Current Pharmaceutical Design, 2005, 11, 4125-4132 4125

Serum Uric Acid and Risk of Coronary Heart Disease

S. Goya Wannamethee*

Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Rowland
Hill St, London NW3 2PF, England

Abstract: Many large epidemiological studies confirmed a positive association between raised serum uric acid
(SUA) levels and risk of coronary heart disease (CHD) or cardiovascular disease (CVD) in the general population,
among hypertensive patients and those with established CHD, stroke, diabetes and heart failure. There is much
controversy concerning the role of SUA as an independent risk factor for CHD as SUA is related to many of the
established risk factors for cardiovascular disease including hypertension, dyslipidaemia, obesity and pre-existing
disease. The epidemiological evidence suggests that SUA is an independent predictor of CVD in subjects with
hypertension and established vascular disease but not in healthy subjects. This evidence suggests that the
influence of SUA on CHD is explained by the secondary association of SUA with other established etiological risk
factors (hypertension, dyslipidaemia, hyperinsulinaemia, obesity and pre-existing disease). There is no evidence so
far to indicate that lowering SUA levels with drug treatment has a beneficial effect on CVD outcome.
In summary, there is little support for an independent causal role for SUA in the development of CHD. However,
SUA may provide useful prognostic information in subjects with hypertension and vascular disease.
Key Words: Serum uric acid, coronary heart disease, hypertension, epidemiology, risk factors.

INTRODUCTION SERUM URIC ACID AND CORONARY HEART

DISEASE
The positive association between serum uric acid (SUA)
and coronary heart disease (CHD) and cardiovascular disease Ever since Gertler et al. [1] reported an association of
(CVD) has been recognised for 50 years [1-4]. The long- elevated SUA with myocardial infarction (MI) in men in
standing debate as to whether uric acid plays an independent 1951, numerous epidemiological studies have confirmed a
causal role in the development of CHD has received much positive association between raised SUA and risk of CHD in
renewed interest in recent years with many reviews and both the general population [2-4, 16-21, 23-28] and high-risk
editorials providing differing views [5-15] and recent studies groups including patients with hypertension [22, 35-40],
providing conflicting results [16-21]. Recent findings from CHD [41], chronic cardiac failure [42], stroke [43, 44] and
the LIFE trial showing lowering of urate to be associated diabetes [45]. The question as to whether high SUA is [1] an
with beneficial effects on CVD events [22] has sparked independent risk factor for CHD [2], a spurious determinant
further the debate [15]. Hyperuricaemia is associated with of CHD through confounding, or [3] a marker of
many established vascular risk factors [2, 4, 16, 23, 25-31]. degenerative vascular disease, has not been fully elucidated.
Thus, the role of SUA as an independent risk factor for CHD Mechanisms by which SUA might influence coronary risk
remains uncertain. Although some studies suggested that include enhanced platelet adhesiveness and aggregation [46,
SUA is an independent risk factor for CHD [1, 18, 19, 23, 47], antioxidant properties and formation of free radicals [48,
24], there is increasing evidence that the association of 49], oxidative stress [50] and renal involvement in hyper-
hyperuricaemia with CHD events is dependent on the tensive disease [7], but none of these mechanisms have been
association between SUA and other risk factors, such as firmly established. However, there is increasing evidence
hypertension, obesity and elevated levels of triglycerides [2- from large prospective studies that the relation between
4, 16, 17, 20, 21, 23-29]. It has also been postulated that raised SUA and risk of CHD in men is mediated through
hyperuricaemia may be part of the insulin resistance other risk factors.
syndrome [32-34]. Some investigators suggested the
independent role of SUA on the risk of CHD in women but EPIDEMIOLOGICAL EVIDENCE
not in men [23, 26]. More recently, SUA was shown to be
The association between SUA and CVD has been studied
an independent predictor of mortality in high-risk groups
in the general population, in hypertensives as well as in
including subjects with hypertension, CHD, stroke, diabetes
patients with vascular disease and diabetes.
and heart failure [22, 35-45]. This review considers the role
of elevated SUA as an independent risk factor for CHD.
General Population
Table 1 summarises the major prospective studies on
*Address correspondence to this author at the Department of Primary Care
and Population Sciences, Royal Free and University College Medical SUA and cardiovascular risk in the general population in the
School, Rowland Hill St, London NW3 2PF, England; Tel: +44 (0) 20 7794 last 25 years. Several large studies found the association of
0500, Ext: 4765; Fax: +44 (0) 20 7794 1224; E-mail: [email protected] SUA with CHD to be explained by diuretic use [17, 25] and

1381-6128/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.

4126 Current Pharmaceutical Design, 2005, Vol. 11, No. 32 S. Goya Wannamethee

Table 1. Major General Population Based Prospective Studies on the Relationship Between Serum Uric Acid (SUA) and Risk of
Cardiovascular Disease (1979-2004)

Independent
Study Subjects Major findings association
with CVD

Chicago Heart association

7,804 M/F SUA independently associated with CVD and CHD
Only Detection project Yes, in women only
26 45-64 yrs deaths in Women but not in men
1979

In subjects without known heart disease SUA associated with Yes, in women and
Social Insurance 3,195 M, 3160 F
27 CVD mortality in women but not in men. SUA associated with in men with CHD
Institution Finland 1982 40-69 yrs
CVD in men with known heart disease only

SUA associated with total CHD events after adjustment for SBP And
Honolulu Heart program 7,705 M
28 cholesterol. No relationship after exclusion of men on hypertensive No
1984 45-68 yrs
treatment

SUA significantly associated with CHD after adjustment for Diuretics in

4 5,019 M/F
Framingham Study 1985 both sexes. Non-significant in multivariate analysis including SBP and No
30-62 yrs
cholesterol

51 1,462 F SUA independently associated with all cause

Gothenburg Study 1988 No
38-60 yrs mortality but not with incidence of MI.

Chicago Heart association

6,797 F SUA independently associated with CVD and Yes
Only Detection project
24 35-64 yrs CHD deaths. Relationship stronger in women 55-64 years (women)
1989

No significant association between SUA and CHD after

Honolulu Heart program 6,411 M
29 adjustment for confounders including DBP and triglycerides In non-drinkers only
1996 45-68 yrs
Significant independent association in non-drinkers only

SUA significantly associated with CHD after adjustment for

British Regional Heart 7,735 M
16 lifestyle factors and pre-existing disease. Non-significant No
Study 1997 40-59 yrs
after adjustment for SBP and cholesterol

Augsburg MONICA 1,044 M Significant association between SUA and CVD mortality Independent of
18 Yes
Cohort 1999 45-64 yrs CVD risk factors including hypertension, Diuretic use and cholesterol

SUA significantly associated with age-adjusted risk for CHD

17 6,763 M/F
Framingham Study 1999 Events and CVD death in women but not in men. Non-significant No
mean 47 yrs
after adjustment for CVD risk factors including diuretic use

19 5,926 M/F Significant association between SUA and CHD and CVD
NHANES I 2000 Yes
25-74 yrs mortality in both men and women after adjustment for risk factors

20 13,504 M/F
ARIC Study 2000 No independent association between SUA and risk of CHD in either sex No
45-64 yrs

National Health Insurance

22,698 M SUA was not associated with CVD deaths or
Corporation (NHIC) Korea No
21 30-77 yrs all cause mortality after adjusting for CVD risk factors
2004

M=male; F=female; M/F=male and female; SUA = serum uric acid; CHD = coronary heart disease; CVD cardiovascular disease; SBP = systolic blood pressure; DBP =
diastolic blood pressure.

the earlier Honolulu Heart Study of over 7,000 men showed factors, including blood pressure and cholesterol [4]. The
no correlation between uric acid and CHD after excluding Framingham Study showed no association between SUA and
men on diuretics [28]. The Coronary Drug Project Research CVD in men, but in women a significant univariate
Group studied 2, 789 men with diagnosed MI aged 30-64 association was seen, which disappeared after adjustment for
years and found the increased risk of CHD to be related to other vascular risk factors, in particular the use of diuretics
use of thiazide diuretics [25]. In contrast, an earlier report [17]. The earlier NHANES study [23] and the Chicago Heart
from the Framingham Study found the relation to be inde- Association Detection Project In Industry study [24] found
pendent of antihypertensive treatment but this relationship the association between SUA and risk of CHD in men to be
was attenuated after adjustment for other vascular risk attenuated after adjustment for a wide range of other vascular
Serum Uric Acid and Risk of Coronary Heart Disease Current Pharmaceutical Design, 2005, Vol. 11, No. 32 4127

risk factors. However, neither of these studies ascertained they observed an independent relationship between SUA and
which factors were responsible for the attenuation. The CHD primarily in women aged 55-64 years (i.e. post-
Social Insurance Institution of Finland Study observed the menopausal) and suggested that hormonal influence may
relationship to be confounded by pre-existing CHD [27]. In a play a role [24]. The reasons for the sex differences are
later analysis from the Honolulu Heart Study, a significant unclear but it has been suggested that there may be an
independent association was seen between SUA and CHD interaction with sex hormones [24]. Women taking both
but only in non-drinkers (lifelong abstainers and ex-drinkers) estrogen and progesterone were shown to have significantly
[29]. This may reflect the high rates of existing CVD in non- lower SUA levels than those who had never used them [52].
drinkers. In the British Regional Heart Study, the increased Postmenopausal women have also been shown to have
risk of CHD appeared to be largely mediated by the higher levels of SUA than other women [23, 52]. It is
association between hyperuricaemia and serum choles-terol possible that elevations in SUA associated with menopausal
[16]. In the ARIC study, no independent association was changes may be responsible for the association seen with
seen between SUA and CHD in either men or women [20]. cardiovascular or CHD mortality in women. In the ARIC
In a recent large prospective study of over 22, 000 Korean study, no association was seen between SUA and an early
men no association was seen between SUA and CVD deaths measure of atherosclerosis (carotid intimal-medial thickness
after adjustment for vascular risk factors including detected by B-mode ultrasonography) in men or women after
hypertension and cholesterol [21]. adjustment for risk factors [52]. In a later study they
observed an association between SUA and CHD incidence in
In contrast, a few recent studies suggested that the women but not in men [20]. However, this association was
association between SUA and CVD may be independent of attenuated after adjustment for vascular risk factors largely
confounding factors. The MONICA Augsburg cohort showed due to systolic blood pressure. Given the inconsistencies
a significant relationship between SUA and risk of seen between population studies and age groups and the lack
cardiovascular mortality independent of vascular risk factors of plausible mechanism the evidence for an independent role
which included hypertension, cholesterol and diuretic use of SUA in the development of CHD in women is weak.
[18]. However, men with prevalent CHD were not excluded
and the association between SUA and death from MI was not Increased Serum Uric Acid in Hypertension
statistically significant [18]. The most recent finding from
the NHANES I study showed an independent role of SUA Several epidemiological and clinical studies reported a
on CVD mortality in contrast to their earlier findings [19]. It significant association between hyperuricaemia and hyper-
is of interest to note that their recent study excluded fewer tension [2, 4, 7, 30, 54]. Hyperuricaemia is a frequent finding
men with disease from the analysis. Only subjects with MI in patients with essential hypertension and earlier studies
and stroke were excluded whereas in the earlier analysis all suggested that hyperuricaemia in hypertensive subjects
men with history of CHD and diabetes were excluded. Thus, reflected early renal vascular involvement associated with
in these two recent positive studies pre-existing CVD could hypertension [55, 56]. However, several studies found eleva-
have confounded the relationship. ted SUA in hypertensives in the absence of clinical renal
disease [57, 58]. It has also been suggested that hyperuri-
Overall, the majority of prospective studies in the general caemia may be induced by antihypertensive treatment [59].
population have not found an independent association Recent studies proposed the role of insulin resistance and
between SUA and CVD in men. adiposity [31-34, 56]. Hyperinsulinaemia secondary to
insulin resistance may enhance renal sodium retention and
SUA and CHD in Women decrease urinary uric acid clearance, thereby contributing to
Although numerous studies in men concluded that the hyperuricaemia and hypertension [60]. In several population
relationship between SUA and CHD is likely to be attribut- studies, univariate associations of hyperuricaemia and both
able to hypertension, use of diuretics, hyperlipidaemia or systolic and diastolic blood pressure were observed but these
pre-existing CHD, some studies in women have observed the relationships were attenuated after adjusting for BMI,
relationship to be independent of these factors [23, 24, 26]. suggesting a major role of adiposity in this association [16,
The NHANES I study observed SUA to be predictive of 26, 54].
CHD mortality in women but not in men even after adjust- The mechanisms underlying the increase in SUA in
ment for these risk factors. However, a weaker significant patients with essential hypertension are still not well under-
association was seen for CHD incidence [23]. This was stood. The evidence that raised SUA in hypertensive sub-
confirmed in their recent study using extended follow-up jects is associated with increased vascular risk or mortality
[19]. Among women in the Gothenburg Study [51] and the independent of other vascular risk factors has been incon-
Framingham Study [4], SUA was independently associated sistent [22, 35-40]. Table 2 summarises the major studies on
with all cause mortality but not with CHD incidence. The SUA and cardiovascular risk in hypertensives. The European
Finnish study observed an independent relationship between Working Party on High Blood Pressure in the Elderly trial
SUA and CVD mortality in women with no heart disease in showed a significant univariate association between initial
the follow-up period between 5 and 12 years but not in the SUA and cardiac mortality but this disappeared after adjust-
first five years [27]. No such association was seen in men. ment for age, gender and previous CVD [35]. The SHEP
The Chicago Heart Association Detection in Industry Study study showed a significant association between SUA and
observed an independent relationship between SUA and risk non-fatal CHD or CHD death in the univariate analysis but
of CVD mortality in women but not in men [26]. In their this was reduced to marginal significance in the multivariate
later study involving over 6, 000 women aged 35-64 years, analysis [36]. In a subsequent analysis Franse et al. explored
4128 Current Pharmaceutical Design, 2005, Vol. 11, No. 32 S. Goya Wannamethee

Table 2. Prospective Studies on Serum Uric Acid (SUA) and Risk of Cardiovascular Disease in Hypertensive Subjects

Study Subjects Major findings

European Working Party

on high Blood pressure 822 hypertensives
35 Initial SUA was not related to CVD or total mortality
In the elderly (M/F) > 60 yrs
(EWPHE) (1991)

Systolic hypertension In
36 4,736 hypertensives SUA significantly associated with non-fatal MI and CHD death.
the elderly Programme (M/F) > 60 yrs Association was of marginal significance in multivariate analysis
(SHEP) (1996)
37
WORKSITE Study 7,978 mild-to moderate Baseline and in treated SUA significantly associated with CVD events
(1999) hypertensives (M/F) 20-85 yrs after adjustment for CVD risk factors including diuretics

38 1,720 subjects with essential J –shaped relationship between SUA and CVD events.Highest
PIUMA Study
hypertension (M/F) Mean age 51 quartile showed significantly increased risk compared to
(2000) nd
yrs 2 quartile after adjustment for CVD risk factors

Baseline SUA independently predicted CHD events The benefits of

39
SHEP Study 4,327 subjects with isolated diuretic antihypertensive therapy was limited to those whose SUA did
(2000) hypertension (M/F) ≥ 60 yrs not increase by 1 mg/100ml. Those with hyperuricaemia showed
the same rate of CVD events as the placebo control group

Systolic Hypertension
40 2,394 subjects with systolic SUA was associated with significantly increased risk of CVD
In China trial hypertension (M/F) ≥ 60 yrs death after adjustment for CVD risk factors including active treatment
(2001)

Baseline SUA was significantly associated with increased vascular events in

22
LIFE study 9,193 high risk subjects with women but not men. The association in women remained significant after
(2004) hypertension (M/F) 55-80 yrs adjustment for the Framingham risk score. In women, attenuating the
increase in SUA in diuretic treated hypertensives reduced CVD events

M/F=male and female; F-U=follow-up; CHD = coronary heart disease; CVD cardiovascular disease; SUA = serum uric acid.

the effects of SUA changes observed during diuretic but not in men after adjustment for the Framingham risk
antihypertensive therapy among the SHEP participants [39]. score [22]. Furthermore, the data suggested that in women,
Baseline SUA independently predicted ‘any cardiovascular diminishing the increase in SUA in treated hypertensives
event’ and CHD but not stroke in subjects with isolated reduced CVD events. However, it is not possible from the
systolic hypertension. The benefit of diuretic treatment was study to assess whether this is due to the specific uric acid-
limited to those whose SUA levels did not increase. Those lowering effect of the drug or whether increased SUA may
who developed hyperuricaemia on diuretic treatment suffered reflect some marker of vascular risk.
CVD event rates similar to that of placebo-treated
participants. Although the study cannot address the issue of Evidence in Disease-Specific Subgroups
causality, the authors concluded that monitoring SUA levels
Table 3 summarises the major prospective studies on
during diuretic therapy may allow identification of patients
SUA and cardiovascular risk in disease-specific subgroups.
remaining at high CHD risk. The Worksite project (USA)
Besides being influenced by other risk factors, SUA may
found a hazard ratio of 1.22 for CVD incidence in the top
also be raised in subjects with established CHD. Few studies
quartile of SUA vs the lowest quartile after controlling for
examined the relationship in subjects with establ-ished
other known vascular risk factors including diuretic use [37].
CHD. In the US Coronary Drug Project, no associa-tion was
In the Piuma Study (Italy) a J-shaped relation was seen
seen between raised SUA and risk of recurrent non-fatal MI
between SUA and cardiovascular events. The highest quartile
in men with pre-existing MI followed-up for three years [25].
of SUA was characterised by a cluster of powerful predictors
In the Social Insurance Institution of Finland Study, no
of increased CVD risk although the association between
association was seen between SUA and risk of cardiovascular
SUA and vascular events persisted after adjustment for
mortality in men without known heart disease. However, in
vascular risk factors and exclusion of subjects with CVD
men with known heart disease hyper-uricaemia was
[38]. It was concluded that raised SUA is a powerful marker
associated with an increase in cardiovascular mortality [27].
for subsequent CVD. In the Systolic Hypertension Trial in
Although the findings were not statistically significant after
China (Syst-China), SUA was independently associated with
adjustment for other vascular risk factors including
an increased risk of CVD mortality in older Chinese patients
antihypertensive treatment and cardiac enlarge-ment, there
with isolated systolic hypertension [40]. The most recent
was still a nearly two-fold increase in risk of cardiovascular
findings from the LIFE study showed raised SUA to be a
mortality. Similarly, in the British Regional Heart Study,
significant independent predictor of CVD death in women
Serum Uric Acid and Risk of Coronary Heart Disease Current Pharmaceutical Design, 2005, Vol. 11, No. 32 4129

Table 3. Prospective Studies on Serum Uric Acid (SUA) and Risk of Cardiovascular Disease in Selected Patient Groups

Study Subjects Major findings

Social Insurance
45 Hyperuricaemia significantly predicted stroke events
Institution Finland 1,017 patients with NIDDM
independent of other CV risk factors
1998

Wong et al.,
43 354 stroke survivors Elevated SUA predicted cardiac death even after adjustment for CVD risk factors
2001
41
AtheroGene Study 1,017 patients with angiographically Raised SUA showed a significant independent positive relationship
2002 proven CHD mean age 62.3 yrs with mortality even after adjustment for diuretic use

Weir et al., 2,498 patients with ischemic stroke or Raised SUA predicted poor outcome (dead or in care)
44
2003 primary intracranial haemorrhage. and higher vascular events independent of other prognostic factors

Anker et al.,
42 194 subjects with chronic heart failure There was a graded relationship between SUA and mortality
2003

M/F=male and female; NIDDM=non-insulin dependent diabetes; CHD=coronary heart disease; SUA = serum uric acid.

the relation between SUA and risk of CHD was only enhances tubular sodium reabsorption, which is accompanied
observed after adjustment in men with previous definite MI by increased reabsorption of uric acid [33]. Insulin resistance
[16]. In a study of 1, 017 patients with angiographically may then be the common factor which links hypertension,
proven CHD, raised SUA was a significant independent hypertriglyceridaemia and hyperuricaemia, which in turn
predictor of mortality even after adjustment for risk factors, leads to CHD.
including diuretic use [41]. SUA is the main end product of purine metabolism
Several studies assessed the predictive value of SUA in generated by xanthine oxidase. Increased urate production
patients with stroke, heart failure and diabetes. There is a could result from high fat diets, from de novo biosynthesis
strong suggestion that SUA is independently predictive of and from the breakdown of tissue nucleic acid. A pure
CVD in these selected subgroups. Anker et al. reported that sucrose diet increases both uric acid and triglycerides [63].
elevated SUA levels were a significant predictor of mortality Thus, an increased lipid metabolism leading to elevated
and need for heart transplantation in patients with congestive triglycerides may enhance uric acid production. It, therefore,
heart failure [42]. The findings raise the question as to seems likely that the association between SUA and CHD
whether SUA itself may be of pathophysiological import- may also be mediated by triglyceride metabolism.
ance in heart failure progression. Wong et al. reported a Xanthine oxidase activity and uric acid synthesis are
relationship between SUA concentrations and subsequent increased in vivo under ischaemic conditions. In the human
cardiac mortality in 354 stroke survivors even after adjust- coronary circulation, hypoxia, caused by transient coronary
ment for risk factors, including diuretic treatment [43]. In artery occlusion, leads to an increase in the local circulating
another study of over 2,000 patients with ischaemic or concentration of uric acid [64]. Therefore, elevated SUA may
primary intracranial haemorrhage, Weir et al. reported raised act as a marker of underlying myocardial ischaemia, which
SUA to be independently predictive of future vascular events provides another possible explanation for a non-causal
and mortality [44]. In a prospective study of over 8,000 association between hyperuricaemia and CVD.
diabetic patients, raised SUA was associated with a signifi-
cant increase in risk of stroke independently of other risk Alternatively, several potential mechanisms have been
factors [45]. suggested by which SUA could have a direct pathogenic role
in CVD or in adversely affecting the clinical manifestations
Thus, overall the evidence suggests that SUA may be a of patients with established atherosclerosis, but none of these
useful prognostic marker in patients with cardiovascular- have been confirmed. There is evidence that increased SUA
related disease. levels promote oxygenation of low density lipoprotein
cholesterol (LDL-C) and facilitate lipid peroxidation [48].
POSSIBLE MECHANISMS LINKING URIC ACID TO Raised SUA levels are also associated with increased
CVD production of oxygen free radicals [49, 50]. Oxidative stress
A growing body of evidence suggest that SUA may be and the oxidation of LDL in the arterial wall by peroxyni-
part of the insulin resistance syndrome [31-34, 61, 62], a trite may play a role in the progression of atherosclerosis
cluster of risk factors including central obesity, hyperten- [65]. Uric acid may be involved in platelet adhesiveness and
sion, glucose intolerance, hypertriglyceridaemia and low aggregation [46, 47]. This has led to the hypothesis that
levels of high density lipoprotein cholesterol (HDL-C). hyperuricaemia may increase the risk for coronary throm-
Insulin resistance and hyperinsulinaemia may decrease renal bosis in patients with underlying CHD [47]. The strongest
excretion of uric acid independently of obesity and creatinine evidence for a pathogenic role for hyperuricaemia in hyper-
clearance [32]. A possible mechanism may be that insulin tension and CVD relates to the possibility that hyperuri-
4130 Current Pharmaceutical Design, 2005, Vol. 11, No. 32 S. Goya Wannamethee

caemia may induce renal disease [7]. Longstanding hyper- information in subjects with hypertension and vascular
uricaemia may result in intrarenal crystal deposition with disease.
subsequent tubulo-interstitial injury and the development of
hypertension [7]. ACKNOWLEDGEMENTS
The author wishes to thank Professor AG Shaper for his
LOWERING OF CIRCULATING URATE LEVELS
helpful comments on the draft.
AND VASCULAR DISEASE
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