Download Elevated uric acid and cardiovascular disease. How strong is the

Intern Emerg Med (2007) 2:320–321
DOI 10.1007/s11739-007-0087-x
LETTER TO THE EDITOR
Elevated uric acid
and cardiovascular disease.
How strong is the evidence
of a pathogenetic link?
V. Toschi
V. Toschi ()
Department of Hematology and Blood Transfusion
Ospedale San Carlo Borromeo
Via Pio II, 3, I-20153 Milan, Italy
e-mail: [email protected]
Received: 20 May 2007 / Accepted in original form: 22 May 2007 /
Published online: 21 December 2007
In a recent issue of this Journal, Montalcini and coworkers
demonstrated that an increase in serum uric acid levels
may be an independent risk factor for atherosclerosis in a
series of healthy postmenopausal women [1]. The possible
causative effect of modifications in uric acid metabolism
in the pathogenesis of cardiovascular disease (CVD) was
also reviewed by Manzato in the same issue of the journal
[2], bringing to the attention of the scientific community
the old concept of the possible role of uric acid as an additional player in the development of atherosclerosis and
arterial thrombosis. Epidemiological studies showed that
elevated serum uric acid may be a risk factor for CVD
independent of other abnormalities commonly observed in
patients with the metabolic syndrome, such as obesity,
dyslipidaemia, hypertension, insulin resistance and glucose intolerance [3–5].
The study by Montalcini et al. [1] tested the pro-atherosclerotic effects of hyperuricaemia by using high-resolution ultrasound, a widely accepted technique able to noninvasively detect early atherosclerotic modifications of
arterial wall in vivo, and specifically an increase in carotid
intima-media thickness. It has been previously shown that
this structural change correlates with future clinical
events, therefore providing reliable information on the
prognostic role of cardiovascular risk factors [6].
The mechanisms potentially involved in the pro-atherosclerotic effect of uric acid are still under investigation
and, as mentioned by Manzato [2], several hypotheses
have been made to explain this issue. One possible pathogenetic mechanism relates to the effect exerted by uric
acid on vascular and inflammatory cells. It has been
demonstrated that uric acid, in a range of concentration of
120–240 µmol/l (6–12 mg/dl), is able to upregulate Creactive protein (CRP) mRNA expression in human umbilical vein endothelial cells (HUVEC) in vitro, thus inducing
CRP release into culture media [7]. In the same experiments uric acid was shown to stimulate human vascular
smooth muscle cell (VSMC) proliferation and migration,
and to inhibit endothelial cell proliferation and nitric oxide
(NO) release. All these effects of uric acid could be
blocked by incubation of vascular cells with anti-CRP
antibodies [7]. Taken together these data suggest that uric
acid may potentially contribute to vasoconstriction and
platelet activation and to atherosclerotic plaque growth,
and that these effects are mediated by locally produced
CRP. Work by the same group showed that hyperuricaemia, obtained in rats by blocking uricase by oxonic
acid, was also able to induce a decrease in serum NO levels together with an increase in systolic blood pressure,
and that this effect was reversed after allopurinol treatment
for 7 days. In additional experiments, uric acid was shown
to dose dependently inhibit both basal and vascular
endothelial growth factor (VEGF)-induced NO production
by bovine endothelial cells in vitro, thus suggesting that
exposure to uric acid may induce endothelial dysfunction
and a pro-atherosclerotic phenotype in these cells [8].
Kanellis and coworkers also demonstrated that uric acid
induced an increase in rat aortic VSMC monocyte
chemoattractant protein-1 (MCP-1) expression in a timeand dose-dependent manner, with a peak at 24 h.
Overexpression of MCP-1 mRNA and protein occurred as
early as 3 h after the incubation of VSMC with uric acid
and was associated with activation of the transcription factors NF-κB and activator protein-1 (AP-1), as well as with
the activation of the mitogen-activated protein kinase
(MAPK) extracellular signalling molecules ERK p44/42
and p38, and with an increase in cyclooxygenase-2 (COX2) mRNA expression [9]. Inhibition of ERK p44/42, p38
and COX-2 each suppressed uric acid-induced MCP-1 production [9]. These data clearly show that uric acid, in its
soluble form, can elicit an inflammatory response in
VSMC, thus providing further evidence of its potential
role in monocyte recruitment, VSMC activation and finally in atherosclerotic plaque growth and rupture.
A large body of experimental data demonstrated that
inflammatory processes play a crucial role in all steps of
atherosclerotic plaque formation and disruption and in its
thrombotic complications, and that these processes are
sustained by a variety of cells such as endothelial cells,
VSMC and macrophages [10].
CRP is one of the most important inflammatory mediators. It is mainly produced by the liver in response to the
proinflammatory cytokine IL-6 which, in turn, is synthe-
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sised in significant amounts at sites of atherosclerotic
plaque growth [10]. Besides its function as a marker and
predictor of CVD and inflammation, CRP possesses
numerous cardiovascular effects such as generation of
oxygen radicals and increased expression of adhesion molecules and of plasminogen activator inhibitor-1 (PAI-1); it
also triggers plaque destabilisation and thrombus formation [11]. Interestingly, Ruggiero et al. recently demonstrated, in a series of 957 subjects aged 65–95, a close relationship between serum uric acid levels and several
inflammatory markers. Specifically, the percentages of
subjects with abnormally high levels of CRP and IL-6
were significantly higher across uric acid quintiles. After
adjustment for age- and disease-related confounders, uric
acid was also significantly and independently associated
with CRP, IL-6 and a number of other proinflammatory
mediators such as IL-18 and TNF-α, thus suggesting that
uric acid may participate in the inflammatory processes
involved in CVD and particularly in atherosclerotic plaque
growth and in its complications [12].
Experimental evidence also shows that activation of
the xanthine-xanthine oxidase system, which catalyses the
production of uric acid from xanthine and hypoxanthine
with increased uric acid production, may be involved in
acute coronary syndromes through the synthesis of vasoactive substances which lead to platelet aggregation and
vasoconstriction [13]. Xanthine oxidase (XO) is also a
source of free radicals and particularly of superoxide
anion, thus potentially contributing to tissue damage during inflammatory processes. Using a well characterised
stenosis canine coronary artery thrombosis model,
Kuwano et al. demonstrated that XO mediates platelet
aggregation and cyclic flow variations (CFVs) produced
by an external constrictor placed at the site of coronary
injured endothelium, as CFVs were significantly reduced
after administration of the specific XO inhibitor allopurinol [14]. Moreover, the transcardiac gradient (difference
from coronary vein and left atrium) of purine metabolites
xanthine and uric acid concentration significantly
increased after the establishment of CFVs and significantly decreased after allopurinol administration. Finally,
platelet studies showed that XO enhanced and allopurinol
inhibited ADP-induced platelet aggregation, thus suggesting that activation of this enzyme may be important in
coronary platelet thrombus formation [14].
Very recently Zakai et al. tried to assess a correlation
between 13 biomarkers, including uric acid and a number of haemostasis and inflammation biomarkers, with
the incidence of CVD among 4510 elderly subjects from
the Cardiovascular Health Study [15]. Over 9 years, with
a total of 1700 CVD events, only IL-6, CRP, D-dimer,
homocysteine, leukocyte count, factor VIII, lipoprotein
(a), fibrinogen and soluble intercellular adhesion molecule-1 (sICAM-1) were found to be significantly associated with CVD, thus questioning the role of uric acid as
an independent risk factor for atherosclerosis and coronary disease.
In conclusion, despite a bulk of knowledge on the
potential role of uric acid in the pathophysiology of atherosclerotic plaque formation and its thrombotic complications, it is still matter of debate if hyperuricaemia is really
important as a CVD risk factor. More data are necessary to
better delineate this issue in order to use uric acid measurement in cardiovascular risk stratification.
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