Group Title: Arthritis Research & Therapy
Title: Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link?
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Title: Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link?
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Edwards, N. L.
Saag, Kenneth
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Abstract: An association between high levels of serum urate and cardiovascular disease has been proposed for many decades. However, it was only recently that compelling basic science data, small clinical trials, and epidemiological studies have provided support to the idea of a true causal effect. In this review we present recently published data that study the association between hyperuricemia and selected cardiovascular diseases, with a final conclusion about the possibility of this association being causal.
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Review

Gout

Hyperuricemia and cardiovascular disease: how strong is the

evidence for a causal link?
Angelo L Gaffo1, N Lawrence Edwards2 and Kenneth G Saag3


1 Birmingham VA Medical Center. 700 19th St S. Birmingham, AL 35233, USA
2Division of Rheumatology, University of Florida. Gainesville, FL 32610, USA
3Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, FOT 820, 1530 3rd Ave South, Birmingham, AL 35294,
USA


Corresponding author: Kenneth G Saag, ksaag@uab.edu


Published: 19 August 2009
This article is online at http://arthritis-research.com/content/11/4/240
C 2009 BioMed Central Ltd



Abstract
An association between high levels of serum urate and cardio-
vascular disease has been proposed for many decades. However,
it was only recently that compelling basic science data, small
clinical trials, and epidemiological studies have provided support to
the idea of a true causal effect. In this review we present recently
published data that study the association between hyperuricemia
and selected cardiovascular diseases, with a final conclusion about
the possibility of this association being causal.


Introduction
Hyperuricemia and gout are closely related conditions that
are prevalent worldwide [1,2]. The impact of these conditions
on quality of life and work productivity has been well
described, and for many years has been solely attributed to
the burden caused by recurrent acute gout flares [3,4]. A
possible link between hyperuricemia and cardiovascular
disease has, however, been a debated clinical topic for many
decades. Is hyperuricemia an independent cause of different
types of cardiovascular disease?

In 1965 Sir Austin Bradford Hill presented considerations for
epidemiological causation (Table 1) [5]. These considerations
have limitations and exceptions but are nonetheless useful in
trying to judge whether a given factor can make the leap from a
simple association to being an independent causative factor. A
more recent useful definition of an epidemiological cause is
offered by Rothman and colleagues as 'an event, condition, or
characteristic that preceded the disease onset and that, had
the event, condition, or characteristic been different in a
specified way, the disease either would not have occurred at all
or would have occurred some time later' [6]. It is well


Arthritis Research & Therapy 2009, 11:240 (doi:10.1186/ar2761)


established that hyperuricemia is a cause of gout. The
association between hyperuricemia and cardiovascular disease
was for many years only speculative, due to the absence of
compelling epidemiological evidence suggesting hyperuricemia
was independently linked with cardiovascular disease [7-9].

The objective of the present review is to present recently
published animal, clinical, and epidemiological evidence that
is contributing to a re-appraisal of the association between
serum urate and cardiovascular diseases. From this evidence
we will then judge the likelihood of a causative association
between hyperuricemia and cardiovascular disease using the
above-mentioned considerations for epidemiological causa-
tion. Readers with an interest in a comprehensive literature
review on the topic could refer to the reviews published by
Feig and colleagues [10], by Baker and colleagues [11], and
by Edwards [1 2].

Serum urate and vascular effects in
laboratory and animal studies
Using a rat animal model in which hyperuricemia was induced
by the administration of the uricase inhibitor oxonic acid, a
renal vascular disease that includes cortical vasoconstriction,
afferent arteriolar swelling, and glomerular hypertension has
been induced [13,14]. These physiological abnormalities
were at least partially reversible by the administration of the
nonreversible xanthine oxidase inhibitor febuxostat [15,16].

Several mechanisms have been postulated and are under
investigation for explaining these perceived endothelial
abnormalities induced by serum urate. Incubation of vascular
smooth muscle cells with uric acid has been found to


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CAD = coronary artery disease; CHD = coronary heart disease; Cl = confidence interval; CKD = chronic kidney disease; IL = interleukin; IMT
intima-media thickness.








Arthritis Research & Therapy Vol 11 No 4 Gaffo et al.



Table 1

Hill's viewpoints or considerations for epidemiological causation


Consideration


Strength


Consistency
Specificity


Temporality
Biologic gradient


Plausibility
Coherence
Experimental evidence
Analogy


Explanation

Strong associations are intuitively considered more compelling. However, weak associations do not rule out
causation.
The association is found in different experiments, with different populations, and with varied circumstances.
The most controversial consideration. A cause leading to a single effect (and vice versa) offers more support for the
causation argument than one cause leading to multiple effects (and vice versa).
The cause must happen before the effect.
A dose-response pattern is present, or incremental amounts of exposure should lead to corresponding increments
in the effect.
The proposed association seems reasonable or probable as a cause. Most subjective consideration.
A causative effect is not in conflict with current knowledge about the pathophysiology of the disease.
The effect can be reduced or altered by reducing or eliminating the proposed cause.
Alternative explanations for the causative effect are evaluated and considered less likely than the one proposed.


stimulate proliferation, angiotensin II production, and oxidative
stress. These changes were reversible by the addition of
captopril or losartan, which suggested an effect mediated
through the renin-angiotensin system [17]. Hemodynamic
abnormalities found in the hyperuricemic rat model were
reversed by the administration of a superoxide scavenger
lending additional support to a link between elevated urate
levels and damage induced by reactive-oxygen species
oxidativee stress) [18].

Alterations in the expression of endothelin-1, which has been
consistently associated with cardiovascular disease, have
also been postulated as a potential mechanism of an asso-
ciation between hyperuricemia and cardiovascular conditions.
Endothelin-1 exerts a powerful vasoconstrictive effect by
binding to the receptors ETA and ETB in human vascular cells
[19]. Human aortic smooth muscle cells exposed to different
concentrations of urate experienced dose-dependent cell
proliferation and phosphorylation-dependent endothelin-1
expression, along with an increased activity of NADPH
oxidase (one mechanism of production of reactive oxygen
species). Interestingly, those effects were reversible after
treatment with antioxidants, such as N-acetylcysteine. The
same group of investigators previously described the same
mechanism of action for an increased production of
endothelin-1 in cardiac fibroblasts [20]. How urate, known as
an extracellular molecule, gains entry into vascular endothelial
cells is still unknown but is possibly related to the
demonstrated capacity of afferent renal arterioles to express
URAT-1 [21]. This molecule is a urate-anion exchange trans-
porter, expression of which had been described only in the
renal tubular epithelium. The presence of URAT-1 in
endothelial cells may allow for explanations of intracellular
effects of urate in endothelial cells.


Serum urate and hypertension
Multiple population-based human studies have established a
strong association between increasing levels of serum urate
and subsequent development of hypertension (for a complete
list, see [10]). This association has even been reported in
subpopulations of individuals, such as those with rheumatoid
arthritis in a recent cross-sectional prevalence study [22]. The
degree to which epidemiological studies can control for
potential confounders is variable, but most studies would
examine the role of diuretics, dietary factors, and alcohol
intake in the reported associations.

Interventional studies are few and occur in very selected
groups of patients. Two recently published studies, however,
have expanded the hypothesized role of hyperuricemia as a
cause of hypertension by determining whether lowering
serum urate improves hypertension in small numbers of
patients.

Thirty adolescents (age 11 to 17 years) with stage 1
hypertension, treatment-na'iVe to antihypertensive medica-
tions, and with hyperuricemia (serum urate >6 mg/dl) were
randomized to allopurinol or placebo in a crossover study
[23]. With 4-week treatment phases and a 2-week washout
period, the patients received 200 mg allopurinol or a
matching placebo. During the allopurinol treatment phases,
both the systolic and diastolic blood pressures were
significantly reduced when compared with the respective
pressures at the end of the placebo phases. These results
were replicated when the pressures were measured by 24-
hour ambulatory measurement. Twenty out of 30 patients
normalized their blood pressures after treatment with
allopurinol versus only one patient out of 30 upon treatment
with placebo.


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Supporting the hypothesis that the effect of urate may be
mediated through stimulation of the renin-angiotensin system
[17], the mean plasma renin activity was significantly
decreased in patients after the allopurinol treatment phases
[23]. These investigators hypothesize that early essential
hypertension, as exemplified by these adolescent subjects, is
both urate sensitive and salt insensitive. As the disease
progresses with characteristic intimal and muscularis
vascular wall changes, however, essential hypertension
becomes urate insensitive and salt sensitive. These results
were supported by the findings from another study that
administrated 300 mg oral allopurinol daily to 48 patients with
hyperuricemia (serum urate >7 mg/dl) for 12 weeks [24]. At
the end of follow-up both systolic and diastolic blood
pressures had small but significant reductions when
compared with their pretreatment levels and with a group of
normouricemic control individuals.

Serum urate and macrovascular disease
Evidence of an association between serum urate levels and
surrogate markers of atherosclerosis, such as the carotid
intima-media thickness (IMT), is starting to emerge. In a
cross-sectional study of 234 healthy postmenopausal women
there was a significant association between serum urate and
IMT, independent of factors such as blood pressure, serum
glucose, serum lipids, creatinine, smoking, and diuretic use
[25]. Thirty patients with hypertension and hyperuricemia had
their carotid IMT compared with that of 25 patients with
hypertension but without hyperuricemia, and compared with
25 aged-matched healthy control individuals [26]. Patients
with both hypertension and hyperuricemia had significantly
greater carotid IMT than either control group, and in the
overall population the carotid IMT was significantly asso-
ciated with levels of serum urate. A significant association
between serum urate and IMT persisted after multivariate
adjustment in a group of 120 obese children [27].

Associations with macrovascular hard clinical endpoints
associated with atherosclerosis have also been described.
Eighty patients younger than 35 years of age clinically
diagnosed with an acute myocardial infarction were divided
among those patients who had coronary artery disease
(CAD) by angiography (n= 36) and those patients with a
normal angiography (n=44) [28]. These groups were not
different with respect to demographic characteristics or
cardiac risk factors at baseline, but mean serum levels of
urate (7.0 mg/dl among those with CAD vs. 4.9 mg/dl in
those without CAD) were the main factor differentiating the
two groups.

Other studies have found serum urate to be a prognostic
factor after an acute or subacute macrovascular disease
event. Higher levels of serum urate concentration were
associated with late mortality, cardiac death, or nonfatal
myocardial infarction in a retrospective cohort of 936 patients
with CAD undergoing elective vascular surgery [29]. A review


Available online http://arthritis-research.com/content/11/4/240



of two large independent studies in the United Kingdom
(UK-TIA Aspirin, a randomized controlled trial; and Oxford TIA
study, a prospective cohort) revealed that higher levels of
serum urate conferred a greater risk for subsequent acute
coronary events in women (but not men) after an acute
ischemic stroke or a transient ischemic attack [30]. Finally,
Lazzeri and colleagues found serum urate to be a significant
and independent predictor of total mortality and inhospital
mortality in a retrospective cohort of 466 patients admitted
with ST-elevation myocardial infarction [31].

An association with stroke and surrogate markers for
cerebrovascular disease has also become evident in recent
years. Using T2 white-matter hyperintense signals in
magnetic resonance imaging as a marker of brain ischemia,
significantly greater frequencies of these T2 white-matter
defects were found in association with higher levels of serum
urate in 46 individuals (with serum urate concentrations
>5.75 and >4.8 mg/dl for men and women, respectively)
compared with 131 control individuals [32]. This association
remained significant after adjustment for demographic and
clinical potential confounders, and was likely to represent a
true ischemic process in the studied population. As a clinical
correlate, the same group of investigators also described an
association between levels of serum urate and cognitive
dysfunction in older adults [33].

To explore the potential for a therapeutic intervention, low
(100 mg/day) and standard (300 mg/day) doses of allo-
purinol were administered to 50 patients with recent ischemic
strokes that were enrolled in a double-blind, randomized,
placebo-controlled study [34]. Allopurinol was well tolerated
and significantly lowered levels of serum urate in the
participants. The medication was associated with a signifi-
cantly attenuated rise in the proinflammatory intracellular
adhesion molecule-1, commonly observed after ischemic
brain injuries. Allopurinol did not, however, reduce the levels
of C-reactive protein or IL-6 as was expected.

Serum urate and cardiovascular mortality
In 1999 the Framingham Heart Study published the results of
their ancillary study on the association of serum urate with
cardiovascular disease and cardiovascular death. A total of
6,763 Framingham Study participants contributed a total of
117,376 person-years of follow-up. No significant associa-
tions were found in men or women after adjustment for
cardiovascular risk factors and diuretic use. These results
raised the question of an association of serum urate with
cardiovascular disease and cardiovascular death probably
confounded by other factors in the cardiovascular disease
causal pathway [8].

Several large epidemiological studies investigating the
association between serum urate levels and cardiovascular
mortality have since been published. The majority had results
in support of the association, but some of the studies


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Arthritis Research & Therapy Vol 11 No 4 Gaffo et al.


Table 2

Analysis of the association between hyperuricemia and cardiovascular disease using Hill's considerations


Consideration


Strength


Consistency

Specificity



Temporality

Biologic gradient

Plausibility
Coherence


Experimental evidence


Analogy


Comment in view of current evidence

Associations with hypertension and cardiovascular mortality are not found to be particularly strong (relative risks and
hazard ratios usually do not duplicate baseline risks) [10]. An exception is the strong association being recently
described with chronic kidney disease [47].
Limited evidence. Most associations have been described in North American and European Caucasian populations.
Some large epidemiological studies are not in favor of the association.
Not applicable for the most part. Cardiovascular diseases are complex and have multiple sufficient causative models,
of which hyperuricemia could be considered an additional component cause. On the other hand, hyperuricemia is
considered causative of other disease processes, like gout. The question of hyperuricemia being a causative factor for
cardiovascular disease at all, or just a well-hidden confounder, has not been conclusively answered.
Evidence from prospective studies has established a temporal relation between hyperuricemia and hypertension,
stroke, cardiovascular mortality, and chronic kidney disease.
Large epidemiological studies in mortality of cardiovascular diseases and development of chronic kidney disease have
established compelling dose-dependent relationships with population concentrations of serum urate [36-38,47].
In view of information provided by basic and animal models, plausibility is good.
Remaining questions about its role in cardiovascular disease given its antioxidant properties [50]. Oxidative stress is
considered a factor in atherosclerosis and cardiovascular disease, so can serum urate be a detrimental factor?
Experiments in animal models have added urate-lowering agents to revert renal vascular disease caused by
hyperuricemia [15,51]. Initial experiences in treating hypertension, ischemic heart disease, and progression of chronic
kidney disease have been published [23,24,34,48].
Additional explanations, mainly that the relation between serum urate and cardiovascular diseases is not independent,
have been progressive addressed. However, more evidence is needed.


reported negative results [11]. In 2000 a longitudinal follow-
up analysis from individuals initially recruited into the National
Health and Nutrition Examination Survey I Epidemiologic
Follow-up Survey was published, describing a significant
independent association between higher concentrations of
serum urate and cardiovascular mortality in both men and
women [35]. In general, the associations were stronger for
women than for men, and an association could not be found
in two small subgroups of men: those taking diuretics and
those with more than one cardiovascular risk factor. The
National Health and Nutrition Examination Survey described
the risk in a population with a better representation of non-
Caucasians and a lower baseline cardiovascular risk than the
one from the Framingham investigators, and its data could be
considered more generalizable.

Other recent studies have provided additional valuable
information by studying larger populations and specific
groups of individuals. Data from the Vorarlberg Health
Monitoring and Promotion Program in Austria were used to
study the association between serum urate and mortality from
coronary heart disease (CHD), from congestive heart failure,
and from stroke in 83,683 healthy men followed for 20 years
[36]. After adjustment for covariates, men with concen-
trations of serum urate >6.7 mg/dl had a significantly greater
risk for death from congestive heart failure and from stroke,
but not from CHD, when compared with those men in the
lower category of serum urate concentration (<4.6 mg/dl).


The hazard ratios for congestive heart failure and stroke were
1.51 (95% confidence interval (CI) = 1.03 to 2.22) and 1.59
(95% Cl = 1.23 to 2.04), respectively. There were significant
dose-response associations between concentrations of
serum urate across categories and risk for death from CHD,
from congestive heart failure, and from stroke in the study
population.

The same group of investigators conducted a similar analysis
in 28,613 women older than 50 years of age selected from
the same population source and followed for 21 years [37]. In
this population the hazard ratios for death from CHD, from
congestive heart failure, and from stroke between women in
the highest category (serum urate >5.4 mg/dl) versus the
lower category (<3.7 mg/dl) were 1.35 (95% Cl = 1.20 to
1.52), 1.58 (95% Cl = 1.10 to 2.10), and 1.25 (95% Cl =
1.01 to 1.56), respectively. Dose-dependent associations
between serum urate concentrations across categories and
hazard ratios for mortality were significant in all cases. This
association was also studied in 3,098 individuals at high
baseline risk for death from CHD [38]. Elevated serum urate
was significantly associated with all-cause mortality, with
each increase (mg/dl) conferring an excess risk for death of
26% (hazard ratio = 1.26, 95% Cl = 1.15 to 1.38). In
contrast, investigators studying 9,105 middle-aged men at
high baseline risk for CHD from the Multiple Risk Factor
Intervention Trial could not replicate a significant hazard ratio
for CHD mortality, death from an acute myocardial infarction,


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Available online http://arthritis-research.com/content/11/4/240


Figure 1


Hypertension


> Coronary heart Disease
Stroke



Atherosclerosis


Hypertension


Coronary heart Disease
Stroke


Atherosclerosis

Theories on the causal association between hyperuricemia and selected cardiovascular diseases. Simple causal diagrams on the association
between hyperuricemia and selected cardiovascular diseases. (a) Hyperuricemia has a direct effect on the development of hypertension and
atherosclerosis, and an indirect effect on the development of coronary heart disease and stroke. (b) Besides the indirect effects described in (a),
hyperuricemia has an independent effect on the development of coronary heart disease and stroke.


or death from any cardiovascular cause when comparing
individuals with and without hyperuricemia [39]. A significant
hazard for death from CHD among patients with gout,
however, was reported (1.35, 95% Cl = 1.06 to 1.72).
Gender differences in the strength of these associations are
not completely defined at this moment, although they seem to
be more pronounced for women.

Reports of an association between levels of serum urate and
cardiovascular mortality and all-cause mortality among
patients with chronic kidney disease (CKD) have been
discordant. Two independent groups of investigators have
reported J-shaped or quadratic associations in patients with
stage 5 CKD [40,41]. In these individuals increased hazard
ratios for all-cause mortality were found among those in the
lower and higher categories of serum urate, compared with
those in the intermediate categories. In 461 patients with
moderate CKD (average glomerular filtration rate 49 to
52 ml/minute) there was no significant difference in cardio-
vascular or all-cause mortality after multivariate adjustment,
between those with and without hyperuricemia [42].

Serum urate and development of chronic
kidney disease
Serum urate has been reported as an independent factor in
the development of CKD and end-stage renal disease


[43-46]. A recently published study has clarified the
contribution of urate as an independent risk factor in the
development of incident stage 3 CKD, defined as a calcu-
lated glomerular filtration rate <60 ml/min [47]. The study
divided the participants (n = 21,475 healthy volunteers
followed for a median period of time of 7 years) into three
categories of serum urate levels: <7.0 mg/dl, 7.0 to
9.0 mg/dl, and >9.0 mg/dl. After adjustment for identified
confounders, both higher categories of serum urate were
associated with significant risks of developing stage 3 CKD
(odds ratio = 1.74 (95% Cl = 1.45 to 2.09) for the inter-
mediate category of serum urate, odds ratio = 3.12 (95% Cl =
2.29 to 4.25) for the higher category of serum urate).
Additional data showed that the adjusted odds ratio
increased linearly up to a level of serum urate approaching
7 mg/dl, after which the slope of the curve increased. This
implied considerably greater risk for developing the outcome
at serum urate levels >7 mg/dl. Previous pilot data that had
explored the possibility of using allopurinol as a pre-emptive
therapy to slow the progression of CKD reported success
after 12 months of follow-up [48].

Reappraisal: hyperuricemia and cardiovascular
diseases
Given the new information available we could attempt, using
Hill's considerations for causation presented earlier, to re-


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Hyperuricemia


Hyperuricemia








Arthritis Research & Therapy Vol 11 No 4 Gaffo et al.



analyze the current status of the association between
hyperuricemia and cardiovascular diseases (Table 2). Signifi-
cant progress in the considerations about temporality,
biological gradient, plausibility, and experimental evidence
has been made. More evidence seems to be needed to
support the considerations about consistency, analogy, and
coherence. The associations between hyperuricemia and
cardiovascular diseases have not been described to be as
strong as associations of cardiovascular disease with
smoking, hyperlipidemia, diabetes, and hypertension [49].
The association between hyperuricemia and cardiovascular
diseases is not specific, but this one (specificity) is probably
the most outdated of Hill's considerations.

We suggest a case for a true causal relationship between
hyperuricemia and cardiovascular diseases. A word of
caution is necessary here, however, as previous epidemio-
logical associations have been proven wrong by well-
controlled prospective studies. A possibility that needs to be
thoroughly investigated is that known or unknown cardio-
vascular risk factors generate hyperuricemia, and that the
latter is just an epiphenomenon with an apparent association
with cardiovascular disease. An additional consideration is
the possibility of a publication bias that over-represents study
results in favor of the association.

Different kinds of studies are still needed to more precisely
describe the nature of this association. More epidemiologic
data are still needed in populations that have not been
studied (for example, younger individuals). Pharmaco-
epidemiological surveillance to determine the impact of newly
approved drugs for gout in cardiovascular outcomes will
hopefully be required in the future by regulatory agencies.
Carefully designed interventional studies involving larger and
more representative groups of individuals should also be
forthcoming.

Finally, if the link between hyperuricemia and cardiovascular
disease proves true, what would be the nature of the
causative association? Is serum urate a direct causative
factor for cardiovascular disease? Or is serum urate a cause
for factors that are in the causal pathway for cardiovascular
disease (such as hypertension, atherosclerosis, metabolic
syndrome)? Examples of simple causal diagrams reflecting
theories around these questions can be seen in Figure 1.


In conclusion, the paradigm of the causative association of
hyperuricemia and cardiovascular diseases seems to have
progressed from one of skepticism to one of increasing
evidence of a true relationship.

Competing interests
KGS is consultant for Takeda, Savient, and Merck. KGS also
has received research grants from Takeda, Savient, and
Merck

Acknowledgements
Research grants were received from Takeda, Savient and Merck.


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