THE ROLE OF HYPERURICEMIA IN ENDOTHELIAL
DYSFUNCTION INDUCED BY HYPERTENSION
GERMAINE SAVOIU*, CORINA SERBAN*, LAVINIA NOVEANU**, O. FIRA-MLADINESCU*,
D. GAITA***, OANA M. DUICU*, ANCA TUDOR****, DANINA MUNTEAN*,
GEORGETA MIHALAS**
* Department of Pathophysiology,“Victor Babes” University of Medicine and Pharmaceutics,
Timisoara
** Department of Physiology, “Victor Babes” University of Medicine and Pharmaceutics, Timisoara
*** Department of Preventive Cardiology and Rehabilitation, “Victor Babes” University of Medicine
and Pharmaceutics, Timisoara
****Department of Medical Informatics, “Victor Babes” University of Medicine and Pharmaceutics,
Timisoara
Abstract. Hyperuricemia (HU) is a well recognized risk factor for cardiovascular diseases.
Intima-media thickness (IMT) of the carotid artery noninvasively assessed by ultrasonography is now
validated as a sensitive marker for atherosclerosis and it is directly associated with increased risk of
cardiovascular disease. The aim of this study was to evaluate the correlations between IMT and uric
acid levels in patients with hypertension (HT). Our study consisted of a group of 30 patients with HT
without HU (male 58%, mean age ± S.D.: 49 ± 10 years), a group of 25 patients with HT and HU
(male 52%, mean age ± S.D: 52 ± 10 years), and a control group of 25 healthy subjects (male 55%,
mean age ± S.D: 50 ± 11 years). All patients in the study groups were examined by high resolution
B-mode ultrasound to measure the IMT of the common carotid artery. IMT values were significantly
higher in the hypertensive patients groups with and without HU, compared to the control group
(0.98 ± 0.28 mm, 1.41 ± 0.31 mm versus 0.56 ± 0.15 mm, respectively, p < 0.001). All patients with
HU had significantly higher carotid IMT compared to the patients without HU. In this study we have
shown that higher serum uric acid levels are associated with atherogenesis independent from
hypertension.
Key words: Hyperuricemia, IMT, atherosclerosis, cardiovascular risk factors.
INTRODUCTION
More than 50 years ago, Gertler noted an association between elevated levels
of serum UA and coronary heart disease [9]. Since then, several studies have
attempted to establish whether UA is related to CHD events, independent of the
known CHD risk factors [4, 8, 13, 20]. The relationship between hyperuricemia
and other cardiovascular risk factors such as, hypertension, obesity, physical effort
Received: August 2008;
in final form November 2008.
ROMANIAN J. BIOPHYS., Vol. 18, No. 4, P. 329–336, BUCHAREST, 2008
330 Germaine Savoiu et al. 2
and HDL-cholesterol diminution, have been demonstrated in many clinical studies,
but the pathogenic mechanisms have not been clarified yet [18]. Several
proatherogenic properties have been attributed to UA including activation of
endothelial cells, platelet activation, and increased platelet adhesiveness. UA has
also been implicated in the pathogenesis of hypertension [10].
The thickness of the common carotid intima-media (IMT) measured by a
noninvasive ultrasound technique is used as a marker of atherosclerotic disease and
is directly associated with a high cardiovascular risk factor [5, 7].
Some other studies have reported that a high IMT value is strongly correlated
with an increase of cardiovascular morbidity in patients with hypertension and
hyperuricemia, but the role of hyperuricemia in the atherosclerosis process has
been not elucidated yet.
The principal goal of this study was to measure carotid intima-media
thickness in hypertensive patients, with or without hyperuricemia.
MATERIALS AND METHODS
The study included 3 groups: the first group consisted of 30 patients (male
58%, mean age ± standard deviation: 49 ± 10) with hypertension (HT) without
hyperuricemia (HU); the second group consisted of 25 patients with HT and HU
(male 52%, mean age ± standard deviation: 52 ± 10); and the third group, was the
control group represented by 25 healthy subjects (male 55%, mean age ± standard
deviation: 50 ± 11). The subjects from the control group had no cardiovascular or
other systemic diseases and physical examination, electrocardiogram, chest
radiography and two-dimensional Doppler echocardiography were normal.
Hypertension was defined as a systolic BP of >140 mmHg and/or a diastolic
BP of >90 mmHg as mean of three measurements in at least three visits at 1-week
intervals or receiving antihypertensive treatment [21].
Hyperuricemia was defined as the serum levels of > 410 µmol/L in men, and
>310 µmol/L in women [14].
Total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels
were measured using standard enzymatic methods (Boehringer-Mannheim) with a
fully automated analyzer (model 717 Roche/Hitachi; Tokyo, Japan). SUA levels
were determined with an enzymatic colorimetric method.
Exclusion criteria were systolic blood pressure of 220 mmHg or higher,
ischemic heart disease, acute coronary syndrome, stroke, or presence of a major
illness such as cancer, liver disease, renal insufficiency, insulin-treated diabetes
and depression.
CAROTID ULTRASONOGRAPHY
Subjects were investigated with a high-resolution B-mode operation system
with linear transducers with 17 MHz frequency. To obtain a quality image, the
3 Hyperuricemia and endothelial dysfunction 331
optimal focal distance was between 30–40 mm, the optimum frames frequency
25 Hz and we have done amplification setups (for minimal intraluminal artifacts).
The compensatory amplification was about 60 dB. Each subject rested in the
supine position for several minutes in a temperature-controlled room. The brachial
artery was identified at 5 cm proximal to the transient bifurcation by using this
High-resolution B-mode ultrasonography. After baseline imaging, a right arm cuff
was inflated to > 50 mm Hg above systolic blood pressure, for 5 minutes. After the
cuff was deflated ischemia-induced distal hyperemia produced a transient increase
of artery diameter. The relative change in mean arterial diameter was calculated as:
% Dilation = [Maximum diameter-Baseline diameter] × 100 / Baseline diameter,
where maximum diameter was the maximum mean diameter observed at 45–60
seconds after cuff release.
For carotid ultrasound study, the image was focused on the posterior (far) of
the left carotid artery. A minimum of 4 measurements of the common carotid far
wall were taken 10 mm proximal to the bifurcation to derive mean carotid IMT.
STATISTICAL ANALYSIS
All the numerical variables were expressed as mean ± SD (standard
deviation). Means were compared using analysis of variance of the Student t-test
and Pearson’s correlation was used to test correlations and results. Statistical
significance was defined as two-sided p < 0.05. The Anova One Way and Post Hoc
Bonferroni tests were used to compare data. All statistical analyses were performed
using Excel Microsoft Office 2003.
RESULTS
Demographic data, distribution of traditional CV risk factors and the
laboratory patient’s data are shown in Table 1. There is no significant statistical
difference between groups concerning sex, age, cardiovascular profile risk and
medical cardiovascular therapy, except for the serum total cholesterol (TC),
triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) (Table 1).
The correlation between serum uric acid level and IMT in the control group
was direct, strong and significant (a = 0.01) (Fig. 1).
Table 1
Physical characteristics and biochemical parameters of the study subjects
Control group
(n = 25)
Group with HT
without HU (n = 30)
Group with HT
and HU (n = 25)
Age (years) 50 ± 11 49 ± 10 52 ± 10
Male (%) 55 58 52
332 Germaine Savoiu et al. 4
Table 1 (continued)
Total cholesterol
(mg/dL)
175 ± 20 223 ± 22 236 ± 41
LDL-cholesterol
(mg/dL)
125 ± 21 135 ± 22 166 ± 38
HDL-cholesterol
(mg/dL)
47 ± 10 42 ± 11 33 ± 7
Triglycerides
(mg/dL)
112 ± 15 154 ± 21 180 ± 72
Systolic blood
pressure (mm Hg)
115 ± 20 150 ± 23 183 ± 19
Diastolic blood
pressure (mm Hg)
75 ± 9 110 ± 20 98 ± 5
Plasma creatinine
(mg/dL)
0.83 ± 20 0.97 ± 20 1.02 ± 21
Uric acid (µmol/L) 277 ± 110 272 ± 52 473 ± 38
Carotid IMT (mm) 0.56 ± 0.15 0.98 ± 0.28 1.41 ± 0.31
Fig. 1. The correlation between serum uric acid level and IMT in the control group.
In the group with HT without HU we found a direct, medium and significant
correlation between serum uric acid level and IMT (a = 0.05) (Fig. 2) and in the
group with HT and HU, the correlation between serum uric acid level and IMT was
direct, strong and significant (a = 0,001) (Fig. 3).
5 Hyperuricemia and endothelial dysfunction 333
Fig. 2. The correlation between serum uric acid level and IMT in the group with HT without HU.
We also noticed that IMT values were significantly higher in patients with
hypertension as compared with the control group. In the other two groups, with
arterial hypertension, the patients with HU presented elevated IMT values
comparatively with the patients without HU.
It was obtained the value of p < 0.001, meaning that between the IMT values
for the three groups, the differences were significant (a = 0.001).
The values were compared for two by two groups, and in each case p was
<0.001, meaning that there were significant differences (a = 0.001).
Fig. 3. The correlation between serum uric acid level and IMT in the group with HT and HU.
334 Germaine Savoiu et al. 6
DISCUSSIONS
Presently, hyperuricemia is often considered as a part of metabolic syndrome
or just a marker of other coronary risk factors such as hypertension, dyslipidemia,
obesity or renal disease [11]. Many studies point out that a high serum uric acid
level may be an independent risk factor associated with cardiovascular events [1, 2,
21].
Uric acid has been shown to stimulate production of monocyte
chemoattractant protein-1 (MCP-1) by vascular smooth muscle cells, interleukin-1,
interleukin-6, and tumor necrosis factor-a (TNF-a) by human mononuclear cells,
and CRP by cultured human vascular cells. Infusion of UA into mice leads to a
marked increase in circulating TNF-a level [6, 11]. On the other hand, because
serum urate has free radical scavenging and antioxidant properties, it has been
suggested that elevation of UA levels occurs in response to systemic inflammation
[12]. Exogenous uric acid gives rise to endothelial dysfunction, and endogenous
uric acid concentrations correlate with the extent of endothelial dysfunction [3, 19].
Recent studies have shown that early diagnosis of atherosclerosis is an
important step in prevention of cardiovascular diseases [3]. Anterior reports
suggested that IMT is the most studied and useful sonographic marker for
precocious atherosclerosis and IMT measure was also postulated as a surrogate
marker for generalized atherosclerosis [5].
Even though hyperuricemia is often seen in hypertensive patients, the
connection between them and the pathogenic mechanism is still unclear. The
present study was made in order to observe if hyperuricemia has a possible role in
developing atherosclerosis in patients with hypertension.
In our study we showed that IMT is higher in patients with hypertension,
with or without hyperuricemia, comparatively with the control group. We proved
that this difference also exists between the two groups of hypertensive patients. We
noticed that there were significant correlations between IMT, serum uric acid levels
and other cardiovascular risk factors. These results indicate that high levels of
serum uric acid are associated with the atherogenic process, independently of
hypertension.
Therefore, high levels of uric acid may be associated with atherosclerosis
development and the action is independent among the other atherosclerotic risk
factors. The uric acid also influences the negative effects of hypertension on the
cardiovascular system in hypertensive patients.
CONCLUSION
In this study we noticed that carotid IMT is increased in patients with
hypertension, with or without hyperuricemia, comparatively to the control group
patients (without hypertension). In hypertensive patients with hyperuricemia IMT
7 Hyperuricemia and endothelial dysfunction 335
was higher than in hypertensive patients without hyperuricemia. These results
suggest that higher serum uric acid levels are associated with atherogenesis.
Therefore, early screening for hyperuricemia and lowering serum uric acid levels
might be beneficial in slowing progression of IMT in hypertensive patients.
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