Association of Serum Uric Acid and Cardiovascular Disease in Healthy Adults

Shaye Kivity, MDa,b,e, Eran Kopel, MD, MPHb,f,*, Elad Maor, MD, PhDa,b,c, Fadi Abu-Bachar, MDa,b, Shlomo Segev, MDd, Yechezkel Sidi, MDb,e, and David Olchovsky, MDa,e
Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, dened as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 1.1 mg/dl for men (n [ 6,580) and 4.4 1.1 mg/dl for women (n [ 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% condence interval 1.08 to 1.41) for women and 1.06 (95% condence interval 1.00 to 1.13) for men (p for interaction [ 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations. 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111:1146e1151)

A few studies have demonstrated an association between serum uric acid (SUA) and cardiovascular disease (CVD) in healthy populations, such as in a population of men without previous CVD or type 2 diabetes mellitus1 and in Chinese men and women with normal levels of triglycerides and blood pressure and without a history of hypertensive or hyperglycemic medication use.2 In the present study, we investigated an association between SUA and CVD outcomes in an apparently healthy population of men and women without diabetes or CVD, particularly regarding the possible interaction between gender and SUA levels with respect to CVD occurrence. Methods This was a retrospective study designed to assess cardiometabolic risk factors in men and women who were
a Department of Internal Medicine A, bDepartment of Internal Medicine C, cThe Leviev Heart Institute, and dThe Institute for Preventive Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel; eSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and fTel Aviv District Health Ofce, Ministry of Health, Tel Aviv, Israel. Manuscript received September 23, 2012; revised manuscript received and accepted December 23, 2012. This work was supported by the Shalvi Foundation for Medical Research (Ramat Gan, Israel) and Mr. Natan Hetz. The sponsors had no role in designing or conducting the study and no role in gathering or analyzing the data or writing the manuscript. Drs. Kivity and Kopel contributed equally to this work. See page 1150 for disclosure information. *Corresponding author: Tel: 972-3-5302464; fax: 972-3-5302011. E-mail address: eran.kopel@mail.huji.ac.il (E. Kopel).

annually evaluated at the Executive Screening Survey at the Sheba Medical Center in Israel from January 2001 to December 2009. The full methods used by this program and the studys denitions were previously published.3,4 Briey, inclusion criteria were age >34 years, availability of follow-up data for 1 visit beyond the baseline visit, and 1 year between these visits. Exclusion criteria were a past or current diagnosis of diabetes or a fasting plasma glucose level >125 mg/dl at the rst visit or CVD (composed of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke). Diagnosis of CVD was the primary composite time-toevent end point of the study. CVD diagnoses were ascertained by patient report, chart review, or both if available, at any annual follow-up visit. Normal laboratory ranges of SUA at the study center were 2.6 to 6.0 mg/dl for women and 3.5 to 7.2 mg/dl for men. The Framingham Heart Studys 10-year risk score for hard coronary heart disease (myocardial infarction or coronary death)5 was available at the baseline of the study. In the univariate analysis of the baseline characteristics, stratied by gender, means and SDs were calculated for continuous variables and frequencies and percentages for categorical variables. For baseline categorical and continuous variables, chi-square test and Students t test were used, respectively, to assess associations with cardiovascular events. The statistical signicance of trends across SUA quartiles of baseline categorical and continuous independent variables was analyzed using chi-square linear-by-linear association test and nonparametric Kruskal-Wallis 1-way
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0002-9149/13/$ - see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.12.034

Preventive Cardiology/Serum Uric Acid and Cardiovascular Disease Table 1 Baseline characteristics of 9,139 cohort participants according to gender and cardiovascular disease outcomes Variable CVD (n 188) Age (yrs) Serum creatinine (mg/dl) Use of diuretics Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Low-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Plasma fasting glucose (mg/dl) Body mass index (kg/m2) Cardiac disease family history Regular physical activity Current smoker Framingham 10-yr risk 5% SUA level (mg/dl) 56.9 9.4 0.89 0.12 6.9% 126.0 20.1 77.1 10.9 126.6 30.9 121.5 59.6 88.2 11.3 25.2 4.0 42.6% 68.6% 16.0% 31.9% 4.8 1.2 Women No CVD (n 2,371) 50.2 9.2 0.88 0.10 4.0% 117.8 17.9 74.6 10.2 120.7 28.8 104.6 52.8 85.4 9.5 24.4 4.1 32.9% 69.3% 15.6% 11.7% 4.4 1.0 p Value <0.001 0.19 0.06 <0.001 0.001 0.007 <0.001 0.001 0.01 0.007 0.84 0.90 <0.001 <0.001 CVD (n 801) 55.1 9.4 1.11 0.14 3.1% 131.0 17.9 80.7 9.7 130.4 28.3 147.7 81.8 91.3 10.2 26.6 3.1 37.2% 66.3% 18.4% 62.3% 6.2 1.2 Men No CVD (n 5,779) 49.9 8.9 1.10 0.13 4.4% 126.5 16.1 80.2 9.8 126.6 27.7 140.3 77.5 88.9 10.0 26.7 3.4 31.4% 67.1% 15.0% 55.7% 6.1 1.1

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p Value <0.001 0.07 0.09 <0.001 0.19 <0.001 0.01 <0.001 0.39 0.001 0.65 0.01 <0.001 0.02

Data are reported as mean SD or as percentages.

Table 2 Baseline characteristics and cardiovascular disease outcomes of 2,559 women according to quartiles of serum uric acid levels Variable 1 (n 688) SUA level (mg/dl) Mean SD Median Range Age (yrs) Serum creatinine (mg/dl) Use of diuretics Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Low-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Plasma fasting glucose (mg/dl) Body mass index (kg/m2) Cardiac disease family history Regular physical activity Current smoker Framingham 10-yr risk 5% Mean follow-up (yrs) No. of incident outcome cases 3.3 0.4 3.4 1.6e3.7 48.0 8.9 0.86 0.09 1.9% 113.2 15.4 72.7 9.7 116.9 26.9 78 (30e286) 82.8 8.8 22.8 3.0 32.1% 69.6% 16.1% 7.4% 4.6 2.0 44 (6.4%) 2 (n 616) 4.0 0.2 4.0 3.8e4.3 49.2 8.5 0.87 0.09 1.5% 115.7 17.0 73.3 9.4 118.0 27.8 85 (30e312) 85.1 9.1 23.8 3.7 32.5% 70.9% 16.9% 9.3% 4.7 2.1 31 (5.0%) Quartile 3 (n 644) 4.7 0.2 4.7 4.4e5.1 51.4 9.0 0.89 0.11 4.3% 119.6 18.1 75.1 10.7 122.8 29.7 98 (30e421) 86.1 9.3 25.0 4.3 34.8% 68.9% 15.8% 13.4% 4.7 2.1 42 (6.5%) 4 (n 611) 5.9 0.7 5.7 5.2e10.5 54.6 9.7 0.91 0.12 9.5% 125.6 19.6 78.1 10.5 127.2 30.4 119 (34e539) 88.9 10.5 26.6 4.4 35.2% 67.6% 13.6% 23.4% 4.8 2.1 71 (11.6%) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.17 0.34 0.19 <0.001 0.38 <0.001 p Value for Trend

Data are reported as mean SD, as percentages, or as median (interquartile range).

analysis of variance, respectively. Multivariate Cox proportional-hazards analysis was used to estimate hazard ratios (HRs) and 95% condence intervals (CIs) for cardiovascular events according to quartiles of SUA levels. The proportional-hazards assumptions were evaluated using log-minus-log plots. We also measured the signicance of the interaction between continuous SUA levels and cardiovascular events, for men and women separately, adjusted within the same full multivariate model. All p-value calculations were 2 tailed and considered statistically signicant if 0.05. Statistical analyses were performed using IBM SPSS version 19.0 (IBM SPSS, Inc., Chicago, Illinois). The

Institutional Ethics Committee of Sheba Medical Center approved the study. Results The study cohort comprised 9,139 patients, of them 2,559 were women (28%) and 6,580 were men (72%). All were Caucasians of Jewish descent. The mean ages were 50.7 9.4 and 50.5 9.1 years for women and men, respectively. The mean SUA level in men (6.2 1.1 mg/dl, range 1.5 to 11.8) was higher than in women (4.4 1.1 mg/dl, range 1.6 to 10.5). The average number

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Table 3 Baseline characteristics and cardiovascular disease outcomes of 6,580 men according to quartiles of serum uric acid levels Variable 1 (n 1,823) SUA level (mg/dl) Mean SD Median Range Age (yrs) Serum creatinine (mg/dl) Use of diuretics Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Low-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Plasma fasting glucose (mg/dl) Body mass index (kg/m2) Cardiac disease family history Regular physical activity Current smoker Framingham 10-yr risk 5% Mean follow-up (yrs) No. of incident outcome cases 4.8 0.5 5.0 1.5e5.4 50.7 9.5 1.07 0.12 3.2% 124.9 15.8 78.9 9.7 126.0 27.2 106 (30e1,285) 88.4 10.1 25.8 3.2 30.5% 67.5% 17.4% 54.4% 4.8 2.1 196 (10.8%) Quartile 2 (n 1,591) 5.8 0.2 5.8 5.5e6.1 50.5 9.1 1.09 0.12 2.9% 125.8 16.3 79.6 9.6 127.5 27.6 119 (31e844) 88.3 9.8 26.5 3.1 31.0% 70.4% 14.3% 56.0% 4.7 2.1 192 (12.1%) 3 (n 1,614) 6.5 0.2 6.5 6.2e6.9 50.3 8.8 1.10 0.13 4.6% 127.6 16.2 80.6 9.5 126.9 28.2 129 (32e866) 89.1 10.1 27.1 3.3 32.3% 66.3% 14.9% 57.5% 4.8 2.1 196 (12.1%) 4 (n 1,552) 7.7 0.7 7.5 7.0e11.8 50.6 8.9 1.14 0.15 6.6% 130.3 17.0 82.1 10.1 127.8 28.3 148 (34e1,216) 90.5 10.0 27.7 3.5 34.9% 63.7% 14.5% 58.4% 4.9 2.1 217 (14.0%) 0.88 <0.001 <0.001 <0.001 <0.001 0.31 <0.001 <0.001 <0.001 0.005 0.004 0.03 0.01 0.08 0.006 p Value for Trend

Data are reported as mean SD, as percentages, or as median (interquartile range).

12

Cardiovascular outcome
No Yes

10

0 Women Men

Gender

Figure 1. Box plot of continuous SUA levels, stratied by gender and cardiovascular outcomes, in 9,139 men and women. Medians and interquartile ranges (IQRs) of uric acid levels are presented for men and women, with and without CVD outcomes. The median uric acid level of women with CVD was 4.8 mg/dl (IQR 3.8 to 5.6, range 2.3 to 8.7), compared with 4.3 mg/dl (IQR 3.7 to 5.0, range 1.6 to 10.5) for women without CVD. The median uric acid level of men with CVD was 6.2 mg/dl (IQR 5.5 to 7.0, range 2.9 to 10.5), compared with 6.1 mg/dl (IQR 5.3 to 6.9, range 1.5 to 11.8) for men without CVD.

of visits to the Executive Screening Survey was 5 (range 2 to 9). During the mean follow-up period of 4.8 years, comprising 43,553 person-years, 801 CVD events occurred in the men and 188 in the women, including a total of 88 ischemic cerebral events for the entire sample (1%). CVD incidence rates were thus 12.2% and 7.3% in men and

women, respectively. For men and women, mean age, systolic blood pressure, and levels of low-density lipoprotein cholesterol, triglycerides, and plasma fasting glucose at baseline time of follow-up were higher in those with CVD outcomes than those without. Mean baseline SUA levels were higher in those with than those without CVD outcomes, although the differences were small for men (Table 1). Stratied by quartiles of SUA levels in women, the mean age, body mass index, and levels of serum creatinine, blood pressure, low-density lipoprotein cholesterol, triglycerides, and plasma fasting glucose increased with increasing SUA levels (Table 2). The rate of CVD occurrence in women was highest in the top SUA quartile compared with the lower 3 quartiles. For men, body mass index and levels of serum creatinine, blood pressure, triglycerides, and plasma fasting glucose increased with increasing SUA levels (Table 3). There was no difference in age for men according to SUA quartile. For men, increased SUA levels were associated with lower rates of routine physical activity and lower rates of smoking, although the magnitudes for both were small. The rate of CVD occurrence in men was highest in the top SUA quartile. Medians and interquartile ranges of continuous SUA levels in women and men with and without CVD outcomes are presented in Figure 1. The multivariate-adjusted HR for each 1 mg/dl increase in SUA with regard to CVD outcomes (Table 4) was signicantly higher for women than for men (p for interaction 0.04). A sensitivity analysis for the group of patients (n 7,956) with normal glucose (<100 mg/dl) was performed with the same multivariate-adjusted model as in Table 4. The multivariate-adjusted HRs for each 1 mg/dl increase in SUA with regard to CVD outcomes were 1.30 (95% CI 1.12 to 1.51) for women and 1.06 (95% CI 0.99 to 1.14) for men (p for interaction 0.02).

Serum uric acid levels (mg/dl)

Preventive Cardiology/Serum Uric Acid and Cardiovascular Disease Table 4 Multivariate-adjusted hazard ratios for cardiovascular disease outcomes by interaction with gender Variable Women (n 2,559 [28%]) No. of incident cardiovascular outcome cases SUA levels (mg/dl) Mean SD Median (interquartile range) Range Multivariate model (95% CI) SUA (1 mg/dl increment) Age (1-yr increment) Serum creatinine (0.1 mg/dl increment) Use of diuretics Systolic blood pressure (10 mm Hg increment) Low-density lipoprotein cholesterol (10 mg/dl increment) Triglycerides (10 mg/dl increment) Plasma fasting glucose (1 mg/dl) Body mass index (1 kg/m2 increment) Cardiac disease family history Regular physical activity Current smoker * Statistically signicant (p 0.05). 188 (7.3%) 4.4 1.0 4.3 (3.7e5.1) 1.6e10.5 1.24 1.06 0.97 0.80 1.10 1.01 1.02 1.02 1.00 1.28 0.86 1.22 (1.08e1.41)* (1.04e1.07)* (0.86e1.11) (0.45e1.42) (1.02e1.18)* (0.96e1.06) (0.99e1.04) (1.00e1.03)* (0.97e1.04) (0.95e1.71) (0.62e1.17) (0.82e1.82) Men (n 6,580 [72%]) 801 (12.2%) 6.2 1.1 6.1 (5.4e6.9) 1.5e11.8 1.06 1.05 0.96 0.37 1.06 1.03 1.02 1.01 0.97 1.18 0.89 1.51 (1.00e1.13) (1.04e1.06)* (0.92e1.01) (0.25e0.56)* (1.02e1.11)* (1.01e1.06)* (1.01e1.03)* (1.00e1.02)* (0.95e0.99)* (1.02e1.37)* (0.76e1.03) (1.25e1.82)* 0.04 0.48 0.85 0.03 0.40 0.41 0.89 0.71 0.12 0.65 0.84 0.35

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p Value for Interaction

In the same multivariate model as in Table 4, the subgroup of women who were not obese (body mass index <30 kg/m2), had an HR for each 1 mg/dl increase in SUA of 1.18 (95% CI 1.01 to 1.39, p 0.04), compared with an HR of 1.27 (95% CI 0.91 to 1.78, p 0.16) in obese women. Nonobese men had an HR of 1.07 (95% CI 1.00 to 1.14, p 0.06) for each 1 mg/dl increase in SUA, compared with an HR of 1.01 (95% CI 0.85 to 1.19, p 0.92) in obese men. Discussion We found a signicant association of SUA level with CVD in women and, to a lesser degree, in men. This interaction with gender was even stronger in the subgroup of patients with normal fasting glucose levels. Because the studys population was composed of Caucasians of Jewish descent, the external validity of our results should be tested in other populations as well. Our main observation is supported by the National Health and Nutrition Examination Survey (NHANES),6 which found an independent association of SUA with CVD mortality that was stronger in women than in men, but contrasts other studies such as an analysis of the Framingham Heart Study7 that reported an absence of an independent association in men and the disappearance of an association in women after adjusting for a number of traditional CVD risk factors, with a substantial contribution of diuretic use to the nonsignicance of SUA for the prediction of cardiovascular morbidity and mortality. In the present study, however, we included diuretic use as well as a wealth of traditional CVD risk factors in the multivariate model, and the association of SUA with CVD was still maintained, particularly in women. Additionally, in our study, the percentage of patients with higher calculated Framingham risk scores increased directly along the quartiles of baseline SUA, more dramatically in

women. Although this correlation of SUA with Framingham risk score was signicant, whether SUA level can signicantly add to the predictive ability of the score in this studys population would require further statistical investigation, by comparing various prediction models with and without SUA for instance. Using the C-statistic, SUA level contributed modestly but signicantly to the predictive value of a comprehensive multivariate model of all-cause mortality outcomes that included Framingham Heart Study score factors, components of metabolic syndrome, and markers of inammation.8 In a recent study, there was also a modest but signicant predictive contribution of SUA level to the multivariate model with respect to 1-year all-cause mortality in patients with acute coronary syndrome; no interaction was found between gender and uric acid in that study.9 Our ndings are also supported by those of a populationbased prospective cohort study of 1,423 middle-aged Finnish men who were initially without CVD, cancer, or diabetes.1 In that study, SUA level was found to be a strong predictor of CVD mortality, independent of variables commonly associated with gout or the metabolic syndrome.1 Similar to the present study, that study included a healthy population. However, in that study, the outcome was cardiovascular mortality, not events. The primary outcome of the NHANES analysis6 was also cardiovascular mortality, not CVD events. We presume that compared with cardiovascular mortality, the rate of CVD events may better reect an actual association, because mortality rates may be associated with additional clinical, socioeconomic, lifestyle, and health care factors. The association of uric acid with CVD is indisputable, given that uric acid is associated with CVD risk factors, such as diabetes and hypertension. Whether uric acid is independently associated with CVD remains unresolved. Moreover, the evidence of an independent role for uric

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acid, at least in some populations, does not indicate causality. Less obvious is the possibility of causality, even without an independent relation. The Framingham Heart Study,7 and more recently Panero et al,10 concluded that uric acid was not a causal risk factor for cardiovascular events, because it was not independent of hypertension. However, if uric acid causes hypertension, and hypertension causes CVD, then uric acid has a causal role in CVD, even if it does not show independence from hypertension when evaluated as a risk factor for CVD.11 The independent impact of gout on the risk for CVD supports a causal role for uric acid,12 in light of the well-established association between uric acid levels and gout. A direct role of uric acid, or xanthine oxidase, a catalyst of the nal stage of uric acid production, on the progression of heart failure has also been demonstrated.13 Differences in results among investigations of SUA and CVD may be due to actual differences in the characteristics of the populations investigated or, alternatively, to differences in research methods that obscure true similarities. A complete exploration of all population characteristics is not possible. Studies generally account for gender, age, and a number of CVD risk factors that differ among studies. Studies that have demonstrated associations between SUA and CVD have been criticized for not considering all possible confounding factors.14 Although serum creatinine and plasma fasting glucose were not included in either the NHANES or Framingham analysis,6,7 many studies published subsequently have included 1 or both of these variables in their analyses.1,8,10,11,15e18 In the present study, we included the 2 variables in the univariate and multivariate analyses, and SUA still retained its signicant association with CVD. The present study also demonstrated that obesity might confound the association of SUA with CVD occurrence, because obese women and men had no signicant association between SUA and CVD, whereas nonobese patients had a stronger association, particularly in women. This confounding was reected in a recent young adult population study,19 which demonstrated that body mass index is a signicant confounder in the association between SUA and carotid artery intima-media thickness, a vascular marker of early, subclinical atherosclerosis. Moreover, body mass index might be actually a mediator in the observed path of association between SUA and CVD.19 Even without a causal role, SUA may be useful as a marker of CVD. Advantages of SUA assessment are the clinical availability and inexpensiveness of the test. Nonetheless, its predictive value, compared with other risk factor markers, needs to be further determined. Not only do the confounding factors considered differ among studies, but the means of accounting for such factors also differ. For example, the present study, as well as the NHANES and Framingham analyses,6,7 stratied for gender, contrasting with studies that assessed men and women together, while only adjusting for gender. In a recent publication of an Italian cohort, which adjusted for but did not stratify by gender, the investigators claimed that the lack of a signicant interaction between gender and SUA was evidence of a similar role of SUA in survival in men and women.10 However, considering the much skewed

distribution of SUA between the genders in that study (30% more men in the highest quartile of SUA than in the lowest quartile), comparable to that observed in the present and in other studies, it would be interesting to examine if genderspecic analyses would yield different results. Higher levels of SUA in men than in women at all ages have been attributed to the uricosuric effect (i.e., the role of gender steroids in uric acid regulation).20 More recently, this effect has also been suggested to explain the lack of association between SUA levels and the prevalence of carotid plaques in women, contrasting with the association observed in men.21 Furthermore, the prevalence of carotid plaques was reportedly higher in postmenopausal women aged 55 years than in younger women.21 Although in the present study, SUA levels were higher in men than in women in every SUA quartile, SUA level was associated with increasing age for women only, as was concordantly described previously in the Framingham Heart Study.7 The effect of the estrogen defense in premenopausal women may explain the lower mean age of women in the lower quartiles of SUA (48 years in the lowest quartile vs 55 years in the highest quartile). In light of the association between hyperuricemia and insulin resistance, the gender-specic difference in the association of SUA with CVD risk observed in our study may relate to a gender-specic difference in the effect of diabetes on CVD. In particular, diabetes has been found to confer a greater risk for CVD in women than in men.22 In the NHANES analysis, SUA was higher in women with diabetes than in women without, but no such difference was found among men with or without diabetes.6 In fact, the signicant interaction of SUA with gender in our model points to a signicantly stronger association with CVD in women compared with men. Moreover, it is evident that in women, the association between SUA and CVD was strong and comparable with the traditional risk factors of age, systolic blood pressure, and plasma fasting glucose, whereas other traditional risk factors were not associated signicantly with CVD in women (i.e., low-density lipoprotein cholesterol) or were with borderline signicance (i.e., triglycerides) within the same multivariate model. In men, these risk factors were signicant, as expected (Table 4). This phenomenon might be explained by the fact that the sample of women was about 60% smaller than the sample of men, and thus there was much less statistical observation power for testing risk factors associations with CVD in women than in men by way of interaction. Nevertheless, the fact that SUA was indeed a signicant risk factor in this model, whereas some of the traditional risk factors were not, only strengthens the medical evidence that women have a different risk prole for CVD that is more dependent on the metabolic syndrome axis than in men. Overall, the fate of SUA research for its future use as an effective clinical tool may lie in the proper methodologic handling of its gender-based differential qualities at baseline and follow-up and with respect to outcomes. Disclosures The authors have no conicts of interest to disclose.

Preventive Cardiology/Serum Uric Acid and Cardiovascular Disease 1. Niskanen LK, Laaksonen DE, Nyyssnen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004;164:1546e1551. 2. Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum 2009;61:225e232. 3. Kivity S, Tirosh A, Segev S, Sidi Y. Fasting glucose levels within the high normal range predict cardiovascular outcome. Am Heart J 2012;164:111e116. 4. Kopel E, Kivity S, Morag-Koren N, Segev S, Sidi Y. Relation of serum lactate dehydrogenase to coronary artery disease. Am J Cardiol 2012;110:1717e1722. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486e2497. 6. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study 1971e1992. JAMA 2000;283:2404e2410. 7. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7e13. 8. Takayama S, Kawamoto R, Kusunoki T, Abe M, Onji M. Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome. Cardiovasc Diabetol 2012;11:2. 9. Ndrepepa G, Braun S, Haase HU, Schulz S, Ranftl S, Hadamitzky M, Mehilli J, Schmig A, Kastrati A. Prognostic value of uric acid in patients with acute coronary syndromes. Am J Cardiol 2012;109: 1260e1265. 10. Panero F, Gruden G, Perotto M, Fornengo P, Barutta F, Greco E, Runzo C, Ghezzo G, Cavallo-Perin P, Bruno G. Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: a population-based study. Atherosclerosis 2012;221:183e188. 11. Iwashima Y, Horio T, Kamide K, Rakugi H, Ogihara T, Kawano Y. Uric acid, left ventricular mass index, and risk of cardiovascular disease in essential hypertension. Hypertension 2006;47:195e202.

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