Abstract
Uric acid (UA) is associated with atherosclerosis, and coronary artery calcium (CAC) is a marker of atherosclerosis. The authors studied the association between UA and CAC. A total of 663 asymptomatic patients (564 men; mean age, 55±7 years) were evaluated for the presence of CAC. The study population was divided into three tertiles according to their UA levels, and the prevalence of CAC was compared between the tertiles. CAC was detected in 349 (53%) patients. Levels of UA were significantly higher in those with CAC than in those without CAC (5.6+1.2 vs 5.3+1.3; P=.003). The odds ratio for the presence of CAC in the highest vs lowest UA tertile was 1.72 (95% confidence interval, 1.17–2.51). The highest UA tertile remained associated with the presence of CAC after adjustment for known cardiovascular risk factors. The results show that high serum UA levels are associated with the presence of CAC.
An association between uric acid (UA) and coronary heart disease (CHD) was found by Gertler and colleagues1 more than 50 years ago. Since then, several studies have attempted to establish whether UA is related to CHD events, independent of conventional CHD risk factors.2, 3, 4 High UA levels have been associated with carotid subclinical atherosclerosis and oxidative stress in a retrospective cohort of the Atherosclerosis Risk in Communities (ARIC) study.5 In a Japanese population, UA was found to be a marker of increased carotid intimal‐media thickness, but only in patients without the metabolic syndrome.6 However, the association between UA levels and CHD events is still a subject of debate. Several studies have found an independent association between UA and CHD events,2, 7 whereas other studies have failed to show any association.3, 4, 5
Coronary artery calcification (CAC) is well accepted as a surrogate marker of the total coronary atherosclerotic burden,8 as confirmed by histopathology9 and intravascular ultrasound studies.10 There is clear evidence that the presence and degree of CAC, as measured by computed tomography (CT), increases the risk of cardiac events11, 12, 13, 14, 15, 16, 17, 18, 19 and all‐cause mortality.20, 21, 22, 23, 24
Several studies have demonstrated a relationship between serum UA levels and CAC score,25, 26, 27 but other studies do not support these findings.28, 29
In light of the debatable association between UA and CAC, we aimed to investigate whether serum UA levels are independently associated with the presence of CAC in patients without known CHD.
Patients and Methods
Patient selection
In this prospective, longitudinal observational study designed to evaluate the long‐term prognostic value of CAC we screened healthy patients for the presence of CAC. Of 1850 patients examined in our annual check‐up clinic between January 2001 and January 2002, we recruited 663 consecutive patients for the present study who fulfilled the inclusion criteria and consented to perform a screening cardiac CT for coronary calcium evaluation. The inclusion criteria for the screening were men older than 40 years and women older than 50 years who were free of cardiovascular (CV) disease and who had data on CV risk factors and levels of serum UA.
Coronary CT
All CT scans were performed on dual‐detector spiral CT without electrocardiographic gating and without contrast injection. Scanning protocol and CAC measurements were performed according to a previously published protocol using the modified Agatston method.30, 31 The reproducibility of calcification scoring by this method is high, with an intra‐class correlation coefficient of 0.99 and an interobserver agreement of 0.94.31 Total CAC score (TCS) was the sum of all individual calcific lesions identified within the area of the coronary arteries. A TCS >0 was considered positive for the presence of CAC. Analysis was performed according to absence or presence of CAC.
Assessment of CV Risk Factors
Height and weight were measured with participants wearing light clothing without shoes. Body mass index (BMI) was calculated as weight (kg) divided by height (m2). Blood pressure (BP) was measured in the seated position after 3 minutes of rest. Hypertension was defined when two separate BP readings were ≥140 mm Hg for systolic BP and/or ≥90 mm Hg for diastolic BP or a history of hypertension was reported or when the patient used antihypertensive medications.
Diabetes mellitus (DM) was defined as a fasting serum glucose >126 mg/dL (7.0 mmol/L) on two separate readings, history of DM, or when the patient used insulin or oral hypoglycemic medications. Hypercholesterolemia was defined when measured total cholesterol was >250 mg/dL or when the patient reported using cholesterol‐lowering medications. Smoking status was determined according to the questionnaire, and participants were divided into current smokers or nonsmokers. Estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation.32
Study Protocol
The clinical demographics of the patients who were eligible to be included in the study were recorded. Serum UA levels were measured on the same day as the CT scan. Serum UA levels were compared between patients with and patients without CAC. The study population was divided into 3 tertiles according to their UA levels and the prevalence of CAC was compared between the tertiles.
Statistical Analysis
Data were analyzed with SPSS (IBM SPSS Statistics, Chicago, IL) software version 21.0. Continuous variables were expressed as mean±standard deviation. Categorical variables were expressed as frequencies (percentage).
The clinical characteristics of study patients were compared with chi‐square tests for categorical variables and independent t test or analysis of variance (ANOVA) for continuous variables between the following groups: patients with and without CAC and between the 3 tertiles of serum UA levels.
Univariate and multivariate logistic regression modeling were performed to analyze the relationship between UA levels and the prevalence of CAC as well as other conventional CHD risk factors and clinical and laboratory parameters. A value of P<.05 was considered to be statistically significant.
Results
Patient characteristics
The study population consisted of 663 patients (85% men) with a mean age of 55.5±7.3 years. Among the study population, 349 (53%) had detectable CAC. Patients with CAC were older, were more likely to be male and smokers, and had higher baseline systolic and diastolic BP, serum glucose, and UA levels. They also had a higher prevalence of hyperlipidemia, DM, and hypertension and lower levels of eGFR (Table 1).
Table 1.
Baseline Characteristics of Study Population According to Presence of Coronary Artery Calcification
| Variable | Study Group | CTS=0 | CTS>0 | P Value |
|---|---|---|---|---|
| N=663 | N=314 (47%) | N=349 (53%) | ||
| Male sex, % | 564 (85) | 245 (78) | 319 (91) | <.001 |
| Age, y | 55.5±7.3 | 53.0±6.8 | 57.8±7.0 | <.001 |
| BMI, kg/m2 | 27.0±3.4 | 26.9±3.6 | 27.1±3.3 | .358 |
| Systolic BP, mm Hg | 126±17 | 123±16 | 129±17 | .001 |
| Diastolic BP, mm Hg | 79±9 | 78±9 | 79±9 | <.001 |
| Heart rate, beats per min | 78±13 | 79±13 | 77±12 | .0857 |
| Associated risk factors, % | ||||
| Hypertension | 180 (27.0) | 59 (18.8) | 121 (34.7) | <.001 |
| Diabetes mellitus | 50 (7.5) | 11 (3.5) | 39 (11.2) | <.001 |
| Hyperlipidemia | 305 (46.0) | 122 (39.6) | 183 (53.4) | .001 |
| Smokers | 115 (17.0) | 41 (17.2) | 74 (27.3) | .006 |
| Positive family history of CHD, % | 172 (26.0) | 75 (24.2) | 97 (28.0) | .264 |
| Laboratory values | ||||
| Serum glucose, mg/dL | 100±23 | 95±15 | 103±27 | <.001 |
| Serum total cholesterol, mg/dL | 200±34 | 200±34 | 201±34 | .749 |
| Serum LDL cholesterol, mg/dL | 127±29 | 126±28 | 128±30 | .289 |
| Serum HDL cholesterol, mg/dL | 45±12 | 46±13 | 45±11 | .14 |
| Serum triglycerides, mg/dL | 143±78 | 145±80 | 141±75 | .546 |
| eGFR, mL/min | 76±12 | 78±13 | 75±12 | .005 |
| Serum uric acid, mg/dL | 5.5±1.3 | 5.3±1.3 | 5.6±1.2 | .003 |
Abbreviations: BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; CTS, total coronary artery calcification score; eGFR, estimated glomerular filtration rate; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein. Values are expressed as number (percentage) or mean±standard deviation.
Relationship between UA levels and patient characteristics
Patient characteristics according to UA tertiles are presented in Table 2. Patients in the highest UA tertile were younger, were more likely to be male, and had higher rates of hypertension, BMI, and serum triglyceride levels and lower serum HDL cholesterol and eGFR levels (Table 2).
Table 2.
Characteristics of Study Population According to Tertiles of Uric Acid
| Variable | Uric Acid | P Value | ||
|---|---|---|---|---|
| Tertile 1 | Tertile 2 | Tertile 3 | ||
| No. | 233 | 226 | 204 | |
| Range of uric acid, mg/dL | <4.9 | 5.0–6.0 | >6.1 | |
| Age, y | 56.9±7.1 | 55.1±7.1 | 54.6±7.6 | .002 |
| Male sex, % | 149 (64.5) | 212 (94.2) | 200 (98.5) | <.001 |
| BMI, kg/m2 | 26.0±3.1 | 27.0±3.3 | 28.1±3.4 | <.001 |
| Systolic BP, mm Hg | 126±16 | 125±15 | 128±18 | .085 |
| Diastolic BP, mm Hg | 78±9 | 79±8 | 80±10 | .206 |
| Heart rate, beats per min | 76±12 | 77±13 | 80±13 | .021 |
| Associated risk factors, % | ||||
| Hypertension | 56 (24.1) | 54 (23.9) | 68 (33.8) | .033 |
| Diabetes mellitus | 21 (9.1) | 18 (8) | 10 (5) | .248 |
| Hyperlipidemia | 95 (41.5) | 110 (50) | 98 (50) | .117 |
| Smokers | 45 (24.1) | 41 (24.6) | 29 (19.1) | .426 |
| Positive family history of CHD, % | 67 (29.1) | 60 (27) | 44 (22) | .232 |
| Laboratory values | ||||
| Serum glucose, mg/dL | 100±30 | 99±18 | 99±16 | .930 |
| Serum cholesterol, mg/dL | 200±35 | 198±32 | 202±35 | .582 |
| Serum LDL cholesterol, mg/dL | 125±30 | 127±28 | 129±30 | .551 |
| Serum HDL cholesterol, mg/dL | 50±14 | 44±11 | 41±9 | <.001 |
| Serum triglycerides, mg/dL | 130±79 | 138±63 | 164±87 | <.001 |
| eGFR, mL/min | 77±13 | 78±11 | 73±12 | <.001 |
| Serum uric acid, mg/dL | 4.1±0.7 | 5.5±0.3 | 7.0±0.8 | .003 |
Abbreviations: BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein. Values are expressed as number (percentage) or mean±standard deviation.
Serum UA tertiles were unrelated to TCS (r=0.08); however, the prevalence of CAC increased in parallel to the increase in UA tertiles (Figure).
Figure 1.
The prevalence of coronary artery calcification (CAC) (%) according to uric acid tertile (tertiles 1–3, uric acid <4.9, 5–6.0, >6.1 mg/dL, respectively). *P=.005.
Relationship between UA levels and presence of CAC
Higher prevalence of CAC was observed in the second and highest UA tertile groups (54% and 59%, respectively, vs 46% in the lowest UA tertile; P=.005). Using the lowest UA tertile as a reference, the unadjusted odds ratio for the presence of CAC in the highest UA tertile was 1.72 (95% confidence interval [CI], 1.17–2.51). The age‐adjusted odds ratio was 1.77 (95% CI, 1.19–2.63) for the second UA tertile and 2.45 (95% CI, 1.61–3.73) for the highest UA tertile. After further adjustment for age, sex, hypertension, eGFR, BMI, DM, and hyperlipidemia, UA levels were still associated with the presence of CAC, with an odds ratio of 1.84 (95% CI, 1.1–3.07) in the highest UA tertile (Table 3).
Table 3.
Presence of Coronary Artery Calcium by Tertiles of Uric Acid
| Variable | Uric Acid | P Value | ||
|---|---|---|---|---|
| Tertile 1 | Tertile 2 | Tertile 3 | ||
| Unadjusted OR | 1.0 | 1.36 (0.94–1.96) | 1.72 (1.17–2.51) | .019 |
| Age adjusted OR | 1.0 | 1.77 (1.19–2.63) | 2.45 (1.61–3.73) | <.001 |
| Multivariate model 1a OR | 1.0 | 1.22 (0.79–1.88) | 1.63 (1.01–2.62) | .045 |
| Multivariate model 2b OR | 1.0 | 1.24 (0.79–1.96) | 1.84 (1.10–3.07) | .021 |
Abbreviation: OR, odds ratio. Values in parentheses are 95% confidence intervals. aAdjusted for age, sex, hypertension, estimated glomerular filtration rate. bAdjusted for age, sex, hypertension, estimated glomerular filtration rate, body mass index, diabetes mellitus, hyperlipidemia.
Discussion
In the present study, we showed that high levels of UA are independently associated with presence of CAC. The association between UA and CHD has been known for many years.1 The presence of CAC is a well‐accepted surrogate marker for total coronary atherosclerosis burden.8, 9, 10 Therefore, it is expected that levels of UA are associated with the presence of CAC.
Several studies have indeed demonstrated a relationship between CAC and serum UA levels,25, 26, 27 but other studies do not support these findings.28, 29
Serum UA was found to be an independent risk factor for the presence of CAC in a group of 442 patients who were evaluated for suspected CHD.27
In an asymptomatic Brazilian population with moderate risk for CHD, high UA levels were independently associated with CAC only in patients with the metabolic syndrome.33 Our study included asymptomatic patients who were routinely screened for the presence of CAC. We did not analyze the data according to the presence of the metabolic syndrome, but the association of UA levels and CAC were still significant after adjustment for most of the components of the metabolic syndrome. Rodrigues and colleagues25 demonstrated that UA levels predicted progression of CAC in patients without renal disease. These results support our findings. Unlike the findings supporting the association between UA and CAC, Neogi28 and Coutinho29 and associates did not observe an independent association between UA and CAC. It is noteworthy that despite the lack of association between UA and CAC, Neogi and colleagues34 demonstrated in the same cohort an association between serum UA and carotid atherosclerosis, suggesting an association between UA and subclinical atherosclerosis.
In light of the conflicting results regarding the association between UA and CAC, our relatively large study supports an independent association. We did not find an association between UA levels and TCS. This may be related to the asymmetric distribution of TCS, as 47% of the study group had TCS=0 and the maximal TCS was 3111 units.
Several proatherogenic properties have been attributed to UA.35, 36 UA may stimulate vascular smooth cell proliferation and induce endothelial dysfunction, thereby accelerating atherosclerosis and coronary calcification.36 On the other hand, a protective role has been attributed to UA as a result of its antioxidant effect.37 Therefore, it is unclear whether UA has a pathogenic role in the development of atherosclerosis or it is a part of a protective mechanism, and therefore serves only as a marker of atherosclerosis.
The results of this study imply that UA can serve as an indicator of subclinical atherosclerosis in asymptomatic patients with low‐moderate CHD risk. It is unclear whether increased UA levels by diuretics are also associated with the presence of CAC. Unfortunately, we are unable to answer this question from the present study since we do not have information regarding the use of diuretics.
In order to assess whether UA has a pathogenic role in the development of atherosclerosis, a randomized study in which UA‐lowering agents are used should be conducted.
Regardless of the role of UA in the pathogenesis of atherosclerosis, it seems reasonable to recommend the institution of lifestyle modification and control of CHD risk factors in patients with elevated UA.
Study Strengths and Limitations
A strength of our study is the use of well‐measured cardiovascular clinical and laboratory risk factors in a relatively large cohort of asymptomatic patients. Our study has several limitations. First, our study group represents a population that participates regularly in an annual survey. These patients represent a distinct population highly willing and motivated to assess their CHD risk and may not represent the general population. Second, we do not have data on drug treatment that may alter UA levels. However, we believe that the use of these agents were not common and therefore could not affect the association between UA and CAC.
Conclusions
We demonstrated in the present study that elevated serum UA levels are associated with the presence of CAC.
Conflict of Interest
None.
J Clin Hypertens (Greenwich). 2014;16:424–428. DOI: 10.1111/jch.12313. © 2014 Wiley Periodicals, Inc.
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