Independent Impact of Gout on Mortality and Risk for

Coronary Heart Disease

Hyon K. Choi, MD, DrPH; Gary Curhan, MD, ScD

Background—Although gout and hyperuricemia are related to several conditions that are associated with reduced survival,
no prospective data are available on the independent impact of gout on mortality. Furthermore, although many studies
have suggested that hyperuricemia is associated with cardiovascular disease (CVD), limited data are available on the
impact of gout on CVD.
Methods and Results—Over a 12-year period, we prospectively examined the relation between a history of gout and the
risk of death and myocardial infarction in 51 297 male participants of the Health Professionals Follow-Up Study. During
the 12 years of follow-up, we documented 5825 deaths from all causes, which included 2132 deaths from CVD and 1576
deaths from coronary heart disease (CHD). Compared with men without history of gout and CHD at baseline, the
multivariate relative risks among men with history of gout were 1.28 (95% confidence interval [CI], 1.15 to 1.41) for
total mortality, 1.38 (95% CI, 1.15 to 1.66) for CVD deaths, and 1.55 (95% CI, 1.24 to 1.93) for fatal CHD. The
corresponding relative risks among men with preexisting CHD were 1.25 (95% CI, 1.09 to 1.45), 1.26 (95% CI, 1.07
to 1.50), and 1.24 (95% CI, 1.04 to 1.49), respectively. In addition, men with gout had a higher risk of nonfatal
myocardial infarction than men without gout (multivariate relative risk, 1.59; 95% CI, 1.04 to 2.41).
Conclusions—These prospective data indicate that men with gout have a higher risk of death from all causes. Among men
without preexisting CHD, the increased mortality risk is primarily a result of an elevated risk of CVD death, particularly
from CHD. (Circulation. 2007;116:894-900.)
Key Words: cardiovascular diseases 䡲 coronary disease 䡲 gout 䡲 mortality 䡲 myocardial infarction

G out is the most common inflammatory arthritis in adult study based on the Multiple Risk Factor Intervention Trial
Downloaded from http://ahajournals.org by on May 30, 2019

males,1– 4 and the overall disease burden of gout remains
substantial and may be growing.5 Many chronic inflammatory
disorders are associated with premature death (eg, rheumatoid
arthritis,6 giant cell arteritis,7 systemic lupus erythematosus,8
and ankylosing spondylitis9). However, it is unknown if gout
affects life expectancy. Although gout and hyperuricemia are
associated with several conditions that are associated with
reduced survival (eg, insulin resistance syndrome, obesity,
and hypertension),2 no large-scale prospective data are avail-
able on the potential independent impact of gout on mortality.
Editorial p 880
Clinical Perspective p 900
Although many studies investigated the relation between
serum urate levels and cardiovascular disorders, little infor-
mation is available on the relation between gout and cardio-
vascular outcomes. In the Framingham Study, serum urate
levels were not independently associated with the risk of
coronary heart disease (CHD),10 but gout was associated with
a 60% increased risk of coronary artery disease.11 Recently, a
(MRFIT) reported that gout was associated with a 26%
increased risk of acute myocardial infarction (MI) (multivar-
iate odds ratio, 1.26; 95% confidence interval [CI], 1.14 to
1.40; P⬍0.001).12 If an independent association existed
between gout and these major outcomes, this information
would substantially add to the overall burden of the disease to
the society. Furthermore, the information would also be
useful for clinicians who care for patients with these disorders
(eg, to increase efforts to prevent cardiovascular disease
[CVD] and premature deaths).
To address these important issues, we prospectively eval-
uated the association between gout and the future risk of
death and MI in the Health Professionals Follow-up Study,
which had a large prospective cohort.
Methods
Study Population
The Health Professionals Follow-up Study is a prospective cohort
study of 51 529 male dentists, optometrists, osteopaths, pharmacists,
podiatrists, and veterinarians who were predominantly white (91%)

Received March 15, 2007; accepted June 15, 2007.

From the Rheumatology Division (H.K.C.), Arthritis Research Centre of Canada, Department of Medicine, Vancouver General Hospital, University
of British Columbia, Vancouver, Canada; the Channing Laboratory (H.K.C., G.C.) and Renal Division (G.C.), Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, Mass, and the Department of Epidemiology (G.C.), Harvard School of Public Health, Boston, Mass.
Correspondence to Dr Hyon K. Choi, Division of Rheumatology, Department of Medicine, University of British Columbia, Arthritis Research Centre
of Canada, 895 West 10th Ave, Vancouver, BC V5Z 1L7, Canada.
© 2007 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.703389

894
 Choi and Curhan
and were 40 to 75 years old in 1986. The participants returned a
mailed questionnaire in 1986 on diet, medical history, and medica-
tions. The 51 297 men who provided the baseline questionnaire
information were included in our analyses.
Members of the cohort have reported information on various
lifestyle factors such as smoking, weight, physical activity, vitamin
supplement use, and medical history such as diabetes mellitus,
hypercholesterolemia, and hypertension biennially since their enroll-
ment. Dietary and alcohol intake was reported in 1986, 1990, and
1994 with a validated semiquantitative food-frequency question-
naire.2,3,13,14 Family history of MI before 60 years of age and height
were reported at baseline. Follow-up rates have averaged 94% for
each 2-year cycle.
Assessment of Gout and CHD
The 1986 baseline questionnaire inquired about a history of
physician-diagnosed gout. Biennial questionnaires mailed between
1988 and 1996 were used to identify newly diagnosed cases of gout.
We ascertained incident cases of gout by the American College of
Rheumatology (ACR) survey gout criteria, as previously de-
scribed.2– 4 In 2000, we mailed a supplementary questionnaire to
those participants with self-reported incident gout diagnosed from
1986 onwards to confirm the report and to ascertain the ACR survey
gout criteria.2– 4,15 The response rate for the supplementary gout
questionnaire was 80%, and 69% of the self-reported gout cases who
returned the questionnaire met the primary end point definition. The
concordance rate of confirmation of the report of gout between the
gout survey criteria and the medical record review was 94%.2– 4
Physician-diagnosed CHD (ie, history of MI, angina, coronary
artery bypass) was also reported through questionnaires. Validation
studies among health professionals16,17 have shown reliable reporting
of CHD events compared with medical record reviews.
In our primary analyses, we used self-reported gout and CHD
status at baseline. We used the self-reports in these case definitions
because our validation of these outcomes was performed among
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those who reported incident diagnoses during the follow-up after
baseline. However, when possible, we used confirmed cases in our
analyses such as the analysis for the relation between incident gout
and the risk of incident MI.
Ascertainment of Deaths and Incident
Myocardial Infarction
Deaths were documented by responses to follow-up questionnaires
by family members, the postal service, and a search of the National
Death Index. Participants who did not respond were assumed to be
alive if they were not listed in the National Death Index. If a death
from cancer or CVD was identified, we sought medical records to
confirm the cause of death. We obtained death certificates when the
cause could not be confirmed by other sources. Cause of death was
decided on the basis of all available information, such as death
certificates, medical records, and autopsy results. We classified
deaths as caused by CHD (International Classification of Diseases,
Ninth Revision, codes 410 to 414), CVD (codes 390 to 459), or all
other causes. These CVD codes include all CHD and other heart
disease, cerebrovascular diseases, hypertension, diseases of arteries
and veins, and other diseases of the circulatory system.
For the analyses of the risk of incident MI, we used MI cases that
were confirmed by review of medical records by physicians with no
knowledge of the risk factor status. We used the World Health
Organization criteria to define MI: symptoms in addition to either
diagnostic electrocardiographic changes or elevated cardiac enzyme
levels.18
Statistical Analyses
We calculated mortality according to history of gout and CHD at
baseline as well as the diagnoses that were updated with each
questionnaire cycle during follow-up. We computed the person-time
of follow-up for each man as the interval between the date on which
the 1986 questionnaire was returned and the date of death from any
cause (or a diagnosis of MI for MI analyses) or the end of the study
Gout and Cardiovascular Mortality 895
period, whichever came first. To investigate the link between gout
and mortality separately with regard to the presence of CHD, our
primary analysis was stratified by history of CHD. Within each
stratified group, the relative risk (RR) of death was calculated by a
comparison of the rate for the referent category of no gout. Duration
of gout was calculated as years since first diagnosis of gout. The
variable was updated with each questionnaire cycle and was divided
into 4 categories (ⱕ5 years, 6 to 10 years, 11 to 15 years, ⱖ16 years).
For the analysis of duration of gout, we used nongout participants as
the reference. We employed Cox proportional hazards regression19
in the analyses. To control as finely as possible for confounding by
age, calendar time, and any possible 2-way interactions between
these 2 time scales, we stratified the analysis jointly by age in months
at start of follow-up and calendar year of the current questionnaire
cycle. Multivariate models were adjusted for age (continuous),
history of hypertension, history of hypercholesterolemia, history of
diabetes mellitus, aspirin use (yes/no), diuretic use (yes/no), smoking
(never, past, current; 1 to 14, 15 to 24, ⱖ25 cigarettes/day), body
mass index (⬍21, 21 to 22.9, 23 to 24.9, 25 to 29.9, ⱖ30), physical
activity (quintiles), alcohol intake (nondrinker, ⬍5, 5 to 9, 10 to 14,
15 to 29, 30 to 49, ⱖ50 g/d), family history of MI (yes/no), total
energy intake (quintiles), trans fat (quintiles), dietary cholesterol
(quintiles), protein (quintiles), linoleic fatty acid (quintiles), and the
ratio of polyunsaturated fat to saturated fat. The SAS PHREG
procedure (SAS Institute, Cary, NC) was used for all analysis, and
the Anderson-Gill data structure20 was used to handle time-varying
covariates efficiently. All covariates except parental history of MI
were updated in each questionnaire cycle. We conducted analyses
stratified by age (⬍60, 60 to 69, and ⱖ70 years), hypertension
(yes/no), hypercholesterolemia (yes/no), and family history of MI
(yes/no). For all RRs, we calculated 95% confidence intervals (CIs).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
During 576 515 person-years of follow-up in 51 297 men, we
documented 5825 deaths (2132 CVD deaths and 1576 CHD
deaths). The characteristics of men according to the catego-
ries of gout and CHD at baseline are shown in Table 1. In this
cohort of men, 4.4% had only gout, 6.9% had only prior
CHD, and 1% had both gout and CHD at baseline. Men with
CHD and gout were more likely to be smokers. A history of
hypertension or hypercholesterolemia was more frequent
among those with gout or MI. Men with CHD more often had
a parental history of MI and used aspirin.
The RR of death from all causes, CVD, and CHD accord-
ing to history of gout and CHD at baseline are presented in
Table 2. Compared with men without history of gout and
CHD at baseline, the multivariate RRs among men with
history of gout were 1.28 (95% CI, 1.15 to 1.41) for total
mortality, 1.38 (95% CI, 1.15 to 1.66) for CVD deaths, and
1.55 (95% CI, 1.24 to 1.93) for fatal CHD. The corresponding
RRs among men with preexisting CHD were 1.25 (95% CI,
1.09 to 1.45), 1.26 (95% CI, 1.07 to 1.50), and 1.24 (95% CI,
1.04 to 1.49) (Table 2). The multivariate RR for non-CVD
deaths was 1.25 (95% CI, 1.10 to 1.41) among men without
preexisting CHD.
We then updated the status of gout and CHD every 2 years
during follow-up. This update resulted in the assignment of
more deaths to the categories with history of gout, CHD, or
both, as more participants developed these conditions during
the study period (Table 3). The overall findings were similar
to the results that used baseline information (Table 2).
Similarly, when we repeated our analyses with only incident
 896 Circulation August 21, 2007

TABLE 1. Age-Standardized Distribution of Potential Coronary Risk Factors

According to History of Gout and CHD in the Health Professionals Follow-Up
Study in 1986.
Disease Status

No CHD CHD

No Gout Gout No Gout Gout

Participants, n 44 978 2280 3546 493
Age, y 54 59 63 65
White, % 91 89 90 94
Current smoker/past smoker, % 9/41 10/46 11/54 19/57
Alcohol, g/day 11 14 10 17
Body mass index, kg/m2 25 27 25 27
Physical activity, METs/wk 21 18 19 20
History of hypertension, % 20 43 38 59
History of hypercholesterolemia, % 10 19 38 48
History of diabetes mellitus, % 3 5 8 11
Parental history of MI before 60 years of age, % 12 14 28 30
Working full/part time, % 86 85 81 77
Aspirin use, % 27 31 61 62
Multiple vitamin use, % 61 62 59 62
Dietary fiber, g/day 21 20 23 20
Saturated fat, g/day 11 11 10 10
Polyunsaturated fat, g/day 6 6 6 6
Trans fat, g/day 1.3 1.3 1.1 1.2
Dietary cholesterol, mg/day 154 157 138 142
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Data presented are means unless otherwise indicated. Except for the data on mean age, all data
shown are standardized to the age distributions of the cohort in 1986. CHD indicates coronary heart
disease; METs, metabolic equivalents.

cases of gout after exclusion of the prevalent cases of gout at
baseline, the results were similar. The multivariate RRs
among men with incident gout were 1.28 (95% CI, 1.13 to
1.46) for all-cause mortality, 1.31 (95% CI, 1.08 to 1.59) for
CVD deaths, and 1.30 (95% CI, 1.04 to 1.62) for CHD deaths,
as compared with those without incident gout.
Risk of total mortality did not change consistently across
categories of gout duration. Compared with men without
gout, the multivariate RRs for all cause mortality were 1.44,
1.37, 1.30, and 1.32 (95% CI, 1.18 to 1.46) for those with
gout diagnosis for ⱕ5 years, 6 to 10 years, 11 to 15 years, and
⬎15 years, respectively. The corresponding RRs for fatal
CHD were 1.56, 1.70, 1.78, and 1.42 (95% CI, 1.18 to 1.71),
respectively.
We examined whether the associations between prior gout
and CHD and mortality varied by other potential risk factors
(Table 4). For these analyses we used updated gout and CHD
status and also updated the stratification variables every 2
years. The RR of death as a result of gout in the oldest age
group tended to be lower than in the younger groups. Other
subgroup analyses consistently suggested an increased all-
cause or CHD mortality among men with gout (Table 4).
The RRs for nonfatal MI according to the presence of
incidence gout (both self-reported cases and confirmed cases)
are shown in Table 5. Participants with confirmed gout by the
ACR criteria15 had a higher risk of nonfatal MI than those
without confirmed gout (multivariate RR, 1.59; 95% CI, 1.04
to 2.41). When we used self-reported cases of incident gout in
our analysis, the risk was only slightly lower and remained
significant (Table 5).
Discussion
Our objective was to prospectively evaluate the potential
associations between history of gout and the risk of mortality
and MI. In this large prospective cohort of men, we found that
men with gout had a higher risk of death from all causes.
Among men without preexisting CHD, the increased mortal-
ity risk was caused by elevated risk of CVD deaths, particu-
larly CHD deaths. Of note, the magnitude of the excess risk
for CHD deaths (55%) was similar to that for nonfatal MI
associated with incident cases of confirmed gout (59%).
These associations were independent of age, body mass
index, smoking, family history of MI, use of diuretic and
aspirin, dietary risk factors, and risk conditions such as
diabetes mellitus, hypercholesterolemia, and hypertension.
The present study provides the first prospective data about the
mortality impact of gout. These findings provide support for
aggressive management of cardiovascular risk factors such as
hypertension, dyslipidemia, and lifestyle factors in patients
with gout.
Several potential mechanisms exist for the observed excess
cardiovascular deaths in patients with gout. Hyperuricemia,
 Choi and Curhan Gout and Cardiovascular Mortality 897

TABLE 2. RRs of Death From All Causes, CVD, and CHD According to Status of
Gout and a Prior CHD at Baseline in 1986 in the Health Professionals Follow-Up
Study (1986 –1998)
Disease Status

No CHD CHD

No Gout Gout No Gout Gout

Deaths from all causes
Cases, n 4017 410 1163 235
Age-adjusted RR (95% CI) 1.0 1.43 (1.29 to 1.58) 1.0 1.45 (1.26 to 1.67)
Multivariate RR (95% CI) 1.0 1.28 (1.15 to 1.41) 1.0 1.25 (1.09 to 1.45)
All cardiovascular deaths
Cases, n 1067 137 761 167
Age-adjusted RR (95% CI) 1.0 1.76 (1.47 to 2.10) 1.0 1.56 (1.32 to 1.85)
Multivariate RR (95% CI) 1.0 1.38 (1.15 to 1.66) 1.0 1.26 (1.07 to 1.50)
Fatal CHD
Cases, n 646 90 692 148
Age-adjusted RR (95% CI) 1.0 1.95 (1.57 to 2.44) 1.0 1.53 (1.28 to 1.83)
Multivariate RR (95% CI) 1.0 1.55 (1.24 to 1.93) 1.0 1.24 (1.04 to 1.49)
RRs were adjusted for age (continuous), history of hypertension, history of hypercholesterolemia,
history of diabetes mellitus, aspirin use (yes/no), diuretic use (yes/no), smoking (never, past, current;
ⱕ14, 15 to 24, ⱖ25 cigarettes/day), body mass index (⬍21, 21 to 22.9, 23 to 24.9, 25 to 28.9,
ⱖ29), physical activity (quintile), alcohol intake (nondrinker, ⬍5, 5 to 9, 10 to 14, 15 to 29, 30 to 49,
ⱖ50 g/day), family history of MI (yes/no), total energy intake (quintile), trans fat (quintile), dietary
cholesterol (quintile), protein (quintile), linoleic fatty acid (quintile), and ratio of polyunsaturated fat to
saturated fat.

the culprit of gout pathogenesis, is associated with CVD in levels and cardiovascular outcomes after adjustment for
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humans, although whether it is an independent risk factor
with a pathogenic role in CVD or only a marker for associated
CVD risk factors, such as insulin resistance, obesity, diuretic
use, hypertension, and renal disease, remains unclear.21,22
Approximately two thirds of previous epidemiological stud-
ies reported an independent link between serum uric acid
various covariates.22 For example, the National Health and
Nutrition Examination Survey (NHANES) I Follow-Up
Study reported that serum uric acid was an independent
predictor of cardiovascular mortality in subjects ⬎45 years
old regardless of sex, menopausal status, diuretic use, pres-
ence of CVD, or race.23 In the Framingham Study, serum

TABLE 3. RRs of Death From All Causes, CVD, and CHD According to Status of
Gout and CHD at Baseline and During Follow-Up in the Health Professionals
Follow-Up Study (1986 –1998)
Disease Status

No CHD CHD

No Gout Gout No Gout Gout

Deaths from all causes
Cases, n 3379 451 1539 456
Age-adjusted RR (95% CI) 1.0 1.36 (1.23 to 1.50) 1.0 1.50 (1.35 to 1.67)
Multivariate RR (95% CI) 1.0 1.25 (1.13 to 1.38) 1.0 1.35 (1.21 to 1.50)
All cardiovascular deaths
Cases, n 784 124 924 300
Age-adjusted RR (95% CI) 1.0 1.61 (1.33 to 1.94) 1.0 1.65 (1.45 to 1.88)
Multivariate RR (95% CI) 1.0 1.32 (1.09 to 1.60) 1.0 1.35 (1.19 to 1.55)
Fatal CHD
Cases, n 434 71 814 257
Age-adjusted RR (95% CI) 1.0 1.73 (1.35 to 2.23) 1.0 1.62 (1.41 to 1.87)
Multivariate RR (95% CI) 1.0 1.44 (1.12 to 1.86) 1.0 1.34 (1.16 to 1.55)
The diagnoses of gout and CHD were updated every 2 years. RRs were adjusted for the same
covariates as in Table 2.
 898 Circulation August 21, 2007

TABLE 4. Subgroup Analysis of Multivariate RRs of Death From All Causes and CHD
According to the Status of Gout and CHD at Baseline and During Follow-Up in the Health
Professionals Follow-Up Study (1986 –1998)
Disease Status

No CHD CHD

No Gout, RR Gout, RR (95% CI) No Gout, RR Gout, RR (95% CI)

All-cause deaths
Age, y
⬍60 (n⫽845) 1.0 1.30 (0.96 to 1.74) 1.0 1.59 (1.02 to 2.49)
60 to 69 (n⫽1816) 1.0 1.35 (1.13 to 1.61) 1.0 1.47 (1.21 to 1.79)
ⱖ70 (n⫽3164) 1.0 1.16 (1.01 to 1.32) 1.0 1.31 (1.15 to 1.50)
Hypertension
No (n⫽2991) 1.0 1.25 (1.06 to 1.47) 1.0 1.53 (1.26 to 1.86)
Yes (n⫽2834) 1.0 1.24 (1.09 to 1.41) 1.0 1.30 (1.14 to 1.48)
Hypercholesterolemia
No (n⫽3758) 1.0 1.30 (1.15 to 1.47) 1.0 1.16 (0.98 to 1.37)
Yes (n⫽2067) 1.0 1.15 (0.96 to 1.37) 1.0 1.50 (1.30 to 1.72)
Family history of MI
No (n⫽5087) 1.0 1.29 (1.16 to 1.43) 1.0 1.32 (1.17 to 1.49)
Yes (n⫽738) 1.0 0.90 (0.63 to 1.29) 1.0 1.47 (1.15 to 1.89)
CHD Deaths
Age, y
⬍60 (n⫽168) 1.0 1.84 (0.93 to 3.61) 1.0 1.73 (1.00 to 3.01)
60 to 69 (n⫽489) 1.0 2.10 (1.38 to 3.18) 1.0 1.58 (1.22 to 2.04)
ⱖ70 (n⫽919) 1.0 0.98 (0.68 to 1.41) 1.0 1.24 (1.03 to 1.49)
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Hypertension
No (n⫽626) 1.0 1.55 (0.98 to 2.47) 1.0 1.72 (1.32 to 2.25)
Yes (n⫽950) 1.0 1.26 (0.93 to 1.71) 1.0 1.30 (1.09 to 1.54)
Hypercholesterolemia
No (n⫽816) 1.0 1.31 (0.93 to 1.83) 1.0 1.17 (0.92 to 1.47)
Yes (n⫽760) 1.0 1.55 (1.05 to 2.30) 1.0 1.47 (1.22 to 1.77)
Family history of MI
No (n⫽1298) 1.0 1.41 (1.07 to 1.85) 1.0 1.24 (1.05 to 1.46)
Yes (n⫽278) 1.0 1.68 (0.84 to 3.36) 1.0 1.82 (1.34 to 2.47)
RRs were adjusted for the same covariates as in Table 2.

urate levels were not independently associated with the risk
of CVD,10 but gout was associated with a 60% increased risk
of CHD in men, primarily attributed to a 2-fold excess of
angina pectoris.11 Furthermore, a recent Finnish prospective
study of middle-aged men found that the RR of CVD death
between extreme tertiles of baseline urate levels was 3.7 after
adjustment for various potential confounders such as biomar-
kers commonly associated with gout, CVD, and metabolic
syndrome.24 Further adjustment for markers related to the
metabolic syndrome (such as triglyceride and high-density
lipoprotein cholesterol level) increased the RR to 4.8. Re-
cently, a study based on MRFIT reported that both hyperuri-
cemia (⬎7.0 mg/dL) and gout were associated with an
increased risk of acute MI (multivariate odds ratio, 1.11 and
1.26, respectively; both P⬍0.001).12 Our results expand on
these previous findings to further support the link between
hyperuricemia, gout, and CVD.
Recently, a novel rodent model of arteriolopathy and
hypertension induced by mild hyperuricemia has brought new
insight into this possible association.21,22,25,26 The rodent
model showed that uric acid could cause renal afferent
arteriolopathy and tubulointerstitial disease, which leads to
hypertension.25,26 The renal lesions and hypertension were
prevented or reversed by a reduction of uric acid levels.25,26
Furthermore, hyperuricemia that occurred as a complication
of diuretic therapy has been implicated as a risk factor for
CVD events. The Systolic Hypertension in the Elderly
Program (SHEP) trial27 found that participants who devel-
oped hyperuricemia while on chlorthalidone therapy sus-
tained CVD events at a rate similar to participants treated
with placebo. Data from the Losartan Intervention for End
Point Reduction in Hypertension (LIFE) trial indicated that
treatment with losartan (a uricosuric angiotensin receptor
blocker) attenuated the time-related increase in serum uric
 Choi and Curhan
TABLE 5. RRs of Incident Nonfatal Myocardial Infarction
According to Presence of Incident Gout During Follow-Up in the
Health Professionals Follow-Up Study (1986 –1998)
No Gout Gout
Using confirmed incident gout*
Cases, n 1152 23
Incidence/100 000 PY 239 461
Age-adjusted RR (95% CI) 1.0 1.85 (1.22 to 2.80)
Multivariate RR (95% CI) 1.0 1.59 (1.04 to 2.41)
Using self-reported incident gout
Cases, n 1122 53
Incidence/100 000 PY 235 481
Age-adjusted RR (95% CI) 1.0 1.79 (1.36 to 2.36)
Multivariate RR (95% CI) 1.0 1.51 (1.14 to 2.00)
Prevalent cases of cardiovascular disorders or gout at baseline were
excluded. The diagnosis of gout was updated every 2 years. RRs were adjusted
for the same covariates as in Table 2 except for baseline cardiovascular
disorders. PY indicates person-years.
*Confirmed by American College of Rheumatology survey criteria.
acid in a statistically significant manner, and this difference
seemed to account for 27% of the total treatment effect on the
composite CVD end points.21,28 Furthermore, presence of
gout per se may pose an increased risk of CVD beyond these
potential contributions from hyperuricemia, as suggested by
the recent study based on MRFIT.12 One possible explanation
for this excess risk independent of uric acid levels is that
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ongoing low-grade inflammation among patients with gout
may promote atherogenesis and thrombogenesis, as seen in
other inflammatory rheumatic disorders associated with
higher risk of CVD (eg, RA or lupus).12
Several strengths and potential limitations of the present
study deserve comment. Our study was considerably larger
than previous studies on gout,1,11,29 –33 and our exposure data
and covariate information were prospectively collected. Be-
cause we did not validate baseline cases of gout, we used
self-reported gout diagnosed by a physician as our primary
definition, which leaves some misclassification inevitable.
Nonetheless, it is unlikely that misclassification of the gout
diagnosis would explain the associations observed in the
present study, as the definition was also successfully used in
pervious studies, such as the Johns Hopkins Precursor Study1
and the recent MRFIT report.12 We also have included this
definition as a secondary definition in our own previous
studies for risk factors for gout2,3 and found that suspected
associations became even stronger when we used more
specific case definitions such as cases that meet the ACR
criteria or crystal-proven or tophaceous gout.2,3 This notion is
further supported by our finding of the significant association
with the risk of MI by use of the incident cases of gout
confirmed by the ACR criteria. Although studies have shown
that xanthine oxidase inhibition (eg, allopurinol use) im-
proves endothelial function in patients with chronic heart
failure, coronary artery disease, or diabetes mellitus,34 –38 the
present study does not address the impact of gout therapy or
disease severity. There was no clearly increased association
with increased duration of gout for all-cause mortality and for
Gout and Cardiovascular Mortality 899
the top duration category in CHD mortality. Potential expla-
nations for this include survival cohort effects (ie, removal of
those most susceptible), certain treatment effect (eg, endothe-
lial benefit of allopurinol34 –38), increased screening and
treatment of preventable conditions among long-standing
gout cases, confounding of unmeasured covariates (eg, dis-
ease severity), and a threshold effect of gout on the outcomes.
Similarly, potential explanations for the trend of a larger RR
for death among younger patients with gout include a survival
cohort effect and increased disease severity among early-
onset gout cases. Evaluation of these factors in future studies
would be valuable.
The restriction to health professionals in our cohort is both
a strength and a limitation. The cohort of well-educated men
minimizes potential for confounding by socioeconomic sta-
tus, and we were able to obtain high-quality data with
minimal loss to follow-up. Although the absolute rates of
death and CVD and distribution of gout may not be repre-
sentative of a random sample of US men, the biological
effects of gout on these outcomes should be similar. Our
findings are most directly generalizable to men ⱖ40 years old
(the most gout-prevalent population29). Given the potential
influence of female hormones on the risk of gout and CVD in
women, prospective studies of women would be valuable.
In conclusion, the present prospective data indicate that
individuals with gout have a higher risk of death from all
causes. Among men without preexisting CHD, the increased
mortality risk is primarily caused by an elevated risk of CVD
death, particularly from CHD. The present findings provide
support for aggressive management of cardiovascular risk
factors in patients with gout.
Acknowledgments
The authors thank Rong Chen for her assistance in statistical
programming.
Sources of Funding
The present work was supported in part by grants from the National
Institutes of Health (DK58573, AA11181, HL35464, and CA55075)
and TAP Pharmaceuticals. The funding sources had no role in the
design, conduct, or reporting of the study or in the decision to submit
the manuscript for publication.
Disclosures
Dr Choi and Dr Curhan have received research funding from TAP
Pharmaceuticals. In addition, Dr Choi has received honoraria from
and serves as a consultant for TAP Pharmaceuticals and Savient.
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CLINICAL PERSPECTIVE
Gout is the most common inflammatory arthritis in adult males, and the overall disease burden of gout remains substantial
and may be growing. However, it is unknown whether gout affects life expectancy. Although gout and hyperuricemia are
associated with several conditions linked to reduced survival (eg, insulin resistance syndrome, obesity, and hypertension),
no large-scale prospective data are available on the potential independent impact of gout on mortality. Furthermore,
although many studies have suggested that hyperuricemia is associated with cardiovascular disease, limited data are
available on the impact of gout on cardiovascular disease. Over a 12-year period, the present study prospectively examined
the relation between a history of gout and the risk of death and myocardial infarction in 51 297 male participants of the
Health Professionals Follow-Up Study. The present study found that men with gout have a 28% higher risk of death from
all causes, a 38% higher risk of cardiovascular disease death, and a 55% higher risk of death from coronary heart disease
than men without gout. Furthermore, men with gout had a 59% higher risk of nonfatal myocardial infarction than men
without gout. These associations were independent of age, body mass index, smoking, family history of myocardial
infarction, use of diuretic and aspirin, dietary risk factors, and risk conditions such as diabetes mellitus, hypercholester-
olemia, and hypertension. These results provide the first prospective data about the mortality impact of gout and further
support the link between hyperuricemia, gout, cardiovascular disease, and death. The present findings provide support for
aggressive management of cardiovascular risk factors in patients with gout.