Gender Differences in the Role of Serum Uric Acid for Predicting Cardiovascular Events in Patients with Coronary Artery Disease

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1 Original ORIGINAL Article ARTICLE Korean Circulation J 007;37: ISSN c 007, The Korean Society of Circulation Gender Differences in the Role of Serum Uric Acid for Predicting Cardiovascular Events in Patients with Coronary Artery Disease Dae-Woo Hyun, MD, Ki-Hong Kim, MD, Hyun-Ju Yoon, MD, Taek-Geun Kwon, MD, Ki-Young Kim, MD and Jang-Ho Bae, MD Department of Cardiology, Heart Center, Konyang University Hospital, Daejeon, Korea ABSTRACT Background and Objectives:Serum uric acid has been reported to be an independent risk factor for coronary artery disease (CAD) and a predictor of mortality in patients with CAD. Yet there is gender difference for the serum uric acid levels. We evaluated the influence of the uric acid levels on major adverse cardiovascular events (MACEs) in patients with CAD according to their gender. Subjects and Methods:Of the 777 patients with angiographically proven CAD, 660 patients (378 males, 57.3%) were followed up a median of 18 month (maximum: 61 month). The MACEs included acute myocardial infarction, cerebral infarction, coronary artery bypass graft, percutaneous coronary intervention due to de novo lesion during follow up, new onset congestive heart failure and sudden cardiac death. Results:MACEs in men were associated with acute coronary syndrome (ACS)(odds ratio (OR):.03, 95% confidence intervals (CI): 1.01 to 3.96, p=0.038), multi-vessel disease (OR: 3.68, 95% CI: 1.8 to 7.47, p=0.000) and the serum uric acid levels (OR: 1.3, 95% CI: 1.01 to 1.50, p=0.044), according to multivariate Cox regression analysis. For women, MACEs were associated with multi-vessel disease (OR:.43, 95% CI: 1.15 to 5.13, p=0.00) and the highest uric acid quartile (OR:.64, 95% CI: 1.31 to 5.30, p=0.006) according to multivariate Cox regression analysis. For all patients, the highest uric acid quartile was associated with an increased risk of MACE (p=0.000), and CHF was the major contributor to the observed MACEs (p=0.004). Conclusion:In male patients with CAD, the serum uric acid level is a predictor of cardiovascular events, and the highest uric acid quartile is a predictor of cardiovascular events in women. (Korean Circulation J 007;37:196-01) KEY WORDS:Uric acid;gender;coronary artery disease. Introduction Elevated serum uric acid(sua), as an end product of purine metabolism, reflects increased xanthine oxidase activity, and this has been shown to be related with endothelial dysfunction, cardiovascular disease and insulin resistance. 1-4) It has recently been reported that SUA is an independent predictor of mortality for patients with coronary artery disease(cad), including acute myocardial infarction(ami) or congestive heart failure(chf), although it does not have a causal role in the development of CAD, death from cardiovascular Received:January 30, 007 Revision Received:February 8, 007 Accepted:March 6, 007 Correspondence:Jang-Ho Bae, MD, Department of Cardiology, Heart Center, Konyang University Hospital, 685 Gasoowon-dong, Seo-gu, Daejeon , Korea Tel: , Fax: jhbae@kyuh.co.kr disease or death from all causes, according to the Framingham heart study. 5-8) However, there is a gender difference in the SUA levels and also in the relation between SUA and cardiovascular disease. 9)10) We performed this study to evaluate the role of the gender differences of the SUA levels on major adverse cardiovascular events(mace) such as death, myocardial infarction, stroke, CHF, percutaneous coronary intervention(pci) and coronary artery bypass graft(cabg) surgery in 660 consecutive patients who suffered with CAD. Subjects and Methods Study design and the patient population All the patients who underwent coronary angiography at Konyang University Hospital were enrolled in a registry that included the baseline demographic, clinical and angiographic characteristics. These patients visited 196

2 Dae-Woo Hyun, et al: Uric Acid and the Prognosis for Female Patients with Coronary Artery Disease 197 hospital once or twice per two months or they were contacted at 6 and 1 months after the procedure and yearly thereafter. The data base was searched for all the patients who had at least 30% luminal stenosis according to coronary angiography and who also had their laboratory data available, including the serum uric acid level within two weeks of angiography; all the patients were treated between June 000 and June 001 at Konyang University Hospital in Daejeon, Korea. These dates were chosen because our practice remained relatively stable with regards to adjunctive medical therapies(in particular clopidogrel) and stent types(bare metal) if they underwent PCI. For patients who underwent two procedures during the study period, only the first procedure was included. The baseline data on the patients was available from the database, including the patients clinical characteristics and medication use. Clinical follow-up Follow up was achieved mainly through the database and a chart review(574, 87.0%), and with telephone calls(86, 13.0%) at 6 months and then yearly after the procedure. The measured outcomes were sudden cardiac death, AMI(defined by an increase in the cardiac biomarkers), CHF(defined by the Framingham criteria for the diagnosis of CHF), PCI or CABG for de novo lesion, and stroke. Statistical analysis The data was analyzed separately for the women and men. Continuous variables are summarized as means ±SDs. Discrete variables are presented as group percentages. Kaplan-Meier estimates were used to describe the survival rates. For the time-to-event analysis, followup began at the date of discharge. One-way analysis of variance, Pearson s chi-squared test and the log-rank test were used to test the significance of group differences. Cox regression analysis was used to estimate the hazard ratios for the SUA levels and the other clinical variables. Results Patient characteristics Of the 777 patients with angiographically proven CAD, 660 patients(378 males, 57.3%) were followed up for a median of 18 months(maximum: 61 months). 117 patients of the 777 patients were excluded due to loss to follow up, and they had unknown clinical outcomes. The patients SUA levels were measured within two weeks of their procedures during the study period. The study patients were divided into four groups according to the quartiles of the serum uric acid levels. For the men, the lowest quartile was SUA(4.30 mg/ dl(n=94, 4.9%), the second quartile was 4.30 mg/ dl<sua(5.17 mg/dl(n=96, 5.4%), the third quartile was 5.17 mg/dl<sua(6.13 mg/dl(n=94, 4.9%), and the highest quartile was SUA>6.13 mg/dl(n=94, 4.9%). For the women, the lowest quartile was SUA (3.51 mg/ dl(n=70, 4.8%), the second quartile was 3.51 mg/ dl<sua(4.33 mg/dl(n=73, 5.9%), the third quartile was 4.33 mg/dl<sua(5.11 mg/dl(n=69, 4.5%), and the highest quartile was SUA>5.11 mg/dl(n=70, 4.8%)(Fig. 1). The median follow up was 7 months (maximum: 6 months). Compared with the women, the men were younger, had a lower body mass index, a greater incidence of acute coronary syndrome, they smoked more, had less hypertensive patients, lower total cholesterol, lower highdensity and low-density lipoprotein cholesterol and higher serum creatinine and SUA. Before the eighth decade, the SUA level was significantly higher in the men than in the women, but the SUA was not significantly different between the genders at the eight and ninth decade(table 1). Clinical outcomes At the end of the follow up period, there were 37 (9.8%) male patients with MACEs, whereas there were 3 female patients(11.3%) patients with MACEs(Table ). According to the MACE-free survival curves by the SUA quartiles, there was no significant divergence among the quartiles for men. For the women, the highest uric acid quartile group showed a significant divergence from the other three quartiles(fig. ). According to the univariate analysis, the incidence of MACEs for the men was associated with ACS, multivessel disease and the SUA level, whereas that of the women was associated with ACS, multi-vessel disease and the highest uric acid quartile(table 3). Those clinical and laboratory variables predicting the univariate risk with a p 0.05 were entered into multivariate Cox regression analysis. Multivariate analysis revealed that Serum uric acid (mg/dl) Men Women Quartile Quartile 3 Quartile 4 Quartiles of Serum Uric Acid Fig. 1. Levels of uric acid according to the quartiles of serum uric acid for the men and women.

3 198 Korean Circulation J 007;37: Table 1. Clinical characteristics of men and women Variables All patients (n=660) Men (n=378) Women (n=8) p Age (years) 59.± ± ± BMI (kg/m ) 4.4±3. 4.8± ± ACS (%) Multi-vessel disease (%) Risk factors Smoking (%) Hypertension (%) Diabetes (%) Dyslipidemia (%) Blood test Total cholesterol (mg/dl) 186.6± ± ± Triglycerides (mg/dl) 187.0± ± ± HDL cholesterol (mg/dl) 41.± ± ± LDL cholesterol (mg/dl) 109.± ± ± Creatinine (mg/dl) 1.0± ± ± Uric acid (mg/dl) Fifth decade 4.9± ± ± Sixth decade 5.0± ±1.5 4.± Seventh decade 4.9± ± ± Eighth decade 4.8± ± ± Ninth decade 4.9± ± ± BMI: body mass index, ACS: acute coronary syndrome, HDL: high density lipoprotein, LDL: low density lipoprotein 1.0 Event-Free cumulative survival A p of Log Rank statistics Quartile Quartile 3 Quartile 4 B p of Log Rank statistics Quartile Quartile 3 Quartile 4 C p of Log Rank statistics Quartile 3 Quartile Quartile Time (months) Time (months) Time (months) Fig.. Kaplan-Meier curve for event-free cumulative survival according to the quartiles of serum uric acid (A: for all patients. B: for men. C: for women). In men, the lowest quartile is SUA 4.30 mg/dl (n=94, 4.9%), the second quartile is 4.30 mg/dl<sua 5.17 mg/dl (n=96, 5.4%), the third quartile is 5.17 mg/dl <SUA 6.13 mg/dl (n=94, 4.9%), and the highest quartile is SUA>6.13 mg/dl (n=94, 4.9%), respectively. In women, the lowest quartile is SUA 3.51 mg/dl (n=70, 4.8%), the second quartile is 3.51 mg/dl<sua 4.33 mg/dl (n=73, 5.9%), the third quartile is 4.33 mg/dl < SUA 5.11 mg/dl (n=69, 4.5%), and the highest quartile is SUA>5.11 mg/dl (n=70, 4.8%), respectively. SUA: serum uric acid. the predictors of MACE were ACS(OR:.09), multivessel disease(or: 3.684) and the SUA level(or: 1.7) in men, while multi-vessel disease(or.431) and the highest uric acid quartile(or.638) were the predictors of MACEs for women(table 4). According to the univariate analysis of the highest uric acid quartile for MACE, the highest uric acid quartile was associated with an increased risk of all MACEs (p=0.000), and CHF was the major contributor to the observed MACEs(p=0.004). For men, the highest uric acid quartile was not significantly associated with an increased risk of AMI, stroke, CABG, PCI, CHF, SCD and all MACEs. For women, the highest uric acid quartile was significantly associated with an increased risk of CHF(OR: 4.741, p=0.003) and all MACEs(OR:.748, p=0.005)(table 5). Discussion The main findings of this study were: 1) the incidence

4 Dae-Woo Hyun, et al: Uric Acid and the Prognosis for Female Patients with Coronary Artery Disease 199 Table. Prevalence of adverse cardiovascular events in the men and women according to the serum uric acid Variables All patients (n=660) Men (n=378) Women (n=8) p AMI 05 (0.8%) 03 (0.8%) 0 (0.7%) 0.90 Stroke 1 (1.8%) 07 (1.9%) 05 (1.8%) CABG 03 (0.5%) 0 (0.5%) 01 (0.4%) 0.74 PCI 1 (3.%) 11 (.9%) 10 (3.5%) CHF 30 (4.5%) 15 (4.0%) 15 (5.3%) SCD 03 (0.5%) 03 (0.8%) 00 (0.0%) AMI: acute myocardial infarction, CABG: coronary artery bypass surgery, PCI: percutaneous coronary intervention, CHF: congestive heart failure, SCD: sudden cardiac death, MACE: major adverse cardiovascular events Table 3. Hazard ratios of the clinical variables for major adverse cardiovascular events in the men and women by univariate Cox regression analysis Univariate predictors of MACE in men Univariate predictors of MACE in women Variables (n=660) OR (95% CI) p OR (95% CI) p Age ( ) ( ) BMI ( ) ( ) ACS.898 ( ) ( ) 0.08 Multi-vessel disease ( ) ( ) Risk factors Smoking ( ) ( ) Hypertension ( ) ( ) Diabetes ( ) ( ) Dyslipidemia ( ) ( ) Blood test Total cholesterol ( ) ( ) Triglycerides ( ) ( ) HDL cholesterol ( ) ( ) LDL cholesterol ( ) ( ) 0.86 Creatinine ( ) ( ) 0.11 Uric acid 1.73 ( ) ( ) Uric acid, highest quartile ( ) ( ) OR: odds ratio, CI: confidence interval, BMI: body mass index, ACS: acute coronary syndrome, HDL: high density lipoprotein, LDL: low density lipoprotein Table 4. Multivariate predictors of MACEs in men and women by Cox regression analysis Multivariate Cox regression of Variables MACE in men OR (95% CI) p ACS (%).09 ( ) Multi-vessel disease (%) ( ) Uric acid 1.7 ( ) Variables Multivariate Cox regression of MACE in women OR (95% CI) p ACS (%) ( ) Multi-vessel disease (%).431 ( ) 0.00 Uric acid, highest quartile.638 ( ) OR: odds ratio, CI: confidence interval, ACS: acute coronary syndrome of MACEs was associated with the SUA levels in men, whereas this was associated with the highest uric acid quartile in women. ) The highest uric acid quartile was associated with MACEs in women, mainly due to CHF, but it was not associated with MACEs in men. Recent studies have revealed the role of SUA as a predictor of mortality for patients with CAD, as well as association between SUA and other cardiovascular diseases or CAD. 5)6)11)1) However, the Framingham heart study failed to disclose the causal role of SUA in the development of CAD, death from cardiovascular disease or death from all causes. 8) Instead, uric acid has quite consistently been shown to be related with insulin resistance, endothelial dysfunction and the cardiovascular risk factors. )3)9)11) These findings represent that the SUA s role for the mortality of patients with CAD is possibly caused by the uric acid-related disorders. 5)6) The significant role of both the SUA and uric acid quartiles in MACEs of this study was mainly caused by the development of CHF in this study population, although each of these factors also showed a significant, but weak association with the development of AMI or PCI, respectively. An increased SUA level reflects the increased xanthine oxidase activity, which produces more free oxygen radicals. 1)14) This increased oxidative

5 00 Korean Circulation J 007;37: Table 5. Odds ratios of the highest uric acid quartile for major adverse cardiovascular events in the men and women by univariate Cox regression analysis MACE All patients Men Women OR (95% CI) p OR (95% CI) p OR (95% CI) p AMI ( ) ( ) ( ) Stroke ( ) ( ) ( ) CABG ( ) ( ) ( ) PCI.316 ( ) ( ) ( ) CHF.840 ( ) ( ) ( ) SCD ( ) ( ) 0.71 Total.887 ( ) ( ) ( ) OR: odds ratio, CI: confidence interval, MACE: major adverse cardiovascular events, AMI: acute myocardial infarction, CABG: coronary artery bypass graft, PCI: percutaneous coronary intervention, CHF: congestive heart failure, SCD: sudden cardiac death stress can induce endothelial dysfunction of the small myocardial vessels, and then myocardial dysfunction. 4) In addition, oxidative stress-induced nitric oxide breakdown decreases the Frank-Starling response in the heart. 14) which is one of the mechanism of decreased heart function by uric acid. SUA may increase in the failing circulation because of increased generation, decreased excretion or a combination of the factors. Further, high SUA levels are a strong independent marker of an impaired prognosis for patients with CHF. 1)7) SUA probably does not have a causal role in developing a poor prognosis. There have been no clinical trials that have specifically examined whether persons with hyperuricemia who are randomized to SUA-lowing therapy, either with allopurinol or a uricosuric agent, have a decreased risk of CAD events. The predictive role of uric acid for the development of heart failure in patients with CAD was also evident in a recent study performed on patients with AMI, 6) although there was a difference for uric acid with regard to mortality. The exact mechanism of uric acid on the development of CAD is not fully understood. Its association with insulin resistance, endothelial dysfunction and increased oxidative stress are possible mechanisms. )3)9)11)15)16) SUA levels rise steadily with age, with the levels in men beginning to rise during puberty. The SUA levels in women remain lower until menopause, possibly due to the effect of estrogen. 17) Although it is unclear how estrogen may lower the SUA levels, it has been observed that the SUA levels increase after menopause and that estrogen may increase the renal clearance of SUA. Several previous studies also have suggested that SUA may be a stronger predictor of CAD in women than for men. 18)19) Moriarity et al 9) reported that SUA was directly associated with the incidence of CAD in women and it was not significantly associated with the incidence of CAD in men. The incidence rate of CAD in women was increased primarily in the highest quartile of uric acid with there being little difference in the CAD incidence in the lower three quartiles. The relative risk in women was elevated only for the highest quartile, possibly suggesting a threshold of effect. Estrogen status is a marker of the prognosis for women with suspected CAD, 0) and SUA in women patients with CAD is also a predictor of cardiovascular events. Although the direct relationship between estrogen and SUA is not fully understood, estrogen may have an important role for the gender difference in the effects of SUA on future adverse cardiovascular events in the patients with CAD. It has been shown that hyperuricemia in the general population is associated with all-cause mortality. Therefore, assessing the SUA may be of good general value for both maintaining health and during illness, but the direct effect of uric acid has not yet been assessed in detail. Conclusion In summary, for the male patients with CAD, the serum uric acid levels are a predictor of cardiovascular events, and the highest uric acid quartile is a predictor of cardiovascular events in women. REFERENCES 1) Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 003;107: ) Mercuro G, Vitale C, Cerquetani E, et al. Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. Am J Cardiol 004;94: ) Ward HJ. Uric acid as an independent risk factor in the treatment of hypertension. Lancet 1998;35: ) Cicoira M, Zanolla L, Rossi A, et al. Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J 00;143: ) Bickel C, Rupprecht HJ, Blankenberg S, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 00; 89:1-7. 6) Kojima S, Sakamoto T, Ishihara M, et al. Prognostic usefulness of serum uric acid after acute myocardial infarction. Am J Cardiol 005;96: ) Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival

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