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From the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine (N.I., R.N.), and Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital (Y.I., E-I.T., M.Y.), Tokyo, Japan.
Correspondence to Dr Nobukazu Ishizaka, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky@umin.ac.jp
Abstract
Objective— There are few data available on possible independent association between uric acid and carotid atherosclerosis. Here we first sought to investigate association between uric acid levels and metabolic syndrome in Japanese; second, we assessed whether there is an independent association of uric acid with prevalence of carotid atherosclerosis in individuals subdivided according to gender and metabolic syndrome status.
Methods and Results— Cross-sectional data from 8144 individuals who underwent general health screening were analyzed. After adjusting for age, total cholesterol, and smoking status, the odds ratios (95% CI) of sex-specific quartiles of serum uric acid for metabolic syndrome were 1.0, 1.06 (0.60 to 1.87), 2.18 (1.30 to 3.64), and 4.17 (2.56 to 6.79) in women, and 1.0, 0.92 (0.74 to 1.14), 1.52 (1.25 to 1.65), and 1.97 (1.61 to 2.40) in men. After adjusting for age, serum levels, total cholesterol, and smoking status, prevalence of carotid plaque was higher in subjects in the second, third, and fourth quartiles of uric acid level with odds ratios (95% CI) of 1.24 (1.01 to 1.52), 1.37 (1.11 to 1.68), and 1.31 (1.05 to 1.63), respectively, in men without metabolic syndrome but not in men with metabolic syndrome or in women with or without metabolic syndrome.
Conclusion— The prevalence of metabolic syndrome showed a graded increase according to serum uric acid values in both genders. In men who did not have metabolic syndrome, uric acid was found to be an independent risk factor for incidence of carotid plaque.
Whether there is an independent association of uric acid with prevalence of carotid atherosclerosis was analyzed. Serum uric acid values are associated with carotid plaque independently of other atherogenic risk factors in men without but not with metabolic syndrome or in women at all.
Key Words: metabolic syndrome ? carotid atherosclerosis ? ultrasonography ? insulin resistance ? multivariate analysis
Introduction
Previous epidemiological studies have suggested that hyperuricemia may be a risk factor for cardiovascular diseases.1–3 Possible explanations for this link may include elevation of uric acid, a natural antioxidant4,5 as a defense mechanism against advanced atherosclerosis,6 or hyperuricemia-induced endothelial dysfunction7 and facilitation of smooth muscle cell proliferation.8 However, on the other hand, many studies argue that the observed association between uric acid and atherosclerosis is attributable to an indirect association of hyperuricemia with cardiovascular risk factors9 or clustering of these metabolic and hemodynamic risk factors, designated "metabolic syndrome."10,11
Although many studies have focused on the presence or absence of an independent relationship between uric acid and coronary and cerebrovascular artery diseases,12–14 thus far, few have examined the independence of the relationship between serum uric acid and carotid atherosclerosis.15,16 To this end, the current study had 2 goals: first, to investigate the association between uric acid levels and metabolic syndrome in individuals undergoing general health screening; and second, to assess whether there was an independent association of uric acid with the prevalence of carotid plaque in individuals with or without metabolic syndrome after adjusting for other confounding risk factors for atherosclerosis. In addition, we also investigated associations between bilirubin, metabolic syndrome, and carotid atherosclerosis because bilirubin also possesses antioxidant properties.17
Methods
Study Subjects
The study was approved by the ethical committee of Mitsui Memorial Hospital. Between September 1994 and December 2003, 8144 subjects underwent general health screening, including carotid ultrasonography and measurements of other metabolic markers necessary to assess the presence or absence of metabolic syndrome, at the Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital. In Japan, regular health check-ups for employees are legally mandated; thus, the majority of these subjects did not have serious health problems. In addition, all or most of the costs of the screening are usually paid by the company to which they belong or by each subject. Individuals who reported current use of antihypertensive or antidiabetic medications were included in the current study. Of the 8144 subjects, the data of basal insulin levels were available for 6339 (2026 women and 4313 men), and the homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) was calculated according to the following formula: HOMA-IR=[fasting immunoreactive insulin (μU/mL)xfasting plasma glucose (mg/dL)]/405.18 HOMA has been validated previously and used in cross-sectional population studies19 such as the current one. Blood samples were taken from subjects who had fasted overnight. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides were determined enzymatically. Serum uric acid was measured by the Uricase-Peroxidase method, and hemoglobin A1C was determined using the latex agglutination immunoassay. Serum total bilirubin levels were measured by the bilirubin oxidase method.
The mean uric acid level was found to be significantly lower in women (4.7±1.0 mg/dL) than in men (6.2±1.2 mg/dL; P<0.0001). Therefore, sex-specific quartiles of serum uric acid were used. The median (range) uric acid values of 3.6 (0.8 to 3.9), 4.3 (4.0 to 4.6), 5.0 (4.7 to 5.3), and 5.8 (5.4 to 8.9) mg/L were used for women, and 4.8 (0.7 to 5.3), 5.8 (5.4 to 6.1), 6.6 (6.2 to 7.0), and 7.6 (7.1 to 11.0) mg/L were used for men (Table 1).
TABLE 1. Baseline Characteristics of Study Subjects
Carotid Ultrasonography
Carotid artery status was studied and analyzed as described previously.10 In brief, this was examined by high-resolution B-mode ultrasonography using a machine (Sonolayer SSA270A; Toshiba) equipped with a 7.5-MHz transducer (PLF-703ST; Toshiba). The carotid arteries were examined bilaterally at the levels of the common carotid, the bifurcation, and the internal carotid arteries from transverse and longitudinal orientations by trained sonographers. The intima-media thickness was measured using a computer-assisted method by experienced sonographers who were unaware of the subjects’ clinical and laboratory findings. Plaque was defined as a clearly isolated focal thickening of the intima-media layer with thickness of 1.3 mm at the common or internal carotid artery or the carotid bulb. Carotid intima-media wall thickening was said to occur when the intima-media thickness, which was measured at the far wall of the distal 10 mm of the common carotid artery, was 1.0 mm.
Criteria for Metabolic Syndrome
Diagnosis of metabolic syndrome was made according to the criteria of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III),20 with body mass index (BMI) used as a surrogate for waist circumference, as has been done in previous other studies, because waist circumference was not available in this study sample. The 5 thresholds used were: (1) triglyceride levels 150 mg/dL; (2) HDL-C levels <40 mg/dL in men or <50 mg/dL in women; (3) fasting plasma glucose levels 110 mg/dL or taking an antidiabetic medication; (4) systolic blood pressure 130 mm Hg or diastolic blood pressure 85 mm Hg or taking an antihypertensive medication; and (5) BMI >25 kg/m2. This BMI cutoff point was chosen instead of previously used values such as 30 kg/m221 because of the discrepancy in BMI between white and Japanese populations in terms of morbidity.22 Metabolic syndrome was diagnosed when 3 of these components were present.
Statistical Analysis
The data in this study were analyzed by the 2 test, ANOVA with a Bonferroni post hoc test, and multivariate logistic regression analysis using computer software StatView version 5.0 (SAS Institute). A value of P<0.05 was taken to be statistically significant. Results are expressed as the mean±SD unless stated otherwise.
Results
Baseline Characteristics
The age of the enrolled subjects ranged from 19 to 88 years (women, 22 to 87 years; men, 19 to 88 years), with a mean age of 56.6±10.5 years (women, 56.4±10.4 years; men, 56.7±10.6 years). BMI, systolic blood pressure, and triglycerides showed a graded increase and HDL-C showed a graded decrease according to the uric acid quartiles (Table 1). In men, the mean age in the second, third, or fourth quartile was lower than that in the first quartile (P<0.0001 for the second and third quartiles and P<0.0001 for the fourth quartile). In contrast, in women, the mean age in either the third or fourth quartile was greater than that in the first quartile (P<0.0001 for the third and fourth quartiles).
Pearson’s correlation coefficients for the relationship between uric acid and each variable were as follows (women/men): age, 0.22/–0.09; BMI, 0.24/0.21; systolic blood pressure, 0.22/0.11; diastolic blood pressure, 0.23/0.13; total bilirubin 0.00/–0.02; TC, 0.14/0.12; triglycerides, 0.19/0.19; HDL-C, –0.09/–0.10; plasma glucose, 0.08/–0.08; and hemoglobin A1C, 0.12/–0.09. A value of P<0.001 was obtained for all of these correlations except for total bilirubin in both genders (NS).
Relationship Between Uric Acid Levels, HOMA-IR, and Prevalence of Metabolic Syndrome
Correlation coefficients for the relationship between uric acid and HOMA-IR, which were available in 6339 subjects (2026 women and 4313 men), were 0.16 (P<0.0001) in women, and 0.09 (P<0.0001) in men. HOMA-IR values in the third and fourth quartiles were significantly higher than in the first quartile in both genders (Figure 1A). Similarly, the prevalence of metabolic syndrome showed a graded increase with uric acid quartiles in both genders (Figure 1B). Multivariate logistic regression analysis adjusted for age, TC, and smoking status showed that individuals in the third and fourth quartiles had a significantly greater prevalence of metabolic syndrome in both genders (Table 2). In this model, TC and former and current smoking were found to be independently associated with metabolic syndrome in men, and age, TC, and current smoking were found to be independently associated with metabolic syndrome in women. Odds ratios (95% CI) were as follows: in men, age (per 1 year), 1.00 (0.99 to 1.01), P=0.80; TC (per 1 mg/dL), 1.01 (1.00 to 1.01), P<0.0001; former smoking, 1.50 (1.25 to 1.80), P<0.0001; and current smoking, 2.02 (1.69 to 2.40), P<0.0001; and in women, age (per 1 year), 1.02 (1.00 to 1.03), P=0.037; TC (per 1 mg/dL), 1.00 (1.00 to 1.01), P=0.040; former smoking, 1.57(0.83 to 3.00), P=0.17; and current smoking, 2.10 (1.36 to 3.23), P=0.0007. When odds ratios were calculated per 1 mg/dL increase, uric acid level was found to be a risk factor for metabolic syndrome, with odds ratios of 1.71 (95% CI, 1.19 to 1.34; P<0.0001) in women and 1.26 (95% CI, 1.49 to 1.97; P<0.0001) in men, after adjusting for age, TC, and smoking status. When adjusted for age, serum TC levels, and smoking status, metabolic syndrome was found to be a statistically significant risk factor for carotid plaque, with odds ratios of 1.99 (95% CI, 1.39 to 2.85; P=0.0002) in women and 1.32 (95% CI, 1.13 to 1.55; P=0.0006) in men.
Figure 1. A, HOMA-IR of each gender according to the uric acid quartile (Q) and gender. B, Prevalence of metabolic syndrome according to the uric acid quartile and gender.
TABLE 2. Multivariate Analysis of the Association Between Uric Acid and Metabolic Syndrome
Relationship Between Uric Acid Levels and Carotid Plaque
When adjusted for age, serum TC levels, and smoking status, metabolic syndrome was found to be independently associated with carotid plaque, with odds ratios of 1.99 (95% CI, 1.39 to 2.85; P=0.0002) in women and 1.32 (95% CI, 1.13 to 1.55; P=0.0006) in men. As shown in Figure 2, the prevalence of carotid plaque in women was increased in the fourth quartile of uric acid, irrespective of the metabolic syndrome status. When multivariate analysis was performed after adjusting for age, TC, smoking status, and components of the metabolic syndrome (BMI, systolic blood pressure, HDL-C, triglycerides, and fasting glucose), the association between uric acid and carotid plaque was statistically significant in men but not in women (Table 3). In this model, odds ratios (95% CI) of other covariates were as follows: in men, age (per 1 year), 1.11(1.10 to 1.11), P<0.0001; TC (per 1 mg/dL), 1.00 (1.00 to 1.01), P=0.0003; former smoking, 1.39 (1.19 to 1.64), P<0.0001; current smoking, 1.51 (1.28 to 1.79), P<0.0001; BMI (per 1 kg/m2), 0.99 (0.97 to 1.02), P=0.54; systolic blood pressure (per 1 mm Hg), 1.01 (1.01 to 1.01), P<0.0001; HDL-C (per 1 mg/dL), 1.00 (0.99 to 1.00), P=0.35; triglycerides (per 1 mg/dL), 1.00, (CI 1.00 to 1.00), P=0.70; fasting glucose (per 1 mg/dL), and 1.00 (1.00 to 1.01), P=0.19; and in women, age (per 1 year), 1.10 (1.09 to 1.12), P<0.0001, TC (per 1 mg/dL), 1.00 (1.00 to 1.01), P=0.21; former smoking, 0.83 (0.46 to 1.50), P=0.54; current smoking, 1.43 (0.96 to 2.14), P=0.079; BMI (per 1 kg/m2), 0.99 (0.95 to 1.03), P=0.65; systolic blood pressure (per 1 mm Hg), 1.01 (1.01 to 1.02), P=0.0005; HDL-C (per 1 mg/dL), 1.00 (0.99 to 1.00), P=0.21; triglycerides (per 1 mg/dL), 1.00 (1.00 to 1.00), P=0.56; and fasting glucose (per 1 mg/dL), 1.01 (1.00 to 1.01), P=0.14. We also analyzed whether the highest quartiles of uric acid levels were associated with increased incidence of carotid plaque using combinations of lower (ie, first, second, and third) quartiles of uric acid as a reference and adjusted for the same covariates in women. The highest quartile of uric acid was found to be associated with carotid plaque, with an odds ratio of 1.45 (95% CI, 1.13 to 1.85; P=0.0033).
Figure 2. Prevalence of carotid plaque according to the uric acid quartile, gender, and metabolic syndrome (MetS). *P<0.05 vs the prevalence in the lowest quartile by 2 test.
TABLE 3. Multivariate Analysis of the Association Between Uric Acid and Carotid Plaque
Then, using the same covariates, multivariate analysis was performed to examine possible associations between uric acid and the incidence of carotid plaque after subdivision of the subjects according to metabolic syndrome status. Uric acid levels were found to be associated with the incidence of carotid plaque in men without metabolic syndrome but not in men with metabolic syndrome or in women with or without metabolic syndrome. When associations between uric acid and carotid plaque were calculated for incremental increases of 1 mg/dL uric acid using the same covariates, uric acid was found to be positively associated with carotid plaque in men without metabolic syndrome with an odds ratio of 1.07 (95% CI, 1.00 to 1.14; P=0.040), but again, not in men with metabolic syndrome or in women with or without metabolic syndrome (data not shown).
A similar analysis was then performed to assess possible associations between uric acid and carotid artery intima-media thickening. When subjects with or without metabolic syndrome were analyzed together, no statistically significant associations between uric acid and carotid intima-media wall thickening were found; odds ratios (95% CI) for the first, second, third, and fourth quartiles were 1.0 (reference), 0.88 (0.57 to 1.37), 0.86 (0.55 to 1.32), and 1.06 (0.70 to 1.61), respectively, in women, and 1.0 (reference), 1.01 (0.80 to 1.27), 1.00 (0.80 to 1.25), and 1.12 (0.89 to 1.43), respectively, in men after adjusting for age, TC, smoking status, BMI, systolic blood pressure, HDL-C, triglycerides, and fasting glucose. Even when individuals were subdivided according to metabolic syndrome status, the relationship was not found to be statistically significant in any of the subgroups (data not shown).
Association Between Serum Total Bilirubin, Metabolic Syndrome, and Carotid Plaque
We next assessed possible associations between serum total bilirubin level, metabolic syndrome, and carotid plaque. After adjusting for age, TC, and smoking status, total bilirubin level was found to be negatively associated with metabolic syndrome, with an odds ratio of 0.70 (95% CI, 0.56 to 0.88; P=0.0017; per 1 mg/dL increase) in men but not women (odds ratio, 0.89; 95% CI, 0.48 to 1.64; P=0.71; per 1 mg/dL increase). Total serum bilirubin level was negatively associated with carotid plaque in women and men, with odds ratios of 0.40 (95% CI, 0.24 to 0.67; P=0.0005; per 1 mg/dL increase) and 0.72 (95% CI, 0.59 to 0.89; P=0.0027; per 1 mg/dL increase), respectively, after adjusting for age, TC, smoking status, BMI, systolic blood pressure, HDL-C, triglycerides, and fasting glucose, which was in agreement with our previous report.23 After subdividing both genders according to metabolic syndrome status, a negative association between uric acid and carotid plaque was statistically significant in all subgroups: 0.50 (95% CI, 0.29 to 0.85; P=0.011; per 1 mg/dL increase) in women without metabolic syndrome, 0.06 (95% CI, 0.01 to 0.38; P=0.0030; per 1 mg/dL increase) in women with metabolic syndrome, 0.78 (95% CI, 0.62 to 0.98; P=0.034; per 1 mg/dL increase) in men without metabolic syndrome, and 0.54 (95% CI, 0.32 to 0.90; P=0.018; per 1 mg/dL increase) in men with metabolic syndrome after adjusting for age, TC, smoking status, BMI, systolic blood pressure, TC, HDL-C, triglycerides, and fasting glucose.
Discussion
We report 2 major findings from the present analysis of a large body of cross-sectional data. First, sex-specific uric acid quartiles are associated with metabolic syndrome, as defined by modified NCEP criteria. Second, uric acid values are associated with carotid plaque independently of other atherogenic risk factors in men without but not with metabolic syndrome or in women at all.
Although hyperuricemia is well recognized as a risk factor for atherosclerotic diseases such as myocardial infarction13 and stroke,24 the independence of this association from other confounding factors has remained controversial. This is mostly because serum uric acid is associated with other cardiovascular risk factors, such as hypertension25 and dyslipidemia.9 In the current study, we also found positive correlations between uric acid and BMI, blood pressure, and triglycerides, and a negative correlation between uric acid and HDL-C. It is also suggested that hyperuricemia is a marker for insulin resistance, an underlying condition of the metabolic syndrome, and that the association between hyperuricemia and cardiovascular disease may be secondary to this association.26 Interestingly, amelioration of insulin resistance by diet or insulin-sensitizing agent decreased the serum uric acid level,27 which may support the notion that hyperuricemia may be a part of insulin resistance syndrome.28 Because insulin resistance and metabolic syndrome are risk factors for carotid atherosclerosis,11 we may have to take these conditions into account when assessing the independence of the relationship between uric acid and atherosclerosis.
Several previous studies have analyzed possible associations between hyperuricemia and coronary heart disease and their independence. Although some studies reported a positive association between hyperuricemia and coronary heart disease,1–3 others did not.29,30 Most of the studies showing negative results advocated, as expected, that the association between uric acid and coronary heart disease is not truly independent, but it is dependent on other risk factors for coronary heart disease.29,30 On the other hand, it is possible that uric acid is an independent risk factor for coronary heart disease in some selected populations, such as alcohol abstainers.31 It has also been reported that the relationship between uric acid and coronary artery disease might be stronger in women, although independence of the association was not always assessed in these reports.3,32,33 Several other studies have investigated the association between uric acid and ischemic stroke24,34,35 and reported that this may be independent of other cardiovascular risk factors.35
On the other hand, only a few previous studies have investigated associations between serum uric acid and carotid atherosclerosis. Pan et al found no statistically significant relationship between uric acid and carotid plaque after adjusting for age and sex, but their study population was rather small (n=145).15 Possible associations between uric acid and carotid atherosclerosis have been most intensively analyzed in the Atherosclerosis Risk in Communities (ARIC) Study, which included >10 000 subjects. In that study, Iribarren et al showed that the association between uric acid and carotid atherosclerosis, assessed by the average intima-media thickness, was statistically significant in white men but not women after adjusting for age, BMI, waist-to-hip ratio, systolic blood pressure, fibrinogen, low-density lipoprotein cholesterol, HDL-C, and ARIC center.16 However, Iribarren et al also showed that this association was no longer statistically significant after further adjustments for diuretic use, alcohol intake, triglycerides, insulin, and renal function. They then concluded that the observed link between uric acid and carotid atherosclerosis is not truly independent.16
Some possible reasons why our conclusions differed from those of Iribarren et al are conceivable. First, we used carotid plaque as an indicator of carotid atherosclerosis, whereas they used carotid intima-media thickness. Carotid plaque has been reported to be more prevalent than intima-media thickening,36,37 which may indicate that the latter is not a premature or less severe lesion of carotid plaque. Therefore, it is possible that carotid plaque and intima-media thickening are associated with different risk factors. In fact, we failed to find a statistically significant association between uric acid and intima-media thickening in the current study. Second, they included alcohol intake as a covariate for the adjustment. The extent to which we should extend covariate factors to prove the independence of the association may be a matter of some dispute; however, the confounding effects of alcohol intake should be assessed in our study samples in future work.
We found that the association between uric acid and incidence of carotid plaque was significant in men but not in women (Table 3). We cannot determine the underlying mechanism to explain this gender difference from this type of study. However, the highest quartile of uric acid levels (5.4 to 8.9 mg/dL) was associated with carotid plaque in women compared with lower quartiles, and uric acid values in the lower 3 quartiles in women would all have been included in the lowest quartiles in men (5.3 mg/dL). These findings suggest that there may be a certain threshold for uric acid levels before proatherogenic properties become apparent, and this may not be dependent on the gender. This possibility requires further investigation in the future.
Because uric acid is also known to have antioxidant activity in the serum, its level may rise as a compensatory mechanism to counteract the increased oxidative stress under the conditions of metabolic syndrome38 or atherosclerosis.6 In our study population, the prevalence of cigarette smoking did not differ among the sex-specific uric acid quartiles for either gender. It is well recognized that cigarette smoking increases the extent of in vivo oxidative stress,39 although we did not measure this factor in the present study. In addition, bilirubin, which is another circulating natural antioxidant,40 was negatively associated with carotid plaque. These findings suggest that it cannot simply be concluded that serum factors that possess antioxidant capacity, such as uric acid and bilirubin, increase in response to oxidative stress or atherosclerosis. Interestingly, we also found that bilirubin was negatively associated with the prevalence of metabolic syndrome in men, which may correspond to the previous finding that bilirubin was negatively correlated to insulin and visceral adipose tissue.41 A causal or resultant relationship has yet to be elucidated; however, the negative association between serum bilirubin and incidence of carotid plaque may in part be attributed to the negative association between serum bilirubin and metabolic syndrome, a reverse scenario to the case of uric acid.
In conclusion, by analyzing the data of individuals who had undergone general health screening, we found that serum uric acid levels are associated with metabolic syndrome in both genders, independent of age, TC, and smoking status. After adjustment for age, TC, smoking status, BMI, systolic blood pressure, TC, HDL-C, triglycerides, and fasting glucose, serum uric acid quartiles were found to be statistically significantly associated with carotid plaque in men without metabolic syndrome but not in those with metabolic syndrome or in women with or without metabolic syndrome. Our findings suggest that the observed association between uric acid and carotid plaque may be attributed to metabolic syndrome–dependent and –independent mechanisms.
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