Serum Urate as an Independent Predictor of Poor Outcome

and Future Vascular Events After Acute Stroke

Christopher J. Weir, PhD; Scott W. Muir, MBChB, MRCP;
Matthew R. Walters, MD, MRCP; Kennedy R. Lees, MD, FRCP
Background and PurposeSerum urate concentration is associated with cardiovascular disease, and hyperuricemia
predicts first-ever stroke. We explored the association of admission urate level with mortality, placement, and risk of
further vascular events after acute stroke.
MethodsIn patients with ischemic stroke or primary intracranial hemorrhage, we determined the association of urate
level with 90-day placement (alive at home, good outcome; dead or living in care, poor outcome) and with the
subsequent occurrence of ischemic stroke, myocardial infarction, or vascular death. In multivariate analysis (logistic
regression for 90-day placement, proportional-hazards regression for time to further vascular event), we adjusted for
stroke severity (modified National Institutes of Health stroke scale) and other clinical, biochemical, and radiological
variables known to influence stroke outcome.
ResultsWe studied 3731 patients and measured serum urate in 2498. Elevated urate level predicted a lower chance of
good 90-day outcome (odds ratio, 0.78 per additional 0.1 mmol/L; 95% confidence interval [CI], 0.67 to 0.91)
independently of stroke severity and other prognostic factors. Vascular event risk increased with urate level (relative
hazard, 1.27 per additional 0.1 mmol/L; 95% CI, 1.18 to 1.36). Higher urate levels have a greater effect on vascular
event rates in the presence of diabetes (additional relative hazard, 1.22 per additional 0.1 mmol/L; 95% CI, 1.06 to 1.41).
ConclusionsIndependently of other prognostic factors, higher serum urate levels predicted poor outcome (dead or in
care) and higher vascular event rates. The role of urate in stroke pathophysiology remains uncertain, but intervention
to lower urate may be worth considering. (Stroke. 2003;34:1951-1957.)
Key Words: mortality stroke, acute survival urate

here is a well-recognized epidemiological link between

elevated serum uric acid and increased cardiovascular
risk. Several large studies have identified an elevated serum
uric acid concentration as a predictor of cardiovascular events
such as myocardial infarction.13 Hyperuricemia also predicts
the development of both hypertension4 and coronary artery
disease5; it is increased in patients with hypertension, and
when present in hypertension, an elevated uric acid level is
associated with increased cardiovascular morbidity and
mortality.4,6
It is a matter of controversy whether serum uric acid is an
independent predictor of mortality and morbidity in patients
with vascular disease or whether it represents an indirect
marker of adverse outcome by reflecting the association
between uric acid and other well-defined cardiovascular risk
factors. Uncertainty about the mechanism by which uric acid
could cause or exacerbate cardiovascular disease, coupled
with the inconclusive clinical and epidemiological data, has
left the issue unresolved.
Despite the clinical and epidemiological evidence, many
authorities do not consider elevated uric acid to be a true

See Editorial Comment, page 1956

cardiovascular risk factor but instead view it as a surrogate
marker. Patients with hyperuricemia often have other wellestablished risk factors for cardiovascular disease such as
hypertension, renal disease, obesity, dyslipidemia, and insulin
resistance.
Elevated serum uric acid independently predicts stroke and
excess mortality in patients with noninsulin-dependent diabetes mellitus,7 whereas in the general elderly population, it is
independently associated with increased incidence of fatal
stroke.8 In diabetic patients, elevated serum uric acid is
thought to play a role, along with obesity, blood pressure, and
insulin resistance, in the metabolic syndrome that may be
responsible for endothelial dysfunction. However, no such
association has been reported thus far in the nondiabetic
stroke population.
Over the last few years, considerable progress has been
made in identifying and treating modifiable risk factors for
stroke. Serum uric acid has traditionally been thought of as an

Received February 6, 2003; final revision received April 4, 2003; accepted April 14, 2003.
From the Acute Stroke Unit, Division of Cardiovascular and Medical Sciences (C.J.W., S.W.M., M.R.W., K.R.L.), and Robertson Centre for
Biostatistics (C.J.W.), University of Glasgow, Glasgow, UK.
Correspondence to Dr C.J. Weir, Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary,
Glasgow, G11 6NT, UK. E-mail c.j.weir@clinmed.gla.ac.uk
2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/01.STR.0000081983.34771.D2

1951
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inert byproduct of the catabolism of ingested and endogenous

nucleoproteins and purines.9 However, if identified as an
etiological agent in the pathogenesis of vascular disease,
hyperuricemia could be targeted therapeutically in the same
way that we now routinely treat other risk factors such as
dyslipidemia and blood pressure after stroke.
We sought, in a population with a diagnosis of acute stroke
or transient cerebral ischemia, to explore the association
between urate level and any prognostic role in outcome or
future vascular morbidity and mortality.

Methods
Study Design
This retrospective analysis was performed on data collected from
3731 patients consecutively admitted to our acute stroke unit
between May 1990 and September 1998. All patients within the
catchment area of our acute stroke unit were admitted within 48
hours of experiencing a new focal or global neurological event. Brain
imaging (either CT or MRI) was performed routinely within 24 to 48
hours of admission. Subjects with subarachnoid or subdural hemorrhage were excluded. Data were collected with regards to patient
demography, medical history, and risk factors for stroke or vascular
disease.
Strokes were classified according to the Oxfordshire Community
Stroke Project (OCSP) system.10 Indexes of stroke severity included
the modified National Institutes of Health Stroke Scale (NIHSS)11
and the Glasgow Coma Scale (GCS).12 Serum urate was measured as
part of a fasting biochemical profile taken on the morning after
admission. The above information was then recorded prospectively
into a computerized database. Serum urate was measured with
standard analytical methods in the hospital biochemistry department.
Follow-up was by record linkage13 to death records from the
Registrar General of Scotland and to hospital discharge records to
obtain information on medical events after stroke. This technique has
been previously validated.14 Record linkage is reliable; however,
admissions to private hospitals or institutions outside Scotland are
not recorded. Study patients were monitored until the end of June
2000, allowing at least 21 months of potential follow-up for each
patient. Outcome was categorized as alive at home, alive in care, or
dead at 90 days after the index stroke. A good outcome after the
index stroke was defined as alive at home after 90 days and bad
outcome as alive in care or dead at 90 days. This outcome was a
marker for functional outcome, which is frequently used as an end
point in trials of therapeutic agents in stroke.
We were granted local Research Ethics Committee approval for
the analysis of the anonymous clinical data. The Privacy Advisory
Committee of the Chief Medical Officer for Scotland approved the
linkage of the clinical data to death and hospital discharge records.

Statistical Analysis
We assessed the effect of serum urate concentration on the 2
outcome possibilities described above. Fishers exact test (binary
variables), the 2 test (categorical variables), the Mann-Whitney test
(continuous variables), and 2 test for linear trend (ordered categorical variables) were used to explore univariate differences in clinical
features between outcome groups. Using multiple logistic regression,
we assessed the effect of serum urate concentration after controlling
for factors known to influence acute stroke outcome. The modeling
had 2 stages. First, the effect of urate level was quantified after
correcting for baseline stroke severity (modified NIHSS). Diabetes
was included in the model, and an interaction term between urate and
presence of diabetes was permitted. This explored the hypothesis that
any effect of urate might be augmented in diabetics. Second, clinical
variables that differed significantly between outcome groups in the
univariate analysis or that are already established as predictors of
stroke outcome were added to the model. Quadratic and log
transformations of variables were included when exploratory analyses showed these to be merited.

TABLE 1.

Study Population Demographics

Variable

n (%)

Men

1786 (48)

Hypertension
No history

1978 (55)

Receiving antihypertensive medication

757 (21)

Not receiving antihypertensive therapy

844 (24)

Diabetes
No history

3233 (90)

Type unknown

87 (2)

Type I

218 (6)

Type II

50 (1)

Current smoker

1675 (48)

Previous stroke

655 (18)

Previous TIA

501 (14)

History of hyperlipidemia

159 (5)

Previous myocardial infarction

558 (16)

History of claudication

272 (8)

Atrial fibrillation

344 (18)

Diuretic use before stroke

718 (19)

Low-dose aspirin use (daily dose300 mg) before stroke

1033 (28)

OCSP classification
Total anterior circulation

915 (25)

Partial anterior circulation

1237 (33)

Posterior circulation

414 (11)

Lacunar syndrome

1103 (30)

Other

48 (1)

TIA vascular event (resolved within 24 h)

415 (11)

Primary intracranial hemorrhage

355 (10)

TIA indicates transient ischemic attack.

We also assessed the relationship between urate level and risk of

a subsequent major vascular event (nonfatal myocardial infarction,
nonfatal stroke, or vascular death). The pattern of event occurrence
was illustrated through Kaplan-Meier curves. Univariate analysis by
log-rank test was performed on cardiovascular risk factors and
recognized prognostic indicators in stroke. Multiple Cox
proportional-hazards analysis15 was then used to assess the association between urate level and vascular event rates after correction for
factors known to influence acute stroke outcome and vascular event
risk. The modeling included 2 stages equivalent to those used in the
multiple logistic regression of outcome. For each variable, the
validity of the proportional-hazards assumption was checked.
In statistical analyses, imputation of the mean value from subjects
in whom data were available replaced missing data on any variable.
The statistical analysis was performed with StatsDirect version 2.0.0
(StatsDirect Ltd).

Results
In total, 3731 patients with a diagnosis of acute stroke were
studied. Demography and risk factor profiles are shown in
Table 1. Median age was 72 years (interquartile range [IQR],
63 to 80 years), and median GCS score was 15 (IQR, 14 to
15). The median modified NIHSS score was 3 (IQR, 2 to 8);
the total NIHSS score had median of 6 (IQR, 3 to 11). Median
urate level was 0.31 mmol/L (IQR, 0.25 to 0.38 mmol/L).
Urate level was missing in 1233 (33%) of the subjects with

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Weir et al
TABLE 2.

Serum Urate and Stroke Outcome

1953

Multivariate Analysis for Favorable 90-Day Outcome (Alive, Living at Home)

Variable

Odds Ratio

95% CI

0.78 (per additional 0.1 mmol/L)

0.670.91

0.0012

0.83 (per additional point)

0.810.85

0.0001

0.95

0.701.28

0.72

0.85 (per additional 0.1 mmol/L when diabetes present)

0.631.13

0.26

1.12

0.941.34

0.22
0.0001

Urate level
Modified NIHSS score
Diabetes
Diabetes and urate interaction
Male sex
Age

0.66 (per additional decade)

0.600.71

Current smoker

0.97

0.821.16

0.78

Previous stroke

0.78

0.630.96

0.022

Atrial fibrillation

1.37

1.031.83

0.030

Low-dose aspirin use (daily dose300 mg) before stroke

1.28

1.051.55

0.014

Primary intracranial hemorrhage

0.49

0.370.64

0.0001

TIA vascular event (resolved within 24 h)

2.64

1.803.86

0.0001

Total GCS, 15 versus 15

2.04

1.672.50

0.0001

Hypertension

1.25

1.051.48

0.011

1.00 per (mm Hg)2

1.001.00

0.020

Creatinine

0.85

0.631.15

0.31

Cholesterol

1.11

0.651.90

0.71

Glucose

0.53

0.410.69

0.0001

Triglyceride

1.37

1.051.79

0.022

Hematocrit

2.82

1.206.64

0.018

Diuretic use before stroke

0.93

0.751.15

0.50

Previous TIA

1.04

0.811.34

0.74

Mean arterial pressure*

TIA indicates transient ischemic attack.

*Quadratic term used.
Natural log transform used.

data on 90-day placement outcome. We found that 355

patients (10%) had primary intracerebral hemorrhage and
3376 (90%) had ischemic stroke.

Outcome at 90 Days
At 90 days, 2361 (64%) were alive at home (good outcome),
whereas 498 (13%) were alive in care and 835 (23%) were
dead (bad outcomes). We lost 37 patients (1%) to follow-up.
Variables associated with bad outcome on univariate analysis included older age, female sex, elevated glucose concentration, primary intracerebral hemorrhage, increased modified
NIHSS, and higher urate values (P0.0001 for all)
Stepwise multiple logistic regression confirmed the relationship between higher urate levels and bad outcome at 90
days (Table 2). This association remained after correcting for
all other known or potential prognostic indicators and allowing for an effect of diabetes (any type versus none) on
outcome. There was no interaction between urate effect and
the presence of diabetes. Diabetes itself was not significantly
associated with bad outcome at 90 days independently of
glucose concentration.

rin in Patients at Risk of Ischaemic Events trial,16 in which

deaths resulting from the index stroke event counted as
vascular death events.
In univariate analysis, diabetes, previous stroke, previous
myocardial infarction, history of claudication, atrial fibrillation, increased age, higher urate level, prestroke diuretic use,
and low-dose aspirin usage all had hazard ratios 1, indicating an increased risk of a major vascular event. In the Figure,

Relationship to Risk of Major Vascular Events

In total, 1855 patients (51%) suffered a recurrent ischemic
stroke, nonfatal myocardial infarction, or death caused by any
vascular cause. The mean duration of follow-up was 2.7
years. The high event rate results partly from our use of the
vascular event definition from the Clopidogrel Versus Aspi-

Kaplan-Meier time-to-event curves by urate level. O Indicates

0.25 mmol/L; , 0.251 to 0.31 mmol/L; , 0.311 to
0.38 mmol/L; and - - -, 0.38 mmol/L.

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TABLE 3.

Multivariate Analysis for Time to Major Vascular Event

Variable
Urate level
Modified NIHSS score

Hazard Ratio

95% CI

1.27 (per additional 0.1 mmol/L)

1.181.36

0.0001

1.11 (per additional unit)

1.101.12

0.0001

1.29

1.111.50

0.0065

1.22 (extra effect per additional

0.1 mmol/L urate if diabetes present)

1.061.41

0.0011

Diabetes
Diabetes and urate interaction

Kaplan-Meier curves show the event rates according to urate

level subdivided by quartile.
Multivariate analysis confirmed that higher urate levels
independently increased event risk (hazard ratio, 1.27 per
additional 0.1 mmol/L; 95% confidence interval [CI], 1.18 to
1.36; P0.0001). Moreover, the effect of urate on the
vascular event rate was greater when diabetes was present (a
further hazard ratio of 1.22 per additional 0.1 mmol/L when
diabetes present; 95% CI, 1.06 to 1.41; P0.0011) (Table 3).
These effects of urate persisted after all other variables
associated with vascular event risk were added to the multivariate model.

Discussion
Serum urate measured within the first 24 hours after hospital
admission for acute stroke is an independent marker of poor
outcome and can predict future vascular events. Urate levels
independently predict a bad outcome as defined by death or
survival in care (indicating a poorer functional outcome) at 90
days after the index stroke. Cerebrovascular patients with
higher serum urate levels are also more likely to experience a
major vascular event. This relationship holds true even after
correction for the presence of established cardiovascular and
cerebrovascular risk factors such as hypertension, diabetes
mellitus, and hyperlipidemia. Although other studies have
found the effect of urate to be related to use of thiazide
diuretics,17 we found it to be independent of thiazide diuretic
use in multivariate analysis.
It is difficult in an observational study to demonstrate a
causal relationship between a factor and disease incidence or
outcome, particularly if the factor is strongly correlated with
other medical conditions known to affect outcome. Criteria
have thus been established18 that determine whether an
observed association may be considered causal. A commentary on the causality of urate in cardiovascular disease19
concluded that because of the statistical complexity created
by the strong correlation between urate level and known
vascular risk factors, the only way to demonstrate an independent effect of urate is to study its effect in patients who
were homogeneous with respect to all other vascular risk
factors. We further analyzed the effect of urate in 2 such
subgroups. Group 1 contained nonsmokers who did not have
diabetes mellitus, hypertension, previous myocardial infarction, atrial fibrillation, hyperlipidemia, or intermittent claudication. Group 2 consisted of hypertensive smokers who had
none of the other risk factors. Analysis in each subgroup gave
results consistent with our main findings.
Previous studies have shown a relation between urate
levels and poor outcome in diabetic cerebrovascular pa-

tients.7 We have shown that this relationship extends to the

cerebrovascular population as a whole. Allowing for the
effect of diabetes (any type versus none) on outcome and
permitting the effect of urate to vary according to whether
diabetes was present, we found no interaction between
urate effect and the presence of diabetes. However, the
lower limit of the CI for the interaction indicates that a
more potent adverse effect of increased urate in diabetics
may exist. Diabetes itself was not significantly associated
with a bad 90-day outcome. In the vascular event data, we
found that the effect of urate on the event rate was greater
when diabetes was present. The lower limit of the CI for
the interaction (hazard ratio, 1.06) indicates that this
augmentation may be small. The upper limit shows that the
interaction may add as much as 150% to the basic urate
effect (1.41 versus the basic urate effect of 1.27). Diabetes
itself was also significantly associated with increased
vascular event risk.
Urate levels were missing in 1233 patients (33%) with
90-day outcome data because of the withdrawal by the
biochemistry service of urate as a routine admission profile
test. Although urate requests remained stroke unit policy
for the next 2 years, this was not applied uniformly by
junior medical staff. Consistency was restored when requests were again automated. We replaced missing data by
the mean level from subjects in whom urate was measured.
This is conservative in that it should dilute the true urate
effect, assuming that the data were missing at random. Of
the patients in whom urate was measured, 67% experienced a favorable outcome compared with 58% of those
without urate data (P0.0001, Fishers exact test). This
may be due partly to patients who died soon after admission being unavailable for routine biochemistry testing.
We repeated our analyses in the subset of patients in whom
urate was measured. The results were similar, confirming
that the association between urate level and outcome is
large in magnitude and stable under several modeling
strategies. Although more sophisticated imputation of the
missing data or a prospective study with complete data is
desirable to confirm our results, we have confidence that
the association we observed is not artifactual.
Although serum uric acid was found in previous studies
to be an independent predictor of stroke or excess mortality in patients with noninsulin-dependent diabetes mellitus, no study has previously shown that serum urate
independently predicts poor outcome in stroke patients
regardless of diabetes. Several studies, however, have
shown a relationship between serum urate and hypertension4,20 and serum urate and coronary heart disease5 in

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Weir et al
certain populations. Many studies have postulated no role
for urate in vascular disease.21 A recent small study even
suggested that high serum urate levels may be neuroprotective in acute stroke, resulting in better functional
outcome at discharge.22
Apart from the interactions between uric acid and other
risk factors, there are several plausible mechanisms
whereby uric acid may directly affect atherogenesis or the
clinical course of cerebrovascular disease. Increased uric
acid levels promote oxygenation of low-density lipoprotein cholesterol and facilitate lipid peroxidation.23 In
addition, increased uric acid levels are associated with
increased production of oxygen free radicals. Each of these
factors is known to play a pivotal role in the progression of
atherosclerosis. Moreover, increased uric acid levels may
be associated with increased platelet adhesiveness, and this
effect could potentiate thrombus formation.24 The Atherosclerosis Risk in Communities study25 observed that the
level of uric acid was directly associated with B-mode
ultrasound carotid intima-media thickness. Studies of the
composition of human atherosclerotic plaque have shown
that urate crystals are more abundant in diseased atherosclerotic plaque than in control artery walls.26 Although
the precise role of uric acid in each of these mechanisms
has yet to be delineated, it is clear that these effects
provide a potential basis for uric acid as a primary
cardiovascular risk factor.
Experimental findings indicate the potential role of uric
acid in the development of hypertension through stimulation of the renin-angiotensin system27 and induction of
sodium sensitivity.28 In rats, uric acid has been shown to
mediate renal disease development by causing glomerular
hypertension29 and hence renal hypertrophy, glomerulosclerosis, and interstitial fibrosis.30 Uric acid also induces
renal arteriolar thickening independently of its effect on
blood pressure.31
Cerebrovascular disease is the most common cause of
disability and the third-most-common cause of death in the
developed world. Traditional risk factors such as hypertension and hypercholesterolemia are now being treated
more aggressively after ischemic stroke following the
results of the Perindopril Protection Against Recurrent
Stroke Study32 and Heart Protection Study,33 respectively.
However, there is a pressing need to identify additional
treatable risk factors that are easily measured and highly
prevalent in the general population. Hyperuricemia is one
such potential risk factor, but more research is needed at
both the scientific and clinical levels before routine treatment of serum urate can be recommended.

Acknowledgments
Dr Weir was supported in this work by a Medical Research Council
Career Development Fellowship. We are grateful to Professor John
Reid, Dr Peter Semple, and Professor Gordon McInnes for permission to study their acute stroke patients. Chris Povey of the National
Health Service (Scotland) Information and Statistics Division performed the follow-up of patients via record linkage.

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Editorial Comment
Elevated Uric Acid and Ischemic Stroke: Accumulating Evidence That It
Is Injurious and Not Neuroprotective
Hyperuricemia was first associated with hypertension and cardiovascular disease in 1879.1 Since that time, many have
attributed this association to a simple clustering of hyperuricemia with well-established cardiovascular risk factors, and an
elevated serum uric acid level by itself has generally been
regarded as insignificant or incidental. A recent reanalysis of the
Framingham study concluded that hyperuricemia was not an
independent risk factor for cardiovascular events after controlling for these other associated factors.2 Nevertheless, other
studies have found an elevated serum uric acid level to be an
independent risk factor for cardiovascular and renal disease
(reviewed elsewhere3). In particular, several studies have reported that hyperuricemia is an independent predictor of stroke
in diabetic subjects,4 individuals with isolated systolic hypertension,5,6 and the general population.7 A new study reported in this
issue of Stroke8 examining 2498 subjects admitted with acute
stroke found that the admission serum uric acid also independently predicted worse outcome and a higher rate of repeated
stroke or other cardiovascular event. Others have also reported
that a higher uric acid level in patients with acute stroke is
associated with poorer outcome.9 These studies suggest that uric
acid may be a true risk factor for stroke and for a poor outcome
after stroke.
Experimental evidence could provide a mechanism to explain
how uric acid may have a pathogenetic role in stroke. Hypertension remains the most common cause of stroke, and there is
increasing evidence that an elevation in uric acid may cause
primary hypertension. Elevated serum uric acid is an independent predictor of hypertension10 and is present in the vast
majority of adolescents with new-onset, untreated primary hypertension.11 Experimentally induced hyperuricemia also causes
hypertension in rats by a renal mechanism linked to inhibition of
nitric oxide, activation of the renin-angiotensin system, and
development of renal arteriolosclerosis.12 Once the renal arteriolosclerosis develops, the kidney drives the hypertension, and
lowering uric acid is no longer protective.13 Prolonged hyperuricemia in rats also causes progressive renal injury via a

crystalline-independent mechanism12 and can accelerate established renal disease14; the mechanism is mediated by an elevation in glomerular pressure and renal vasoconstriction.15 Finally,
uric acid stimulates synthesis of monocyte chemoattractant
protein-1 by rat vascular smooth muscle cells,16 which is known
to have a key role in stimulating macrophage infiltration in
atherosclerotic vessels.17 It is of interest that uric acid is strongly
associated with carotid18,19 and coronary20 atherosclerosis, especially in women.
There is also a potential pathogenetic mechanism to explain
why an elevated serum uric acid at the time of stroke may be
injurious. Recent evidence suggests that acute ischemic stroke
results in generation of local oxidants that augment local injury
and increase infarct size.21 Acute stroke is associated with a
rapid decrease in serum antioxidants22,23 that recover slowly
over the subsequent week.24 Individuals with lower plasma
antioxidants at the time of acute stroke have a poorer outcome.25
Uric acid is often considered an antioxidant and has been shown
to scavenge hydrogen peroxide and hydroxyl radicals, to block
nitrotyrosine formation from peroxynitrite, and to preserve
extracellular superoxide dismutase.26,27 Several studies suggest
that its antioxidant properties may have a beneficial role in
multiple sclerosis, Parkinsons disease, and Alzheimers disease.28 One might therefore expect that having elevated uric acid
during an acute stroke would be beneficial. However, only 1
small study has reported that elevated uric acid is associated with
good outcome after an ischemic stroke,29 whereas 2 other
studies, including the large series reported in the current issue,
found the opposite.8,9 One explanation is that uric acid, being an
aqueous antioxidant, can become a pro-oxidant under certain
circumstances, particularly if other antioxidants such as ascorbate are low.30 Thus, the fall in ascorbate (vitamin C) levels with
acute stroke could predispose the serum uric acid to take on
pro-oxidant properties. Consistent with this hypothesis is the
observation that in acute stroke, those with high uric acid and
low ascorbate levels have the worst outcome.24

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Weir et al
Further studies are needed to prove whether uric acid has a
pathogenetic role in hypertension, vascular disease, atherosclerosis, and stroke. It will also be important to determine whether
lowering uric acid levels reduces the frequency of stroke. One
wonders if the increased benefit of losartan over atenolol in the
Losartan Intervention For Endpoint Reduction in Hypertension
Study may relate in part to the uricosuric effect of losartan and
the consequent lower uric acid levels.31 It is also important to
assess whether elevated uric acid levels, especially when coupled with low ascorbate levels, may function more as a prooxidant than as an antioxidant. It is of interest that there is often
a J-shaped curve when one compares uric acid levels with
cardiovascular events,3 because this might suggest that low uric
acid levels may increase mortality as a result of inadequate
antioxidant levels and high levels of uric acid may function more
as a pro-oxidant to increase the predisposition for the development of hypertension and vascular disease. It may also explain
why studies in rats suggest that administering uric acid is
beneficial in ischemic stroke32; in this case, uric acid may be
functioning more as an antioxidant because uric acid levels are
lower in rats as a result of the presence of the enzyme uricase. In
the meantime, studies such as the one in the current issue8
provide strong evidence that an elevated uric acid is injurious
rather than protective in subjects with acute stroke.

Acknowledgments
This work is supported by NIH grants DK-52121, HL-68607, and
1P50-DK064233 01. Dr Kanellis is supported by a CJ Martin
Fellowship from the Australian National Health and Medical Research Council.

John Kanellis, MD, Guest Editor

Richard J. Johnson, MD, Guest Editor
Section of Nephrology
Baylor College of Medicine
Houston, Texas

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Editorial CommentElevated Uric Acid and Ischemic Stroke: Accumulating Evidence

That It Is Injurious and Not Neuroprotective
John Kanellis and Richard J. Johnson
Stroke. 2003;34:1956-1957; originally published online July 3, 2003;
doi: 10.1161/01.STR.0000081984.07414.EF
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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