Cent. Eur. J. Med. • 4(3) • 2009 • 272-278 DOI: 10.2478/s11536-009-0026-5

Central European Journal of Medicine

The concentration of uric acid in patients with metabolic syndrome and cardiovascular diseases Research Article

Jan Kowalski1, Anna Krzemińska1, Maciej Banach2, Lucjan Pawlicki1, Dorota Śliwczyńska-Rodziewicz1, Marcin Barylski1* 1

Department of Internal Diseases and Cardiological Rehabilitation, Medical University of Lodz, 90-647 Lodz, Poland 2

Department of Hypertension, Medical University of Lodz, 90-549 Lodz, Poland

Received 25 January 2009; Accepted 26 January 2009

Abstract: T he association of elevated serum uric acid (hyperuricemia, gout) with the presence of classical coronary risk factors and coronary artery disease (CAD) or myocardial infarction (MI) has been analysed in many epidemiological studies. Numerous studies have revealed that hypertension, high body mass index (BMI), lipid disorders (especially raised triglyceride (TG) levels and low high dense lipoprotein cholesterol (HDL-C) level), and increased creatinine or insulin levels have caused hyperuricemia. Gout has often occurred with typical disorders for the metabolic syndrome X. Significant correlation of the serum uric level and the CAD presence and severity of coronary atherosclerosis confirmed by coronary angiography has been observed in women. Hyperuricemia has also indirect influence on progress of CAD by physical activity restriction, what causes sedentary mode of life and lead to obesity. Therefore, we conducted our study in order to estimate uric acid levels in patients with metabolic syndrome and coexisting cardiovascular system diseases. Keywords: H  yperuricemia • Metabolic syndrome • Cardiovascular diseases

© Versita Warsaw and Springer-Verlag Berlin Heidelberg.

1. Introduction During the last several years the conception of metabolic syndrome (MS) became a frequently used term in medical literature. MS is a combination of medical disorders that increase the risk of developing atherosclerosis and type II diabetes and their cardiovascular complications. All MS definitions contain the following risk factors: central obesity, lipid disorders, carbohydrate metabolism disorders and arterial hypertension [1-3]. It is said that these factors cause chronic inflammation of endothelium which speeds up and maintains processes of atherogenesis; this is connected with an increased risk of cardiovascular incidents and development of type 2 diabetes [4-7]. Adipose tissue affects the intensity of inflammation of blood vessel walls, which change the profile of produced adipocytokines, which in turn leads to further activation of endothelial inflammatory response. It was proven that there is a connection between levels

of acute-phase proteins such as: CRP and fibrinogen and inflammatory response of endothelium [8,9]. On the other hand increased production of uric acid may lead to increased synthesis of oxygen free radicals which impairs endothelial function by decreased synthesis of nitric oxide (NO) [10]. It seems that damage of endothelium during inflammation is an important link in the pathogenesis of arterial hypertension and atherosclerosis, which leads to the development of ischemic heart disease. Chronic inflammatory processes are responsible for further courses of cardiovascular diseases, causing their temporal exacerbation as well as many complications. Therefore, we conducted our study in order to estimate uric acid levels in patients with metabolic syndrome and coexisting cardiovascular system diseases.

* E-mail: [email protected] 272

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Figure 1.

Prevalence of MS symptoms in patients with cardiovasular disease.

Agreement of Bioethics Committee of Medical University in Lodz was obtained. All patients agreed to participate in the research study by signing the consent form.

2. Material and Methods 2.1 Patients’ characteristics

The study included 137 patients (72 men and 65 women) with MS and coexisting cardiovascular diseases, aged 27-56 yrs (avg. 42±10,8 yrs). Among patients with MS, arterial hypertension was diagnosed in 59 subjects (group I), ischemic heart disease in 50 subjects (group II), type 2 diabetes in 28 subjects (group III). The reason of hospitalization was the diagnosis of new or exacerbated cardiovascular disease. Arterial hypertension was diagnosed by 24 hour ambulatory blood pressure monitoring (ABPM). Ischemic heart disease diagnosis was based on results of coronarography or medical documentation provided by patients (hospital or outpatients department). Type 2 diabetes was diagnosed according to medical documentation or during the patient’s stay in clinic (fasting plasma glucose level ≥126 mg/dl or plasma glucose >200 mg/dl two hours after oral glucose load) [4-6]. Metabolic syndrome was diagnosed according to NCEP ATP III criteria (2001) updated in year 2005: • central obesity: - waist circumference > 102 cm in males - waist circumference > 88 cm in females • triglyceride level ≥ 150 mg/dl • HDL-C level: < 40 mg/dl in males < 50 mg/dl in females • arterial blood pressure ≥ 130/85 mmHg • fasting plasma glucose ≥ 110 mg/dl To diagnose MS at least three of the above criteria were required.

2.2 Estimation of uric acid in serum Uric acid levels were measured with a set of reagents Acide Urique Enzymatique – PAP 150 using enzymatic method. Uric acid level > 7mg/dl in serum was assessed as high (hyperuricemia). 2.3 Statistical analysis

The data was analyzed using Student’s t-test for independent groups. The comparisons between each measurement were performed with the t-test for paired data. Values are expressed as a mean ± SD. The probability value p < 0,05 was considered significant.

3. Results In the study group of 137 patients with MS and coexisting cardiovascular diseases the most common were: obesity (89,78%) and arterial hypertension (89,78%), followed by hypertriglyceridemia (61,31%), reduced cholesterol HDL level (56,93%), hyperglycemia (54,01%), higher fibrinogen level (31,39%) and hyperuricemia (30,40%) (Figure 1). In patients with MS and cardiovascular system diseases, the average level of uric acid in the serum was 5,82±1,55mg/dl. The highest average levels of uric acid were observed in patients with ischemic heart disease (group II) and was 5,91±1,57mg/dl. In the group with arterial hypertension (group I) average level of uric acid was 5,78±1,32mg/dl and in the group with type 2 diabetes (group III) was 5,76±1,93mg/dl (Figure 2). 273

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The concentration of uric acid in patients with metabolic syndrome and cardiovascular diseases

Figure 2.

Level of uric acid in patients with MS and cardiovasular disease.

Figure 3.

Prevalence of hyperuricemia in patients with MS and cardiovasular disease.

Figure 4. Correlation between WHR and level of uric acid in patients

Figure 5. Correlation between HDL cholesterol and level of uric acid

The highest percentage of patients with MS and hyperuricemia was in a group with ischemic heart disease (34,04%), followed by the group with type 2 diabetes (28,57%) and arterial hypertension (28%). The differences between groups were not statistically significant (p>0,05) (Figure 3). In patients with MS and cardiovascular diseases there was a positive correlation between index waist-hip ratio (WHR) and uric acid level in serum (Figure 4). There was negative correlation between cholesterol HDL level and uric acid in serum (Figure 5).

predisposition, excessive alimentation and lack of physical activity. Elements of metabolic syndrome are: obesity, hyperlipidaemia, diabetes, arterial hypertension and metabolic arthritis. Metabolic syndrome increases prevalence of ischemic heart disease, steatohepatitis and gallstones. The clinical and epidemiological studies confirmed connection between hyperuricemia and prevalence of myocardial infarction, stroke and arterial hypertension [11,12]. Sundström and associates revealed in Framingham Study, that levels of uric acid in serum is an independent risk factor which leads to development of arterial hypertension [13]. Bogalusa Heart Study revealed that hyperuricemia may lead to arterial hypertension [14]. Freedman and associates basing on NHANES study (National Health and Nutrition Examination Study) revealed that each rise of uric acid of 60µmol/l is connected with development of ischemic heart disease in women by 48% [15]. Hyperuricemia coexists with obesity, glucose intolerance, insulin resistance and lipid disorders. Therefore, we conducted our study in order to estimate uric acid levels in patients with metabolic syndrome and cardiovascular system diseases. We found hyperuricemia in 30,4% of patients with MS and cardiovascular system diseases (arterial

with MS and cardiovasular disease.

4. Discussion In the 1920s, it was observed that risk factors of atherosclerosis coexist more often with themselves. In 1923, Swedish doctor, E. Kylin described and suggested a combined treatment of hyperglycemia, hyperuricemia and arterial hypertension. Since this time an increased observation of coexisting metabolic disorders such as obesity, lipid disorders, carbohydrate metabolism disorder and arterial hypertension was noted. The term “metabolic syndrome” was formed in 1981 by Hanefeld and Leonhardt, who found its causes in: genetic

in patients with MS and cardiovasular disease.

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hypertension, ischemic heart disease, type 2 diabetes). Hyperuricemia in patients with MS and coexisting ischemic heart disease was observed in 34,04% of patients, hyperuricemia in patients with coexisting type 2 diabetes was observed in 28,57% of patients, and hyperuricemia in patients with coexisting arterial hypertension was observed in 28% of patients. There were not statistical differences between groups. Kostka-Jeziorny and Tykarski estimated the prevalence of hyperuricemia in patients with primary, untreated arterial hypertension. In 266 patients with arterial hypertension, authors diagnosed hyperuricemia in 41 patients but 255 patients had normal uric acid levels. So the prevalence of hyperuricemia in newly diagnosed or untreated first or second degree arterial hypertension was 15,4% [16]. In our study the prevalence of hyperuricemia was two times higher in patients with MS and coexisting arterial hypertension. The prevalence of hyperuricemia in subjects with arterial hypertension is much higher than in general population (3%-54% vs 0,5%-14%). In treated arterial hypertension, the prevalence of hyperuricemia is higher (30%-58%) compared to untreated arterial hypertension (3%-38%), which is the evidence for unfavorable influence of hypotensive drugs on level of uric acid in serum. Diuretics, especially thiazid and excluding indapamide, increase level of uric acid in serum. Beta blockers have the same effect except for carvedilol and nebivolol. Calcium channel blockers, which are used in hypotensive chronic treatment don’t affect the level of uric acid in serum. ACE inhibitors decrease the level of uric acid in serum through increases of uric acid removal, renal clearance. Strong uricosouristic effects and decreased levels of uric acid in serum were observed after using angiotensin II receptor antagonists (losartan and valsartan). Having in mind that arterial hypertension is the main element of MS (in our study it was in 90% of patients), hyperuricemia was in 28% of patients from group with arterial hypertension, treatment of arterial hypertension should be based on drugs that don’t affect metabolism, especially angiotensinconverting enzyme inhibitors and sartans. It is said, that hyperuricemia is in 2%-50% of patients with type 2 diabetes. In our study hyperuricemia in patients with MS and coexisting type 2 diabetes was in 28,57% patients. Correlation between level of uric acid and level of glucose in serum is contrary. Correlation between hyperuricemia, metabolic arthritis and type 2 diabetes was observed by Berowitz and Mikkelson [17,18]. In the other publications this correlation wasn’t confirmed [19,20]. Yano, Klein, Hermann and associates informed about negative correlation between level of uric acid in serum and diabetes [21-23]. It

might be caused by opposing influence of glucose and insulin on uric acid level in serum and its excretion with urine. Hyperglycemia leads to decreased level of uric acid in serum [24,25], but insulin resistance and hyperinsulinemia leads to hyperuricemia through uric acid clearance lowering [26,27]. Epidemiological studies didn’t reveal any correlation between metabolic arthritis and diabetes, and a correlation between hyperuricemia and hyperglycemia [18]. Existing of hyperuricemia in 30% patients with MS and type 2 diabetes should be taken into consideration in dietetic and pharmacological treatment. Fructose leads to increased level of uric acid in serum so this fact should be considered in dietetic recommendations [28]. Allopurinol intensifies hypoglycemic activation of chlorpropamidum in patients with diabetes (especially in coexisting renal failure). Hyperuricemia is a risk factor which leads to the development of atherosclerosis. It isn’t certain if this risk factor is completely independent or only increases other coronary risk factors. Reduction of higher level of uric acid isn’t an obligatory activity in the primary prevention of cardiovascular diseases. In our study, 34,04% patients with MS and coexisting ischemic heart disease had hyperuricemia. In Framingham studies, 10 years observation of patients with hyperuricemia revealed that patients with hyperuricemia two times more often had ischemic heart disease. Bickel and associates emphasized a similar relationship assessing the degree of intensity of atherosclerosis in angiography [29]. Moreover authors noted that uric acid is an independent risk factor of mortality in patients with ischemic heart disease. Mortality increased from 3,4% to 17,1% in patients with levels of uric acid in serum 5,1mg/dl in comparison to patients with level of uric acid 7,1mg/dl. Okraska-Bylica and associates revealed that hyperuricemia appeared in 21,5% of women with ischemic heart disease [30]. Many authors agreed that an appearance of ischemic heart disease in women in comparison to men is strongly connected with specivic levels of uric acid in serum. Some studies identify a connection between hyperuricemia and cardiovascular risk factors. Bogalusa study (The Bogalusa Heart Study) [31] and CARDIA (The Coronary Artery Risk Development In young Adults) [32] highlighted the fact that levels of uric acid are inversely proportional to level of HDL cholesterol and they are not positively connected with values of arterial hypertension, body mass index, level of triglycerides and level of creatinine in serum and level of fasting insulin. Moreover hyperuricemia is more frequent in patients with obesity (11,4%) and in patients with overweight (5,7%), than in slim patients (3,4%).

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Many authors made note of the apparent correlation between hyperuricemia and obesity [33-35]. Tykarski revealed that level of uric acid correlates with body mass index [36]. It was revealed that levels of uric acid in serum stronger correlates with adipose tissue weight, but doesn’t correlate with fat-free body mass [37]. A strong positive correlation between level of uric acid in serum and waist to hip ratio was revealed by Lee and associates and it proves that visceral adipose tissue plays an important role in patients with MS [38]. In our study in patients with MS and cardiovascular diseases positive correlation was revealed between level of uric acid in serum and waist to hip ratio (WHR). Studies have proven that leptin is a determining factor of coexisting obesity and hyperuricemia. Hyperuricemia is independently connected with levels of leptin [26]. There is an adverse correlation between uric acid and certain levels of HDL cholesterol in serum. In our studies we have confirmed this relationship. In patients with MS and cardiovascular diseases we revealed an adverse correlation between levels of uric acid and level of HDL cholesterol in serum. Chronic hyperuricemia leads to many unfavorable consequences in human organisms: vascular smooth muscles hyperplasia, endothelial dysfunction, internal activation of renin-angiotensin-aldosterone system [39,40].

These disorders may connect hyperuricemia with cardiovascular diseases. We should remember that uric acid synthesis from oxypurines produces free radicals which play an important role in the damage of vessels. Increased production of uric acid in patients with MS and cardiovascular diseases may cause major synthesis of free radicals, which may eventually lead to a dysfunction of endothelium through reduced production of nitric oxide. That is why allopurinol, which is xanthine oxidase inhibitor, causes the improvement of endothelial function in patients with hyperuricemia, by lowering the amount of produced free radicals [41-44]. In conclusion: (1) hyperuricaemia in patients with metabolic syndrome and cardiovascular diseases is more common than in the rest of the population; (2) hyperuricemia in patients with metabolic syndrome and cardiovascular diseases is a result of inflammatory processes which may lead to faster development of atherosclerosis; (3) in patients with metabolic syndrome and cardiovascular diseases treatment should include drugs that are metabolically neutral.

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