the initial segment of the internal carotid artery was relatively enlarged). Normal was de ned as IMT < 1.0 mm, and thickened was de ned as 1.0 mm ≤ IMT < 1.5 mm. A plaque was de ned as a focal structure invading the arterial lumen greater than 50% of the peripheral IMT value or IMT ≥ 1.5 mm [22].

Covariable selection
By consulting experts in the eld of cardiovascular and cerebrovascular diseases and referring to relevant information, 51 factors that may be related to atherosclerosis were selected. Combined with our data, 26 variables were retained, and 20 covariates were nally included after variables with more than 30% missing data were eliminated. The included factors were sex, age, BMI, central obesity, hypertension, pulse, creatinine(Cre), fasting blood glucose(FBG), HDL-C, LDL-C, hemoglobin, mean platelet volume(MPV), globulin, total cholesterol(TC), triglycerides(TG), Aspartate aminotransferase(AST), glutamate pyruvic transa(ALT), gamma-glutamyltransferase(GGT), SUA, and urine pH.

Statistical analysis
Categorical variables are presented as frequencies (relative frequencies), while continuous variables are presented as the mean ± standard deviation. The Wilcoxon rank sum test was used to compare the rates of each variable between the normal, thickened and plaque groups, and P < 0.05 was considered to be statistically signi cant. The reference intervals of all physical examination variables were in accordance with the physical examination standards of the First A liated Hospital of Chongqing Medical University (Appendix 1). SUA was divided into categories. Since the critical value of hyperuricemia was 428 µmol/L for males and 357 µmol/L for females, after rounding up, > 430 µmol/L and > 360 µmol/L were used as the highest SUA levels in the male and female groups, respectively, and the group intervals were 70 µmol/L for males and 50 µmol/L for females. The population was divided into ve groups according to the serum

CIMT thickened and plaque prevalence in males and females
A total of 15,843 persons (73.90% male, mean age 52 ± 12 (20-92)) who met the inclusion and exclusion criteria were selected. According to the classi cation standard of carotid intima media thickness, 61.90% of the people had normal CIMT. Thickened was found in 9.51% of the participants, and the plaque prevalence was 28.59%. The prevalence of CIMT thickened and plaque in the male population was higher than that in the female population (P < 0.0001), and the speci c proportion distribution is shown in Fig. 1. Table 1 shows the distribution of various variables in the normal, thickened and plaque groups of CIMT in different male and female populations. With increasing age, the incidence of thickened and plaque in CIMT gradually increased. The thickened rate of CIMT in patients with central obesity and hypertension was signi cantly higher than that in patients without central obesity and hypertension. Univariate analysis showed that age, BMI, central obesity, hypertension, FBG, urine pH, TC, TG, LDL-C, hemoglobin, AST, ALT, urea, Cre, and SUA had signi cant effects on CIMT in the male population. In the female population, the variables that had a signi cant in uence on CIMT were age, BMI, central obesity, hypertension, pulse, FBG, urine pH, TC, TG, HDL-C, LDL-C, hemoglobin, ALT, GGT, urea, Cre, and SUA. (2) "a" represents the Kruskal-Wallis rank sum test.

Correlation between serum uric acid and carotid intima media thickness
The correlation analysis results of SUA and CIMT are shown in Fig. 2. Since sex had a signi cant effect on the correlation between the two, males and females were analyzed separately. The results showed that in the male population, the risk of CIMT thickening was not signi cantly different in the group with higher SUA compared to the group with the lowest in the unadjusted Model 1. However, after adjusting for age (Model 2) and for age, BMI, central obesity, and hypertension (Model 3), the risk of CIMT thickening was signi cantly increased in the group with higher SUA levels. After adjustment for all risk factors, the risk of CIMT thickening increased signi cantly with the increase in SUA level (≤ 220 µmol/L as the reference group, 220-290 µmol/L: OR = 1.591, 95% CI:

Strati ed analysis according to age
The overall analysis showed that the relationship between SUA and CIMT tended to be stable after age was included in the model (Model 2, Model 3, and Model 4) (Fig. 2). Obviously, age had a signi cant in uence on the correlation between SUA and CIMT, so we further analyzed the correlation between these variables in each age group. The result is shown in Fig. 3. We found no association between SUA and CIMT in male and female aged 18-45 years. In male ≥ 60 years old, an increase in SUA concentration signi cantly increased the risk of CIMT thickening (≤ 220 µmol/L as the reference group, > 430 µmol/L: OR = 1.972, 95% CI:[1.2,3.238];P < 0.05) (Fig. 3 Male). There was a signi cant correlation between SUA and CIMT in female aged 45-60 years and ≥ 60 years (≤ affected by atherosclerosis. With increasing age, the function of the human body declines, and the effect of uric acid in the human body also changes, which may be the reason for the occurrence of this result. It has been reported that serum uric acid levels are higher in postmenopausal women than in premenopausal women [42,43]. Our study shows that SUA exhibits an association with CIMT at a younger age in females than in men, menopause may play a role in uric acid's effect in the body perhaps due to female hormone level changes before and after menopause [44].
This study aimed to explore the relationship between SUA and CIMT. The main limitations of this study are as follows: rst, due to the limitations of physical examination data, all risk factors for atherosclerosis, such as smoking, drinking and disease history, were not included in the multifactor regression model, which may introduce some bias to the results. Second, although our study concluded that serum uric acid levels were associated with carotid intima thickness, the cross-sectional nature of the study makes it impossible to elucidate a cause-effect relationship. Third, our study was single centered, and the participants were all Chinese, so the applicability of the ndings to other ethnic groups may be limited. Fourth, since female hormone levels were not included in the physical examination data, the differences between male and female results in terms of age could not be further explored. We will conduct prospective studies in this regard in the future. Despite these limitations, we believe that the conclusion of this study provides theoretical support for further clinical studies and have important implications for the clinical prevention and treatment of carotid atherosclerosis.

Conclusion
In summary, in this study, we explored the correlation between SUA and CIMT in detail by gender and age and found that after adjusting for traditional cardiovascular risk factors, both men and women with high uric acid had a signi cantly increased risk of CIMT thickening and plaque. In the subgroup analysis by age, a signi cant association was found only in men ≥ 60 years and women 45-60 and ≥ 60 years. It is suggested that uric acid is closely related to the occurrence and development of carotid atherosclerosis, which may be a cause of cardiovascular events. This relationship may be strengthened with increasing age, and the degree of association in the female population is greater than that in the male population. Ethics approval and consent to participate Since our study used physical examination data in hospital, this study was exempt from ethical approval from Chongqing Medical University Institutional Review Board. The requirement for informed consent was waived as the database was constructed after anonymization according to strict con dentiality guidelines.

Figure 1
Normal, thickened and plaque incidence of CIMT in males and females  Forest map of correlation analysis strati ed by age Notes: (1) There were too few males 18-45 years old with a level ≤220 μmol/L, so this population was combined with the 220-290 μmol/L population. (2) There were too few females 18-45 years old with a level ≤210 μmol/L, so this population was combined with the 210-260 μmol/L population.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. Appendix1.docx