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Serum uric acid levels predict the severity and morphology of coronary atherosclerosis detected by multidetector computed tomography
Atherosclerosis 213 (2010) 178–183
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Serum uric acid levels predict the severity and morphology of coronary atherosclerosis detected by multidetector computed tomography Ergün Barıs¸ Kaya a , Hikmet Yorgun a , U˘gur Canpolat a,∗ , Tuncay Hazırolan b , Hamza Sunman a , Ays¸egül Ülgen a , Ahmet Hakan Ates a , Kudret Aytemir a , Lale Tokgözo˘glu a , Giray Kabakcı a , Deniz Akata b , Ali Oto a a b
Department of Cardiology, Hacettepe University, Ankara, Turkey Department of Radiology, Hacettepe University, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 24 June 2010 Received in revised form 19 August 2010 Accepted 24 August 2010 Available online 21 September 2010 Keywords: Coronary atherosclerosis Serum uric acid Multidetector computed tomography
a b s t r a c t In this study, we aimed to evaluate whether serum uric acid (UA) was associated with the severity and morphology of coronary atherosclerotic plaques (CAP) shown by multidetector computed tomography (MDCT). The study population consisted of 982 patients (58% men) who underwent dual-source 64 slice MDCT for the assessment of coronary artery disease (CAD). Coronary arteries were evaluated on 16 segment basis and critical coronary plaque was described as luminal narrowing >50%, whereas plaque morphology was assessed on per segment basis. Serum UA levels were determined using commercially available assay kits. The critical atherosclerotic lesions were detected in 454/982 (46.2%) subjects by MDCT. Serum UA levels were found to be higher in patients with any coronary plaque (6.9 ± 1.5 mg/dL vs. 5.1 ± 1.3 mg/dL, p < 0.01). Also UA level was higher in patients with critical stenosis compared to noncritical stenosis (6.1 ± 1.5 mg/dL vs. 5.4 ± 1.3 mg/dL, p < 0.001). Subjects having primarily calcified plaques have higher UA levels compared to other plaque subtypes (5.5 ± 1.3 for non-calcified plaques, and 5.6 ± 1.2 for mixed plaques, 6.6 ± 1.6 for calcified plaques, p < 0.001). This independent association was remained after multinominal regression analysis (OR: 1,987; 95% CI; 1.69–2.32; p < 0.01). Our study demonstrated that serum UA level was significantly associated with the severity and the calcified morphology of CAP detected by MDCT. Further prospective clinical studies are needed to clarify the exact physiopathologic role of UA in CAD. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Several epidemiological studies have shown that increased serum uric acid (UA) level, which is the main end product of purine metabolism, was associated with cardiovascular diseases [1]. The relationship between higher serum UA levels and several cardiovascular risk factors, endothelial dysfunction and subclinical atherosclerosis was shown in previous studies [2–4]. Although the pathogenesis of this relation is not clear for today, recent studies suggested paradoxical oxidant and inflammatory properties in contrary to previous hypothesis regarding its antioxidant properties [5–7]. There were few studies in the literature assessing the relationship between serum UA levels and angiographic severity of
∗ Corresponding author at: Hacettepe University, Faculty of Medicine, Department of Cardiology, Sıhhiye-06100, Ankara, Turkey. Tel.: +90 312 305 1780; fax: +90 312 305 4137. E-mail address: dru [email protected] (U. Canpolat). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.08.077
coronary artery disease (CAD) [8,9]. A recent study investigating the association between UA levels and angiographic severity of CAD concluded that UA level was associated with the presence but not with the severity of CAD [9]. The relationship between serum UA levels and coronary artery calcification was also assessed and higher UA levels were found to be independently associated with coronary artery calcification in subjects with the metabolic syndrome [10]. Multidetector computed tomography (MDCT) coronary angiography is an established quantitative and objective method for the non-invasive evaluation of coronary atherosclerosis [11–13]. Coronary MDCT can also give additional information regarding plaque morphology and plaque remodeling in addition to the severity of coronary atherosclerosis [14]. Beyond the degree of luminal narrowing, plaque composition can give valuable data about the various clinical manifestations of CAD [15,16]. To our knowledge, there is no published data on the relationship between serum UA levels and the severity and morphology of coronary atherosclerotic plaques (CAP) detected by MDCT. In this study, we aimed to assess the relationship of the serum UA levels with several indices of the
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coronary atherosclerosis using dual-source 64 slice MDCT in a large cohort of subjects without a history of CAD. 2. Methods 2.1. Study sample This cross-sectional study was performed in a consecutive subset of patients, who admitted to our Cardiology Department for cardiovascular evaluation and in whom MDCT coronary angiography was performed for the suspicion of CAD after clinical assessment. Patients with a history of CAD, heart failure, renal dysfunction (serum creatinine levels ≥1.5 mg/dL), hepatic and hemolytic disorders, concomitant inflammatory diseases, neoplastic diseases or any other systemic disorders, alcohol consumption, vitamin use (including vitamin C, niacin, folate), and patients taking diuretic medications or UA lowering medications like allopurinol were excluded from the study. This study was approved by the local ethics committee and informed consent was taken from each participant. 2.2. Baseline definitions and risk factor assessment All subjects provided details of their demographics, medical histories, and medication usages at the time of clinical consultation. Blood pressure was obtained in a sitting position after approximately 5 min and hypertension was defined as a diastolic blood pressure ≥90 mm Hg or a systolic blood pressure ≥140 mm Hg or the self-reported use of antihypertensive drug(s) [17]. Diabetes mellitus was diagnosed in patients with a history of oral antidiabetic, insulin medication or fasting blood glucose ≥126 mg/dL at study entrance [18]. A history of cigarette smoking was considered present if a subject was a current smoker. A positive family history was defined as CAD in a parent or sibling noted under the age of 55 for men and 65 for women. Height and weight were measured according to a standardized protocol. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Metabolic syndrome (MS) was defined by the presence of ≥3 of the following criteria: obesity assessed by body mass index ≥30 kg/m2 ; serum triglyceride (TG) level ≥150 mg/dL; highdensity lipoprotein (HDL) cholesterol levels <40 mg/dL in men and <50 mg/dL in women; fasting glucose level ≥100 mg/dL; blood pressure ≥130/85 mm Hg or medically treated hypertension [19]. Pre-test probability for obstructive CAD was calculated for individual patients using age, sex, and symptoms [20]. Framingham risk score was used to predict 10 year risk of CAD [21]. 2.3. Blood sample collection and measurement of biochemical markers Venous blood samples were obtained by the venipuncture of the large antecubital veins of the patients. Blood samples were obtained after an overnight fasting and the serum levels TG, total cholesterol, low-density lipoprotein (LDL) cholesterol, HDL cholesterol and fasting glucose were determined using commercially available assay kits (Hitachi P800, Holliston, Massachusetts, USA) at the time of cardiovascular evaluation. Serum UA levels were determined with enzymatic colorimetric method by clinical chemistry auto-analyzer (Aeroset, Abbott Laboratory, Abbott Park, IL, USA). 2.4. Coronary MDCT All subjects underwent coronary MDCT imaging using dualsource 64 slice MDCT scanner (Somatom Definition; Siemens, Erlangen, Germany). All subjects were in sinus rhythm without
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tachycardia, so beta-blockers were not given before scanning. Sublingual nitrate (5 mg of isosorbide dinitrate, Fako Isordil) was given 2–4 min before image acquisition to dilate the coronary arteries. The coronary angiographic scan was obtained with injection of 80 mL of nonionic contrast medium (350 mg I/mL iomeprol, Bracco Omnipaque) at a flow rate of 6 mL/s followed by 50 mL of saline solution with same injection rate to wash out the contrast material from the right ventricle. Contrast administration was controlled with bolus tracking. The scan parameters were detector collimation, 32 mm × 0.6 mm; slice acquisition, 64 mm × 0.6 mm; gantry rotation time, 330 ms; temporal resolution, 83 ms; pitch, 0.2–0.47 adapted to the heart rate; tube current, 390 mAs per rotation; tube potential, 120 kV. Scanning time was approximately 5.7–8.4 s, depending on the cardiac dimensions and pitch, in a single breath hold in the craniocaudal direction. Prospective ECG tube-current modulation (ECG pulsing) for radiation dose reduction was used for all patients. Retrospective gating technique was used to synchronize data reconstruction with the ECG signal. The reconstructions were made in all cardiac phases at 50-ms intervals at a slice thickness of 0.75 mm and a reconstruction increment of 0.5 mm. The reconstruction interval with the fewest motion artifacts was chosen and used for further analysis.
2.5. MDCT evaluation All images were interpreted immediately after scanning by an experienced radiology practitioner who was unaware of the clinical presentation of patients. Coronary artery plaque (CAP) was defined as any clearly discernible structure attributable to the coronary artery wall in at least 2 independent image planes. Nonsignificant CAP was defined as lesions causing ≤50% luminal narrowing, significant CAP was defined as lesions causing >50% luminal narrowing. For categorization of the CAP, the coronary system was divided into 16 separate segments based on a modified American Heart Association classification using original axial images, thin slice, maximal intensity projections, and cross-sectional reconstructions orthogonal to the long axis of each coronary segment (0.75 mm thickness) [22]. For each segment, CAPs were categorized as (1) none, (2) calcified plaque (CP) (defined as a CT density more than the contrast-enhanced coronary lumen), (3) non-calcified plaque (NCP) (defined as a CT density less than the contrast-enhanced coronary lumen but greater than the surrounding tissue), (4) mixed plaque (MP) (having both calcified and non-calcified components) (Fig. 1). All plaque components and significant stenosis were assessed on per segment basis.
2.6. Statistical analysis Continuous variables were expressed as mean ± SD and categorical variables were expressed as percentages. Categorical variables were analyzed by chi-square test. Comparisons of continuous variables between the two groups were performed using the independent samples t-test. To determine independent predictors of the severity and morphology of coronary atherosclerosis, multiple logistic regression analysis was performed by including the parameters, which were significantly different between the groups. To evaluate whether the risk factor profiles were different across the 3 groups of subjects with exclusively NCP, MP, or CP, we performed ANOVA test and chi-square trend test for categorical variables. Multinominal logistic regression analysis was performed to determine the independent predictors of the morphology of CAP, between NCP, MP, or CP. Statistical analyses were performed using SPSS statistical software (version 15.0; SPSS Inc., Chicago, IL). A p value <0.05 was considered statistically significant.
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Fig. 1. Contrast-enhanced multidetector computed tomographic image of (A), nonsignificant, non-calcified plaque at proximal right coronary artery (RCA) (arrow); (B) nonsignificant, mixed plaque at the middle RCA (arrows); (C) significant non-calcified plaque at the proximal left anterior descending artery (LAD) (arrow) and (D) significant calcified plaque at the middle LAD (arrow).
3. Results Our study population consisted of 982 subjects (mean age 58.6 ± 11.4 years, and 58% men). Basal characteristics of subjects were shown in Table 1. Among the patients that were analyzed, 68.1% of them had hypertension, 22.4% of them had diabetes mellitus, 38.7% of them were smoker, and 10% of them had a history of premature CAD in their family. Critical coronary plaques were detected in 454/982 (46.2%) of subjects. The percentage of patients with non-critical plaques was 32.1% (n = 315) and normal coronary arteries were found in 213 patients (21.7%). The baseline characteristics of two groups categorized according to the severity of coronary atherosclerotic lesions detected by MDCT were shown in Table 1. Age, hypertension, family history of premature CAD, body mass index and serum creatinine levels were similar between two groups. Compared with subjects having non-critical coronary stenosis, subjects with critical stenosis had a significantly higher prevalence of diabetes mellitus (30% vs. 20.4%, p < 0.001) and smoking history (48.8% vs. 34.3%, p < 0.001). Serum total cholesterol, LDL cholesterol and triglyceride levels were higher in patients with critical stenosis but HDL cholesterol serum levels were higher in non-critical stenosis group. Lipid lowering therapy with statins was higher in the critical stenosis group (70.3% vs. 58.3%, p < 0.01). Serum UA levels were found to be higher in patients with critical stenosis than without critical stenosis (6.1 ± 1.5 mg/dL vs. 5.4 ± 1.3 mg/dL; p < 0.001). In the logistic regression analysis, male gender (odds ratio (OR), 1.64; 95% confidence interval (CI), 1.18–2.27, p = 0.003), diabetes mellitus (OR, 1.59; 95% CI, 1.12–2.24; p = 0.009), total cholesterol (OR, 2.01; 95%CI, 1.63–3.34; p < 0.001), LDL cholesterol (OR, 2.45;
95%CI, 1.72–3.47; p < 0.001), and serum UA levels (OR, 1.49; 95%CI, 1.08–2.05; p = 0.015) remained significant predictors of the severity of coronary atherosclerosis after adjustment for other risk factors (Fig. 2). In our study group, MS was detected in 317 patients (32.2%). Serum UA levels were higher in the patients with critical stenosis than without critical stenosis, independent from the presence of MS. However, in contrast to NCP and MP, higher serum UA levels were associated with calcific CAP in patients with MS when compared to patients lacking MS (5.9 ± 1.7 mg/dL vs. 5.5 ± 1.6 mg/dL; p < 0.01). We also analyzed the association of serum UA levels with plaque morphology of the coronary arteries. Among 982 patients, 769 (78.3%) patients have atherosclerotic plaques in coronary arteries. When subjects were stratified into having primarily mixed, non-calcified and calcified plaque (defined as >70% of all segments
Fig. 2. Association between critical coronary plaque and several cardiovascular risk factors including male gender, diabetes mellitus, LDL cholesterol, total cholesterol and serum uric acid levels in multiple logistic regression analysis (p < 0.05).
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Table 1 Basal characteristics of patients having critical stenosis and non-critical stenosis. Non-critical stenosis (n = 315)
Critical stenosis (n = 454)
p value
Age (years) Gender: male (%)
60.3 ± 10.6 53.0
61.1 ± 9.9 69.9
NS <0.001
Clinical presentation Symptomatic patients (%, n) Asymptomatic patients (%, n)
45.7 (144) 54.3 (171)
68.5 (380) 31.5 (174)
<0.001 <0.001
Pre-test probability of CAD Low (<15%) Intermediate (15–85%) High (>85%)
17.9 72 10.1
16.1 66.1 17.8
<0.001
Hypertension (%) Diabetes mellitus (%) History of smoking (%) History of premature CAD (%) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) BMI (kg/m2 )
70.0 20.4 34.3 8.0 198.9 ± 45.8 151.9 ± 72.6 50.5 ± 14.3 125.1 ± 38.8 5.4 ± 1.3 28.1 ± 4.5
73.6 30.0 48.8 11.6 207.9 ± 47.9 165.8 ± 92.4 47.7 ± 15.3 130.8 ± 42.1 6.1 ± 1.5 27.6 ± 4.1
NS 0.001 <0.001 NS 0.036 0.023 0.019 0.044 <0.001 NS
Framingham risk score Low risk (%, n) Intermediate risk (%, n) High risk (%, n)
22.2 (70) 48.9 (154) 28.9 (91)
31.5 (143) 42.0 (191) 26.5 (120)
0.017
Serum creatinine (mg/dL) Acetylsalicylic acid (%) Beta blocker (%) Calcium channel blocker (%) ACE inhibitors (%) Angiotensin receptor blockers (%) Statins (%)
0.9 ± 0.2 73.2 64.8 12.8 26.5 25.6 58.3
0.9 ± 0.3 76.4 67.2 15.9 29.2 28.1 70.3
NS NS NS NS NS NS <0.001
BMI: body mass index; CAD: coronary artery disease, HDL: high-density lipoprotein; LDL: low-density lipoprotein; ACE: Angiotensin converting enzyme; NS: nonsignificant.
including CAP), 430 (55.9%) patients have NCP, 146 (19.0%) have MP, and 193 (25.1%) have CP (Table 2). The patients having primarily CP have higher serum UA levels compared with normal coronary artery, NCP and MP (6.6 ± 1.6 vs. 5.2 ± 1.3 for normal coronaries, 5.5 ± 1.3 for NCP, and 5.6 ± 1.2 for MP, respectively, p < 0.001). In the multinominal logistic regression analysis age, male gender, total cholesterol, LDL cholesterol, smoking and diabetes mellitus seemed significant predictors of primarily NCP (OR: 1.07, p < 0.001; OR: 0.39, p < 0.001; OR: 2.07, p < 0.001; OR: 2.53, p < 0.001, OR: 1.87, p < 0.001; OR: 1.87, p < 0.001, respectively, Table 3) after
adjustment for other risk factors. Serum UA levels were not a significant predictor of NCP in multinominal logistic regression (p = 0.549). Age, male gender, total cholesterol, LDL cholesterol, smoking and diabetes mellitus remained significant predictors of primarily MP (OR: 1.07, p < 0.001; OR: 0.57, p < 0.001; OR: 2.45, p < 0.001; OR: 2.84, p < 0.001; OR: 1.62, p < 0.001; OR: 1.779, p < 0.001, respectively). Serum UA levels were not a significant predictor of MP in multinominal logistic regression similar to NCP (p = 0.164). In contrast to NCP and MP, serum UA levels appeared a significant predictor of CP (OR: 1.98, p < 0.001). Older age, total cholesterol, LDL cholesterol and diabetes mellitus remained the sig-
Table 2 Basal characteristics of patients having mixed, non-calcified and calcified plaques.
n Age (years) Gender: male (%) Hypertension (%) Diabetes mellitus (%) Smoking (%) History of premature CAD (%) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) BMI (kg/m2 ) Serum creatinine (mg/dL) Framingham risk score Low risk (%, n) Intermediate risk (%, n) High risk (%, n)
Non-calcified plaque
Mixed plaque
Calcified plaque
p value
430 60.8 ± 10.1 65.7 71.4 26.5 46.8 10.2 198.6 ± 46.3 161.2 ± 86.7 48.4 ± 14.6 124.8 ±40.6 5.5 ± 1.3 27.5 ± 4.0 0.9 ± 0.2
146 61.1 ± 11.3 58.2 65.7 24.6 41.0 6.7 202.9 ± 48.4 164.1 ± 93.5 49.3 ± 13.4 128.0 ± 40.1 5.6 ± 1.2 28.2 ± 5.3 0.9 ± 0.2
193 61.4 ± 10.6 59.6 78.8 26.4 36.5 10.4 212.6 ± 43.9 156.5 ± 78.1 49.5 ± 17.7 135.8 ± 36.3 6.6 ± 1.6 28.2 ± 4.4 1.0 ± 0.3
NS NS 0.028 NS 0.036 NS 0.007 NS NS 0.016 <0.001 NS NS
31.4 (135) 47.4 (204) 21.2 (91)
25.4 (37) 43.1 (63) 31.5 (46)
21.2 (41) 40.4 (78) 38.4 (74)
BMI: body mass index; CAD: coronary artery disease, HDL: high-density lipoprotein; Hx: history; LDL: low-density lipoprotein; NS: nonsignificant.
<0.001
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Table 3 Multinominal regression analysis demonstrating the association between cardiovascular risk profiles and the morphology of primarily non-calcified coronary atherosclerotic plaque (>70%), primarily mixed plaque (>70%), and primarily calcified plaque (>70%). Variable
Age, years Gender, male Hypertension Total cholesterol LDL cholesterol Diabetes mellitus Smoking Uric acid
Primarily non-calcified plaque
Primarily mixed plaque
Primarily calcified plaque
OR (95% CI)
p value
OR (95% CI)
p value
OR (95% CI)
p value
1.07 (1.05–1.09) 0.39 (0.27–0.55) 1.06 (0.75–1.51) 2.07 (1.61–3.34) 2.53 (1.81–3.53) 1.87 (1.23–2.85) 1.87 (1.33–2.65) 1.04 (0.91–1.18)
0.01 0.01 0.70 0.01 0.01 0.01 0.01 0.54
1.07 (1.05–1.10) 0.57 (0.35–0. 93) 0.73 (0.45–1.18) 2.45 (1.63–3.98) 2.84 (1.73–4.68) 1.77 (1.03–3.06) 1.62 (1.01–2.62) 1.13 (0.95–1.34)
0.01 0.02 0.20 0.01 0.01 0.03 0.04 0.16
1.07 (1.05–1.09) 0.69 (0.43–1.09) 1.31 (0.81–2.12) 1.51 (1.01–2.37) 1.57 (1.02–2.41) 1.89 (1.13–3.15) 1.15 (0.73–1.80) 1.98 (1.69–2.32)
0.01 0.11 0.26 0.01 0.01 0.15 0.54 0.01
OR: odds ratio; CI: confidence interval, LDL: low-density lipoprotein.
nificant predictor of calcified coronary plaque (OR: 1.07, p < 0.001; OR: 1.51, p < 0.05; OR: 1.57, p < 0.05; OR: 1.89, p < 0.05, respectively). 4. Discussion In this study, we aimed to assess the association between serum UA levels and the severity and morphology of CAP detected by MDCT coronary angiography in a cohort of patients who admitted to our department for the evaluation of CAD. To the best of our knowledge, this is the first study in the literature investigating the role of serum UA levels and coronary atherosclerosis shown by MDCT coronary angiography. Our results demonstrated that increasing serum UA levels were associated with the severity and calcific morphology of CAP. There were several studies documenting the independent relationship between serum UA levels and cardiovascular diseases [23–25]. Although serum UA has antioxidant properties by scavengering free radicals, the antioxidant state is paradoxically reversed in the late stages of the atherosclerotic process [6,26]. The association between serum UA and inflammatory markers including leukocytes, neutrophils, C-reactive protein, IL-1, IL-6, IL-18 and TNF-␣ was found in a large population-based sample of older persons [27]. Although there were promising results regarding the role of serum UA as a marker for CVD, whether high serum UA is an innocent bystander or increased as a compensatory attempt to counteract the oxidative stress is still unclear. Endothelial dysfunction is accepted as an early process in the development of atherosclerosis [28]. The relationship between serum UA level and flow-mediated dilatation (FMD) of brachial artery was reported in many studies and it was concluded that increased serum UA level is correlated with a decrease in FMD, a surrogate measure of endothelial dysfunction [6,29]. Higher serum UA levels were also associated with angiographically proven CAD. Gur et al. [9] examined the relation of serum UA levels with the presence and severity of angiographic CAD and concluded that UA level was associated with the presence but not with the severity of CAD. However, Tatli et al. [30] stated that higher serum UA levels were associated with critical CAD in young patients (<35 years) with acute myocardial infarction. In our study, male gender, diabetes mellitus, dyslipidemia, and serum UA were seemed as the significant predictors of the severity of CAP after adjustment of other risk factors. The relationship between CAP subtypes and traditional CV risk factors was shown in several studies. Coutinho et al. [4] examined the association of serum UA with the presence and quantity of coronary artery calcification (CAC) which revealed an association between UA and the presence and quantity of CAC, but not independent from traditional risk factors. Recently, in a crosssectional study including 559 subjects by Santos et al. [10], higher UA level was independently associated with the presence and severity of CAC with the relation being especially strong in those
with metabolic syndrome. Our study results were in line with those previous studies revealing an independent association between serum UA levels and CP. Furthermore, higher serum UA levels were associated with CP in patients with metabolic syndrome when compared to patients lacking metabolic syndrome. However CP does not represent the entire atherosclerotic burden of coronary arteries and NCP were associated with acute coronary syndrome more than calcified plaques [31]. MDCT coronary angiography is a rapidly evolving method for the evaluation of CAD with high sensitivity and specificity, providing both visualization of the vessel lumen and the coronary vessel wall including plaque morphology [32]. In addition to luminal narrowing, characterization of plaque composition (i.e., CP, NCP, or MP) gives important information regarding clinical manifestations of CAD [16]. In a study by Bamberg et al. [33] younger age, hyperlipidemia and a family history of CAD were significantly associated with the extent of NCP, and older age was a predictor of the presence of MP and CP. In a recent study by Rivera et al. [34], male gender and age were the strongest multivariate predictors for the presence of CP (male gender: OR 4.78; 95% CI 2.48, 9.23; age: OR 2.75; 95% CI 2.12, 3.58). Our study revealed that, in addition to older age, LDL cholesterol, diabetes mellitus and serum UA levels were also associated with the presence of CP according to the multivariate regression analysis. Serum UA was not associated with non-calcified or mixed plaques. Results of this study should be interpreted in the light of some limitations. First, this study was a cross-sectional study in a group of patients in whom non-invasive assessment for CAD was needed and the aim was to define the relationship between serum UA levels and CAP. Therefore prospective studies are needed to clarify the exact role of serum UA in the process of coronary atherosclerosis. Second, because of racial differences between the prevalence, extent and morphology of coronary atherosclerosis, those findings could not be generalized to all populations. In this study, CAPs were evaluated visually however more precise methods to quantificate the CAP were necessary for more accurate conclusions. Finally, the potential advantages of MDCT coronary angiography over invasive coronary angiography should be weighted against the time consuming nature of CAP evaluation and additional radiation exposure although novel MDCT algorithms may reduce the radiation dose dramatically. In conclusion, our study revealed that higher serum UA levels were associated both with the severity and morphology – calcified plaque – of coronary atherosclerosis detected by MDCT. Thus, beyond a simple and inexpensive marker of CAD risk and subclinical atherosclerosis, serum UA levels seem to be independently associated with the severity of CAP. Moreover, serum UA is associated with calcific coronary plaque, which is an independent predictor of CAD and cardiovascular outcomes. Further prospective clinical studies are needed to clarify the exact physiopathologic role of serum UA in CAD.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Serum uric acid levels predict the severity and morphology of coronary atherosclerosis detected by multidetector computed tomography Ergün Barıs¸ Kaya a , Hikmet Yorgun a , U˘gur Canpolat a,∗ , Tuncay Hazırolan b , Hamza Sunman a , Ays¸egül Ülgen a , Ahmet Hakan Ates a , Kudret Aytemir a , Lale Tokgözo˘glu a , Giray Kabakcı a , Deniz Akata b , Ali Oto a a b
Department of Cardiology, Hacettepe University, Ankara, Turkey Department of Radiology, Hacettepe University, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 24 June 2010 Received in revised form 19 August 2010 Accepted 24 August 2010 Available online 21 September 2010 Keywords: Coronary atherosclerosis Serum uric acid Multidetector computed tomography
a b s t r a c t In this study, we aimed to evaluate whether serum uric acid (UA) was associated with the severity and morphology of coronary atherosclerotic plaques (CAP) shown by multidetector computed tomography (MDCT). The study population consisted of 982 patients (58% men) who underwent dual-source 64 slice MDCT for the assessment of coronary artery disease (CAD). Coronary arteries were evaluated on 16 segment basis and critical coronary plaque was described as luminal narrowing >50%, whereas plaque morphology was assessed on per segment basis. Serum UA levels were determined using commercially available assay kits. The critical atherosclerotic lesions were detected in 454/982 (46.2%) subjects by MDCT. Serum UA levels were found to be higher in patients with any coronary plaque (6.9 ± 1.5 mg/dL vs. 5.1 ± 1.3 mg/dL, p < 0.01). Also UA level was higher in patients with critical stenosis compared to noncritical stenosis (6.1 ± 1.5 mg/dL vs. 5.4 ± 1.3 mg/dL, p < 0.001). Subjects having primarily calcified plaques have higher UA levels compared to other plaque subtypes (5.5 ± 1.3 for non-calcified plaques, and 5.6 ± 1.2 for mixed plaques, 6.6 ± 1.6 for calcified plaques, p < 0.001). This independent association was remained after multinominal regression analysis (OR: 1,987; 95% CI; 1.69–2.32; p < 0.01). Our study demonstrated that serum UA level was significantly associated with the severity and the calcified morphology of CAP detected by MDCT. Further prospective clinical studies are needed to clarify the exact physiopathologic role of UA in CAD. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Several epidemiological studies have shown that increased serum uric acid (UA) level, which is the main end product of purine metabolism, was associated with cardiovascular diseases [1]. The relationship between higher serum UA levels and several cardiovascular risk factors, endothelial dysfunction and subclinical atherosclerosis was shown in previous studies [2–4]. Although the pathogenesis of this relation is not clear for today, recent studies suggested paradoxical oxidant and inflammatory properties in contrary to previous hypothesis regarding its antioxidant properties [5–7]. There were few studies in the literature assessing the relationship between serum UA levels and angiographic severity of
∗ Corresponding author at: Hacettepe University, Faculty of Medicine, Department of Cardiology, Sıhhiye-06100, Ankara, Turkey. Tel.: +90 312 305 1780; fax: +90 312 305 4137. E-mail address: dru [email protected] (U. Canpolat). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.08.077
coronary artery disease (CAD) [8,9]. A recent study investigating the association between UA levels and angiographic severity of CAD concluded that UA level was associated with the presence but not with the severity of CAD [9]. The relationship between serum UA levels and coronary artery calcification was also assessed and higher UA levels were found to be independently associated with coronary artery calcification in subjects with the metabolic syndrome [10]. Multidetector computed tomography (MDCT) coronary angiography is an established quantitative and objective method for the non-invasive evaluation of coronary atherosclerosis [11–13]. Coronary MDCT can also give additional information regarding plaque morphology and plaque remodeling in addition to the severity of coronary atherosclerosis [14]. Beyond the degree of luminal narrowing, plaque composition can give valuable data about the various clinical manifestations of CAD [15,16]. To our knowledge, there is no published data on the relationship between serum UA levels and the severity and morphology of coronary atherosclerotic plaques (CAP) detected by MDCT. In this study, we aimed to assess the relationship of the serum UA levels with several indices of the
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coronary atherosclerosis using dual-source 64 slice MDCT in a large cohort of subjects without a history of CAD. 2. Methods 2.1. Study sample This cross-sectional study was performed in a consecutive subset of patients, who admitted to our Cardiology Department for cardiovascular evaluation and in whom MDCT coronary angiography was performed for the suspicion of CAD after clinical assessment. Patients with a history of CAD, heart failure, renal dysfunction (serum creatinine levels ≥1.5 mg/dL), hepatic and hemolytic disorders, concomitant inflammatory diseases, neoplastic diseases or any other systemic disorders, alcohol consumption, vitamin use (including vitamin C, niacin, folate), and patients taking diuretic medications or UA lowering medications like allopurinol were excluded from the study. This study was approved by the local ethics committee and informed consent was taken from each participant. 2.2. Baseline definitions and risk factor assessment All subjects provided details of their demographics, medical histories, and medication usages at the time of clinical consultation. Blood pressure was obtained in a sitting position after approximately 5 min and hypertension was defined as a diastolic blood pressure ≥90 mm Hg or a systolic blood pressure ≥140 mm Hg or the self-reported use of antihypertensive drug(s) [17]. Diabetes mellitus was diagnosed in patients with a history of oral antidiabetic, insulin medication or fasting blood glucose ≥126 mg/dL at study entrance [18]. A history of cigarette smoking was considered present if a subject was a current smoker. A positive family history was defined as CAD in a parent or sibling noted under the age of 55 for men and 65 for women. Height and weight were measured according to a standardized protocol. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Metabolic syndrome (MS) was defined by the presence of ≥3 of the following criteria: obesity assessed by body mass index ≥30 kg/m2 ; serum triglyceride (TG) level ≥150 mg/dL; highdensity lipoprotein (HDL) cholesterol levels <40 mg/dL in men and <50 mg/dL in women; fasting glucose level ≥100 mg/dL; blood pressure ≥130/85 mm Hg or medically treated hypertension [19]. Pre-test probability for obstructive CAD was calculated for individual patients using age, sex, and symptoms [20]. Framingham risk score was used to predict 10 year risk of CAD [21]. 2.3. Blood sample collection and measurement of biochemical markers Venous blood samples were obtained by the venipuncture of the large antecubital veins of the patients. Blood samples were obtained after an overnight fasting and the serum levels TG, total cholesterol, low-density lipoprotein (LDL) cholesterol, HDL cholesterol and fasting glucose were determined using commercially available assay kits (Hitachi P800, Holliston, Massachusetts, USA) at the time of cardiovascular evaluation. Serum UA levels were determined with enzymatic colorimetric method by clinical chemistry auto-analyzer (Aeroset, Abbott Laboratory, Abbott Park, IL, USA). 2.4. Coronary MDCT All subjects underwent coronary MDCT imaging using dualsource 64 slice MDCT scanner (Somatom Definition; Siemens, Erlangen, Germany). All subjects were in sinus rhythm without
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tachycardia, so beta-blockers were not given before scanning. Sublingual nitrate (5 mg of isosorbide dinitrate, Fako Isordil) was given 2–4 min before image acquisition to dilate the coronary arteries. The coronary angiographic scan was obtained with injection of 80 mL of nonionic contrast medium (350 mg I/mL iomeprol, Bracco Omnipaque) at a flow rate of 6 mL/s followed by 50 mL of saline solution with same injection rate to wash out the contrast material from the right ventricle. Contrast administration was controlled with bolus tracking. The scan parameters were detector collimation, 32 mm × 0.6 mm; slice acquisition, 64 mm × 0.6 mm; gantry rotation time, 330 ms; temporal resolution, 83 ms; pitch, 0.2–0.47 adapted to the heart rate; tube current, 390 mAs per rotation; tube potential, 120 kV. Scanning time was approximately 5.7–8.4 s, depending on the cardiac dimensions and pitch, in a single breath hold in the craniocaudal direction. Prospective ECG tube-current modulation (ECG pulsing) for radiation dose reduction was used for all patients. Retrospective gating technique was used to synchronize data reconstruction with the ECG signal. The reconstructions were made in all cardiac phases at 50-ms intervals at a slice thickness of 0.75 mm and a reconstruction increment of 0.5 mm. The reconstruction interval with the fewest motion artifacts was chosen and used for further analysis.
2.5. MDCT evaluation All images were interpreted immediately after scanning by an experienced radiology practitioner who was unaware of the clinical presentation of patients. Coronary artery plaque (CAP) was defined as any clearly discernible structure attributable to the coronary artery wall in at least 2 independent image planes. Nonsignificant CAP was defined as lesions causing ≤50% luminal narrowing, significant CAP was defined as lesions causing >50% luminal narrowing. For categorization of the CAP, the coronary system was divided into 16 separate segments based on a modified American Heart Association classification using original axial images, thin slice, maximal intensity projections, and cross-sectional reconstructions orthogonal to the long axis of each coronary segment (0.75 mm thickness) [22]. For each segment, CAPs were categorized as (1) none, (2) calcified plaque (CP) (defined as a CT density more than the contrast-enhanced coronary lumen), (3) non-calcified plaque (NCP) (defined as a CT density less than the contrast-enhanced coronary lumen but greater than the surrounding tissue), (4) mixed plaque (MP) (having both calcified and non-calcified components) (Fig. 1). All plaque components and significant stenosis were assessed on per segment basis.
2.6. Statistical analysis Continuous variables were expressed as mean ± SD and categorical variables were expressed as percentages. Categorical variables were analyzed by chi-square test. Comparisons of continuous variables between the two groups were performed using the independent samples t-test. To determine independent predictors of the severity and morphology of coronary atherosclerosis, multiple logistic regression analysis was performed by including the parameters, which were significantly different between the groups. To evaluate whether the risk factor profiles were different across the 3 groups of subjects with exclusively NCP, MP, or CP, we performed ANOVA test and chi-square trend test for categorical variables. Multinominal logistic regression analysis was performed to determine the independent predictors of the morphology of CAP, between NCP, MP, or CP. Statistical analyses were performed using SPSS statistical software (version 15.0; SPSS Inc., Chicago, IL). A p value <0.05 was considered statistically significant.
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Fig. 1. Contrast-enhanced multidetector computed tomographic image of (A), nonsignificant, non-calcified plaque at proximal right coronary artery (RCA) (arrow); (B) nonsignificant, mixed plaque at the middle RCA (arrows); (C) significant non-calcified plaque at the proximal left anterior descending artery (LAD) (arrow) and (D) significant calcified plaque at the middle LAD (arrow).
3. Results Our study population consisted of 982 subjects (mean age 58.6 ± 11.4 years, and 58% men). Basal characteristics of subjects were shown in Table 1. Among the patients that were analyzed, 68.1% of them had hypertension, 22.4% of them had diabetes mellitus, 38.7% of them were smoker, and 10% of them had a history of premature CAD in their family. Critical coronary plaques were detected in 454/982 (46.2%) of subjects. The percentage of patients with non-critical plaques was 32.1% (n = 315) and normal coronary arteries were found in 213 patients (21.7%). The baseline characteristics of two groups categorized according to the severity of coronary atherosclerotic lesions detected by MDCT were shown in Table 1. Age, hypertension, family history of premature CAD, body mass index and serum creatinine levels were similar between two groups. Compared with subjects having non-critical coronary stenosis, subjects with critical stenosis had a significantly higher prevalence of diabetes mellitus (30% vs. 20.4%, p < 0.001) and smoking history (48.8% vs. 34.3%, p < 0.001). Serum total cholesterol, LDL cholesterol and triglyceride levels were higher in patients with critical stenosis but HDL cholesterol serum levels were higher in non-critical stenosis group. Lipid lowering therapy with statins was higher in the critical stenosis group (70.3% vs. 58.3%, p < 0.01). Serum UA levels were found to be higher in patients with critical stenosis than without critical stenosis (6.1 ± 1.5 mg/dL vs. 5.4 ± 1.3 mg/dL; p < 0.001). In the logistic regression analysis, male gender (odds ratio (OR), 1.64; 95% confidence interval (CI), 1.18–2.27, p = 0.003), diabetes mellitus (OR, 1.59; 95% CI, 1.12–2.24; p = 0.009), total cholesterol (OR, 2.01; 95%CI, 1.63–3.34; p < 0.001), LDL cholesterol (OR, 2.45;
95%CI, 1.72–3.47; p < 0.001), and serum UA levels (OR, 1.49; 95%CI, 1.08–2.05; p = 0.015) remained significant predictors of the severity of coronary atherosclerosis after adjustment for other risk factors (Fig. 2). In our study group, MS was detected in 317 patients (32.2%). Serum UA levels were higher in the patients with critical stenosis than without critical stenosis, independent from the presence of MS. However, in contrast to NCP and MP, higher serum UA levels were associated with calcific CAP in patients with MS when compared to patients lacking MS (5.9 ± 1.7 mg/dL vs. 5.5 ± 1.6 mg/dL; p < 0.01). We also analyzed the association of serum UA levels with plaque morphology of the coronary arteries. Among 982 patients, 769 (78.3%) patients have atherosclerotic plaques in coronary arteries. When subjects were stratified into having primarily mixed, non-calcified and calcified plaque (defined as >70% of all segments
Fig. 2. Association between critical coronary plaque and several cardiovascular risk factors including male gender, diabetes mellitus, LDL cholesterol, total cholesterol and serum uric acid levels in multiple logistic regression analysis (p < 0.05).
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Table 1 Basal characteristics of patients having critical stenosis and non-critical stenosis. Non-critical stenosis (n = 315)
Critical stenosis (n = 454)
p value
Age (years) Gender: male (%)
60.3 ± 10.6 53.0
61.1 ± 9.9 69.9
NS <0.001
Clinical presentation Symptomatic patients (%, n) Asymptomatic patients (%, n)
45.7 (144) 54.3 (171)
68.5 (380) 31.5 (174)
<0.001 <0.001
Pre-test probability of CAD Low (<15%) Intermediate (15–85%) High (>85%)
17.9 72 10.1
16.1 66.1 17.8
<0.001
Hypertension (%) Diabetes mellitus (%) History of smoking (%) History of premature CAD (%) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) BMI (kg/m2 )
70.0 20.4 34.3 8.0 198.9 ± 45.8 151.9 ± 72.6 50.5 ± 14.3 125.1 ± 38.8 5.4 ± 1.3 28.1 ± 4.5
73.6 30.0 48.8 11.6 207.9 ± 47.9 165.8 ± 92.4 47.7 ± 15.3 130.8 ± 42.1 6.1 ± 1.5 27.6 ± 4.1
NS 0.001 <0.001 NS 0.036 0.023 0.019 0.044 <0.001 NS
Framingham risk score Low risk (%, n) Intermediate risk (%, n) High risk (%, n)
22.2 (70) 48.9 (154) 28.9 (91)
31.5 (143) 42.0 (191) 26.5 (120)
0.017
Serum creatinine (mg/dL) Acetylsalicylic acid (%) Beta blocker (%) Calcium channel blocker (%) ACE inhibitors (%) Angiotensin receptor blockers (%) Statins (%)
0.9 ± 0.2 73.2 64.8 12.8 26.5 25.6 58.3
0.9 ± 0.3 76.4 67.2 15.9 29.2 28.1 70.3
NS NS NS NS NS NS <0.001
BMI: body mass index; CAD: coronary artery disease, HDL: high-density lipoprotein; LDL: low-density lipoprotein; ACE: Angiotensin converting enzyme; NS: nonsignificant.
including CAP), 430 (55.9%) patients have NCP, 146 (19.0%) have MP, and 193 (25.1%) have CP (Table 2). The patients having primarily CP have higher serum UA levels compared with normal coronary artery, NCP and MP (6.6 ± 1.6 vs. 5.2 ± 1.3 for normal coronaries, 5.5 ± 1.3 for NCP, and 5.6 ± 1.2 for MP, respectively, p < 0.001). In the multinominal logistic regression analysis age, male gender, total cholesterol, LDL cholesterol, smoking and diabetes mellitus seemed significant predictors of primarily NCP (OR: 1.07, p < 0.001; OR: 0.39, p < 0.001; OR: 2.07, p < 0.001; OR: 2.53, p < 0.001, OR: 1.87, p < 0.001; OR: 1.87, p < 0.001, respectively, Table 3) after
adjustment for other risk factors. Serum UA levels were not a significant predictor of NCP in multinominal logistic regression (p = 0.549). Age, male gender, total cholesterol, LDL cholesterol, smoking and diabetes mellitus remained significant predictors of primarily MP (OR: 1.07, p < 0.001; OR: 0.57, p < 0.001; OR: 2.45, p < 0.001; OR: 2.84, p < 0.001; OR: 1.62, p < 0.001; OR: 1.779, p < 0.001, respectively). Serum UA levels were not a significant predictor of MP in multinominal logistic regression similar to NCP (p = 0.164). In contrast to NCP and MP, serum UA levels appeared a significant predictor of CP (OR: 1.98, p < 0.001). Older age, total cholesterol, LDL cholesterol and diabetes mellitus remained the sig-
Table 2 Basal characteristics of patients having mixed, non-calcified and calcified plaques.
n Age (years) Gender: male (%) Hypertension (%) Diabetes mellitus (%) Smoking (%) History of premature CAD (%) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) BMI (kg/m2 ) Serum creatinine (mg/dL) Framingham risk score Low risk (%, n) Intermediate risk (%, n) High risk (%, n)
Non-calcified plaque
Mixed plaque
Calcified plaque
p value
430 60.8 ± 10.1 65.7 71.4 26.5 46.8 10.2 198.6 ± 46.3 161.2 ± 86.7 48.4 ± 14.6 124.8 ±40.6 5.5 ± 1.3 27.5 ± 4.0 0.9 ± 0.2
146 61.1 ± 11.3 58.2 65.7 24.6 41.0 6.7 202.9 ± 48.4 164.1 ± 93.5 49.3 ± 13.4 128.0 ± 40.1 5.6 ± 1.2 28.2 ± 5.3 0.9 ± 0.2
193 61.4 ± 10.6 59.6 78.8 26.4 36.5 10.4 212.6 ± 43.9 156.5 ± 78.1 49.5 ± 17.7 135.8 ± 36.3 6.6 ± 1.6 28.2 ± 4.4 1.0 ± 0.3
NS NS 0.028 NS 0.036 NS 0.007 NS NS 0.016 <0.001 NS NS
31.4 (135) 47.4 (204) 21.2 (91)
25.4 (37) 43.1 (63) 31.5 (46)
21.2 (41) 40.4 (78) 38.4 (74)
BMI: body mass index; CAD: coronary artery disease, HDL: high-density lipoprotein; Hx: history; LDL: low-density lipoprotein; NS: nonsignificant.
<0.001
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Table 3 Multinominal regression analysis demonstrating the association between cardiovascular risk profiles and the morphology of primarily non-calcified coronary atherosclerotic plaque (>70%), primarily mixed plaque (>70%), and primarily calcified plaque (>70%). Variable
Age, years Gender, male Hypertension Total cholesterol LDL cholesterol Diabetes mellitus Smoking Uric acid
Primarily non-calcified plaque
Primarily mixed plaque
Primarily calcified plaque
OR (95% CI)
p value
OR (95% CI)
p value
OR (95% CI)
p value
1.07 (1.05–1.09) 0.39 (0.27–0.55) 1.06 (0.75–1.51) 2.07 (1.61–3.34) 2.53 (1.81–3.53) 1.87 (1.23–2.85) 1.87 (1.33–2.65) 1.04 (0.91–1.18)
0.01 0.01 0.70 0.01 0.01 0.01 0.01 0.54
1.07 (1.05–1.10) 0.57 (0.35–0. 93) 0.73 (0.45–1.18) 2.45 (1.63–3.98) 2.84 (1.73–4.68) 1.77 (1.03–3.06) 1.62 (1.01–2.62) 1.13 (0.95–1.34)
0.01 0.02 0.20 0.01 0.01 0.03 0.04 0.16
1.07 (1.05–1.09) 0.69 (0.43–1.09) 1.31 (0.81–2.12) 1.51 (1.01–2.37) 1.57 (1.02–2.41) 1.89 (1.13–3.15) 1.15 (0.73–1.80) 1.98 (1.69–2.32)
0.01 0.11 0.26 0.01 0.01 0.15 0.54 0.01
OR: odds ratio; CI: confidence interval, LDL: low-density lipoprotein.
nificant predictor of calcified coronary plaque (OR: 1.07, p < 0.001; OR: 1.51, p < 0.05; OR: 1.57, p < 0.05; OR: 1.89, p < 0.05, respectively). 4. Discussion In this study, we aimed to assess the association between serum UA levels and the severity and morphology of CAP detected by MDCT coronary angiography in a cohort of patients who admitted to our department for the evaluation of CAD. To the best of our knowledge, this is the first study in the literature investigating the role of serum UA levels and coronary atherosclerosis shown by MDCT coronary angiography. Our results demonstrated that increasing serum UA levels were associated with the severity and calcific morphology of CAP. There were several studies documenting the independent relationship between serum UA levels and cardiovascular diseases [23–25]. Although serum UA has antioxidant properties by scavengering free radicals, the antioxidant state is paradoxically reversed in the late stages of the atherosclerotic process [6,26]. The association between serum UA and inflammatory markers including leukocytes, neutrophils, C-reactive protein, IL-1, IL-6, IL-18 and TNF-␣ was found in a large population-based sample of older persons [27]. Although there were promising results regarding the role of serum UA as a marker for CVD, whether high serum UA is an innocent bystander or increased as a compensatory attempt to counteract the oxidative stress is still unclear. Endothelial dysfunction is accepted as an early process in the development of atherosclerosis [28]. The relationship between serum UA level and flow-mediated dilatation (FMD) of brachial artery was reported in many studies and it was concluded that increased serum UA level is correlated with a decrease in FMD, a surrogate measure of endothelial dysfunction [6,29]. Higher serum UA levels were also associated with angiographically proven CAD. Gur et al. [9] examined the relation of serum UA levels with the presence and severity of angiographic CAD and concluded that UA level was associated with the presence but not with the severity of CAD. However, Tatli et al. [30] stated that higher serum UA levels were associated with critical CAD in young patients (<35 years) with acute myocardial infarction. In our study, male gender, diabetes mellitus, dyslipidemia, and serum UA were seemed as the significant predictors of the severity of CAP after adjustment of other risk factors. The relationship between CAP subtypes and traditional CV risk factors was shown in several studies. Coutinho et al. [4] examined the association of serum UA with the presence and quantity of coronary artery calcification (CAC) which revealed an association between UA and the presence and quantity of CAC, but not independent from traditional risk factors. Recently, in a crosssectional study including 559 subjects by Santos et al. [10], higher UA level was independently associated with the presence and severity of CAC with the relation being especially strong in those
with metabolic syndrome. Our study results were in line with those previous studies revealing an independent association between serum UA levels and CP. Furthermore, higher serum UA levels were associated with CP in patients with metabolic syndrome when compared to patients lacking metabolic syndrome. However CP does not represent the entire atherosclerotic burden of coronary arteries and NCP were associated with acute coronary syndrome more than calcified plaques [31]. MDCT coronary angiography is a rapidly evolving method for the evaluation of CAD with high sensitivity and specificity, providing both visualization of the vessel lumen and the coronary vessel wall including plaque morphology [32]. In addition to luminal narrowing, characterization of plaque composition (i.e., CP, NCP, or MP) gives important information regarding clinical manifestations of CAD [16]. In a study by Bamberg et al. [33] younger age, hyperlipidemia and a family history of CAD were significantly associated with the extent of NCP, and older age was a predictor of the presence of MP and CP. In a recent study by Rivera et al. [34], male gender and age were the strongest multivariate predictors for the presence of CP (male gender: OR 4.78; 95% CI 2.48, 9.23; age: OR 2.75; 95% CI 2.12, 3.58). Our study revealed that, in addition to older age, LDL cholesterol, diabetes mellitus and serum UA levels were also associated with the presence of CP according to the multivariate regression analysis. Serum UA was not associated with non-calcified or mixed plaques. Results of this study should be interpreted in the light of some limitations. First, this study was a cross-sectional study in a group of patients in whom non-invasive assessment for CAD was needed and the aim was to define the relationship between serum UA levels and CAP. Therefore prospective studies are needed to clarify the exact role of serum UA in the process of coronary atherosclerosis. Second, because of racial differences between the prevalence, extent and morphology of coronary atherosclerosis, those findings could not be generalized to all populations. In this study, CAPs were evaluated visually however more precise methods to quantificate the CAP were necessary for more accurate conclusions. Finally, the potential advantages of MDCT coronary angiography over invasive coronary angiography should be weighted against the time consuming nature of CAP evaluation and additional radiation exposure although novel MDCT algorithms may reduce the radiation dose dramatically. In conclusion, our study revealed that higher serum UA levels were associated both with the severity and morphology – calcified plaque – of coronary atherosclerosis detected by MDCT. Thus, beyond a simple and inexpensive marker of CAD risk and subclinical atherosclerosis, serum UA levels seem to be independently associated with the severity of CAP. Moreover, serum UA is associated with calcific coronary plaque, which is an independent predictor of CAD and cardiovascular outcomes. Further prospective clinical studies are needed to clarify the exact physiopathologic role of serum UA in CAD.
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