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, defined 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% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence 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.
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 mellitus and in Chinese men and women with normal levels of triglycerides and blood pressure and without a history of hypertensive or hyperglycemic medication use. 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 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 study’s definitions were previously published.
Briefly, 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 first 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-to-event 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 Study’s 10-year risk score for hard coronary heart disease (myocardial infarction or coronary death) was available at the baseline of the study.
In the univariate analysis of the baseline characteristics, stratified 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 Student’s t test were used, respectively, to assess associations with cardiovascular events. The statistical significance 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 analysis of variance, respectively. Multivariate Cox proportional-hazards analysis was used to estimate hazard ratios (HRs) and 95% confidence 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 significance 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 significant 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 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 ).
| Variable | Women | Men | ||||
|---|---|---|---|---|---|---|
| CVD (n = 188) | No CVD (n = 2,371) | p Value | CVD (n = 801) | No CVD (n = 5,779) | p Value | |
| Age (yrs) | 56.9 ± 9.4 | 50.2 ± 9.2 | <0.001 | 55.1 ± 9.4 | 49.9 ± 8.9 | <0.001 |
| Serum creatinine (mg/dl) | 0.89 ± 0.12 | 0.88 ± 0.10 | 0.19 | 1.11 ± 0.14 | 1.10 ± 0.13 | 0.07 |
| Use of diuretics | 6.9% | 4.0% | 0.06 | 3.1% | 4.4% | 0.09 |
| Systolic blood pressure (mm Hg) | 126.0 ± 20.1 | 117.8 ± 17.9 | <0.001 | 131.0 ± 17.9 | 126.5 ± 16.1 | <0.001 |
| Diastolic blood pressure (mm Hg) | 77.1 ± 10.9 | 74.6 ± 10.2 | 0.001 | 80.7 ± 9.7 | 80.2 ± 9.8 | 0.19 |
| Low-density lipoprotein cholesterol (mg/dl) | 126.6 ± 30.9 | 120.7 ± 28.8 | 0.007 | 130.4 ± 28.3 | 126.6 ± 27.7 | <0.001 |
| Triglycerides (mg/dl) | 121.5 ± 59.6 | 104.6 ± 52.8 | <0.001 | 147.7 ± 81.8 | 140.3 ± 77.5 | 0.01 |
| Plasma fasting glucose (mg/dl) | 88.2 ± 11.3 | 85.4 ± 9.5 | 0.001 | 91.3 ± 10.2 | 88.9 ± 10.0 | <0.001 |
| Body mass index (kg/m 2 ) | 25.2 ± 4.0 | 24.4 ± 4.1 | 0.01 | 26.6 ± 3.1 | 26.7 ± 3.4 | 0.39 |
| Cardiac disease family history | 42.6% | 32.9% | 0.007 | 37.2% | 31.4% | 0.001 |
| Regular physical activity | 68.6% | 69.3% | 0.84 | 66.3% | 67.1% | 0.65 |
| Current smoker | 16.0% | 15.6% | 0.90 | 18.4% | 15.0% | 0.01 |
| Framingham 10-yr risk ≥5% | 31.9% | 11.7% | <0.001 | 62.3% | 55.7% | <0.001 |
| SUA level (mg/dl) | 4.8 ± 1.2 | 4.4 ± 1.0 | <0.001 | 6.2 ± 1.2 | 6.1 ± 1.1 | 0.02 |
Stratified 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.
| Variable | Quartile | p Value for Trend | |||
|---|---|---|---|---|---|
| 1 (n = 688) | 2 (n = 616) | 3 (n = 644) | 4 (n = 611) | ||
| SUA level (mg/dl) | |||||
| Mean ± SD | 3.3 ± 0.4 | 4.0 ± 0.2 | 4.7 ± 0.2 | 5.9 ± 0.7 | — |
| Median | 3.4 | 4.0 | 4.7 | 5.7 | — |
| Range | 1.6–3.7 | 3.8–4.3 | 4.4–5.1 | 5.2–10.5 | — |
| Age (yrs) | 48.0 ± 8.9 | 49.2 ± 8.5 | 51.4 ± 9.0 | 54.6 ± 9.7 | <0.001 |
| Serum creatinine (mg/dl) | 0.86 ± 0.09 | 0.87 ± 0.09 | 0.89 ± 0.11 | 0.91 ± 0.12 | <0.001 |
| Use of diuretics | 1.9% | 1.5% | 4.3% | 9.5% | <0.001 |
| Systolic blood pressure (mm Hg) | 113.2 ± 15.4 | 115.7 ± 17.0 | 119.6 ± 18.1 | 125.6 ± 19.6 | <0.001 |
| Diastolic blood pressure (mm Hg) | 72.7 ± 9.7 | 73.3 ± 9.4 | 75.1 ± 10.7 | 78.1 ± 10.5 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 116.9 ± 26.9 | 118.0 ± 27.8 | 122.8 ± 29.7 | 127.2 ± 30.4 | <0.001 |
| Triglycerides (mg/dl) | 78 (30–286) | 85 (30–312) | 98 (30–421) | 119 (34–539) | <0.001 |
| Plasma fasting glucose (mg/dl) | 82.8 ± 8.8 | 85.1 ± 9.1 | 86.1 ± 9.3 | 88.9 ± 10.5 | <0.001 |
| Body mass index (kg/m 2 ) | 22.8 ± 3.0 | 23.8 ± 3.7 | 25.0 ± 4.3 | 26.6 ± 4.4 | <0.001 |
| Cardiac disease family history | 32.1% | 32.5% | 34.8% | 35.2% | 0.17 |
| Regular physical activity | 69.6% | 70.9% | 68.9% | 67.6% | 0.34 |
| Current smoker | 16.1% | 16.9% | 15.8% | 13.6% | 0.19 |
| Framingham 10-yr risk ≥5% | 7.4% | 9.3% | 13.4% | 23.4% | <0.001 |
| Mean follow-up (yrs) | 4.6 ± 2.0 | 4.7 ± 2.1 | 4.7 ± 2.1 | 4.8 ± 2.1 | 0.38 |
| No. of incident outcome cases | 44 (6.4%) | 31 (5.0%) | 42 (6.5%) | 71 (11.6%) | <0.001 |
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 .
| Variable | Quartile | p Value for Trend | |||
|---|---|---|---|---|---|
| 1 (n = 1,823) | 2 (n = 1,591) | 3 (n = 1,614) | 4 (n = 1,552) | ||
| SUA level (mg/dl) | |||||
| Mean ± SD | 4.8 ± 0.5 | 5.8 ± 0.2 | 6.5 ± 0.2 | 7.7 ± 0.7 | — |
| Median | 5.0 | 5.8 | 6.5 | 7.5 | — |
| Range | 1.5–5.4 | 5.5–6.1 | 6.2–6.9 | 7.0–11.8 | — |
| Age (yrs) | 50.7 ± 9.5 | 50.5 ± 9.1 | 50.3 ± 8.8 | 50.6 ± 8.9 | 0.88 |
| Serum creatinine (mg/dl) | 1.07 ± 0.12 | 1.09 ± 0.12 | 1.10 ± 0.13 | 1.14 ± 0.15 | <0.001 |
| Use of diuretics | 3.2% | 2.9% | 4.6% | 6.6% | <0.001 |
| Systolic blood pressure (mm Hg) | 124.9 ± 15.8 | 125.8 ± 16.3 | 127.6 ± 16.2 | 130.3 ± 17.0 | <0.001 |
| Diastolic blood pressure (mm Hg) | 78.9 ± 9.7 | 79.6 ± 9.6 | 80.6 ± 9.5 | 82.1 ± 10.1 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 126.0 ± 27.2 | 127.5 ± 27.6 | 126.9 ± 28.2 | 127.8 ± 28.3 | 0.31 |
| Triglycerides (mg/dl) | 106 (30–1,285) | 119 (31–844) | 129 (32–866) | 148 (34–1,216) | <0.001 |
| Plasma fasting glucose (mg/dl) | 88.4 ± 10.1 | 88.3 ± 9.8 | 89.1 ± 10.1 | 90.5 ± 10.0 | <0.001 |
| Body mass index (kg/m 2 ) | 25.8 ± 3.2 | 26.5 ± 3.1 | 27.1 ± 3.3 | 27.7 ± 3.5 | <0.001 |
| Cardiac disease family history | 30.5% | 31.0% | 32.3% | 34.9% | 0.005 |
| Regular physical activity | 67.5% | 70.4% | 66.3% | 63.7% | 0.004 |
| Current smoker | 17.4% | 14.3% | 14.9% | 14.5% | 0.03 |
| Framingham 10-yr risk ≥5% | 54.4% | 56.0% | 57.5% | 58.4% | 0.01 |
| Mean follow-up (yrs) | 4.8 ± 2.1 | 4.7 ± 2.1 | 4.8 ± 2.1 | 4.9 ± 2.1 | 0.08 |
| No. of incident outcome cases | 196 (10.8%) | 192 (12.1%) | 196 (12.1%) | 217 (14.0%) | 0.006 |
The multivariate-adjusted HR for each 1 mg/dl increase in SUA with regard to CVD outcomes ( Table 4 ) was significantly 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).
| Variable | Women | Men | p Value for Interaction |
|---|---|---|---|
| (n = 2,559 [28%]) | (n = 6,580 [72%]) | ||
| No. of incident cardiovascular outcome cases | 188 (7.3%) | 801 (12.2%) | — |
| SUA levels (mg/dl) | |||
| Mean ± SD | 4.4 ± 1.0 | 6.2 ± 1.1 | — |
| Median (interquartile range) | 4.3 (3.7–5.1) | 6.1 (5.4–6.9) | — |
| Range | 1.6–10.5 | 1.5–11.8 | — |
| Multivariate model (95% CI) | |||
| SUA (1 mg/dl increment) | 1.24 (1.08–1.41) ∗ | 1.06 (1.00–1.13) | 0.04 |
| Age (1-yr increment) | 1.06 (1.04–1.07) ∗ | 1.05 (1.04–1.06) ∗ | 0.48 |
| Serum creatinine (0.1 mg/dl increment) | 0.97 (0.86–1.11) | 0.96 (0.92–1.01) | 0.85 |
| Use of diuretics | 0.80 (0.45–1.42) | 0.37 (0.25–0.56) ∗ | 0.03 |
| Systolic blood pressure (10 mm Hg increment) | 1.10 (1.02–1.18) ∗ | 1.06 (1.02–1.11) ∗ | 0.40 |
| Low-density lipoprotein cholesterol (10 mg/dl increment) | 1.01 (0.96–1.06) | 1.03 (1.01–1.06) ∗ | 0.41 |
| Triglycerides (10 mg/dl increment) | 1.02 (0.99–1.04) | 1.02 (1.01–1.03) ∗ | 0.89 |
| Plasma fasting glucose (1 mg/dl) | 1.02 (1.00–1.03) ∗ | 1.01 (1.00–1.02) ∗ | 0.71 |
| Body mass index (1 kg/m 2 increment) | 1.00 (0.97–1.04) | 0.97 (0.95–0.99) ∗ | 0.12 |
| Cardiac disease family history | 1.28 (0.95–1.71) | 1.18 (1.02–1.37) ∗ | 0.65 |
| Regular physical activity | 0.86 (0.62–1.17) | 0.89 (0.76–1.03) | 0.84 |
| Current smoker | 1.22 (0.82–1.82) | 1.51 (1.25–1.82) ∗ | 0.35 |
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