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Uric acid level and its association with carotid intima–media thickness in patients with hypertension
Atherosclerosis 197 (2008) 159–163
Uric acid level and its association with carotid intima–media thickness in patients with hypertension ¨ Yusuf Tavil a,∗ , Mehmet G¨ung¨or Kaya a , Suna Ozhan Oktar b , Nihat Sen a , Kaan Okyay a , H¨useyin U˘gur Yazıcı a , Atiye Cengel a a b
Gazi University Medical School, Department of Cardiology, Ankara, Turkey Gazi University Medical School, Department of Radiology, Ankara, Turkey
Received 17 November 2006; received in revised form 10 February 2007; accepted 8 March 2007 Available online 9 April 2007
Abstract Objective: Carotid intima–media thickness (C-IMT) measured noninvasively by ultrasonography is now widely used as a surrogate marker for atherosclerotic disease and directly associated with increased risk of cardiovascular disease. Hyperuricemia (HU) is a well recognized risk factor for cardiovascular diseases. The independence of this association from other confounding factors has remained controversial. But the possible contributory effect of HU to carotid intima–media thickness (C-IMT) produced by hypertension (HT) has not been clarified yet. The study was designed to assess the C-IMT in patients with hypertension (HT) with or without HU. Methods: The study participants consisted of 30 patients (men 60%, mean age ± S.D.: 49 ± 11 years) with HT without HU, and 25 patients with HT and HU (men 52%, mean age ± S.D.: 52 ± 12 years), and 25 age-matched healthy control subjects (men 56%, mean age ± S.D.: 50 ± 13 years). All study groups were examined by B-mode ultrasound to measure the C-IMT at the far wall of the common carotid artery. Results: C-IMT were significantly higher in the patient groups (HT without HU and HT with HU) compared to the control cases (0.70 ± 0.14, 0.83 ± 0.16 versus 0.57 ± 0.16, mm, respectively, p < 0.001). In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU. In stepwise linear regression analysis, we found that serum uric acid (SUA) levels independently but modestly associated with C-IMT (β = 0.42, p = 0.002). Conclusion: We have shown that higher SUA levels are associated with atherogenesis independent from hypertension. Prospective studies will be necessary to confirm and extend these findings including early screening for hyperuricemia and lowering of SUA level looking at potential benefits in slowing progression of C-IMT in hypertensive patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Hypertension; Hyperuricemia; atherosclerosis; Carotid intima–media thickness
1. Introduction Several previous studies have suggested that serum uric acid (SUA) is an important, independent risk factor for cardiovascular (CV) disease [1,2]. However, the relationships between hyperuricemia (HU) and other cardiovascular risk factors including, hypertension (HT), hyperinsulinemia, ∗ Corresponding author at: Gazi University faculty of Medicine, Department of Cardiology, Besevler, Ankara, Turkey. Tel.: +90 312 2025647; fax: +90 312 2129012. E-mail address: [email protected] (Y. Tavil).
0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.03.008
reduced physical activity, increased body mass index, and decreased HDL cholesterol are demonstrated in many clinical studies, pathogenetic mechanisms between them are not yet well understood [3,4]. Possible pathophysiological link may be related to higher levels of SUA which has contributory effect on atherosclerotic process by several ways including deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation [5–8]. Carotid intima–media thickness (C-IMT) measured noninvasively by ultrasonography is now widely used as a surrogate marker for atherosclerotic disease and directly
160
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associated with increased risk of cardiovascular disease [9,10]. Even though, previous studies have reported that increased values of C-IMT was strongly associated with increased CV morbidity in both of the patients with hypertension and hyperuricemia, the contributory effect of HU to atherogenetic progression produced by hypertension has not been clarified yet. Accordingly, this study was designed to examine C-IMT in patients with HT with or without HU.
2. Methods The study was conducted on the subjects who had been attended to our outpatient clinic between October 2004 and April 2006. The study participants consisted of 30 patients (men 60%, mean age ± S.D.: 49 ± 11 years) with HT without HU, and 25 patients with HT with HU (men 52%, mean age ± S.D.: 52 ± 12 years), and 25 age-matched healthy control subjects (men 56%, mean age ± S.D.: 50 ± 13 years). The control subjects had no cardiovascular or any other systems disease, and had normal physical examination, chest roentgenogram, electrocardiogram, and two-dimensional and Doppler echocardiogram. Blood pressures were measured to the nearest 5 mmHg with a standard mercury column sphygmomanometer on the right arm of subjects sitting after 5 min rest. Korotkoff phases I and V were taken to present systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. Hypertension was defined as a systolic BP of >140 mmHg and/or a diastolic BP of >90 mmHg as mean of three measurements in at least three visits at 1-week intervals or receiving antihypertensive treatment [11]. Hyperuricemia was defined as the serum levels of >410 mol/l in men, and >310 mol/l in women [12]. Fasting blood glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels were recorded. Blood samples were drawn by venipuncture to perform routine blood chemistry. SUA levels were determined with enzymatic colourimetric method by clinical chemistry auto-analyzer (Aeroset, Abbott Laboratory, Abbott Park, IL, USA). Smoking was defined as current smoking or having a history of habitual smoking. The body mass index (BMI) was defined as the weight (kg) divided by the square of the height (m). Exclusion criteria were systolic blood pressure of 220 mmHg or higher, ischemic heart disease, acute coronary syndrome, stroke, or presence of a major illness such as cancer, liver disease, renal insufficiency, insulin-treated diabetes and depression. The study was approved by the local ethics committee, and patients gave informed consent.
3. Carotid ultrasonography All patients were evaluated by high-resolution ultrasound using the Logiq 9 system (GE Medical Systems, Milwaukee,
WI) and a 7.5 MHz linear array transducer. The transducer was manipulated so that the near and far walls of the CCA were parallel to the transducer footprint, and the lumen diameter was maximized in the longitudinal plane. A region 1 cm proximal to the carotid bifurcation was identified, and the IMT of the far wall was evaluated as the distance between the lumen–intima interface and the media–adventitia interface. The IMT measurement was obtained from four contiguous sites at 1-mm intervals, and the average of the four measurements was used for analyses. After, the measurements were taken from both right and left CCA, the average of both values was calculated. All measurements were made manually on still images obtained during the sonographic scanning. The carotid plaques were excluded while measuring IMT. The intraobserver variability of ultrasonographic measurements was <6% and all examinations were performed by a single experienced examiner who was blinded to the clinical and biochemical data
4. Statistical analysis All numeric variables were expressed as mean ± S.D. and normally distributed. The study groups were compared for various numeric parameters by one-way analysis of variance and by post hoc Tukey’s test for multiple comparisons. Multiple linear regression analysis and simple linear tests were used to assess univariate and multivariate relations between SUA, C-IMT and various variables. Probability values of p < 0.05 were considered significant. All statistical analyses were carried out using statistical software (SPSS, version 10.0 for Windows; SPSS Inc., Chicago, IL, USA).
5. Results Distribution of cardiovascular risk factors, demographic characteristics, and laboratory measurements of the study participants are shown in Table 1. There was no statistically significant difference between the groups in terms of gender, age, cardiovascular risk profile and cardiovascular medical therapy except total cholesterol, LDL-cholesterol, and plasma triglyceride (Table 1). According to the carotid IMT, the patients with HT had significantly higher carotid IMT compared to control subjects. In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU (0.83 ± 0.16 mm versus 0.70 ± 0.14 mm versus 0.57 ± 0.16 mm, respectively, p < 0.001, Table 1, Fig. 1). The results of simple and multiple linear regression analysis which shows that the association between SUA and C-IMT is independent of other significant variables are summarized in Table 2. When SUA level was taken as dependent and age, BMI, SBP, lipids, and C-IMT as independent variables, we found that serum UA levels independently associated
Y. Tavil et al. / Atherosclerosis 197 (2008) 159–163
161
Table 1 The Physical characteristics and biochemical parameters of the study groups
Age (years) Male gender (%) BMI (kg m−2 ) Heart rate (beats/min) Smokers (%) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Plasma triglyceride (mg/dl) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Plasma creatinine (mg/dl) Fasting glucose (mg/dl) Serum uric acid (mol/l) Carotid IMT (mm) Cardiovascular medication ASA, n (%) Beta-blockers, n (%) ACE inhibitors or Angiotensin receptor blocker, n (%) Ca2+ -antagonists, n (%) Cholesterol-lowering drugs, n (%)
Control (n = 25)
HT without HU (n = 30)
HT with HU (n = 25)
p-Value
50 ± 13 14 (56) 22 ± 4 82 ± 10 7 (28) 185 ± 20 128 ± 27 47 ± 14 167 ± 80 118 ± 21 77 ± 9 0.85 ± 0.20 98 ± 14 280 ± 120 0.57 ± 0.16
49 ± 11 18 (60) 23 ± 6 76 ± 9 10 (33) 214 ± 22 135 ± 29a 45 ± 13 175 ± 75* 152 ± 23* 110 ± 18* 0.98 ± 0.20 92 ± 13 270 ± 50 0.70 ± 0.14a
52 ± 12 13 (52) 25 ± 4 82 ± 8 8 (32) 225 ± 32a 142 ± 35a 42 ± 12 188 ± 96a 160 ± 11a 104 ± 17a 1.04 ± 0.21 104 ± 9 470 ± 40a,b 0.83 ± 0.16a,b
NS NS NS NS NS 0.04 0.02 NS 0.05 0.001 0.001 NS NS 0.001 0.001
– – – – –
22 (73) 12 (30) 16 (53) 8 (26) 19 (63)
21 (84) 9 (36) 15 (50) 8 (32) 16 (65)
NS NS NS NS NS
Values are mean ± S.D. or numbers (%). Probabilities determined by one way analysis of variance or χ2 tests. ACE, angiotensin-converting enzyme; ASA, acetylsalicylic acid; BMI, body mass index; HDL, high-density lipoprotein HT, hypertension; HU, hyperuricemia; IMT, intima–media thickness. a Control group vs. patient groups. b HT without HU group vs. the HT with HU group; NS, not significant, p > 0.05.
Table 2 Simple and multiple regression analysis of serum uric acid and carotid intima–media thickness in hypertensive patients SUA
Age BMI Total cholesterol LDL-cholesterol HDL-cholesterol Plasma triglyceride Systolic blood pressure Fasting glucose SUA C-IMT
C-IMT
Simple regression, r
Multivariate regression (standardized), β
Simple regression, r
Multivariate regression (standardized), β
0.27* 0.15 0.04 0.11 −0.34* 0.13 0.24* 0.11 – 0.47**
0.12 0.18 0.10 0.16 0.31* 0.12 0.15 0.01 – 0.42**
0.35** 0.13 0.34** 0.25* −0.014 0.29* 0.38* 0.23* 0.49** –
0.14 0.12 0.21 0.13 0.08 0.12 0.19 0.14 0.48** –
BMI, body mass index; C-IMT, carotid intima–media thickness; SUA, serum uric acid. * p < 0.05. ** p < 0.01.
with carotid IMT (β = 0.42, p = 0.002) and HDL-cholesterol (β = 0.31, p < 0.01). Although, SUA were significantly correlated with age and SBP, these associations were not shown by stepwise linear regression. When C-IMT was taken as dependent and age, SUA, BMI, SBP, and lipids as independent variables, we found that C-IMT independently associated only with SUA (β = 0.48, p < 0.001). According to the correlation analysis, there were significantly correlations between C-IMT and age, total cholesterol, LDL-cholesterol, plasma triglyceride, SBP, fasting glucose except HDL cholesterol (Fig. 2).
6. Discussion In this study, we have shown that carotid IMT is increased in patients with hypertension with or without HU when compared with the control subjects. We have also demonstrated that this difference is valid between two hypertensive groups. In addition, there were significant correlations between carotid IMT measurement, SUA level, and other major atherosclerotic risk factors. These results have indicated that higher SUA levels are associated with atherogenesis independent from hypertension.
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Fig. 1. Box plots showing the mean of carotid intima–media thickness within study groups (abbreviation as in Table 1).
In recent years, increased attention has been focused on the fact that prediction of atherosclerosis has been more important because development in preventive medicine have been presenting new treatment modalities. Previous reports have suggested that carotid IMT is at present the best studied and useful sonographic marker for early atherosclerotic vascular wall involvement [13–15]. The assessment of carotid IMT is postulated a surrogate marker of generalized atherosclerosis. It has been reported that the patients who have elevated level of SUA have an increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels [16]. Actually, hyperuricemia has often been considered a part of the metabolic syndrome or simply a marker of other coronary disease risk factors such as hypertension, dyslipidemia, obesity, glucose intolerance, and renal disease [17–19]. However, multiple studies provide strong evidence that elevated uric acid may also bear independent risk factor association with cardiovascular mortality [20–22]. Although, HU is frequently encountered in hypertensive patients, the linking between them with regard to the pathogenetic mechanism is unclear.
Fig. 2. Linear regression curve of the relation between carotid intima–media thickness and serum uric acid level.
In this respect, the present study was designed to interrogate whether HU has possible role in developing and/or contributing of atherosclerosis independent from hypertension in patients with hypertension. Several lines of experimental evidence are suggesting that uric acid is associated with injurious effects on the vasculature and renal tissues. Studies in rats show that elevated uric acid levels following administration of a uricase inhibitor increase blood pressure as well as produce a primary arteriopathy independent of blood pressure [23]. These effects, possibly mediated via activation of the rennin–angiotensin system and down-regulation of nitric oxide synthase, could be ameliorated by treatment with allopurinol or benziodarone [23]. Exogenous uric acid gives rise to endothelial dysfunction, and endogenous uric acid concentrations correlate with the extent of endothelial dysfunction [24]. Similarly, patients with gout have a high incidence of renovascular histological abnormalities including atherosclerosis, arteriosclerosis, glomerulosclerosis, and tubular atrophy [25]. Furthermore, urate crystals have also been proposed, including noxious effects, such as; proinflammatory, activating complement, stimulating neutrophils to release proteases and oxidants, stimulate macrophages, and activate platelets and the coagulation cascade [26]. Moreover, it has been reported that uric acid stimulate vascular smooth cell proliferation and upregulates the expression of platelet derived growth factor and monocyte chemoattractant protein-1 [27,28]. Therefore, UA is the major end-product of purine metabolism, UA may reflect the generation of superoxide and resultant oxidative stress via the xanthine oxidase system [29]. Briefly, higher levels of serum UA may have associated with development of atherosclerosis that is independent of other confounding atherosclerotic risk factor. Accordingly, we have found that HU have augmented the adverse affect of HT on cardiovascular system in patients with HT.
7. Study limitations The main limitations of this study were the lack of insulin resistance or insulin sensitivity index (e.g. homeostasis model assessment (HOMA-IR)). Therefore, we were unable to examine whether the patients with HU had higher levels of insulin resistance than patients without HU. Our findings need to be confirmed by other studies and further studies are obviously required to understand these relationships. Second, we have shown only association between C-IMT and serum uric acid instead of causality due to the study design. Third, we could investigate atherosclerosis with ultrasonographic imaging of carotid arteries in the study population; coronary angiographic data for excluding coronary artery disease was unavailable. Meanwhile, absence of clinical symptoms and demonstrable wall motion abnormalities on echocardiography decreased the possibility of coronary artery disease. Additionally, because of ethical considerations, patients were studied under concurrent medications, and this might have
Y. Tavil et al. / Atherosclerosis 197 (2008) 159–163
had an influence on the precision of the measurements of carotid IMT. 8. Conclusion In the present study, we have found that carotid IMT is increased in patients with hypertension with or without HU when compared with the control subjects. In patients who had both HT and HU had increased carotid IMT compared to the patients who did not have HU. In addition, there were significant associations between carotid IMT measurement, SUA level, and other major atherosclerotic risk factors. These results have indicated that higher SUA levels are associated with atherogenesis independent from hypertension. Prospective studies will be necessary to confirm and extend these findings including early screening for hyperuricemia and lowering of SUA level looking at potential benefits in slowing progression of C-IMT in hypertensive patients. References [1] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7–13. [2] Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J. Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year followup of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand 1988;224:549–55. [3] Bonora E, Targher G, Zenere MB, et al. Relationship of uric acid concentration to cardiovascular risk factors in young men. The role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord 1996;20:975–80. [4] Vuorinen-Markkola H, Yki-J¨arvinen H. Hyperuricemia and insulin resistance. J Clin Endocrinol Metab 1994;78:25–9. [5] Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 2000;35:746–51. [6] Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002;105: 2619–24. [7] Leyva F, Anker S, Swan JW, et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997;18:858–65. [8] Mustard JF, Murphy EA, Ogryzlo MA, Smythe HA. Blood coagulation and platelet economy in subjects with primary gout. Can Med Assoc J 1963;89:1207–11. [9] Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk In Communities (ARIC) study, 1987–1993. Am J Epidemiol 1997;146:483–94.
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[10] Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal–medial thickness is related to cardiovascular risk factors measured from childhood through middle age. The Muscatine Study. Circulation 2001;104:2815–9. [11] Anon. World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151–83. [12] Ruilope LM, Garc´ıa Puig J. Hyperuricemia and renal function. Curr Hypertens Rep 2001;3:197–202. [13] Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74:1399–406. [14] Ebrahim S, Papacosta O, Whincup P, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:841–50. [15] Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. Common carotid intima–media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation 1999;100:951–7. [16] Breckenridge A. Hypertension and hyperuricaemia. Lancet 1966;1:15–8. [17] Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 1999;33:225–34. [18] Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991;266:3008–11. [19] Timar O, Sestier F, Levy E. Metabolic syndrome X: a review. Can J Cardiol 2000;16:779–89. [20] Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144–50. [21] Persky VW, Dyer AR, Idris-Soven E, et al. Uric acid: a risk factor for coronary heart disease? Circulation 1979;59:969–77. [22] Ward HJ. Uric acid as an independent risk factor in the treatment of hypertension. Lancet 1998;352:670–1. [23] Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:991–7. [24] Waring WS, Webb DJ, Maxwell SR. Effect of local hyperuricemia on endothelial function in the forearm vascular bed. Br J Clin Pharmacol 2000;49:511. [25] Gonick HC, Rubini MD, Gleason IO, Sommers SC. The renal lesion in gout. Arch Intern Med 1965;62:667–74. [26] Gordon TP, Terkeltaub R, Ginsberg MH. Gout: crystal-induced inflammation. In: Gallin JI, Goldstein IM, Snyderman R, editors. Inflammation: Basic Principles and Clinical Correlates. New York: Raven; 1988. p. 775–83. [27] Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem 1991;266:8604–8. [28] Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;4:1287–93. [29] McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159–63.
Uric acid level and its association with carotid intima–media thickness in patients with hypertension ¨ Yusuf Tavil a,∗ , Mehmet G¨ung¨or Kaya a , Suna Ozhan Oktar b , Nihat Sen a , Kaan Okyay a , H¨useyin U˘gur Yazıcı a , Atiye Cengel a a b
Gazi University Medical School, Department of Cardiology, Ankara, Turkey Gazi University Medical School, Department of Radiology, Ankara, Turkey
Received 17 November 2006; received in revised form 10 February 2007; accepted 8 March 2007 Available online 9 April 2007
Abstract Objective: Carotid intima–media thickness (C-IMT) measured noninvasively by ultrasonography is now widely used as a surrogate marker for atherosclerotic disease and directly associated with increased risk of cardiovascular disease. Hyperuricemia (HU) is a well recognized risk factor for cardiovascular diseases. The independence of this association from other confounding factors has remained controversial. But the possible contributory effect of HU to carotid intima–media thickness (C-IMT) produced by hypertension (HT) has not been clarified yet. The study was designed to assess the C-IMT in patients with hypertension (HT) with or without HU. Methods: The study participants consisted of 30 patients (men 60%, mean age ± S.D.: 49 ± 11 years) with HT without HU, and 25 patients with HT and HU (men 52%, mean age ± S.D.: 52 ± 12 years), and 25 age-matched healthy control subjects (men 56%, mean age ± S.D.: 50 ± 13 years). All study groups were examined by B-mode ultrasound to measure the C-IMT at the far wall of the common carotid artery. Results: C-IMT were significantly higher in the patient groups (HT without HU and HT with HU) compared to the control cases (0.70 ± 0.14, 0.83 ± 0.16 versus 0.57 ± 0.16, mm, respectively, p < 0.001). In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU. In stepwise linear regression analysis, we found that serum uric acid (SUA) levels independently but modestly associated with C-IMT (β = 0.42, p = 0.002). Conclusion: We have shown that higher SUA levels are associated with atherogenesis independent from hypertension. Prospective studies will be necessary to confirm and extend these findings including early screening for hyperuricemia and lowering of SUA level looking at potential benefits in slowing progression of C-IMT in hypertensive patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Hypertension; Hyperuricemia; atherosclerosis; Carotid intima–media thickness
1. Introduction Several previous studies have suggested that serum uric acid (SUA) is an important, independent risk factor for cardiovascular (CV) disease [1,2]. However, the relationships between hyperuricemia (HU) and other cardiovascular risk factors including, hypertension (HT), hyperinsulinemia, ∗ Corresponding author at: Gazi University faculty of Medicine, Department of Cardiology, Besevler, Ankara, Turkey. Tel.: +90 312 2025647; fax: +90 312 2129012. E-mail address: [email protected] (Y. Tavil).
0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.03.008
reduced physical activity, increased body mass index, and decreased HDL cholesterol are demonstrated in many clinical studies, pathogenetic mechanisms between them are not yet well understood [3,4]. Possible pathophysiological link may be related to higher levels of SUA which has contributory effect on atherosclerotic process by several ways including deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation [5–8]. Carotid intima–media thickness (C-IMT) measured noninvasively by ultrasonography is now widely used as a surrogate marker for atherosclerotic disease and directly
160
Y. Tavil et al. / Atherosclerosis 197 (2008) 159–163
associated with increased risk of cardiovascular disease [9,10]. Even though, previous studies have reported that increased values of C-IMT was strongly associated with increased CV morbidity in both of the patients with hypertension and hyperuricemia, the contributory effect of HU to atherogenetic progression produced by hypertension has not been clarified yet. Accordingly, this study was designed to examine C-IMT in patients with HT with or without HU.
2. Methods The study was conducted on the subjects who had been attended to our outpatient clinic between October 2004 and April 2006. The study participants consisted of 30 patients (men 60%, mean age ± S.D.: 49 ± 11 years) with HT without HU, and 25 patients with HT with HU (men 52%, mean age ± S.D.: 52 ± 12 years), and 25 age-matched healthy control subjects (men 56%, mean age ± S.D.: 50 ± 13 years). The control subjects had no cardiovascular or any other systems disease, and had normal physical examination, chest roentgenogram, electrocardiogram, and two-dimensional and Doppler echocardiogram. Blood pressures were measured to the nearest 5 mmHg with a standard mercury column sphygmomanometer on the right arm of subjects sitting after 5 min rest. Korotkoff phases I and V were taken to present systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. Hypertension was defined as a systolic BP of >140 mmHg and/or a diastolic BP of >90 mmHg as mean of three measurements in at least three visits at 1-week intervals or receiving antihypertensive treatment [11]. Hyperuricemia was defined as the serum levels of >410 mol/l in men, and >310 mol/l in women [12]. Fasting blood glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels were recorded. Blood samples were drawn by venipuncture to perform routine blood chemistry. SUA levels were determined with enzymatic colourimetric method by clinical chemistry auto-analyzer (Aeroset, Abbott Laboratory, Abbott Park, IL, USA). Smoking was defined as current smoking or having a history of habitual smoking. The body mass index (BMI) was defined as the weight (kg) divided by the square of the height (m). Exclusion criteria were systolic blood pressure of 220 mmHg or higher, ischemic heart disease, acute coronary syndrome, stroke, or presence of a major illness such as cancer, liver disease, renal insufficiency, insulin-treated diabetes and depression. The study was approved by the local ethics committee, and patients gave informed consent.
3. Carotid ultrasonography All patients were evaluated by high-resolution ultrasound using the Logiq 9 system (GE Medical Systems, Milwaukee,
WI) and a 7.5 MHz linear array transducer. The transducer was manipulated so that the near and far walls of the CCA were parallel to the transducer footprint, and the lumen diameter was maximized in the longitudinal plane. A region 1 cm proximal to the carotid bifurcation was identified, and the IMT of the far wall was evaluated as the distance between the lumen–intima interface and the media–adventitia interface. The IMT measurement was obtained from four contiguous sites at 1-mm intervals, and the average of the four measurements was used for analyses. After, the measurements were taken from both right and left CCA, the average of both values was calculated. All measurements were made manually on still images obtained during the sonographic scanning. The carotid plaques were excluded while measuring IMT. The intraobserver variability of ultrasonographic measurements was <6% and all examinations were performed by a single experienced examiner who was blinded to the clinical and biochemical data
4. Statistical analysis All numeric variables were expressed as mean ± S.D. and normally distributed. The study groups were compared for various numeric parameters by one-way analysis of variance and by post hoc Tukey’s test for multiple comparisons. Multiple linear regression analysis and simple linear tests were used to assess univariate and multivariate relations between SUA, C-IMT and various variables. Probability values of p < 0.05 were considered significant. All statistical analyses were carried out using statistical software (SPSS, version 10.0 for Windows; SPSS Inc., Chicago, IL, USA).
5. Results Distribution of cardiovascular risk factors, demographic characteristics, and laboratory measurements of the study participants are shown in Table 1. There was no statistically significant difference between the groups in terms of gender, age, cardiovascular risk profile and cardiovascular medical therapy except total cholesterol, LDL-cholesterol, and plasma triglyceride (Table 1). According to the carotid IMT, the patients with HT had significantly higher carotid IMT compared to control subjects. In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU (0.83 ± 0.16 mm versus 0.70 ± 0.14 mm versus 0.57 ± 0.16 mm, respectively, p < 0.001, Table 1, Fig. 1). The results of simple and multiple linear regression analysis which shows that the association between SUA and C-IMT is independent of other significant variables are summarized in Table 2. When SUA level was taken as dependent and age, BMI, SBP, lipids, and C-IMT as independent variables, we found that serum UA levels independently associated
Y. Tavil et al. / Atherosclerosis 197 (2008) 159–163
161
Table 1 The Physical characteristics and biochemical parameters of the study groups
Age (years) Male gender (%) BMI (kg m−2 ) Heart rate (beats/min) Smokers (%) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Plasma triglyceride (mg/dl) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Plasma creatinine (mg/dl) Fasting glucose (mg/dl) Serum uric acid (mol/l) Carotid IMT (mm) Cardiovascular medication ASA, n (%) Beta-blockers, n (%) ACE inhibitors or Angiotensin receptor blocker, n (%) Ca2+ -antagonists, n (%) Cholesterol-lowering drugs, n (%)
Control (n = 25)
HT without HU (n = 30)
HT with HU (n = 25)
p-Value
50 ± 13 14 (56) 22 ± 4 82 ± 10 7 (28) 185 ± 20 128 ± 27 47 ± 14 167 ± 80 118 ± 21 77 ± 9 0.85 ± 0.20 98 ± 14 280 ± 120 0.57 ± 0.16
49 ± 11 18 (60) 23 ± 6 76 ± 9 10 (33) 214 ± 22 135 ± 29a 45 ± 13 175 ± 75* 152 ± 23* 110 ± 18* 0.98 ± 0.20 92 ± 13 270 ± 50 0.70 ± 0.14a
52 ± 12 13 (52) 25 ± 4 82 ± 8 8 (32) 225 ± 32a 142 ± 35a 42 ± 12 188 ± 96a 160 ± 11a 104 ± 17a 1.04 ± 0.21 104 ± 9 470 ± 40a,b 0.83 ± 0.16a,b
NS NS NS NS NS 0.04 0.02 NS 0.05 0.001 0.001 NS NS 0.001 0.001
– – – – –
22 (73) 12 (30) 16 (53) 8 (26) 19 (63)
21 (84) 9 (36) 15 (50) 8 (32) 16 (65)
NS NS NS NS NS
Values are mean ± S.D. or numbers (%). Probabilities determined by one way analysis of variance or χ2 tests. ACE, angiotensin-converting enzyme; ASA, acetylsalicylic acid; BMI, body mass index; HDL, high-density lipoprotein HT, hypertension; HU, hyperuricemia; IMT, intima–media thickness. a Control group vs. patient groups. b HT without HU group vs. the HT with HU group; NS, not significant, p > 0.05.
Table 2 Simple and multiple regression analysis of serum uric acid and carotid intima–media thickness in hypertensive patients SUA
Age BMI Total cholesterol LDL-cholesterol HDL-cholesterol Plasma triglyceride Systolic blood pressure Fasting glucose SUA C-IMT
C-IMT
Simple regression, r
Multivariate regression (standardized), β
Simple regression, r
Multivariate regression (standardized), β
0.27* 0.15 0.04 0.11 −0.34* 0.13 0.24* 0.11 – 0.47**
0.12 0.18 0.10 0.16 0.31* 0.12 0.15 0.01 – 0.42**
0.35** 0.13 0.34** 0.25* −0.014 0.29* 0.38* 0.23* 0.49** –
0.14 0.12 0.21 0.13 0.08 0.12 0.19 0.14 0.48** –
BMI, body mass index; C-IMT, carotid intima–media thickness; SUA, serum uric acid. * p < 0.05. ** p < 0.01.
with carotid IMT (β = 0.42, p = 0.002) and HDL-cholesterol (β = 0.31, p < 0.01). Although, SUA were significantly correlated with age and SBP, these associations were not shown by stepwise linear regression. When C-IMT was taken as dependent and age, SUA, BMI, SBP, and lipids as independent variables, we found that C-IMT independently associated only with SUA (β = 0.48, p < 0.001). According to the correlation analysis, there were significantly correlations between C-IMT and age, total cholesterol, LDL-cholesterol, plasma triglyceride, SBP, fasting glucose except HDL cholesterol (Fig. 2).
6. Discussion In this study, we have shown that carotid IMT is increased in patients with hypertension with or without HU when compared with the control subjects. We have also demonstrated that this difference is valid between two hypertensive groups. In addition, there were significant correlations between carotid IMT measurement, SUA level, and other major atherosclerotic risk factors. These results have indicated that higher SUA levels are associated with atherogenesis independent from hypertension.
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Fig. 1. Box plots showing the mean of carotid intima–media thickness within study groups (abbreviation as in Table 1).
In recent years, increased attention has been focused on the fact that prediction of atherosclerosis has been more important because development in preventive medicine have been presenting new treatment modalities. Previous reports have suggested that carotid IMT is at present the best studied and useful sonographic marker for early atherosclerotic vascular wall involvement [13–15]. The assessment of carotid IMT is postulated a surrogate marker of generalized atherosclerosis. It has been reported that the patients who have elevated level of SUA have an increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels [16]. Actually, hyperuricemia has often been considered a part of the metabolic syndrome or simply a marker of other coronary disease risk factors such as hypertension, dyslipidemia, obesity, glucose intolerance, and renal disease [17–19]. However, multiple studies provide strong evidence that elevated uric acid may also bear independent risk factor association with cardiovascular mortality [20–22]. Although, HU is frequently encountered in hypertensive patients, the linking between them with regard to the pathogenetic mechanism is unclear.
Fig. 2. Linear regression curve of the relation between carotid intima–media thickness and serum uric acid level.
In this respect, the present study was designed to interrogate whether HU has possible role in developing and/or contributing of atherosclerosis independent from hypertension in patients with hypertension. Several lines of experimental evidence are suggesting that uric acid is associated with injurious effects on the vasculature and renal tissues. Studies in rats show that elevated uric acid levels following administration of a uricase inhibitor increase blood pressure as well as produce a primary arteriopathy independent of blood pressure [23]. These effects, possibly mediated via activation of the rennin–angiotensin system and down-regulation of nitric oxide synthase, could be ameliorated by treatment with allopurinol or benziodarone [23]. Exogenous uric acid gives rise to endothelial dysfunction, and endogenous uric acid concentrations correlate with the extent of endothelial dysfunction [24]. Similarly, patients with gout have a high incidence of renovascular histological abnormalities including atherosclerosis, arteriosclerosis, glomerulosclerosis, and tubular atrophy [25]. Furthermore, urate crystals have also been proposed, including noxious effects, such as; proinflammatory, activating complement, stimulating neutrophils to release proteases and oxidants, stimulate macrophages, and activate platelets and the coagulation cascade [26]. Moreover, it has been reported that uric acid stimulate vascular smooth cell proliferation and upregulates the expression of platelet derived growth factor and monocyte chemoattractant protein-1 [27,28]. Therefore, UA is the major end-product of purine metabolism, UA may reflect the generation of superoxide and resultant oxidative stress via the xanthine oxidase system [29]. Briefly, higher levels of serum UA may have associated with development of atherosclerosis that is independent of other confounding atherosclerotic risk factor. Accordingly, we have found that HU have augmented the adverse affect of HT on cardiovascular system in patients with HT.
7. Study limitations The main limitations of this study were the lack of insulin resistance or insulin sensitivity index (e.g. homeostasis model assessment (HOMA-IR)). Therefore, we were unable to examine whether the patients with HU had higher levels of insulin resistance than patients without HU. Our findings need to be confirmed by other studies and further studies are obviously required to understand these relationships. Second, we have shown only association between C-IMT and serum uric acid instead of causality due to the study design. Third, we could investigate atherosclerosis with ultrasonographic imaging of carotid arteries in the study population; coronary angiographic data for excluding coronary artery disease was unavailable. Meanwhile, absence of clinical symptoms and demonstrable wall motion abnormalities on echocardiography decreased the possibility of coronary artery disease. Additionally, because of ethical considerations, patients were studied under concurrent medications, and this might have
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had an influence on the precision of the measurements of carotid IMT. 8. Conclusion In the present study, we have found that carotid IMT is increased in patients with hypertension with or without HU when compared with the control subjects. In patients who had both HT and HU had increased carotid IMT compared to the patients who did not have HU. In addition, there were significant associations between carotid IMT measurement, SUA level, and other major atherosclerotic risk factors. These results have indicated that higher SUA levels are associated with atherogenesis independent from hypertension. Prospective studies will be necessary to confirm and extend these findings including early screening for hyperuricemia and lowering of SUA level looking at potential benefits in slowing progression of C-IMT in hypertensive patients. References [1] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7–13. [2] Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J. Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year followup of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand 1988;224:549–55. [3] Bonora E, Targher G, Zenere MB, et al. Relationship of uric acid concentration to cardiovascular risk factors in young men. The role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord 1996;20:975–80. [4] Vuorinen-Markkola H, Yki-J¨arvinen H. Hyperuricemia and insulin resistance. J Clin Endocrinol Metab 1994;78:25–9. [5] Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 2000;35:746–51. [6] Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002;105: 2619–24. [7] Leyva F, Anker S, Swan JW, et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997;18:858–65. [8] Mustard JF, Murphy EA, Ogryzlo MA, Smythe HA. Blood coagulation and platelet economy in subjects with primary gout. Can Med Assoc J 1963;89:1207–11. [9] Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk In Communities (ARIC) study, 1987–1993. Am J Epidemiol 1997;146:483–94.
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