- Email: [email protected]
Serum uric acid in hypertensive patients with and without peripheral arterial disease
Atherosclerosis 168 (2003) 163 /168 www.elsevier.com/locate/atherosclerosis
Serum uric acid in hypertensive patients with and without peripheral arterial disease Michel Langlois a,*, Dirk De Bacquer b, Daniel Duprez c,d, Marc De Buyzere c, Joris Delanghe e, Victor Blaton a a
Department of Clinical Chemistry, AZ St-Jan AV Hospital, Ruddershove 10, B-8000 Brugge, Belgium Department of Public Health, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium c Department of Cardiovascular Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium d Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA e Department of Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium b
Received 23 September 2002; received in revised form 6 February 2003; accepted 24 February 2003
Abstract Background: Uric acid is frequently elevated in hypertension. In addition to renal and metabolic disturbances, lower limb ischemia might contribute to hyperuricemia among hypertensives complicated by peripheral arterial disease (PAD). Objective: To test the hypothesis that uric acid status is related to lower limb function in hypertensives with PAD. Methods: Serum and 24-h urine uric acid levels and other risk factors were examined in 145 hypertensives free of PAD and 166 hypertensives with PAD. Ankle/ brachial index (ABI) and absolute claudication distance (in PAD) on a treadmill test (ACD) were assessed. Results: In multiple regression analysis for serum uric acid in the total group, PAD emerged as an independent determinant (P /0.03) next to age (P/ 0.005), triglycerides (P/0.04), and insulin (P/0.02). Serum uric acid concentrations were higher in hypertensives with PAD (4049/ 101 vs. 3479/80 mmol/l, P B/0.001) independent of components of the metabolic syndrome (body mass index, triglycerides, insulin) and of age, gender, diabetes mellitus, pulse pressure, cholesterol, C-reactive protein, and treatment. After adjustment for kidney function by uric acid/creatinine ratio, values remained higher in hypertensives with PAD (P/0.01). Uric acid excretion was higher in the PAD group (P B/0.001), whereas uric acid clearance was comparable between both groups. In multiple regression analysis for ACD (3579/183 m) in the PAD group, serum uric acid (P/0.02), C-reactive protein (P B/0.0001), age (P/0.02), and smoking (P/0.004) were independently associated. ABI (0.629/0.17) was not related to uric acid in PAD patients. Conclusion: Hyperuricemia is more pronounced in hypertensives complicated by PAD and is associated with worse functional status of the peripheral circulation. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hypertension; Peripheral vascular disease; Atherosclerosis; Risk factors; Claudication
1. Introduction Hyperuricemia is a frequent finding in patients with hypertension [1], in which it has been associated with impaired renal blood flow (hypertensive nephrosclerosis), metabolic syndrome (hyperinsulinemia/insulin resistance), hyperlipidemia, and diuretic treatment [1 /4]. Recent studies demonstrated that uric acid is an independent risk factor for cardiovascular events in
* Corresponding author. Tel.: /32-50-452640; fax: /32-50-452619. E-mail address: [email protected] (M. Langlois).
hypertensive patients [5 /7] as well as in the general population [8,9], although the association remains controversial [10,11]. Most investigations have addressed uric acid status for coronary events in hypertension, whereas peripheral atherosclerosis has received much less attention. Peripheral arterial disease (PAD) is a severe but underestimated atherosclerotic complication of hypertension and has a major impact on the quality of life because of intermittent claudication [12 /14]. Moreover, it is associated with an increased cardiovascular and cerebrovascular morbidity and mortality [12 /14]. In clinical practice, PAD is defined noninvasively by the
0021-9150/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0021-9150(03)00093-5
164
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
Table 1 Clinical characteristics of the study population
Age (years) Male gender (%) BMI (kg/m2) Diabetes mellitus (%) Current smoking (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Diuretic treatment (%) Aspirin intake (%) ABI ACD (m)
Hypertension without PAD (n/145)
Hypertension with PAD (n/166)
Significancea
65.29/9.0 42.8 27.89/4.4 20.8 31.5 146.79/16.1 89.49/11.1 57.39/14.3 23.4 24.4 /0.90 /
67.39/8.6 74.7 27.09/4.3 24.7 30.2 150.39/23.7 85.19/10.3 65.29/19.0 36.8 70.4 0.629/0.17 356.69/183.2
P /0.01 P B/0.001 P /0.30 P /0.48 P /0.89 P /0.53 P /0.001 P B/0.001 P /0.008 P B/0.001
Values are mean9/S.D. or percentages. PAD, peripheral arterial disease; BMI, body mass index; ABI, ankle/brachial index; ACD, absolute claudication distance. a According to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables.
determination of the ankle/brachial systolic blood pressure index (ABI) and functionally assessed by absolute claudication distance (ACD) on a treadmill test [15 /17]. The disabling pain of intermittent claudication arises from lower limb ischemia and hypoxia during walking. Tissue hypoxia could be expected to enhance uric acid production [4]. In this context, we aimed to test the hypothesis that hyperuricemia might be more pronounced in hypertension complicated by PAD, and that serum uric acid concentration might be associated with functional status (walking distance) of the lower limbs.
2. Methods 2.1. Patients The study population consisted of 145 essential hypertensive patients free of PAD from the Hypertension Unit and 166 hypertensives with PAD (Fontaine stage II) from the Vascular Medicine Unit of the Ghent University Hospital. Hypertension was defined along the WHO/ISH criteria and was present for at least 12 months [18]. Informed consent was obtained from the patients, and the study was approved by the ethical committee of the Ghent University Hospital. Patients with either surgical revascularisation or percutaneous transluminal angioplasty procedures at the lower limb arteries were not included, as well as patients with acute myocardial infarction, angina pectoris, heart failure, coronary revascularisation procedures, or cerebrovascular events during the last 6 months prior to the study. Patients were also excluded if they had gout, alcohol intake /20 g/day, or contraindications to perform a treadmill test (chronic obstruc-
tive pulmonary disease, cardiac rhythm disturbances, orthopaedic or neurological conditions, foot ulcers). PAD patients had been motivated to participate in an exercise rehabilitation program that includes three walking sessions a week with a duration greater than 30 min per session with near maximal pain during training as end point, and program length of greater than 6 months [19,20]. On the day of the examinations for this study, none of the PAD patients had exercised prior to blood sampling. All patients were on a low-purine diet, and were treated with diuretics (31%) or b-blockers (64%), calcium antagonists (44%), angiotensin-converting enzyme inhibitors (35%), aspirin (160 mg/day) (45%), and lipid-lowering agents (20%) in varying combinations. None of the patients took angiotensin II receptor antagonists or uricosuric agents. All women were postmenopausal and did not receive hormonal replacement therapy. As shown in Table 1, patient characteristics did not differ between hypertensives with PAD and those without PAD except for male predominance, age, diastolic blood pressure, pulse pressure, diuretic treatment and aspirin intake. 2.2. Biochemical investigations Fasting blood samples were taken between 08:00 and 09:00 h. Serum uric acid, creatinine, glucose, and lipids (total cholesterol, HDL-cholesterol, triglycerides) were assayed spectrophotometrically using commercial reagents on a Modular analyser (Roche). Uric acid/ creatinine ratios were calculated to adjust for kidney function. Serum insulin concentration was measured by an immunometric chemiluminescence assay (Immulite 2000, DPC). Serum C-reactive protein (hs-CRP) was assayed using high-sensitive latex-enhanced immunone-
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
phelometry (Dade Behring). Intra-assay coefficients of variation were B/3.6% for uric acid, B/3.7% for creatinine, B/1.6% for glucose, B/1.8% for lipids, B/ 8.2% for insulin, and B/3.8% for hs-CRP. Urine was collected over 24 h for the analysis of uric acid and creatinine excretion using the method described above (Roche). Uric acid/creatinine ratio, uric acid clearance, and creatinine clearance were calculated. 2.3. Clinical examinations After blood sampling, all subjects underwent clinical examinations including blood pressure measurements at the left and right brachial artery by sphygmomanometry (three times in sitting position with 2-min intervals) and 12-lead ECG. Body mass index (BMI) was calculated as body weight (kg) divided by the square of the height (m2). After a 10 min supine rest, arterial systolic blood pressures at the left and the right brachial and posterior tibial arteries were measured in supine position using Doppler 8 MHz ultrasound device (Scimed Digitop 840S). Ankle/brachial index was calculated for both legs and the lowest ABI was taken as study parameter. Thereafter, PAD patients underwent a standardised graded treadmill protocol with a speed of 3 km/h and adjustable grade. For the first 5 min, the patients had to walk at a grade of 0%, then the grade increased every 5 min by 5% up to 15% [21,22]. All patients were accustomed to treadmill tests and had at least three tests during the last 12 months. ACD on the present treadmill test was taken as study parameter. 2.4. Statistics Values are expressed as mean and S.D. or as median and interquartile range (IR) where appropriate. Statistical differences were evaluated according to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables. The strength of associations was quantified through Spearman rank correlation coefficients. Multivariate analyses were performed with serum uric acid, ABI, and ACD as dependent variables. Statistical analysis was carried out using SAS software. A level of a /0.05 was used to indicate statistical significance.
3. Results 3.1. Serum uric acid and other risk factors As shown in Table 2, serum uric acid concentrations were higher in hypertensive patients with PAD (404.39/ 100.6 mmol/l) than in those without PAD (346.69/79.5
165
mmol/l) (P B/0.001). Serum uric acid/creatinine ratio was also higher in the PAD group (P /0.01). Total cholesterol, triglycerides, and hs-CRP showed higher serum concentrations in PAD patients, whereas serum HDLcholesterol was lower in the PAD group. Fasting glucose and insulin levels were comparable between both groups (Table 2). In the total population, uric acid concentrations were significantly higher in males (P B/0.001), diabetics (P / 0.006), and in patients taking aspirin (P /0.001) and diuretics (P B/0.001). No significant differences in uric acid status were found between smokers and nonsmokers (P /0.32). Serum uric acid correlated with age (r /0.11, P B/0.05), BMI (r/0.18, P B/0.01), HDL-cholesterol (r//0.28, P B/0.001), triglycerides (r/0.37, P B/0.001), glucose (r/0.34, P B/0.001), insulin (r /0.22, P /0.001), diastolic blood pressure (r/ /0.13, P B/0.05), and pulse pressure (r/0.12, P B/ 0.05). Age, gender, BMI, diabetes mellitus, pulse pressure, hs-CRP, total cholesterol, HDL-cholesterol, triglycerides, insulin, diuretic treatment, and aspirin intake were included as covariates in a multiple regression analysis for serum uric acid to evaluate potential confounding by these variables. In this model (Table 3), age (P /0.005), triglycerides (P /0.04), insulin (P /0.02) and PAD (P /0.03) were independently associated with hyperuricemia in the combined study population. 3.2. Urinary uric acid excretion Uric acid excretion measured in 24 h-urine collections was higher (P B/0.001) in hypertensive patients with PAD (median: 3.24 mmol/day) than in those without PAD (2.73 mmol/day) (Table 2). Uric acid/creatinine ratios were also higher in the PAD group (P /0.006). Uric acid excretion correlated with serum uric acid concentration (r /0.46, P /0.001). Uric acid clearance and creatinine clearance were not significantly different between both groups. 3.3. Vascular investigations ABI was /0.90 for all hypertensives without PAD. ACD and ABI of hypertensive patients with PAD were 356.69/183.2 m and 0.629/0.17, respectively. Serum uric acid concentration correlated negatively with ACD in Spearman rank analysis (r//0.25, P B/0.005). ACD was lower among smokers (P /0.007). Table 4(left) shows a multiple regression analysis with ACD as dependent variable. In this model, serum uric acid (P /0.02) as well as age (P /0.02), smoking (P / 0.004), and serum hs-CRP (P B/0.0001) were independently associated with ACD. In Spearman rank analysis, ACD correlated with ABI (r/0.27, P /0.002) but not with pulse pressure. Serum
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
166
Table 2 Biochemical measurements in serum and 24-h urine collections Hypertension without PAD (n/145)
Hypertension with PAD (n/166)
Significancea
Serum Uric acid (mmol/l) Creatinine (mmol/l) Uric acid/creatinine ratio Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) Triglycerides (mmol/l) Glucose (mmol/l) Insulin (mU/l) Hs-CRP (mg/l)
346.69/79.5 88.4 (82.2 /99.0) 3.75 (3.21 /4.46) 5.899/1.08 1.419/0.44 1.53 (1.09 /2.11) 6.109/2.04 12.5 (11.4 /14.6) 2.32 (1.28 /3.66)
404.39/100.6 90.2 (82.2 /107.0) 4.20 (3.46 /5.35) 6.389/1.30 1.059/0.33 1.93 (1.28 /2.98) 6.069/1.86 12.2 (10.9 /14.4) 4.60 (2.00 /8.70)
P B/0.001 P /0.28 P /0.01 P /0.001 P B/0.001 P B/0.001 P /0.93 P /0.09 P B/0.001
24-h urine Uric acid excretion (mmol/day) Uric acid/creatinine ratio Uric acid clearance (ml/min) Creatinine clearance (ml/min)
2.73 0.26 5.50 70.9
3.24 0.32 5.71 73.3
P B/0.001 P /0.006 P /0.19 P /0.81
(2.18 /3.07) (0.21 /0.32) (4.26 /6.27) (63.3 /90.4)
(2.74 /3.97) (0.26 /0.42) (5.12 /6.58) (61.9 /85.8)
Values are mean9/S.D. or median and interquartile range. PAD, peripheral arterial disease; hs-CRP, C-reactive protein; HDL, high-density lipoprotein. a According to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables.
Table 3 Multiple regression analysis for uric acid in the total population b (S.E.) Intercept PAD (yes vs. no) Age (years) Triglycerides (mmol/l) Insulin (mU/l)
139.99 37.62 (17.65) 2.25 ( 0.80) 12.30 (5.89) 7.66 (3.12)
t -Statistic
emerged as significantly associated independent variables.
Significance
4. Discussion 2.13 2.82 2.09 2.46
P /0.03 P /0.005 P /0.04 P /0.02
Variables that did not reach significance: gender, BMI, total cholesterol, HDL-cholesterol, hs-CRP, diabetes mellitus, pulse pressure, diuretic treatment, aspirin intake.
uric acid concentration was not related to ABI. In multiple regression analysis for ABI (Table 4(right)), only age (P /0.002) and serum hs-CRP (P B/0.0001)
Uric acid, generated from xanthine by the enzyme xanthine oxidase, is the major end-product of purine metabolism [23]. Normal serum concentrations are generally B/420 mmol/l ( B/7 mg/dl) for men and B/ 350 mmol/l ( B/6 mg/dl) for women [23]. In essential hypertension, serum uric acid concentration is frequently increased in association with the multimetabolic or X syndrome [1,4]. In this study, we found that hyperuricemia among hypertensives is more pronounced in those complicated by PAD than in uncomplicated hypertension. The observed effect of PAD on serum uric
Table 4 Multiple regression analyses for ACD and ABI in the PAD group ACD
Intercept Age (years) Smoking (yes vs. no) Uric acid (mmol/l) hs-CRP (mg/l)
ABI
b (S.E.)
t -Statistic
Significance
b (S.E.)a
t -Statistic
Significance
935.4 /4.36 (1.78) /96.41 (32.85) /0.40 (0.17) /16.24 (3.26)
/2.45 /2.94 /2.32 /4.98
P/0.02 P/0.004 P/0.02 P B/0.0001
14.34 /0.056 /0.107 /0.002 /0.140
/3.21 /0.33 /1.10 /4.61
P /0.002 P /0.74 P /0.27 P B/0.0001
(0.017) (0.328) (0.001) (0.030)
Other variables that did not reach significance: gender, BMI, total cholesterol, HDL-cholesterol, triglycerides, insulin, diabetes mellitus, pulse pressure, ABI (in the model for ACD), diuretic use, aspirin intake. a Regression coefficients multiplied by a factor 10.
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
acid concentration was independent of components of the metabolic syndrome (BMI, triglycerides, insulin) and potential confounders such as age, gender, cholesterol, hs-CRP, diabetes mellitus, pulse pressure, diuretic treatment and aspirin intake. Hyperuricemia reflects an increase in the uric acid pool, which may be the result of uric acid overproduction, of insufficient uric acid excretion, or of a combination of both [23]. Renal impairment as well as hyperinsulinemia might increase serum uric acid levels because of diminished excretion rate [1,3,4,23]. In our study, the relative hyperuricemia in the PAD group remained significant after adjustment for kidney function (uric acid/creatinine ratio). Furthermore, uric acid clearance and creatinine clearance were comparable among both groups. Total urinary uric acid excretion was higher in the PAD group. Therefore, we suggest that the higher uric acid status in PAD is attributable to an increase in endogenous uric acid production and not to a decreased kidney function or uric acid clearance. In this study, PAD patients had been in a supervised exercise program, which may have influenced their serum uric acid levels. However, moderate exercise of mild intensity does not change uric acid levels significantly [24]. In the supervised training of PAD patients enrolled in our study, only very moderate levels of exercise intensity are reached. On the day of the examinations for this study, none of the PAD patients had exercised prior to blood sampling. We found that hyperuricemia in PAD patients with hypertension is associated with a worse functional status of the peripheral circulation, as evidenced by more pronounced claudication (low ACD) on a treadmill test. A number of studies have compared the reproducibility of the initial and ACD, with most demonstrating that ACD is more reproducible and, therefore, presumably the more appropriate measurement to use as a study end point [21,22]. ACD also has the theoretical justification that it probably more truly represents real life, where the patient is likely to walk even after the first appearance of claudication discomfort. We found that high serum uric acid concentration was independently associated with low ACD in multiple regression analysis. In our model, serum uric acid as well as age, smoking, and serum hs-CRP emerged as significant predictors of ACD. The observed association between ACD and hs-CRP was most significant and is concordant with earlier observations from our unit [25]. This effect is attributable to inflammatory processes involved in the progression of atherosclerotic vascular lesions [26]. However, this strong association did not prevent uric acid from being an independent determinant of ACD. Smoking, which in our study had no effect on uric acid status but appeared as a significant covariate for ACD, has also been demonstrated to affect walking distance in other studies [25,27].
167
In contrast to CRP, serum uric acid was not associated with ABI, which has been proposed as a prognostic parameter in PAD [15,16]. Our results are in the same line as those obtained in the Edinburgh Artery Study [28], where uric acid was found to be associated with lower limb ischemia (reactive hyperemia test) independently of peripheral arterial narrowing (ABI). In another clinical setting (chronic heart failure), hyperuricemia has been associated with worse functional capacity [29], impaired blood flow in the lower limbs [30], and high vascular resistance [31]. In hypercholesterolaemic patients, high uric acid concentrations were associated with more extensive atherosclerosis in the femoral artery (greater arterial edge roughness) assessed from arteriograms [32]. These findings support the hypothesis that impaired tissue blood flow may be involved in the higher production of uric acid. Peripheral vascular damage may lead to severe tissue hypoxia causing adenine nucleotide breakdown and increasing production of uric acid [4]. In the peripheral vasculature, endothelial cells are the predominant site of the enzyme xanthine oxidase and uric acid production which have been linked to vascular dysfunction [33] and free radical generation under hypoxic conditions [4]. Higher levels of uric acid and xanthine oxidase have been found in atherosclerotic plaque than in healthy vascular tissue [34]. These data suggest that hyperuricemia could be linked to the pathophysiological processes involved in the progression of atherosclerosis. The association between hyperuricemia and atherosclerosis might look paradoxical because uric acid is one of the major plasma antioxidants and hyperuricemia has been proposed to be a compensatory mechanism to counteract free radical injury to the arterial wall [35]. However, there is evidence that increased uric acid levels could have prooxidant effects and promote lipid oxidation in vascular tissue [1,36]. In this study, hypertensives with PAD were defined by symptoms of claudication (Fontaine stage II). It cannot be excluded that the ‘‘control’’ hypertension group comprised a few patients with asymptomatic PAD. Indeed, the Edinburgh Artery Study has demonstrated that up to 20% of the population at risk have asymptomatic PAD [28], and 2 /5% of hypertensives were shown to have PAD [12]. However, all ‘‘control’’ hypertensive patients enrolled in our study were free of clinical symptoms of PAD and all of them had ABI/0.90. In summary, hyperuricemia among essential hypertensives is more pronounced in those complicated by PAD and is associated with a worse functional state of the peripheral circulation. Further studies are needed to clarify the pathophysiological mechanism of hyperuricemia in hypertension complicated by peripheral atherosclerosis.
168
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
Acknowledgements Michel Langlois is recipient of a postdoctoral fellowship of the Fund for Scientific Research (FWO), Flanders, Belgium.
References [1] Ward HJ. Uric acid as an independent risk factor in the treatment of hypertension. Lancet 1998;352:670 /1. [2] Messerli FH, Frohlich ED, Dreslinsky GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med 1980;93:817 /21. [3] Facchini F, Chen YDI, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance and plasma uric acid concentration. J Am Med Assoc 1991;266:3008 /11. [4] Garcı´a Puig J, Ruilope LM. Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 1999;17:869 /72. [5] Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in succesfully treated hypertensive patients. Hypertension 1999;34:144 /50. [6] Franse LV, Pahor M, Di Bari M, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000;18:1149 /54. [7] Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA Study. Hypertension 2000;36:1072 /8. [8] Alderman MH. Serum uric acid as a cardiovascular risk factor for heart disease. Curr Hypertens Rep 2001;3:184 /9. [9] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality in the NHANES I epidemiologic follow-up study, 1971 /1992. National Health and Nutrition Examination Survey. J Am Med Assoc 2000;283:2404 /10. [10] 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. [11] Wannamethee SG. Serum uric acid is not an independent risk factor for coronary heart disease. Curr Hypertens Rep 2001;3:190 /6. [12] Makin A, Lip GY, Silverman S, Beevers DG. Peripheral vascular disease and hypertension: a forgotten association? J Hum Hypertens 2001;15:447 /54. [13] Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997;2:221 /6. [14] Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Circulation 1995;92:614 /21. [15] Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housley E, Ruckley CV. Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. Br Med J 1996;313:1440 /4. [16] Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol 1999;19:538 /45. [17] Duprez D, De Backer T, De Buyzere M, Clement DL. Estimation of walking distance in intermittent claudication: need for standardization. Eur Heart J 1999;20:641 /4.
[18] World Health Organisation. International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151 /83. [19] Remijnse-Tamerius HCM, Duprez D, De Buyzere M, Oeseburg B, Clement DL. Why is training effective in the treatment of patients with intermittent claudication? Int Angiol 1999;18:103 / 12. [20] Regensteiner J, Gardner A, Hiatt W. Exercise testing and exercise rehabilitation for patients with peripheral arterial disease: status 1997. Vasc Med 1997;2:147 /55. [21] Chandry H, Holland A, Dormandy J. Comparison of graded versus constant treadmill test protocols for quantifying intermittent claudication. Vasc Med 1997;2:93 /7. [22] Gardner A, Skinner JS, Cantwell BW, Smith LK. Progressive versus single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc 1991;23:402 /8. [23] Ruilope LM, Garcı´a Puig J. Hyperuricemia and renal function. Curr Hypertens Rep 2001;3:197 /202. [24] Green HJ, Fraser IG. Differential effects of exercise intensity on serum uric acid concentration. Med Sci Sports Exerc 1988;20:55 / 9. [25] Langlois M, Duprez D, Delanghe J, De Buyzere M, Clement DL. Vitamin C status is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 2001;103:1863 /8. [26] Ross R. Atherosclerosis */an inflammatory disease. New Engl J Med 1999;340:115 /26. [27] Cahan MA, Montgomery P, Otis RB, Clancy R, Flinn W, Gardner A. The effect of cigarette smoking on six-minute walk distance in patients with intermittent claudication. Angiology 1999;50:537 /46. [28] Lowe GD, Fowkes FG, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993;87:1915 /20. [29] 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. [30] Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart 1997;78:39 /43. [31] Doehner W, Rauchhaus M, Florea VG, et al. Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance. Am Heart J 2001;141:792 / 9. [32] Bergstrand L. Femoral and coronary atherosclerosis in patients with hyperlipidemia. Arteriographic findings correlated to clinical and biochemical parameters. Acta Radiol Suppl 1994;392:1 /27. [33] Maxwell AJ, Bruinsma KA. Uric acid is closely related to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol 2001;38:1850 /8. [34] Patetsios P, Song M, Shutze WP, et al. Identification of uric acid and xanthine oxidase in atherosclerotic plaque. Am J Cardiol 2001;88:188 /91. [35] Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131 /9. [36] Bagnati M, Perugini C, Cau C, Bordone R, Albano E, Bellomo G. When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid. Biochem J 1999;340:143 /52.
Serum uric acid in hypertensive patients with and without peripheral arterial disease Michel Langlois a,*, Dirk De Bacquer b, Daniel Duprez c,d, Marc De Buyzere c, Joris Delanghe e, Victor Blaton a a
Department of Clinical Chemistry, AZ St-Jan AV Hospital, Ruddershove 10, B-8000 Brugge, Belgium Department of Public Health, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium c Department of Cardiovascular Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium d Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA e Department of Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium b
Received 23 September 2002; received in revised form 6 February 2003; accepted 24 February 2003
Abstract Background: Uric acid is frequently elevated in hypertension. In addition to renal and metabolic disturbances, lower limb ischemia might contribute to hyperuricemia among hypertensives complicated by peripheral arterial disease (PAD). Objective: To test the hypothesis that uric acid status is related to lower limb function in hypertensives with PAD. Methods: Serum and 24-h urine uric acid levels and other risk factors were examined in 145 hypertensives free of PAD and 166 hypertensives with PAD. Ankle/ brachial index (ABI) and absolute claudication distance (in PAD) on a treadmill test (ACD) were assessed. Results: In multiple regression analysis for serum uric acid in the total group, PAD emerged as an independent determinant (P /0.03) next to age (P/ 0.005), triglycerides (P/0.04), and insulin (P/0.02). Serum uric acid concentrations were higher in hypertensives with PAD (4049/ 101 vs. 3479/80 mmol/l, P B/0.001) independent of components of the metabolic syndrome (body mass index, triglycerides, insulin) and of age, gender, diabetes mellitus, pulse pressure, cholesterol, C-reactive protein, and treatment. After adjustment for kidney function by uric acid/creatinine ratio, values remained higher in hypertensives with PAD (P/0.01). Uric acid excretion was higher in the PAD group (P B/0.001), whereas uric acid clearance was comparable between both groups. In multiple regression analysis for ACD (3579/183 m) in the PAD group, serum uric acid (P/0.02), C-reactive protein (P B/0.0001), age (P/0.02), and smoking (P/0.004) were independently associated. ABI (0.629/0.17) was not related to uric acid in PAD patients. Conclusion: Hyperuricemia is more pronounced in hypertensives complicated by PAD and is associated with worse functional status of the peripheral circulation. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hypertension; Peripheral vascular disease; Atherosclerosis; Risk factors; Claudication
1. Introduction Hyperuricemia is a frequent finding in patients with hypertension [1], in which it has been associated with impaired renal blood flow (hypertensive nephrosclerosis), metabolic syndrome (hyperinsulinemia/insulin resistance), hyperlipidemia, and diuretic treatment [1 /4]. Recent studies demonstrated that uric acid is an independent risk factor for cardiovascular events in
* Corresponding author. Tel.: /32-50-452640; fax: /32-50-452619. E-mail address: [email protected] (M. Langlois).
hypertensive patients [5 /7] as well as in the general population [8,9], although the association remains controversial [10,11]. Most investigations have addressed uric acid status for coronary events in hypertension, whereas peripheral atherosclerosis has received much less attention. Peripheral arterial disease (PAD) is a severe but underestimated atherosclerotic complication of hypertension and has a major impact on the quality of life because of intermittent claudication [12 /14]. Moreover, it is associated with an increased cardiovascular and cerebrovascular morbidity and mortality [12 /14]. In clinical practice, PAD is defined noninvasively by the
0021-9150/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0021-9150(03)00093-5
164
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
Table 1 Clinical characteristics of the study population
Age (years) Male gender (%) BMI (kg/m2) Diabetes mellitus (%) Current smoking (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Diuretic treatment (%) Aspirin intake (%) ABI ACD (m)
Hypertension without PAD (n/145)
Hypertension with PAD (n/166)
Significancea
65.29/9.0 42.8 27.89/4.4 20.8 31.5 146.79/16.1 89.49/11.1 57.39/14.3 23.4 24.4 /0.90 /
67.39/8.6 74.7 27.09/4.3 24.7 30.2 150.39/23.7 85.19/10.3 65.29/19.0 36.8 70.4 0.629/0.17 356.69/183.2
P /0.01 P B/0.001 P /0.30 P /0.48 P /0.89 P /0.53 P /0.001 P B/0.001 P /0.008 P B/0.001
Values are mean9/S.D. or percentages. PAD, peripheral arterial disease; BMI, body mass index; ABI, ankle/brachial index; ACD, absolute claudication distance. a According to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables.
determination of the ankle/brachial systolic blood pressure index (ABI) and functionally assessed by absolute claudication distance (ACD) on a treadmill test [15 /17]. The disabling pain of intermittent claudication arises from lower limb ischemia and hypoxia during walking. Tissue hypoxia could be expected to enhance uric acid production [4]. In this context, we aimed to test the hypothesis that hyperuricemia might be more pronounced in hypertension complicated by PAD, and that serum uric acid concentration might be associated with functional status (walking distance) of the lower limbs.
2. Methods 2.1. Patients The study population consisted of 145 essential hypertensive patients free of PAD from the Hypertension Unit and 166 hypertensives with PAD (Fontaine stage II) from the Vascular Medicine Unit of the Ghent University Hospital. Hypertension was defined along the WHO/ISH criteria and was present for at least 12 months [18]. Informed consent was obtained from the patients, and the study was approved by the ethical committee of the Ghent University Hospital. Patients with either surgical revascularisation or percutaneous transluminal angioplasty procedures at the lower limb arteries were not included, as well as patients with acute myocardial infarction, angina pectoris, heart failure, coronary revascularisation procedures, or cerebrovascular events during the last 6 months prior to the study. Patients were also excluded if they had gout, alcohol intake /20 g/day, or contraindications to perform a treadmill test (chronic obstruc-
tive pulmonary disease, cardiac rhythm disturbances, orthopaedic or neurological conditions, foot ulcers). PAD patients had been motivated to participate in an exercise rehabilitation program that includes three walking sessions a week with a duration greater than 30 min per session with near maximal pain during training as end point, and program length of greater than 6 months [19,20]. On the day of the examinations for this study, none of the PAD patients had exercised prior to blood sampling. All patients were on a low-purine diet, and were treated with diuretics (31%) or b-blockers (64%), calcium antagonists (44%), angiotensin-converting enzyme inhibitors (35%), aspirin (160 mg/day) (45%), and lipid-lowering agents (20%) in varying combinations. None of the patients took angiotensin II receptor antagonists or uricosuric agents. All women were postmenopausal and did not receive hormonal replacement therapy. As shown in Table 1, patient characteristics did not differ between hypertensives with PAD and those without PAD except for male predominance, age, diastolic blood pressure, pulse pressure, diuretic treatment and aspirin intake. 2.2. Biochemical investigations Fasting blood samples were taken between 08:00 and 09:00 h. Serum uric acid, creatinine, glucose, and lipids (total cholesterol, HDL-cholesterol, triglycerides) were assayed spectrophotometrically using commercial reagents on a Modular analyser (Roche). Uric acid/ creatinine ratios were calculated to adjust for kidney function. Serum insulin concentration was measured by an immunometric chemiluminescence assay (Immulite 2000, DPC). Serum C-reactive protein (hs-CRP) was assayed using high-sensitive latex-enhanced immunone-
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
phelometry (Dade Behring). Intra-assay coefficients of variation were B/3.6% for uric acid, B/3.7% for creatinine, B/1.6% for glucose, B/1.8% for lipids, B/ 8.2% for insulin, and B/3.8% for hs-CRP. Urine was collected over 24 h for the analysis of uric acid and creatinine excretion using the method described above (Roche). Uric acid/creatinine ratio, uric acid clearance, and creatinine clearance were calculated. 2.3. Clinical examinations After blood sampling, all subjects underwent clinical examinations including blood pressure measurements at the left and right brachial artery by sphygmomanometry (three times in sitting position with 2-min intervals) and 12-lead ECG. Body mass index (BMI) was calculated as body weight (kg) divided by the square of the height (m2). After a 10 min supine rest, arterial systolic blood pressures at the left and the right brachial and posterior tibial arteries were measured in supine position using Doppler 8 MHz ultrasound device (Scimed Digitop 840S). Ankle/brachial index was calculated for both legs and the lowest ABI was taken as study parameter. Thereafter, PAD patients underwent a standardised graded treadmill protocol with a speed of 3 km/h and adjustable grade. For the first 5 min, the patients had to walk at a grade of 0%, then the grade increased every 5 min by 5% up to 15% [21,22]. All patients were accustomed to treadmill tests and had at least three tests during the last 12 months. ACD on the present treadmill test was taken as study parameter. 2.4. Statistics Values are expressed as mean and S.D. or as median and interquartile range (IR) where appropriate. Statistical differences were evaluated according to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables. The strength of associations was quantified through Spearman rank correlation coefficients. Multivariate analyses were performed with serum uric acid, ABI, and ACD as dependent variables. Statistical analysis was carried out using SAS software. A level of a /0.05 was used to indicate statistical significance.
3. Results 3.1. Serum uric acid and other risk factors As shown in Table 2, serum uric acid concentrations were higher in hypertensive patients with PAD (404.39/ 100.6 mmol/l) than in those without PAD (346.69/79.5
165
mmol/l) (P B/0.001). Serum uric acid/creatinine ratio was also higher in the PAD group (P /0.01). Total cholesterol, triglycerides, and hs-CRP showed higher serum concentrations in PAD patients, whereas serum HDLcholesterol was lower in the PAD group. Fasting glucose and insulin levels were comparable between both groups (Table 2). In the total population, uric acid concentrations were significantly higher in males (P B/0.001), diabetics (P / 0.006), and in patients taking aspirin (P /0.001) and diuretics (P B/0.001). No significant differences in uric acid status were found between smokers and nonsmokers (P /0.32). Serum uric acid correlated with age (r /0.11, P B/0.05), BMI (r/0.18, P B/0.01), HDL-cholesterol (r//0.28, P B/0.001), triglycerides (r/0.37, P B/0.001), glucose (r/0.34, P B/0.001), insulin (r /0.22, P /0.001), diastolic blood pressure (r/ /0.13, P B/0.05), and pulse pressure (r/0.12, P B/ 0.05). Age, gender, BMI, diabetes mellitus, pulse pressure, hs-CRP, total cholesterol, HDL-cholesterol, triglycerides, insulin, diuretic treatment, and aspirin intake were included as covariates in a multiple regression analysis for serum uric acid to evaluate potential confounding by these variables. In this model (Table 3), age (P /0.005), triglycerides (P /0.04), insulin (P /0.02) and PAD (P /0.03) were independently associated with hyperuricemia in the combined study population. 3.2. Urinary uric acid excretion Uric acid excretion measured in 24 h-urine collections was higher (P B/0.001) in hypertensive patients with PAD (median: 3.24 mmol/day) than in those without PAD (2.73 mmol/day) (Table 2). Uric acid/creatinine ratios were also higher in the PAD group (P /0.006). Uric acid excretion correlated with serum uric acid concentration (r /0.46, P /0.001). Uric acid clearance and creatinine clearance were not significantly different between both groups. 3.3. Vascular investigations ABI was /0.90 for all hypertensives without PAD. ACD and ABI of hypertensive patients with PAD were 356.69/183.2 m and 0.629/0.17, respectively. Serum uric acid concentration correlated negatively with ACD in Spearman rank analysis (r//0.25, P B/0.005). ACD was lower among smokers (P /0.007). Table 4(left) shows a multiple regression analysis with ACD as dependent variable. In this model, serum uric acid (P /0.02) as well as age (P /0.02), smoking (P / 0.004), and serum hs-CRP (P B/0.0001) were independently associated with ACD. In Spearman rank analysis, ACD correlated with ABI (r/0.27, P /0.002) but not with pulse pressure. Serum
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
166
Table 2 Biochemical measurements in serum and 24-h urine collections Hypertension without PAD (n/145)
Hypertension with PAD (n/166)
Significancea
Serum Uric acid (mmol/l) Creatinine (mmol/l) Uric acid/creatinine ratio Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) Triglycerides (mmol/l) Glucose (mmol/l) Insulin (mU/l) Hs-CRP (mg/l)
346.69/79.5 88.4 (82.2 /99.0) 3.75 (3.21 /4.46) 5.899/1.08 1.419/0.44 1.53 (1.09 /2.11) 6.109/2.04 12.5 (11.4 /14.6) 2.32 (1.28 /3.66)
404.39/100.6 90.2 (82.2 /107.0) 4.20 (3.46 /5.35) 6.389/1.30 1.059/0.33 1.93 (1.28 /2.98) 6.069/1.86 12.2 (10.9 /14.4) 4.60 (2.00 /8.70)
P B/0.001 P /0.28 P /0.01 P /0.001 P B/0.001 P B/0.001 P /0.93 P /0.09 P B/0.001
24-h urine Uric acid excretion (mmol/day) Uric acid/creatinine ratio Uric acid clearance (ml/min) Creatinine clearance (ml/min)
2.73 0.26 5.50 70.9
3.24 0.32 5.71 73.3
P B/0.001 P /0.006 P /0.19 P /0.81
(2.18 /3.07) (0.21 /0.32) (4.26 /6.27) (63.3 /90.4)
(2.74 /3.97) (0.26 /0.42) (5.12 /6.58) (61.9 /85.8)
Values are mean9/S.D. or median and interquartile range. PAD, peripheral arterial disease; hs-CRP, C-reactive protein; HDL, high-density lipoprotein. a According to Fisher’s exact test for proportions or the Mann /Whitney test for continuous variables.
Table 3 Multiple regression analysis for uric acid in the total population b (S.E.) Intercept PAD (yes vs. no) Age (years) Triglycerides (mmol/l) Insulin (mU/l)
139.99 37.62 (17.65) 2.25 ( 0.80) 12.30 (5.89) 7.66 (3.12)
t -Statistic
emerged as significantly associated independent variables.
Significance
4. Discussion 2.13 2.82 2.09 2.46
P /0.03 P /0.005 P /0.04 P /0.02
Variables that did not reach significance: gender, BMI, total cholesterol, HDL-cholesterol, hs-CRP, diabetes mellitus, pulse pressure, diuretic treatment, aspirin intake.
uric acid concentration was not related to ABI. In multiple regression analysis for ABI (Table 4(right)), only age (P /0.002) and serum hs-CRP (P B/0.0001)
Uric acid, generated from xanthine by the enzyme xanthine oxidase, is the major end-product of purine metabolism [23]. Normal serum concentrations are generally B/420 mmol/l ( B/7 mg/dl) for men and B/ 350 mmol/l ( B/6 mg/dl) for women [23]. In essential hypertension, serum uric acid concentration is frequently increased in association with the multimetabolic or X syndrome [1,4]. In this study, we found that hyperuricemia among hypertensives is more pronounced in those complicated by PAD than in uncomplicated hypertension. The observed effect of PAD on serum uric
Table 4 Multiple regression analyses for ACD and ABI in the PAD group ACD
Intercept Age (years) Smoking (yes vs. no) Uric acid (mmol/l) hs-CRP (mg/l)
ABI
b (S.E.)
t -Statistic
Significance
b (S.E.)a
t -Statistic
Significance
935.4 /4.36 (1.78) /96.41 (32.85) /0.40 (0.17) /16.24 (3.26)
/2.45 /2.94 /2.32 /4.98
P/0.02 P/0.004 P/0.02 P B/0.0001
14.34 /0.056 /0.107 /0.002 /0.140
/3.21 /0.33 /1.10 /4.61
P /0.002 P /0.74 P /0.27 P B/0.0001
(0.017) (0.328) (0.001) (0.030)
Other variables that did not reach significance: gender, BMI, total cholesterol, HDL-cholesterol, triglycerides, insulin, diabetes mellitus, pulse pressure, ABI (in the model for ACD), diuretic use, aspirin intake. a Regression coefficients multiplied by a factor 10.
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
acid concentration was independent of components of the metabolic syndrome (BMI, triglycerides, insulin) and potential confounders such as age, gender, cholesterol, hs-CRP, diabetes mellitus, pulse pressure, diuretic treatment and aspirin intake. Hyperuricemia reflects an increase in the uric acid pool, which may be the result of uric acid overproduction, of insufficient uric acid excretion, or of a combination of both [23]. Renal impairment as well as hyperinsulinemia might increase serum uric acid levels because of diminished excretion rate [1,3,4,23]. In our study, the relative hyperuricemia in the PAD group remained significant after adjustment for kidney function (uric acid/creatinine ratio). Furthermore, uric acid clearance and creatinine clearance were comparable among both groups. Total urinary uric acid excretion was higher in the PAD group. Therefore, we suggest that the higher uric acid status in PAD is attributable to an increase in endogenous uric acid production and not to a decreased kidney function or uric acid clearance. In this study, PAD patients had been in a supervised exercise program, which may have influenced their serum uric acid levels. However, moderate exercise of mild intensity does not change uric acid levels significantly [24]. In the supervised training of PAD patients enrolled in our study, only very moderate levels of exercise intensity are reached. On the day of the examinations for this study, none of the PAD patients had exercised prior to blood sampling. We found that hyperuricemia in PAD patients with hypertension is associated with a worse functional status of the peripheral circulation, as evidenced by more pronounced claudication (low ACD) on a treadmill test. A number of studies have compared the reproducibility of the initial and ACD, with most demonstrating that ACD is more reproducible and, therefore, presumably the more appropriate measurement to use as a study end point [21,22]. ACD also has the theoretical justification that it probably more truly represents real life, where the patient is likely to walk even after the first appearance of claudication discomfort. We found that high serum uric acid concentration was independently associated with low ACD in multiple regression analysis. In our model, serum uric acid as well as age, smoking, and serum hs-CRP emerged as significant predictors of ACD. The observed association between ACD and hs-CRP was most significant and is concordant with earlier observations from our unit [25]. This effect is attributable to inflammatory processes involved in the progression of atherosclerotic vascular lesions [26]. However, this strong association did not prevent uric acid from being an independent determinant of ACD. Smoking, which in our study had no effect on uric acid status but appeared as a significant covariate for ACD, has also been demonstrated to affect walking distance in other studies [25,27].
167
In contrast to CRP, serum uric acid was not associated with ABI, which has been proposed as a prognostic parameter in PAD [15,16]. Our results are in the same line as those obtained in the Edinburgh Artery Study [28], where uric acid was found to be associated with lower limb ischemia (reactive hyperemia test) independently of peripheral arterial narrowing (ABI). In another clinical setting (chronic heart failure), hyperuricemia has been associated with worse functional capacity [29], impaired blood flow in the lower limbs [30], and high vascular resistance [31]. In hypercholesterolaemic patients, high uric acid concentrations were associated with more extensive atherosclerosis in the femoral artery (greater arterial edge roughness) assessed from arteriograms [32]. These findings support the hypothesis that impaired tissue blood flow may be involved in the higher production of uric acid. Peripheral vascular damage may lead to severe tissue hypoxia causing adenine nucleotide breakdown and increasing production of uric acid [4]. In the peripheral vasculature, endothelial cells are the predominant site of the enzyme xanthine oxidase and uric acid production which have been linked to vascular dysfunction [33] and free radical generation under hypoxic conditions [4]. Higher levels of uric acid and xanthine oxidase have been found in atherosclerotic plaque than in healthy vascular tissue [34]. These data suggest that hyperuricemia could be linked to the pathophysiological processes involved in the progression of atherosclerosis. The association between hyperuricemia and atherosclerosis might look paradoxical because uric acid is one of the major plasma antioxidants and hyperuricemia has been proposed to be a compensatory mechanism to counteract free radical injury to the arterial wall [35]. However, there is evidence that increased uric acid levels could have prooxidant effects and promote lipid oxidation in vascular tissue [1,36]. In this study, hypertensives with PAD were defined by symptoms of claudication (Fontaine stage II). It cannot be excluded that the ‘‘control’’ hypertension group comprised a few patients with asymptomatic PAD. Indeed, the Edinburgh Artery Study has demonstrated that up to 20% of the population at risk have asymptomatic PAD [28], and 2 /5% of hypertensives were shown to have PAD [12]. However, all ‘‘control’’ hypertensive patients enrolled in our study were free of clinical symptoms of PAD and all of them had ABI/0.90. In summary, hyperuricemia among essential hypertensives is more pronounced in those complicated by PAD and is associated with a worse functional state of the peripheral circulation. Further studies are needed to clarify the pathophysiological mechanism of hyperuricemia in hypertension complicated by peripheral atherosclerosis.
168
M. Langlois et al. / Atherosclerosis 168 (2003) 163 /168
Acknowledgements Michel Langlois is recipient of a postdoctoral fellowship of the Fund for Scientific Research (FWO), Flanders, Belgium.
References [1] Ward HJ. Uric acid as an independent risk factor in the treatment of hypertension. Lancet 1998;352:670 /1. [2] Messerli FH, Frohlich ED, Dreslinsky GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med 1980;93:817 /21. [3] Facchini F, Chen YDI, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance and plasma uric acid concentration. J Am Med Assoc 1991;266:3008 /11. [4] Garcı´a Puig J, Ruilope LM. Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 1999;17:869 /72. [5] Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in succesfully treated hypertensive patients. Hypertension 1999;34:144 /50. [6] Franse LV, Pahor M, Di Bari M, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000;18:1149 /54. [7] Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA Study. Hypertension 2000;36:1072 /8. [8] Alderman MH. Serum uric acid as a cardiovascular risk factor for heart disease. Curr Hypertens Rep 2001;3:184 /9. [9] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality in the NHANES I epidemiologic follow-up study, 1971 /1992. National Health and Nutrition Examination Survey. J Am Med Assoc 2000;283:2404 /10. [10] 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. [11] Wannamethee SG. Serum uric acid is not an independent risk factor for coronary heart disease. Curr Hypertens Rep 2001;3:190 /6. [12] Makin A, Lip GY, Silverman S, Beevers DG. Peripheral vascular disease and hypertension: a forgotten association? J Hum Hypertens 2001;15:447 /54. [13] Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997;2:221 /6. [14] Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Circulation 1995;92:614 /21. [15] Leng GC, Fowkes FG, Lee AJ, Dunbar J, Housley E, Ruckley CV. Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. Br Med J 1996;313:1440 /4. [16] Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol 1999;19:538 /45. [17] Duprez D, De Backer T, De Buyzere M, Clement DL. Estimation of walking distance in intermittent claudication: need for standardization. Eur Heart J 1999;20:641 /4.
[18] World Health Organisation. International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151 /83. [19] Remijnse-Tamerius HCM, Duprez D, De Buyzere M, Oeseburg B, Clement DL. Why is training effective in the treatment of patients with intermittent claudication? Int Angiol 1999;18:103 / 12. [20] Regensteiner J, Gardner A, Hiatt W. Exercise testing and exercise rehabilitation for patients with peripheral arterial disease: status 1997. Vasc Med 1997;2:147 /55. [21] Chandry H, Holland A, Dormandy J. Comparison of graded versus constant treadmill test protocols for quantifying intermittent claudication. Vasc Med 1997;2:93 /7. [22] Gardner A, Skinner JS, Cantwell BW, Smith LK. Progressive versus single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc 1991;23:402 /8. [23] Ruilope LM, Garcı´a Puig J. Hyperuricemia and renal function. Curr Hypertens Rep 2001;3:197 /202. [24] Green HJ, Fraser IG. Differential effects of exercise intensity on serum uric acid concentration. Med Sci Sports Exerc 1988;20:55 / 9. [25] Langlois M, Duprez D, Delanghe J, De Buyzere M, Clement DL. Vitamin C status is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 2001;103:1863 /8. [26] Ross R. Atherosclerosis */an inflammatory disease. New Engl J Med 1999;340:115 /26. [27] Cahan MA, Montgomery P, Otis RB, Clancy R, Flinn W, Gardner A. The effect of cigarette smoking on six-minute walk distance in patients with intermittent claudication. Angiology 1999;50:537 /46. [28] Lowe GD, Fowkes FG, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993;87:1915 /20. [29] 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. [30] Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart 1997;78:39 /43. [31] Doehner W, Rauchhaus M, Florea VG, et al. Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance. Am Heart J 2001;141:792 / 9. [32] Bergstrand L. Femoral and coronary atherosclerosis in patients with hyperlipidemia. Arteriographic findings correlated to clinical and biochemical parameters. Acta Radiol Suppl 1994;392:1 /27. [33] Maxwell AJ, Bruinsma KA. Uric acid is closely related to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol 2001;38:1850 /8. [34] Patetsios P, Song M, Shutze WP, et al. Identification of uric acid and xanthine oxidase in atherosclerotic plaque. Am J Cardiol 2001;88:188 /91. [35] Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131 /9. [36] Bagnati M, Perugini C, Cau C, Bordone R, Albano E, Bellomo G. When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid. Biochem J 1999;340:143 /52.