The association between serum uric acid level and coronary artery disease

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1 ORIGINAL PAPER The association between serum uric acid level and coronary artery disease O. Sinan Deveci, 1 G. Kabakci, 2 S. Okutucu, 2 E. Tulumen, 2 H. Aksoy, 2 E. Baris Kaya, 2 B. Evranos, 2 K. Aytemir, 2 L. Tokgozoglu, 2 A. Oto 2 1 Department of Cardiology, Kecioren Research and Training Hospital, Ankara, Turkey 2 Department of Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey Correspondence to: Onur Sinan Deveci, Department of Cardiology, Kecioren Research and Training Hospital, Ankara, Turkey Tel.: Fax: onurdeveci@yahoo.co.uk Disclosures The authors of this manuscript have nothing to declare. SUMMARY Objective: This study was designed to determine the relationship between serum uric acid level and the presence and severity of coronary artery disease (CAD). Methods: A total of 1012 patients who underwent coronary angiography were included in this study. All patients were assessed for the presence of cardiovascular risk factors and ongoing medications. Serum uric acid and creatinine level, as well as a fasting lipid profile and fasting blood glucose, were measured in all patients before the procedure. The severity of CAD was assessed by the Gensini score. Results: Of 1012 patients (mean age, 59.4 ± years), 680 were men (mean age, 58.7 ± 10.5 years) and 332 were women (mean age, 61.0 ± 9.51 years). Of the study patients, 703 (69%) were hypertensive, 292 (28.9%) were diabetic (DM), 304 (30%) had a smoking history, 306 (30%) had low high-density lipoprotein cholesterol levels and 350 (34%) had hypertriglyceridaemia. CAD was present in 689 (68%) patients who were assessed by coronary angiography. One-, twoand three-vessel disease was detected in 32.6%, 32.5% and 34.9% of the patients respectively; left main coronary artery lesion was detected in 15% of the patients. A statistically significant difference in the mean uric acid concentrations was found between the patients with or without CAD [380 ± 121 lmol l (6.39 ± 2.04 mg dl) vs ± 83.2 lmol l (5.44 ± 1.40 mg dl) p < 0.001]. Based on logistic regression analysis, the increased serum uric acid level was found to be associated with the presence of CAD in both men and women (p < 0.001). The increased serum uric acid level was also found to be associated with the severity of CAD in both men and women based on multivariate linear regression analysis (p < 0.001). Conclusion: In conclusion, serum uric acid level was found to be associated with the presence and severity of CAD. What s known Although elevated uric acid levels have been shown to be associated with angiographic evidence of coronary artery disease, whether uric acid actually contributes to the disease progress has been the subject of debate. What s new A strong association has been found between serum uric acid level and the presence and severity of coronary artery disease. In addition to the evaluation of conventional risk factors in daily clinical practice, the measurement of uric acid level might provide significant prognostic benefits in terms of global cardiovascular risk and management of patients. Introduction Despite recent advances in treatment methods, cardiovascular diseases remain as the leading cause of death in all developed countries. The relationship between increased serum uric acid level and the development of cardiovascular disease has been investigated for more than 50 years (1). In some studies, uric acid was found to be an independent risk factor for both cardiovascular and renal diseases (2 4). The effects of uric acid on the development of cardiovascular and renal diseases have been demonstrated in animal models and cell cultures (5 7). In contrast, a number of studies have suggested that uric acid is not independent of other established risk factors, especially hypertension, for the development of cardiovascular disease (8,9). Although elevated uric acid levels have been shown to be associated with angiographic evidence of coronary artery disease (CAD), whether uric acid actually contributes to the disease progress has been the subject of debate. This study was planned to investigate whether there is an association between serum uric acid level and the presence and extent of CAD. Methods The study population consisted of 1012 patients in whom elective coronary angiography was performed in our centre between April 2006 and May 2008 because of cardiac symptoms, ECG changes or a positive stress test. Of these patients, 332 were 900 doi: /j x

2 Coronary artery disease and uric acid level 901 women and 680 were men. Exclusion criteria were the first 4 weeks of acute coronary syndrome, previous percutaneous coronary intervention stent implantation and or previous coronary artery bypass grafting, presence of heart failure, alcohol consumption, vitamin use (including vitamin C, niacin, folate), active infectious or autoimmune diseases, neoplastic disease, chronic liver disease and patients with severely impaired renal function (GFR <30ml min) (10). The glomerular filtration rates (GFR) of the patients were calculated by the Modification of Diet in Renal Disease formula (11), using age, gender, serum creatinine and race variables. This study was designed as an observational prospective cohort study. The patients were assessed a day prior to coronary angiography and a full clinical history was obtained, including information about cardiovascular risk factors, smoking habits and ongoing medications. Body weight, height, waist and hip circumference were measured and recorded for all patients. The body mass index (BMI) of patients was calculated. Patients were diagnosed as hypertensive if the systolic and diastolic blood pressures were > mmhg for diabetic subjects and > mmhg for non-diabetic subjects respectively, or if the patient was on antihypertensive medication. Patients in whom the fasting plasma glucose was > 126 mg dl or 6.9 mmol l (if the blood glucose level is greater than or equal to 126 mg dl, the person is retested) or patients, on antidiabetic medication, were diagnosed with diabetes mellitus (DM). HbA1c levels were obtained from all diabetic subjects. 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 of uric acid (UA), triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols and fasting glucose were analysed using commercially available assay kits (Hitachi 911 Analyser; Sentinel Ch., Milan, Italy) at the time of cardiovascular evaluation. Serum uric acid was measured with spectrophotometry. The uric acid is oxidised with uricase to peroxide, which in turn generates quinonamine (12), measured at 546 nm (Reagence from Boehringer Mannheim Imprecision: coefficient of variation (CV) = 3.8% at the 427 lmol l-level, reference interval male mg dl, lmol l). High LDL-cholesterol levels were defined as > 130 mg dl, (3.36 mmol l) and low HDL-cholesterol levels were defined as < 40 mg dl (1.036 mmol l) for both gender. Informed consent was obtained in accordance with the study protocol approved by the local ethics committee. Coronary Angiography and Gensini Score Selective coronary angiography was performed in all patients under local anaesthesia via femoral artery using the Judkins technique (13). All coronary angiograms were evaluated by two experienced cardiologists who were blinded to the laboratory results of the patients. The severity of the each lesion was assessed by quantitative coronary angiography. The presence and total severity of CAD was assessed according to the Gensini scoring system (14). In this system, angiographic stenosis between 0% and 25% is scored as 1 point, between 25% and 50% is scored as 2 points, between 50% and 75% is scored as 4 points, between 75% and 90% is scored as 8 points, between 90% and 99% is scored as 16 points and total occlusion is scored as 32 points. These scores are multiplied by the coefficient defined for each coronary artery and segment, and the results are then added. The presence of CAD has been defined as the Gensini score being > 0. In cases with discrepancies between Gensini scores, angiograms were re-evaluated to reach a consensus. Intra-observer agreement for the Gensini Scores was substantial, Simple agreement (SA) was 96% and Kappa (K) = , (p < 0.001). Similarly, interobserver agreement was also satisfactory, SA was 92%, K = , (p < 0.001). Statistical analysis Data are demonstrated as mean ± SD for normally distributed continuous variables, median (minimum maximum) for skew-distributed continuous variables and frequencies for categorical variables. Independent sample t-test and the v 2 -test were performed for the comparison of categorical variables. Mean values of normally distributed continuous variables were compared by analysis of variance (ANOVA). Skew-distributed continuous variables were compared by Mann Whitney U-test. Multivariate logistic regression analysis was performed to assess the effects of age, gender, diabetes, hypertension, total cholesterol, LDL, HDL, BMI and uric acid on CAD. Multivariate linear regression analysis was performed to evaluate the effects of the same variables on the severity of CAD, as defined by the Gensini score. Spearman correlation analysis was used to assess the relationship between the Gensini score and uric acid. One-way ANOVA was performed using the Games Howell test to compare Gensini scores of four different groups classified according to the serum uric acid quartiles. Homogeneity of variances was tested by the Welch test (15). Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) for Windows, version 15 (SPSS Inc., Chicago, IL, USA) and two-tailed p-value less than 0.05 was considered statistically significant.

3 902 Coronary artery disease and uric acid level Results Of 1012 patients (mean age, 59.4 ± years), 680 were men (mean age, 58.7 ± 10.5 years) and 332 were women (mean age, 61.0 ± 9.51 years). CAD was present in 689 (68%) patients. Patients were allocated into two groups in terms of presence of CAD. Patients with Gensini scores > 0 were defined as the group with CAD, and those with Gensini score of 0 were classified as the group without CAD. Demographic characteristics, the distribution of cardiovascular risk factors, uric acid levels and the Gensini scores of the groups are presented in Table 1. One-, two- and three-vessel diseases were detected in 32.6%, 32.5% and 34.9% of patients with CAD respectively, and left main coronary artery lesion was detected in 15% of the patients. The mean Gensini score was 34.3 ± 33.7 in the group with CAD. Patients with or without CAD were similar in terms of age (59.5 ± 9.7 years vs ± 10.1 years) and gender (66% man vs. 68% man). DM was significantly more frequent (35% vs. 15%, p = 0.036), and the LDL-C level was significantly higher [119.3 ± 33.6 mg dl (3.08 ± 0.87 mmol l) vs ± 38.7 mg dl (3.2 ± 1.0 mmol l), p = 0.045] in patients with CAD. No significant difference was found between patients with or without CAD in terms of systolic ( ± 27.2 vs ± 28.2 mmhg) and diastolic blood pressure (84.2 ± 14.4 vs ± 13.6 mmhg), HDL-C level [46.2 ± 14.3 mg dl (1.19 ± 0.37 mmol l) vs ± 11.5 mg dl (1.18 ± 0.29 mmol l)], renal function (GFR 79.2 ± 16.1 ml min vs ± 19.7 ml min) and smoking habit (31% vs. 33%). There was no significant difference between patients with or without CAD in terms of the use of thiazide diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and loop diuretics. The ongoing medications of patients with or without CAD are shown in Table 1. There was a statistically significant difference between the mean uric acid levels of patients with or without CAD [6.39 ± 2.04 (380 ± 121 lmol l) vs ± 1.40 mg dl (323.5 ± 83.2 lmol l)] respectively, p < 0.001). When patients were stratified into four groups according to their serum uric acid quartiles, the Gensini score was found to be significantly increased Table 1 Demographic features, distribution of classical risk factors, uric acid levels and distribution of Gensini scores in patients with or without CAD Features CAD ()), n = 686 CAD (+), n = 326 p-value Age (years) 59.5 ± ± Gender (male %) Waist circumference (cm) 95.9 ± ± Hip circumference (cm) ± ± BMI (kg m 2 ) ± ± GFR (MDRD) ml min 79.2 ± ± Total cholesterol (mmol l) 4.9 ± ± LDL-C (mmol l) 3.08 ± ± HDL-C (mmol l) 1.19 ± ± Uric acid (lmol l) ± ± Hypertension (%) Systolic blood pressure (mmhg) ± ± Diastolic blood pressure (mmhg) 84.2 ± ± Diabetes mellitus (%) Duration of diabetes mellitus (months)* 61.5 ( ) ( ) Smoking (%) Thiazide diuretics (%) ACE inhibitors (%) Angiotensin receptor blockers (%) Beta blockers (%) < 0.01 Acetyl salicylic acid (%) < 0.01 Calcium channel blockers (%) < 0.01 Loop diuretics (%) *Expressed as median, 2.5th and 97.5th percentile data. ACE, angiotensin converting enzyme; BMI, body mass index; CAD, coronary artery disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; MDRD, modification of diet in renal disease formula; NS, not significant.

4 Coronary artery disease and uric acid level 903 across the quartiles and a statistically significant difference was noted between the groups by one-way ANOVA (p = 0.001; Figure 1). Increase in the Gensini score and frequency of CAD were exponential after the second quartile. The HbA1c levels were similar between the different UA quartiles. Detailed demographic characteristics, the distribution of cardiovascular risk factors and the Gensini scores of the groups according to uric acid quartiles are presented in Table 2. Serum uric acid level and risk factors associated with the CAD (age, gender, DM, hypertension, smoking, BMI, total cholesterol, LDL, HDL) were evaluated in a stepwise multivariate logistic regression analysis. Age, male gender, DM, high LDL-C level, low HDL-C level and increased serum uric acid level were found to be independent risk factors for the presence of CAD in all groups (for uric acid hazard ratio 1.31; 95% CI: , p < 0.001) (Table 3). Logistic regression analysis demonstrated that age, low HDL-C level, DM and increased uric acid level were the independent risk factors for the presence of CAD in women (for uric acid hazard ratio 1.29; 95% CI: , p < 0.001), whereas independent risk factors for the presence of CAD were age, increased total cholesterol, increased LDL- C, DM, smoking and increased uric acid in men (for uric acid hazard ratio 1.48; 95% CI: , p < 0.001) (Table 4). The effects of the same risk factors on the severity of CAD assessed by the Gensini score were put into model in multivariate linear regression analysis and the factors affecting the angiographic severity of CAD were determined. According to this analysis, the increased serum uric acid level was found to be an independent risk factor of the severity of CAD in both men and women (p < 0.001, b = 0.514; p < 0.001, b = respectively). Spearman correlation analysis demonstrated a positive correlation between the serum uric acid level and the severity of CAD (p < 0.001, r = 0.541) (Figure 2). When patients were classified into three groups according to their Gensini score, mean serum uric acid level was found to be significantly increased across the tertiles, and a statistically significant difference was detected between the tertiles by one-way ANOVA (p = 0.015; Figure 3). By the receiver operating curve analysis, a uric acid level of 6.86 mg dl (408 lmol l) was found to be the most appropriate cut-off point with the sensitivity 40%, the specificity 87.9%, the positive predictive value 87.7% and the negative predictive value 41% for the detection of CAD. Six hundred and 86 patients (mean Gensini score, 13.1 ± 19.0) were noted to be below and 317 patients (mean Gensini score, 45.8 ± 41.0) were noted to be above this cut-off value. When statistical power calculation was performed for two sample tests [uric acid cut-off Mean Gensini + 1 standart deviation p = <279 µmol/l µmol/l µmol/l >428 µmol/l 1st quartile 2nd quartile 3rd quartile Serum uric acid level 4th quartile Figure 1 Mean Gensini score in different serum uric acid quartiles

5 904 Coronary artery disease and uric acid level Table 2 Demographic features, distribution of classical risk factors and distribution of Gensini scores according to the serum uric acid quartiles Features First quartile < 279 lmol l Second quartile lmol l Third quartile lmol l Fourth quartile > 428 lmol l p-value Age (years) 58.8 ± ± ± ± Gender (male %) BMI (kg m 2 ) 27.9 ± ± ,3 ± ± GFR (MDRD) ml min 80.9 ± ± ± ± Total cholesterol (mmol l) 4.75 ± ± ± ± LDL-C (mmol l) 3.08 ± ± ± ± HDL-C (mmol l) 1.17 ± ± ± ± Hypertension (%) Systolic blood pressure (mmhg) ± ± ± ± Diastolic blood pressure (mmhg) 84.2 ± ± ± ± Diabetes mellitus (%) Duration of diabetes mellitus* (months) 61 ( ) 55 ( ) 59 ( ) 66 ( ) HbA1c (%) 7.29 ± ± ± ± Smoking (%) Thiazide diuretics (%) ACE inhibitors (%) Angiotensin receptor blockers (%) Beta blockers (%) Acetyl salicylic acid (%) Calcium channel blockers (%) Loop diuretics (%) CAD (Gensini Score 1) Mean Gensini Score 13.0 ± ± ± ± *Expressed as median, 2.5th and 97.5th percentile data. ACE: angiotensin converting enzyme; BMI, Body mass index; CAD, coronary artery disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; MDRD, modification of diet in renal disease formula; NS: not significant. HbA1c values were given for the diabetic subjects. Table 3 Results of logistic regression analysis for several risk factors effective on the presence of CAD Variable b p-value Odds ratio CI (95%) Lower Upper Age Gender Hypertension Smoking DM LDL-C HDL-C ) Uric acid BMI GFR BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol. level of 6.86 mg dl, (408 lmol l)] using mean values (Gensini scores), power of our study was close to 1 (0.997; alpha error level = 5%). Discussion The main findings of this study are as follows: (i) the serum uric acid level is higher in patients with CAD compared with patient without CAD, (ii) the serum uric acid level is associated with the presence and severity of CAD in both men and women, and (iii) presence and severity of CAD are higher in patients belonging to higher serum uric acid quartile group with respect to lower serum uric acid quartile group. Uric acid is the end-product of purine catabolism. It has antioxidant properties and is responsible for scavenging of 60% of the free radicals in human serum (16). In addition to being an effective extracellular antioxidant, uric acid also stimulates granulocyte adhesion to endothelial cells and liberation of peroxide and superoxide free radicals (17). A close relationship has been observed between high serum uric acid level and inflammatory markers, such as the total number of leukocytes, the number of neutrophils, C-reactive protein, interleukins and tumour necrosis factor alpha (18 20). Uric acid acts like an antioxidant in the early stages of the atherosclerotic process and also is the strongest

6 Coronary artery disease and uric acid level 905 Table 4 Results of logistic regression analysis of various risk factors effective on the presence of CAD in terms of gender Variable b p-value Odds ratio CI (95%) Lower Upper Men Age Total cholesterol LDL-C ) HDL-C ) Uric acid Hypertension ) Diabetes mellitus BMI GFR Smoking Women Age Total cholesterol ) LDL-C HDL-C Uric acid Hypertension Diabetes mellitus BMI GFR Smoking BMI, body mass index; CI, confidence interval; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol. determinant of plasma antioxidant capacity (21). When serum uric acid level rise above 6 mg dl (356.8 lmol l) in women and mg dl ( lmol l) in men, this antioxidant state is paradoxically reversed into a pro-oxidant state in the later stages of the atherosclerotic process. This paradoxal state appears to be dependent on several environmental factors, such as stage of the disease process, acidity of the tissues, reduction in other local antioxidants and the presence of oxidant substances and enzymes (21 23). Several epidemiological studies have identified an association between increased serum uric acid and cardiovascular risk in the general population. In the MONICA Augsburg study (24), which included a total of 1044 male patients, an increased serum uric acid level was found to be an independent risk factor for total and cardiovascular mortality. In a substudy of LIFE (25), baseline serum uric acid level was reported to be significantly associated with increased rate of the composite outcome of CV death, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke in the entire population. Nevertheless, the uric acid level-by-gender interaction was significant, and this association was reported to be significant only in women. In another study by Niskanen et al. (2), it was demonstrated that high serum uric acid level results in a 2.5-fold increase in cardiovascular mortality, independent from the presence of gout arthritis and metabolic syndrome. According to the National Health and Nutrition Examination Survey I data, cardiovascular mortality is increased 1.77-fold in men and 3.0-fold in women who had uric acid levels in the upper quartile (3). In our study, logistic regression analysis demonstrated that increased uric acid level was an independent risk factor for the presence of CAD both in men and women. One difficulty in determining whether uric acid per se should be considered a cardiovascular risk factor is that elevated uric acid levels are often associated with established cardiovascular risk factors. The elevation of uric acid levels in patients with cardiovascular disease could simply be a consequence of the presence of conditions such as reduced GFR, diuretic use, tissue ischaemia, oxidative stress or renal vasoconstriction (26,27). In the study by Culleton et al. (9), conducted on 6763 individuals from the Framingham heart study, it was reported that uric acid was not a causal risk factor for cardiovascular events because uric acid was not independent of hypertension. Similar to this study, no relationship has been found between the serum uric acid level and cardiovascular mortality and morbidity in the ARIC study (28). In our study, the mean uric acid level was significantly higher in the group of patients with CAD, although there was no significant difference between the groups of patients with or without CAD in terms of systolic and diastolic blood pressures, GFRs and diuretic use. Despite several studies investigated the relationship between uric acid and the presence of CAD (1 9), very few studies have addressed the relationship between the serum uric acid level and the severity of CAD. Tuttle et al. (29) have reported that the uric acid level was correlated with the CAD severity score in women; however, such relationship was not reported for men. Lu et al. (30) have reported that there was no relationship between serum uric acid levels and the severity of CAD. Nevertheless, the study populations in these two studies were smaller than this study, and the severity of CAD was evaluated by different methods. In another study, in evaluating the relationship between serum uric acid level and the severity of CAD assessed by the Gensini score, the uric acid level has been reported to be correlated with the presence, but not the severity of CAD (31). The sample size of this study was also

7 906 Coronary artery disease and uric acid level Gensini Score r = Uric acid level (mg/dl) Figure 2 The correlation between serum uric acid levels and the severity of coronary artery disease (CAD) in patients with CAD (r is the correlation coefficient) Mean serum uric acid level + 1 standart deviation p = st tertile 2nd tertile Gensini score 3rd tertile Figure 3 Mean serum uric acid concentrations in different Gensini score groups of patients smaller than this study, and no information regarding ongoing medications was provided. The main limitation that needs to be acknowledged regarding this study is the possible and unknown effects of the ongoing medications other than diuretics on the uric acid metabolism. Conclusion In conclusion, a strong association has been found between serum uric acid level and the presence and severity of CAD. In addition to the evaluation of conventional risk factors in daily clinical practice, the

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