Published online before print December 27, 2005, doi: 10.1161/01.HYP.0000200033.14574.14
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2006;47:195.)
© 2006 American Heart Association, Inc.
Original Articles |
Uric Acid, Left Ventricular Mass Index, and Risk of Cardiovascular Disease in Essential Hypertension
From the Department of Geriatric Medicine (Y.I., H.R., T.O.), Graduate School of Medicine, Osaka University, and Division of Hypertension and Nephrology (T.H., K.K., Y.K.), Department of Medicine, National Cardiovascular Center, Osaka, Japan.
Correspondence to Takeshi Horio, Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail thorio{at}ri.ncvc.go.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Elevated serum uric acid (UA) is frequently encountered in individuals with hypertension, but whether the relationship between UA and cardiovascular events is circumstantial or causal remains to be answered. We examined the association between serum UA and left ventricular mass index (LVMI) and investigated prospectively whether the combination of UA and LVMI can predict the incidence of cardiovascular disease (CVD) in asymptomatic subjects with essential hypertension. A total of 619 subjects (mean age, 61 years; 52% female) free of prior CVD were included in this study. A significant association between UA and LVMI was also confirmed in multiple regression analysis (male: F=4.29, P<0.04; female: F=4.24, P<0.05). During follow-up (mean, 34 months), 28 subjects (14 female) developed CVD including myocardial infarction, angina pectoris, congestive heart failure, cerebral infarction, and transient cerebral ischemia. Sex-specific median values were used to separate the higher group from the lower group of UA and LVMI. Kaplan–Meier curves showed a significantly poorer survival rate in the group with higher UA and LVMI (LVMI, male: >126.9, female: >112.0 g/m2; UA, male: >374.7, female: >303.3 µmol/L; log-rank
2=13.18; P<0.01). Multivariate Cox regression analysis showed that the combination of higher UA and LVMI was an independent predictor for CVD events (hazard ratio, 2.38; P<0.03). Our findings demonstrate that UA is independently associated with LVMI and suggest that the combination of hyperuricemia combined with left ventricular hypertrophy is an independent and powerful predictor for CVD. The association between UA and CVD events may be introduced in part because of a direct association of UA with LVMI.
Key Words: uric acid • cardiovascular diseases • hypertrophy • risk factors
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Effective prevention of cardiovascular disease (CVD) requires the early detection and correction of predisposing conditions and risk factors in susceptible patients. Hypertension is a common risk factor for CVD, and the cardiovascular prognosis in patients with hypertension depends not only on the level of blood pressure (BP), but also on the presence of associated risk factors. Hyperuricemia is frequently encountered in hypertensive patients.1 Several large epidemiologic studies have identified an association between increased serum uric acid (UA) and cardiovascular risk in the general population2–6 and among patients with hypertension.7,8 Other recent reports have also confirmed these associations by angiographic procedure.9,10 Some studies have claimed that UA is an independent risk factor for CVD, whereas others have failed to identify UA as a significant and independent risk factor.11–13 Thus, the status of UA as an independent risk marker remains controversial, and whether the relationship between UA level and cardiovascular events is circumstantial or causal remains to be answered.2 On the other hand, the level of serum UA is affected by or linked to many factors, such as obesity, insulin resistance, dyslipidemia, and hypertension, all of which are also associated with left ventricular hypertrophy (LVH). In a recent report, in female subjects, UA level was independently associated with the presence of LVH detected by echocardiography.14 These results suggest that UA level may be related to left ventricular mass index (LVMI).
In hypertension, LVH is initially a compensatory process against abnormal loading conditions, but it is also the first step toward the development of overt clinical disease, such as CVD.15 In essential hypertension, the risk of future CVD complications is higher in patients with LVH on echocardiography than in those with normal left ventricular (LV) mass.15,16 Thus, assessment of LV mass by echocardiography is a well-established procedure to estimate the risk of CVD in hypertensives.
The hypothesis that the combination of serum UA level and LVMI may be a strong predictor of CVD has never been examined. In this study, we investigated the relationship between UA level and LVMI in essential hypertensive subjects. Furthermore, we also examined prospectively the relations of UA level, LVMI, and their combination to the incidence of CVD during follow-up in asymptomatic hypertensive subjects.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Subjects
A total of 619 hypertensive subjects who had good-quality echocardiographic recordings were enrolled and monitored for 33.5±0.8 months in this study. All of the subjects were selected from patients who were admitted and underwent medical investigation at the National Cardiovascular Center in Osaka, Japan. Hypertension was defined as a systolic BP of
140 mm Hg and/or a diastolic BP of 90 mm Hg on repeated measurements or receiving antihypertensive treatment. Diabetes mellitus was defined according to the American Diabetes Association criteria.17 Smoking was defined as current smoking or having a history of habitual smoking. Ischemic heart disease was defined as a 75% organic stenosis of 1 major coronary artery as confirmed by coronary angiography or a history of myocardial infarction or percutaneous transluminal coronary angioplasty. Renal insufficiency was defined as a serum creatinine concentration >176.8 µmol/L. All of the subjects enrolled in this study had essential hypertension. Exclusion criteria included ischemic heart disease, acute coronary syndrome, congestive heart failure (CHF; New York Heart Association class II or greater), chronic renal insufficiency, valvular heart disease, old cerebral infarction, and history of transient ischemic attack. Participants with moderate or severe aortic or mitral regurgitation or a heart rate >100 bpm were also excluded. The study protocol was approved by the ethics committee of our institution. All of the subjects enrolled in this study were Japanese, and all of the subjects gave informed consent to participate in this study.
Baseline Clinical Characteristics
After fasting overnight, BP was measured with an appropriate arm cuff and a mercury column sphygmomanometer on the left arm after a resting period of 10 minutes in the supine position. After BP measurements, venous blood sampling from all of the subjects was performed. Height and body weight were measured, and body mass index (BMI) was calculated. Insulin sensitivity was estimated using the homeostatic model assessment index; that is, plasma glucose levelx(plasma insulin level/22.5). Urine samples were collected for 24 hours and used to evaluate creatinine clearance (Ccr). The following parameters were also determined: total cholesterol (T-chol), triglycerides (TG), high-density lipoprotein cholesterol (HDL-chol), serum UA, serum creatinine, and C-reactive protein (CRP) levels. Serum UA levels were determined by the uricase-peroxidase method.18
Echocardiographic Methods and Calculation of Derived Variables
Imaging and Doppler echocardiography were performed in all of the participants in this study. Studies were performed with phased-array echocardiography with M-mode, 2D, pulsed, and color-flow Doppler capabilities. LV internal dimension and septal and posterior wall thickness were measured at end-diastole and end-systole according to the American Society of Echocardiography recommendations.19,20 Color-flow Doppler recordings were used to check for aortic and mitral regurgitation, as described previously.21 End-diastolic dimensions were used to calculate LV mass by a previously reported formula.22 LV mass was considered an unadjusted variable and was normalized by body surface area and expressed as LVMI.
The LV diastolic filling pattern was recorded from the apical transducer position with subjects in the left lateral decubitus position, with the sample volume situated between the mitral leaflet tips. The leading edge of the transmitral Doppler flow pattern was traced to derive the peak of early diastolic and atrial phase LV filling (E-velocity and A-velocity, respectively), their ratio (E/A ratio), and the deceleration time of early diastolic LV filling (DcT). All of the measurements were performed by a trained investigator who was blinded to the clinical data of the subjects.
Clinical End Points
For survival analysis, observation began on the date of echocardiography, with verified dates updated through March 2004. All of the subjects were followed at the National Cardiovascular Center in Osaka and treated by implementation of standard lifestyle and pharmacological measures. All of the subjects were periodically referred to our institution for BP control and other diagnostic procedures. CVD events of interest in this study were myocardial infarction and angina pectoris confirmed by electrocardiographic changes, coronary angiography and/or myocardial scintigraphy findings, stroke and transient cerebral ischemia confirmed by clinical symptoms, computed tomography and magnetic resonance angiography and/or cerebrovascular angiography findings, and CHF requiring hospitalization. CHF was diagnosed from clinical symptoms and findings (paroxysmal nocturnal dyspnea or cough, pulmonary rales because of pulmonary congestion, distended jugular veins, neck vein distension, enlarging heart size, pleural effusion and/or acute pulmonary edema on chest radiography, hepatojugular reflux, bilateral ankle edema, shortness of breath on ordinary exertion, and/or heart rate of 120 bpm). The cause of death was classified as CVD if there was sudden death from CVD by an independent review panel of physicians who were unaware of the echocardiographic and clinical findings. Events that were more equivocal, such as unrecognized myocardial infarction, angina pectoris, and transient cerebral ischemia, were not included as CVD for this analysis. Furthermore, patients with clinical evidence of pneumonia or uremia were excluded. For patients who experienced multiple nonfatal episodes of CVD, the analysis included only the first event.
Statistical Analysis
Parametric data are presented as mean±SE. The relations between LVMI or serum UA and various parameters were assessed using univariate linear regression analysis and Pearson’s correlation coefficient. Multiple linear regression analysis was applied to identify independent determinants of LVMI after adjustment for potential confounding factors affecting LVMI.
Serum UA level and LVMI were stratified into 4 groups according to median values of baseline serum UA level and LVMI by each sex. One-way ANOVA with Dunnett multiple comparison posttest was used to analyze data among 4 groups. Event-free survival analysis was performed with the Kaplan–Meier method to plot the cumulative incidence of CVD, and the groups were compared by the Mantel log rank test. Cox proportional hazard analysis was used to examine the association between variables and the cumulative incidence of CVD. With respect to serum UA and LVMI, the cumulative incidence of CVD was calculated using the group with lower UA and LVMI as a reference for each other. These effects were measured by hazard ratios (HRs) and their 95% CIs based on Cox regression models. We used multivariable Cox proportional hazards regression models to examine the relations of serum UA and LVMI to CVD events, after accounting for relevant variables using a P value of <0.05 as the selection criterion. A P value <0.05 was considered statistically significant. All of the calculations were performed using a standard statistical package (JMP 4.0, SAS Institute).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Association Between UA and LVMI
The baseline clinical and biochemical characteristics of the study subjects, analyzed on the basis of sex, are shown in Table 1. UA level and LVMI were significantly higher in men than in women. At baseline, 78.5% of the study patients were taking antihypertensive drugs, and 21.5% were complying with lifestyle measures only. Diuretics, ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and calcium-channel blockers were used alone or in various combinations in 11.3%, 26.7%, 33.9%, and 62.8% of the study patients, respectively. In addition, 9.0% of the study subjects were taking urate-lowering medication (allopurinol and probenecid).
|
We first examined the simple correlations between serum UA and clinical variables after dividing the subjects into 2 groups according to sex (Table 2). In both male and female subjects, UA level was significantly associated with BMI, TG, HDL-chol, Ccr, and LVMI. In addition, only in female subjects, there was a significant association between UA level and CRP, smoking, taking diuretics, and taking urate-lowering medication.
|
The simple correlations between LVMI and clinical variables were also examined (Table 2). In male subjects, LVMI was significantly correlated with duration of hypertension, systolic BP, pulse pressure, heart rate, T-chol, UA, and CRP and was significantly higher in smokers and those taking urate-lowering medication. In female subjects, LVMI was significantly correlated with age, BMI, duration of hypertension, systolic BP, pulse pressure, heart rate, TG, HDL-chol, homeostatic model assessment index, and UA and was significantly higher in diabetics.
Multiple linear regression analysis was performed including age, duration of hypertension, BMI, systolic and diastolic BP, heart rate, T-chol, TG, HDL-chol, Ccr, CRP, smoking, and diabetes and revealed that UA was independently associated with LVMI in male and female subjects (Table 3). In addition, even after adjustment for taking diuretics and taking urate-lowering medication, UA was still independently associated with LVMI (male, F=4.831, P=0.0290; female, F=4.591, P=0.0330).
|
To exclude the effect of drugs on UA level, we next examined the association between UA and LVMI after excluding subjects receiving diuretics and urate-lowering medication (male; n=232, female; n=273). Even after excluding these subjects, a significant association between UA and LVMI was observed (male: r=0.16, female: r=0.17, P<0.01 respectively).
LVH was considered to be present when LVMI was >125 for men and >110 g/m2 for women.23 UA level was significantly higher in subjects with LVH (male, 383.4±6.2 versus 363.5±6.6; female, 323.5±6.2 versus 303.0±6.5 µmol/L, P<0.03 respectively). A significant association between UA and LVH was also confirmed in multiple regression analysis including age, duration of hypertension, BMI, systolic and diastolic BP, heart rate, T-chol, TG, HDL-chol, Ccr, CRP, smoking, and diabetes (male, 384.5±7.6 versus 363.7±8.0, F=4.3, P<0.04; female, 329.7±9.1 versus 302.0±10.5 µmol/L, F=5.8, P<0.02).
The association between LV diastolic function and UA level was examined, and a significant association between UA and DcT was observed (Table 2). On the other hand, UA was not significantly associated with E-velocity, A-velocity, and E/A ratio. It is well described that early diastolic relaxation decreases with increasing age.24 In the present study, we also found that DcT had a significant positive relationship with age (male: r=0.36, female: r=0.30, P<0.01 respectively), but not heart rate (male: r=–0.05, female: r=–0.01) and body surface area (male: r=0.07, female: r=0.05). Even after adjustment for age, DcT was significantly related to UA level (male: F=4.34, P<0.04; female: F=3.99, P<0.05).
Predictive Value of Serum UA and LVMI for CVD
Because of the sex difference in serum UA levels and LVMI values, different median values for men and women were used to separate the higher group from the lower group in each variable. Demographic and hemodynamic data of the subjects grouped according to the median value of serum UA (male: 374.7; female: 303.3 µmol/L) and LVMI (male: 126.9; female: 112.0 g/m2) in each sex. As a result, the total subjects were divided into 4 groups as follows; lower LVMI and UA, lower LVMI and higher UA, higher LVMI and lower UA, and higher LVMI and UA. The baseline clinical and biochemical characteristics of the study subjects are shown in Table 4. There was a trend toward higher age, longer duration of hypertension, higher systolic BP, higher pulse pressure, and lower heart rate with increasing LVMI. On the other hand, the groups with higher UA showed higher BMI and lower Ccr. In addition, the group with higher LVMI and UA showed significantly lower HDL-chol and Ccr than that with higher LVMI and lower UA. At the follow-up contact, the proportions of subjects treated with diuretics, alone or combined with other agents, during follow-up were 6.8%, 11.9%, 9.6%, and 16.6% (P<0.05 versus lower LVMI and UA), respectively, in the 4 groups. The proportions of subjects treated with urate-lowering medication were 3.7%, 9.8%, 13.2% (P<0.05 versus lower LVMI and UA), and 10.7%, respectively.
|
During the follow-up period, 28 patients (4.5%; 14 female) developed CVD. There were 11 subjects with CHF, 1 with myocardial infarction, 8 with angina pectoris, 7 with cerebral infarction, and 1 with transient cerebral ischemia. Serum UA level and LVMI were significantly higher in patients who developed CVD during the follow-up period than in event-free subjects (UA: 385.3±16.8 versus 341.8±3.6 µmol/L, LVMI: 139.5±5.8 versus 122.1±1.3 g/m2, P<0.01, respectively). Life table analyses of CVD throughout the follow-up period according to the 4 groups of baseline serum UA and LVMI are plotted in Figure 1. These curves illustrate significantly poorer survival in the group with higher UA and LVMI.
|
We next performed Cox regression analysis to examine whether the influence of higher UA and LVMI on CVD events was independent of other risk factors. As shown in Table 5, the risk for CVD was significantly higher in the group with higher UA and LVMI compared with that with lower UA and LVMI (HR, 2.70). In addition, age, duration of hypertension, pulse pressure, and Ccr were also significantly associated with the incidence of CVD. In multivariate Cox regression analysis, the combination of serum UA level and LVMI was an independent predictor for CVD (HR, 2.38).
|
In addition, the influence of the combination of UA and LVMI on CVD events was also examined by dividing the 4 groups according to the normal levels of UA (UA level 
420 in men and 390 µmol/L in women) and with/without LVH; that is, normal UA and without LVH (n=244), hyperuricemia and without LVH (n=53), normal UA and LVH (n=245), and hyperuricemia and LVH (n=77). The independent predictive value of the hyperuricemia and LVH for CVD events was also confirmed by the Kaplan–Meier method (log-rank 2=5.58; P=0.0355) and by Cox regression analysis (HR, 1.7; 95% CI, 0.78 to 3.41; P<0.03). In multivariate Cox regression analysis, the combination of hyperuricemia and LVH was an independent predictor for CVD events (HR, 1.8; 95% CI, 0.85 to 3.48; P<0.05).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study documented and validated that serum UA level is associated with LVMI, and the results of multiple linear regression analysis indicated that serum UA is independently associated with LVMI. Compared with the group with lower UA and LVMI, the group with higher UA and LVMI showed a condition of increased risk for cardiovascular and renal morbidity, such as significantly longer duration of hypertension, higher pulse pressure, worse dyslipidemia, and lower Ccr. Even after adjustment for other clinical factors, higher UA level and LVMI and age were independent predictors for CVD.
Our results suggest that serum UA is independently associated with LVMI, whereas an elevation of UA is associated with an actual metabolic disorder, and whether an elevation of serum UA level is the cause or result of LVH is unclear. The association between UA and LVMI might relate to an association of UA with other risk factors, especially including renal dysfunction, oxidative stress, severity of hypertension, and obesity. Renal dysfunction increases serum UA and activates the renin–angiotensin system, and angiotensin II is essential for the development of LVH.25 UA is the final breakdown product of dietary or endogenous purines and is generated by xanthine oxidase (XO). A net release of urate in coronary heart disease26 and the presence of XO in the human heart has been demonstrated.27 UA may reflect the generation of superoxide and resultant oxidative stress via the XO system.28 Furthermore, the independent association between UA and the severity of hypertension is well accepted.1 On the other hand, there is a possibility that UA itself may induce LVH. Previous reports have shown that UA impaired NO generation and induced endothelial dysfunction and smooth muscle cell proliferation.29,30 In experimental and in vitro systems, UA appears to have the ability to induce inflammatory mediators, such as tumor necrosis factor 
,31 and potentially stimulates mitogen-activated protein kinases,32 which are known to induce cardiac hypertrophy.33,34 These results suggest that cardiac hypertrophy may be, at least in part, attributable to an increase in UA itself, via stimulation of endothelial dysfunction, smooth muscle cell proliferation, and inflammation.
Our results showed that the incidence of CVD in subjects with higher UA and LVMI was 
2.4-fold higher than that in subjects with lower UA and LVMI, even after adjustment for confounding factors. Thus, our results indicate that hypertensive subjects with LVH and hyperuricemia have an increased risk of developing CVD and suggest that the assessments of serum UA level and LVMI by echocardiography are useful and sensitive for predicting the risk for CVD. Many epidemiologic studies have attempt to identify whether hyperuricemia is an independent risk factor for CVD, but the results obtained were controversial after adjusting for other CVD risk factors, especially including LVH determined by electrocardiography.7,8,13 Although hyperuricemia itself may have the ability to increase the risk of CVD, our results suggest that the association between UA and CVD events may be introduced in part because of a direct association of UA with LVMI. On the other hand, all of the antihypertensive drugs failed to show a cardioprotective effect in this study. Previous epidemiologic studies have also shown that UA level was independently predictive for the development of CVD even after antihypertensive treatment.7,8,35,36 Furthermore, in the Systolic Hypertension in the Elderly Program trial, a subanalysis showed that the cardioprotection by diuretics was lost in those treated patients in whom UA levels increased.36
One notable result of this study is that, in the group with higher LVMI, the risk of CVD became higher with increasing UA level. This result may have been introduced because of decreased renal function and HDL-chol level, which are established risk factors for CVD, in subjects with hyperuricemia and LVH. Apart from renal function and lipid metabolism, there are other possible mechanisms by which the risk for CVD became higher with increasing UA levels. Several mechanisms have been proposed to account for the association between hyperuricemia and CVD, including the following: (1) the direct relationship of UA with severity of hypertension,1 in which the predictive relationship of UA with BP is dose dependent;37 (2) increased oxidative stress;38 (3) a subtle reduction in glomerular filtration rate leading to impaired renal UA clearance;39 (4) impaired NO production,38 which activates the renin–angiotensin system40 and induces endothelial dysfunction and smooth muscle cell proliferation;29,30 (5) impaired platelet adhesiveness, disturbed hemorheology, and aggregation;38 and (6) synthesis of monocyte chemoattractant protein-1 in vascular smooth muscle cells,41 which is a chemokine that is importantly involved in CVD.42 On the other hand, the close association between LVH and CVD events may be explained by decreased myocardial contractility, severe diastolic filling abnormalities, and increased oxygen requirement of the myocardium.43 Our results showed that more severe relaxation impairment was observed in hyperuricemic subjects with LVH, and this "impaired relaxation" is known to be associated with increased risk of CVD.44 In addition, a weak but significant association between UA and DcT, a marker of relaxation impairment, was observed in this study, and higher UA levels may contribute to the progression of LV dysfunction. Consequently, we propose the idea that, in subjects with LVH, severe hypertension, activation of oxidative stress and the renin–angiotensin system, stimulation of production of cytokines from leukocytes and chemokines from vascular smooth muscle cells, and more impaired relaxation may occur with increasing UA levels and enhance the risk for CVD.
The limitations of this study include missing baseline data and potentially important characteristics, such as menopause, alcohol intake, and a high-purine diet, which are also associated with a higher serum UA level. Because our data were obtained in subjects with treated essential hypertension at the start of the study, these results could underestimate the involvement of BP itself in the development of LVH and CVD events.
Perspectives
Our results demonstrate that UA is independently associated with LVMI and suggest that the combination of hyperuricemia with LVH is a powerful independent predictor for CVD. The association between UA and CVD events may be introduced in part because of a direct association of UA with LVMI. In hypertensive as well as LVH subjects, assessment of UA levels may help to refine CVD risk stratification. A crucial next step is to investigate whether UA is causally linked to LVH in a longitudinal setting. If so, hypouricemic agents might be used in clinical practice for LVH risk reduction in hypertensive patients. A large prospective population–based study will be important to confirm our preliminary observations.
|
Acknowledgments |
|---|
We thank Chikako Tokudome for her secretarial assistance.
Received September 26, 2005; first decision October 23, 2005; accepted December 5, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH. Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension. 2005; 45: 18–20.
2. Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004; 164: 1546–1551.
3. Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995; 141: 637–644.
4. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA. 2000; 283: 2404–2410.
5. Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J. Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand. 1988; 224: 549–555.[Medline] [Order article via Infotrieve]
6. Klein R, Klein BE, Cornoni JC, Maready J, Cassel JC, Tyroler HA. Serum uric acid. Its relationship to coronary heart disease risk factors and cardiovascular disease, Evans County, Georgia. Arch Intern Med. 1973; 132: 401–410.
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: 1072–1078.
8. Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension. 1999; 34: 144–150.
9. Short RA, Johnson RJ, Tuttle KR. Uric acid, microalbuminuria and cardiovascular events in high-risk patients. Am J Nephrol. 2005; 25: 36–44.[CrossRef][Medline] [Order article via Infotrieve]
10. Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary artery disease. Am J Cardiol. 2001; 87: 1411–1414.[CrossRef][Medline] [Order article via Infotrieve]
11. Staessen J. The determinants and prognostic significance of serum uric acid in elderly patients of the European Working Party on High Blood Pressure in the Elderly trial. Am J Med. 1991; 90: 50S–54S.[Medline] [Order article via Infotrieve]
12. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart. 1997; 78: 147–153.
13. 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.
14. Viazzi F, Parodi D, Leoncini G, Parodi A, Falqui V, Ratto E, Vettoretti S, Bezante GP, Del Sette M, Deferrari G, Pontremoli R. Serum uric acid and target organ damage in primary hypertension. Hypertension. 2005; 45: 991–996.
15. Casale PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH. Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med. 1986; 105: 173–178.
16. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991; 114: 345–352.
17. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003; 26 (Suppl 1): S5–S20.[CrossRef][Medline] [Order article via Infotrieve]
18. Domagk GF, Schlicke HH. A colorimetric method using uricase and peroxidase for the determination of uric acid. Anal Biochem. 1968; 22: 219–224.[CrossRef][Medline] [Order article via Infotrieve]
19. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. Am Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989; 2: 358–367.[Medline] [Order article via Infotrieve]
20. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978; 58: 1072–1083.
21. Cooper JW, Nanda NC, Philpot EF, Fan P. Evaluation of valvular regurgitation by color Doppler. J Am Soc Echocardiogr. 1989; 2: 56–66.[Medline] [Order article via Infotrieve]
22. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986; 57: 450–458.[CrossRef][Medline] [Order article via Infotrieve]
23. Hammond IW, Devereux RB, Alderman MH, Lutas EM, Spitzer MC, Crowley JS, Laragh JH. The prevalence and correlates of echocardiographic left ventricular hypertrophy among employed patients with uncomplicated hypertension. J Am Coll Cardiol. 1986; 7: 639–650.[Abstract]
24. Kitzman DW, Sheikh KH, Beere PA, Philips JL, Higginbotham MB. Age-related alterations of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading conditions. J Am Coll Cardiol. 1991; 18: 1243–1250.[Abstract]
25. Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T. Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation. 2001; 104: 346–351.
26. De Scheerder IK, van de Kraay AM, Lamers JM, Koster JF, de Jong JW, Serruys PW. Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusions during coronary angioplasty: potential mechanisms for free radical generation. Am J Cardiol. 1991; 68: 392–395.[CrossRef][Medline] [Order article via Infotrieve]
27. Wajner M, Harkness RA. Distribution of xanthine dehydrogenase and oxidase activities in human and rabbit tissues. Biochim Biophys Acta. 1989; 991: 79–84.[Medline] [Order article via Infotrieve]
28. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985; 312: 159–163.[Abstract]
29. 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: 8604–8608.
30. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005; 67: 1739–1742.[CrossRef][Medline] [Order article via Infotrieve]
31. Netea MG, Kullberg BJ, Blok WL, Netea RT, van der Meer JW. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood. 1997; 89: 577–582.
32. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002; 40: 355–360.
33. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997; 95: 1247–1252.
34. Sugden PH, Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res. 1998; 83: 345–352.
35. Wang JG, Staessen JA, Fagard RH, Birkenhager WH, Gong L, Liu L. Prognostic significance of serum creatinine and uric acid in older Chinese patients with isolated systolic hypertension. Hypertension. 2001; 37: 1069–1074.
36. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens. 2000; 18: 1149–1154.[CrossRef][Medline] [Order article via Infotrieve]
37. Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. 2003; 42: 247–252.
38. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003; 41: 1183–1190.
39. Vaziri ND, Freel RW, Hatch M. Effect of chronic experimental renal insufficiency on urate metabolism. J Am Soc Nephrol. 1995; 6: 1313–1317.[Abstract]
40. Eslami P, Corry DB, Nyby MD, Tuck ML. Inhibition of oxidative stress and improvement of nitric oxide production by ACE inhibitors and AT1 receptor blockers in uric acid stimulated vascular smooth muscle cells. Am J Hypertens. 2004; 17 (Suppl 1): S154–S155.
41. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003; 41: 1287–1293.
42. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
43. Devereux RB, Roman MJ, Palmieri V, Okin PM, Boman K, Gerdts E, Nieminen MS, Papademetriou V, Wachtell K, Dahlof B. Left ventricular wall stresses and wall stress-mass-heart rate products in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint reduction in hypertension. J Hypertens. 2000; 18: 1129–1138.[CrossRef][Medline] [Order article via Infotrieve]
44. Schillaci G, Pasqualini L, Verdecchia P, Vaudo G, Marchesi S, Porcellati C, de Simone G, Mannarino E. Prognostic significance of left ventricular diastolic dysfunction in essential hypertension. J Am Coll Cardiol. 2002; 39: 2005–2011.
This article has been cited by other articles:
 |
|
 |
|
  X. Gao, L. Qi, N. Qiao, H. K. Choi, G. Curhan, K. L. Tucker, and A. Ascherio Intake of Added Sugar and Sugar-Sweetened Drink and Serum Uric Acid Concentration in US Men and Women Hypertension, August 1, 2007; 50(2): 306 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Krishnan, C. K. Kwoh, H. R. Schumacher, and L. Kuller Hyperuricemia and Incidence of Hypertension Among Men Without Metabolic Syndrome Hypertension, February 1, 2007; 49(2): 298 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Sanders Uric Acid: An Old Dog with New Tricks? J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1767 - 1768. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||