Gout and CHF Eswar Krishnan
HYPERURICEMIA AND INCIDENT HEART FAILURE
Eswar Krishnan MD, M.Phil
Asst Professor in Medicine
Department of Medicine
Stanford University School of Medicine
Address for correspondence
1000 Welch Road, Suite 203
Stanford, CA 94304
Telephone: (650) 725-8004
Fax: (650) 723-9656
e-mail: [email protected]
Abstract 213
Total Words 5187
References 37
Tables 3
Figure 1
Subject codes (8) Epidemiology, (110)Congestive heart failure
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Gout and CHF Eswar Krishnan
Abstract (213 words)
Background: Hyperuricemia, a known correlate of oxidative stress, is a marker for adverse
prognosis among individuals with heart failure. However, the relationship between
hyperuricemia and the risk for incidence of heart failure in a community-based population has
not been studied.
Methods and Results: We prospectively analyzed the relationship between serum uric acid
concentration at baseline and subsequent heart failure among the participants of the
Framingham Offspring cohort (mean baseline age 36 years, women 52%). Using Cox
regressions we calculated the risk of heart failure with increasing serum uric acid after adjusting
for sex , age, smoking, body mass index, renal dysfunction, diuretics, systolic blood pressure,
valvular heart disease, diabetes, alcohol, and use of anti-hypertensive medications. The
incidence rates of heart failure was ~6 fold higher among those at the highest quartile of serum
uric acid (>6.3 mg/dl) compared to those at the lowest quartile (<3.4mg/dl). The adjusted hazard
ratio for the highest quartile of serum uric acid compared to the lowest was 2.1 (1.04-4.22). The
relationship between hyperuricemia and heart failure was found in participants without metabolic
syndrome and other subgroups as well.
Conclusions: Hyperuricemia is a novel, independent, risk factor for heart failure in a group of
young general community dwellers. This has implications for development of preventive
strategies for heart failure.
Key words: uric acid, heart failure, risk
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s we calculated the risk of heart failure with increasing serum uric acid after adju
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rates of heart failure was ~6 fold higher among those at the highest quartile of se
am Offspring cohort (mean baseline age 36 years, women 52%). Using Cox
s we calculated the risk of heart failure with increasing serum uric acid after adju
ge, smoking, body mass index, renal dysfunction, diuretics, systolic blood pressu
eart disease, diabetes, alcohol, and use of anti-hypertensive medications. The
rates of heart failure was ~6 fold higher among those at the highest quartile of se
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Gout and CHF Eswar Krishnan
Nearly 5 million Americans currently suffer from heart failure and approximately 550,000
new cases of heart failure are now diagnosed each year1. Heart failure is associated with high
risk of morbidity, mortality and hospital utilization in the United States2. The established risk
factors for heart failure include male sex, hypertension, valvular heart disease, coronary artery
disease, and obesity3. In spite of the progress made in its management, the mortality from heart
failure remains high, underlining the need for identification of novel risk factors that may be
amenable to intervention.
Earlier studies have shown that heart failure is often associated with hyperuricemia4, 5.
Hyperuricemia is associated with worse hemodynamic measures such as increased left atrial
pressure and decreased cardiac index among patients with primary pulmonary hypertension,
cor pulmonale and dilated cardiomyopathy in a small case series6. Among those with
established heart failure, hyperuricemia is a risk factor for adverse outcomes including
mortality5, 7-15.
Serum uric acid may be useful for prognostication among those with preexisting heart
failure5, 10-15. Hyperuricemia can predict heart failure among those with preexisting
hypertension16. There have not been any studies that examined hyperuricemia as independent
risk factors for heart failure risk among the general population. The single available study from
Austria, did not account for confounders such as valvular heart disease and diuretics, and renal
disease suggested that highest quantiles of serum uric acid was associated with elevated risk
for death from heart failure17.
Hyperuricemia can be easily detected in routine medical care. If indeed presence of
hyperuricemia provides additional information on future heart failure risk (over and above other
risk factors), it has the potential to be a screening tool. Accordingly, we hypothesized that
hyperuricemia is a risk factor for heart failure independent of other known risk factors.
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and decreased cardiac index among patients with primary pulmonary hypertensio
n
d
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rum uric acid may be useful for prognostication among those with preexisting he
and decreased cardiac index among patients with primary pulmonary hypertensio
nale and dilated cardiomyopathy in a small case series6. Among those with
d heart failure, hyperuricemia is a risk factor for adverse outcomes including
7-15.
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Methods
Study cohort and data source
We used data from the Framingham Offspring Study, a longitudinal observational study
of children of the original Framingham Heart Study cohort and their spouses18. All participants of
the Framingham Offspring Cohort that began in 1971 were eligible to be included in the present
study. The data for our analyses were obtained from the National Heart Lung and Blood Institute
(NHLBI) limited access dataset program. This analysis protocol was approved by the Stanford
University institutional review board. We excluded all the subjects who did not have uric acid
measurement.
Follow up and observation period
Participants were under surveillance for cardiovascular events and were followed up
approximately every four years by study visits that included medical review, physical
examination and laboratory testing. In the present analyses we used data collected from the first
through seventh study visit. The exact number of days from baseline to each study
visit/outcome event was utilized in our analyses. The median follow up of this cohort was 29
years and the cumulative observation time was 135,991 person-years.
For analyses of the effects of serum uric acid, each observation started in the first
(baseline) visit and ended at the day of outcome event, death or last contact with the study. In
using such a definition, we acknowledge that the duration of hyperuricemia for each individual in
the observation period is an underestimation of the true duration of hyperuricemia. In all
analyses, the observation ended at the time of death, last contact or the outcome event.
Measurement of covariates
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rticipants were under surveillance for cardiovascular events and were followed u
on and laboratory testing. In the present analyses we used data collected from th
and observation period
rticipants were under surveillance for cardiovascular events and were followed u
tely every four years by study visits that included medical review, physical
on and laboratory testing. In the present analyses we used data collected from th
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Exercise, diet, drugs, and state of hydration, may result in transient fluctuations of uric
acid levels and one measurement of uric acid may not be an accurate metric of the
hyperuricemic ‘trait’. We examined this possibility in our data by calculating the probability of an
individual participant changing the quartile of uric acid during the time interval between the first
and second visit (i.e. transition probability) each of the uric aid stratum. Since this estimate was
~20%,, we deemed the variability to be too high and serum uric acid was measured at the first
and the second visits and averaged to arrive at a mean value that replaced the single baseline
measurement. Serum uric acid was assayed using the uricase method. Information on renal
dysfunction, obesity measures, blood pressure, serum lipids, serum glucose, smoking, alcohol,
aspirin, antihypertensive, and anti-diabetic medication use were available at all visits.
Detailed information on individuals’ diabetes/hypertesion medications such as name, dosage,
duration of treatment were not available. For the purpose of this study, participants with a
cardiac murmur at the time of the first study visit were assessed to have valvular heart disease,
a risk factor for heart failure. Participants were evaluated for coronary artery disease at baseline
and at subsequent visits by medical history, clinician assessment, and electrocardiogram.
The determination of renal dysfunction at baseline was made by the study physician. Serum
creatinine or other laboratory measures of renal function was not available for this analysis.
Gout was defined as a study physician diagnosis of definite gouty arthritis19.
Outcome Assessment
Heart failure: Heart failure events (both hospitalized and non-hospitalized) were
adjudicated by a study physician panel according to predetermined Framingham criteria shown
in Table 1. 20, 21. Heart failure was considered to be present if two major or one major and two
minor criteria were present in the absence of alternative explanation for the clinical picture
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nformation on individuals’ diabetes/hypertesion medications such as name, dosa
f
urmur at the time of the first study visit were assessed to have valvular heart dise
or for heart failure. Participants were evaluated for coronary artery disease at ba
nformation on individuals’ diabetes/hypertesion medications such as name, dosa
f treatment were not available. For the purpose of this study, participants with a
urmur at the time of the first study visit were assessed to have valvular heart dise
or for heart failure. Participants were evaluated for coronary artery disease at ba
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Gout and CHF Eswar Krishnan
(please see appendix for further details). There were no participants with heart failure at
baseline.
Statistical analysis
Risk factors for heart failure: Our primary analyses addressed the question-Does
elevated serum uric acid independently predict the risk for incident heart failure? We used Cox
proportional hazards regression model to study the relationship between baseline serum uric
acid level, and heart failure. In these regressions, the time variable was defined as the period
(number of days) from the baseline date to the date of incidence of heart failure or the date of
last study visit. Observations of patients who did not die or develop heart failure were censored
at the time of last observation. In the primary analyses the baseline values of the covariates
were used to adjust for confounding. However, the relationship between hyperuricemia and
other cardiovascular risk factors are complex (Figure 1) since hyperuricemia is a risk factor for
kidney disease, hypertension, and atherosclerotic cardiovascular diseases22-27. Changes in
health conditions over time such as increased blood pressure and worse renal function can
potentially be a cause and a consequence of hyperuricemia. Thus using time varying measures
of these covariates may be problematic. Therefore, in addition to Cox regressions with time-
varying values of covariates, we preformed extensive stratified analyses such as for those who
did not meet the ATP criteria for metabolic syndrome baseline28, and who died of any cause
during the follow-up, and those who survived until the cut-off date for observation (visit 7).
Results
Overall, of the 4989 participants in the Offspring study there were 4912 eligible
participants with 196 incident cases of heart failure. Participants who developed heart failure
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of last observation. In the primary analyses the baseline values of the covariate
to adjust for confounding. However, the relationship between hyperuricemia an
i o
e n
ditions over time such as increased blood pressure and worse renal function ca
of last observation. In the primary analyses the baseline values of the covariate
to adjust for confounding. However, the relationship between hyperuricemia an
iovascular risk factors are complex (Figure 1) since hyperuricemia is a risk facto
ease, hypertension, and atherosclerotic cardiovascular diseases22-27. Changes in
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were more likely to be older, male and with a worse traditional risk factor profile, have gout and
currently used allopurinol, a uric acid reducing medication. These individuals had a greater
prevalence of gout and higher serum uric acid concentration. Increasing serum concentrations
of serum uric acid was associated with worse cardiovascular risk (Table 2).
Over the follow-up period, the cumulative incidence of gout were 12.6% (n=171) and
4.5% (n=192) among heart failure and no heart failure groups respectively (p<0.001). Overall,
155 participants with gout reported using allopurinol during the follow up. Only 2 participants
without gout reported using allopurinol.
Figure 2 shows the heart failure-free survival curve. Those in the higher quartiles of
serum uric acid had greater incidence of heart failure (Table 3). Proportional hazards
assumptions were met in all the Cox regression models. In these models, increasing level of
serum uric acid was associated with increased risk for heart failure, in unadjusted, and age-sex
adjusted models (Table 3). In multivariable regressions, the increased risk relationship between
uric acid level and heart failure was most evident in the highest quartile.
In this cohort of relatively young adults (median baseline age 36 years, inter-quartile
range 28-44), the prevalence of documented coronary artery disease at baseline was infrequent
(n=6) and exclusion of these individuals did not change our overall risk estimate. There were no
participants with renal dysfunction at the baseline. Multivariable Cox regressions were
performed for each of the following sub groups: participants who did not use diuretics, any blood
pressure medications, non-diabetics, participants who did not develop renal dysfunction anytime
during follow up, and those who did not develop the metabolic syndrome (Table 4). The link
between hyperuricemia and heart failure was consistent across all these analyses.
Analyses for survivor effect: When the multivariable analyses were repeated separately
among the 892 participants who died during follow-up from any cause and those who survived
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ns were met in all the Cox regression models. In these models, increasing level
c acid was associated with increased risk for heart failure, in unadjusted, and age
models able 3 In multivariable re essions, the increased risk relationsh bet
evel and heart failure was most evident in the highest quartile
c acid had greater incidence of heart failure (Table 3). Proportional hazards
ns were met in all the Cox regression models. In these models, increasing level
c acid was associated with increased risk for heart failure, in unadjusted, and age
models (Table 3). In multivariable regressions, the increased risk relationship bet
evel and heart failure was most evident in the highest quartile by guest on April 27, 2018
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until the 7th visit, each unit increase in serum uric acid increased the risk for incident heart failure
for the deceased (n=125, hazard ratio 1.2(0.9-1.5)) and survivors (n=76, hazard ratio 1.1(0.9-
1.5)) although neither reached statistical significance.
Gender effects In multivariable regressions, the impact of such statistical interaction was
tested for but was found to be statistically insignificant (p=0.21). Further, when data were
analyzed for men and women separately, the risk estimates were greater than unity but not
statistically significant in both groups owing to small number of events in each.
Discussion
We report for the first time that hyperuricemia is a risk factor for heart failure in a large
prospective study of a community dwelling population. Similar to the Vorarlberg study, this risk
was most evident at serum uric acid levels greater than ~6 mg/dl- a cut-off point close to the
solubility of urate in the normal human body17.
Our observation is not unexpected given the knowledge about the significance of
hyperuricemia as a marker of abnormal oxidative metabolism29. Serum uric acid level is an
index of oxidative stress in the human body 30. Serum uric acid is known to contribute to
endothelial dysfunction by impairing nitric oxide production31. Serum uric acid has also been
shown to be inversely correlated with the measures of functional capacity and maximal oxygen
intake5. Among patients with chronic heart failure, serum uric acid concentrations are associated
with greater activity of superoxide dismutase and endothelium dependent vasodliatation32.
Another potential pathophysiological link between hyperuricemia and heart failure might
be through inflammation. Asymptomatic hyperuricemia is a pro-inflammatory state associated
with higher levels of serum markers of inflammation, such as CRP, interleukin-6, and neutrophil
count 31, 33 34. Among patients with heart failure, hyperuricemia is associated with higher levels
Page 8
e report for the first time that hyperuricemia is a risk factor for heart failure in a la
e stud of a communi dwellin lation. Similar to the Vorarlber stud this
evident at serum uric acid levels greater than ~6 mg/dl- a cut-off point close to th
r observation is not unexpected given the knowledge about the significance of
e report for the first time that hyperuricemia is a risk factor for heart failure in a la
e study of a community dwelling population. Similar to the Vorarlberg study, this
evident at serum uric acid levels greater than ~6 mg/dl- a cut-off point close to th
f urate in the normal human body17.
r observation is not unexpected given the knowledge about the significance of
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of markers of endothelial activation such as the soluble intercellular adhesion molecule(ICAM)-1
and inflammatory markers such as interleukin-6, tumor necrosis factor- and its receptors 12.
Similar observations have been made in other population-based studies 35 and hospital-based
studies 11, 12. The risk of heart failure was proportionate to the degree of elevation of serum uric
acid among patients with gout 36. Locally, even when there is no active arthritis, the synovial
fluid of patients with gout show low grade inflammatory activity37.
Elevated levels of serum uric acid among normal individuals predict hypertension38 38, 39,
renal dysfunction 25 coronary artery disease22 , and portends reduced life expectancy40.
Lowering of serum uric acid with allopurinol can reduce blood pressure among hypertensives41,
42. This raises the possibility of the hyperuricemia-heart failure link being mediated by
hypertension, a hypothesis that cannot be directly tested in observational studies such as ours.
Nevertheless, other studies have shown that hyperuricemia is an independent risk factor for
heart failure among those who already have hypertension 16. In our study, this link was
consistently observed in a) time-varying Cox models where incident hypertension was adjusted
for and b) in stratified analyses of participants who did not develop hypertension.
The significance of our observation lies in its use for developing a risk prediction rule for
heart failure. While observations we have made raise the possibility of primary prevention of
heart failure, the literature is conflicting on whether a reduction in serum uric acid will result in
measurable clinical benefit among those with established heart failure43, 44. Some even argue
that increased serum uric acid cause by diuretic use might have a beneficial role in itself 44. On
the other hand, the uricosuric property of Losartan, an antihypertensive has been thought to
have a beneficial effect among patients with hypertension and left ventricular hypertrophy in the
LIFE study45. The putative mechanisms by which uric acid reduction treatments have shown
benefit is also unclear. Specifically, it is unclear if the observed benefit from the use of Xanthine
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ses the possibility of the hyperuricemia-heart failure link being mediated by
on, a hypothesis that cannot be directly tested in observational studies such as
ess, other studies have shown that hyperuricemia is an independent risk factor fo
r
l u
ses the possibility of the hyperuricemia-heart failure link being mediated by
on, a hypothesis that cannot be directly tested in observational studies such as
ess, other studies have shown that hyperuricemia is an independent risk factor fo
re among those who already have hypertension 16. In our study, this link was
ly observed in a) time-varying Cox models where incident hypertension was adju
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Oxidase inhibitors is mediated through reduction in serum uric acid levels or some other
mechanism. Inhibition of Xanthine Oxidase enzyme by allopurinol has beneficial effects in terms
of improved peripheral vasodilator capacity, systemic blood flow, and clinical outcomes 46 47.
Randomized controlled studies have also been unclear about the putative benefit of allopurinol
or its metabolite oxypurinol on established heart failure. While La Plata study showed
improvement in left ventricular ejection fraction with use of allopurinol48, the OPT-CHF study did
not show an overall benefit49. In our study, the majority of patients with gout were treated with
allopurinol; the number of participants with gout but not on allopurinol was too few for
meaningful comparison. If indeed allopurinol is protective from heart failure, the excess risk for
serum uric acid we have found is likely to be an underestimate.
Limitations apply to our analysis. Our observational data on serum uric acid are
essentially left-truncated. In other words, we know the severity of hyperuricemia but not the
duration of hyperuricemia. Additionally, the long interval between follow-up visits (~4 years)
may be too long to capture heart failure that results in death in shorter time. : The distribution
of serum uric acid concentrations among men and women were different, the former
having higher concentrations. Thus the lowest quartile of the pooled data was
constituted mainly by women and the highest quartile by men. The gender-uric acid
statistical interaction was insignificant, but limitations in statistical power precluded a
more detailed analysis.
In summary, this large prospective study found that hyperuricemia is associated with
greater incidence of heart failure. Future studies of various urate reduction strategies with
adequate power to detect small improvement in clinical outcomes would be needed to
determine whether, if at all, heart failure is preventable. Given the increasing prevalence and
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y left-truncated. In other words, we know the severity of hyperuricemia but not th
f r
o u
mitations apply to our analysis. Our observational data on serum uric acid are
y left-truncated. In other words, we know the severity of hyperuricemia but not th
f hyperuricemia. Additionally, the long interval between follow-up visits (~4 year
o long to capture heart failure that results in death in shorter time. : The distribu
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Gout and CHF Eswar Krishnan
serious health impact of heart failure, even such small clinical benefit can translate into
substantial public health benefit.
Page 11
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Gout and CHF Eswar Krishnan
Acknowledgements:
None
Funding Sources:
The Framingham Offspring Study (FOS) is conducted and supported by the National Heart Lung
Blood Institute (NHLBI) in collaboration with the FOS Study Investigators. This manuscript was
prepared using a limited access dataset Dr. Krishnan obtained from the NHLBI and does not
necessarily reflect the opinions or views of the FOS or the NHLBI. Dr Krishnan conceived the
manuscript idea, designed the analysis plan, performed statistical analysis, interpreted the
results, drafted the manuscript and will serve as the guarantor.
This publication was made possible by in part Grant Number KL2 RR024154-01 from the
National Center for Research Resources (NCRR), a component of the National Institutes of
Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility
of the authors and do not necessarily represent the official view of NCRR, NHLBI or the NIH.
Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the
Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch
/overview-translational.asp. No commercial products are discussed in this manuscript.
Disclosures
Dr. Krishnan has received grant support from Takeda Pharmaceuticals of North America Inc.
Deerfield, IL. (formerly TAP Pharmaceutical Products, Inc) and had held stock in Savient
Pharmaceuticals. He has served as an advisor/consultant for both these companies. Proprietary
products manufactured by these companies are not named/discussed in this manuscript.
Page 12
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enter for Research Resources (NCRR), a component of the National Institutes o
H
cation was made possible by in part Grant Number KL2 RR024154-01 from the
enter for Research Resources (NCRR), a component of the National Institutes o
H), and NIH Roadmap for Medical Research. Its contents are solely the respon
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References
1. . Heart disease and stroke statistics-2006 update. Dallas, TX: American Heart
Association; 2006.
2. Gwadry-Sridhar FH, Flintoft V, Lee DS, Lee H, Guyatt GH. A systematic review and
meta-analysis of studies comparing readmission rates and mortality rates in patients with
heart failure. Arch Intern Med. 2004;164:2315-2320.
3. Kenchaiah S, Narula J, Vasan RS. Risk factors for heart failure. Med Clin North Am.
2004;88:1145-1172.
4. Thomas RD, Newill A, Morgan DB. The cause of the raised plasma urea of acute heart
failure. Postgrad Med J. 1979;55:10-14.
5. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC,
Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart
failure. Eur Heart J. 1997;18:858-865.
6. Hoeper MM, Hohlfeld JM, Fabel H. Hyperuricaemia in patients with right or left heart
failure. Eur Respir J. 1999;13:682-685.
7. Pascual-Figal DA, Hurtado-Martinez JA, Redondo B, Antolinos MJ, Ruiperez JA, Valdes
M. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure
patients. Eur J Heart Fail. 2007;9:518-524.
8. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH,
Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski
P, Coats AJ. Uric acid and survival in chronic heart failure: validation and application in
metabolic, functional, and hemodynamic staging. Circulation. 2003;107:1991-1997.
Page 13
e.e MeMeMeMeMeMeMedd d d d d d ClClClClClClClininininininin NNNN N N Norororororororththttttt AAAAAAAmmmmmmm
omas RD, Newill A, Morgan DB. The cause of the raised plasma urea of acute h
u
yva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC,
a
omas RD, Newill A, Morgan DB. The cause of the raised plasma urea of acute h
ure. Postgrad Med J. 1979;55:10-14.
yva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC,
ats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic
by guest on April 27, 2018
http://circheartfailure.ahajournals.org/D
ownloaded from
Gout and CHF Eswar Krishnan
9. Niizeki T, Takeishi Y, Arimoto T, Okuyama H, Nozaki N, Hirono O, Tsunoda Y,
Watanabe T, Nitobe J, Miyashita T, Takahashi H, Koyama Y, Kubota I. Hyperuricemia
associated with high cardiac event rates in the elderly with chronic heart failure. J
Cardiol. 2006;47:219-228.
10. Kojima S, Sakamoto T, Ishihara M, Kimura K, Miyazaki S, Yamagishi M, Tei C, Hiraoka
H, Sonoda M, Tsuchihashi K, Shimoyama N, Honda T, Ogata Y, Matsui K, Ogawa H.
Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese
Acute Coronary Syndrome Study). Am J Cardiol. 2005;96:489-495.
11. Olexa P, Olexova M, Gonsorcik J, Tkac I, Kisel'ova J, Olejnikova M. Uric acid--a marker
for systemic inflammatory response in patients with congestive heart failure? Wien Klin
Wochenschr. 2002;114:211-215.
12. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson PA,
Coats AJ. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart
J. 1998;19:1814-1822.
13. Doehner W, von Haehling S, Anker SD. Uric acid as a prognostic marker in acute heart
failure--new expectations from an old molecule. Eur J Heart Fail. 2007;9:437-439.
14. Kittleson MM, St John ME, Bead V, Champion HC, Kasper EK, Russell SD, Wittstein IS,
Hare JM. Increased levels of uric acid predict haemodynamic compromise in patients
with heart failure independently of B-type natriuretic peptide levels. Heart. 2007;93:365-
367.
15. Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights
regarding the role of xanthine oxidase and uric acid in disease pathophysiology.
Circulation. 2003;107:1951-1953.
16. Samuelsson O, Wilhelmsen L, Pennert K, Berglund G. Angina pectoris, intermittent
claudication and congestive heart failure in middle-aged male hypertensives.
Page 14
ovovaa M.M.M.M.M.M.M. U U U U UU Uririririririric c c cc cc acacacacacacacididididididid--------- aa a a a a a mmmmmmm
e heaaaaaartrtrtrtrtrtrt fffffffaiaiaiaiaiailululululululurerererererere??????? WiWiWiWiWiWWieeeene
o
yva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson
a H
1
ochenschr. 2002;114:211-215.
yva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson
ats AJ. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur H
1998;19:1814-1822.
by guest on April 27, 2018
http://circheartfailure.ahajournals.org/D
ownloaded from
Gout and CHF Eswar Krishnan
Development and predictive factors during long-term antihypertensive care. The Primary
Preventive Trial, Goteborg, Sweden. Acta Med Scand. 1987;221:23-32.
17. Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, Diem G, Pfeiffer K,
Ulmer H. Serum uric acid and risk of cardiovascular mortality: a prospective long-term
study of 83,683 Austrian men. Clin Chem. 2008;54:273-284.
18. Dawber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community:
the Framingham Study. Ann N Y Acad Sci. 1963;107:539-556.
19. Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: the
Framingham Study. J Clin Epidemiol. 1988;41:237-242.
20. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive
heart failure: the Framingham study. N Engl J Med. 1971;285:1441-1446.
21. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension
to congestive heart failure. Jama. 1996;275:1557-1562.
22. Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular
disease: recent developments, and where do they leave us? Am J Med. 2005;118:816-
826.
23. Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute myocardial
infarction. Arthritis Rheum. 2006;54:2688-2696.
24. Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH. Long-term cardiovascular
mortality among middle-aged men with gout. Arch Intern Med. 2008;168:1104-1110.
25. Avram Z, Krishnan E. Hyperuricaemia--where nephrology meets rheumatology.
Rheumatology (Oxford). 2008;47:960-964.
26. Krishnan E. Gout and coronary artery disease: epidemiologic clues. Curr Rheumatol
Rep. 2008;10:249-255.
Page 15
ural hhhhhhhisissississtototototototoryryryryryryry ooooooofffffff cococococococongngnngngngn ese
a
vy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hyperte
c
ker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascul
art failure: the Framingham study. N Engl J Med. 1971;285:1441-1446.
vy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hyperte
congestive heart failure. Jama. 1996;275:1557-1562.
ker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascul
by guest on April 27, 2018
http://circheartfailure.ahajournals.org/D
ownloaded from
Gout and CHF Eswar Krishnan
27. Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of
hypertension among men without metabolic syndrome. Hypertension. 2007;49:298-303.
28. Grundy SM, Brewer HB, Jr., Cleeman JI, Smith SC, Jr., Lenfant C. Definition of
metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American
Heart Association conference on scientific issues related to definition. Circulation.
2004;109:433-438.
29. Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein
expression: implication on cell proliferation and nitric oxide production of human vascular
cells. J Am Soc Nephrol. 2005;16:3553-3562.
30. Johnson RJ, Rodriguez-Iturbe B, Kang DH, Feig DI, Herrera-Acosta J. A unifying
pathway for essential hypertension. Am J Hypertens. 2005;18:431-440.
31. Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation,
and vascular disease. Semin Nephrol. 2005;25:39-42.
32. Alcaino H, Greig D, Chiong M, Verdejo H, Miranda R, Concepcion R, Vukasovic JL,
Diaz-Araya G, Mellado R, Garcia L, Salas D, Gonzalez L, Godoy I, Castro P, Lavandero
S. Serum uric acid correlates with extracellular superoxide dismutase activity in patients
with chronic heart failure. Eur J Heart Fail. 2008;10:646-651.
33. Coutinho Tde A, Turner ST, Peyser PA, Bielak LF, Sheedy PF, 2nd, Kullo IJ.
Associations of serum uric acid with markers of inflammation, metabolic syndrome, and
subclinical coronary atherosclerosis. Am J Hypertens. 2007;20:83-89.
34. Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD, Lauretani F, Bandinelli S,
Senin U, Ferrucci L. Uric acid and inflammatory markers. Eur Heart J. 2006;27:1174-
1181.
Page 16
Acostaaaaaaa JJJJJJJ AAAAAAA unununununununifififififififyiyiyiyyiyiy nngngngngngn
t
nellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammati
d
caino H, Greig D, Chiong M, Verdejo H, Miranda R, Concepcion R, Vukasovic JL
thway for essential hypertension. Am J Hypertens. 2005;18:431-440.
nellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammati
d vascular disease. Semin Nephrol. 2005;25:39-42.
caino H, Greig D, Chiong M, Verdejo H, Miranda R, Concepcion R, Vukasovic JL
by guest on April 27, 2018
http://circheartfailure.ahajournals.org/D
ownloaded from
Gout and CHF Eswar Krishnan
35. Frohlich M, Imhof A, Berg G, Hutchinson WL, Pepys MB, Boeing H, Muche R, Brenner
H, Koenig W. Association between C-reactive protein and features of the metabolic
syndrome: a population-based study. Diabetes Care. 2000;23:1835-1839.
36. Annemans L, Spaepen E, Gaskin M, Bonnemaire M, Malier V, Gilbert T, Nuki G. Gout in
the UK and Germany: prevalence, comorbidities and management in general practice
2000-2005. Ann Rheum Dis. 2008;67:960-966.
37. Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the
synovial fluid of patients with untreated gout. Arthritis Rheum. 1991;34:141-145.
38. Krishnan E, Kwoh C, Schumacher HR, Kuller L. Hyperuricemia and incidence of
hypertension among men without metabolic syndrom. Hypertension. 2007:1-2.
39. Sundstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of
serum uric acid to longitudinal blood pressure tracking and hypertension incidence.
Hypertension. 2005;45:28-33.
40. Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y, Odaka M,
Yamaguchi M, Yosida H, Morisawa H, Murayama T. Does hyperuricemia affect
mortality? A prospective cohort study of Japanese male workers. J Epidemiol.
2000;10:403-409.
41. Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, Uz E, Akcay A, Yigitoglu R,
Covic A. Effect of treatment of hyperuricemia with allopurinol on blood pressure,
creatinine clearence, and proteinuria in patients with normal renal functions. Int Urol
Nephrol. 2007;39:1227-1233.
42. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents
with newly diagnosed essential hypertension: a randomized trial. Jama. 2008;300:924-
932.
43. Doehner W, Anker SD. Uric acid in chronic heart failure. Semin Nephrol. 2005;25:61-66.
Page 17
aa aandndndndndndnd i i i ii iincncncncncncncidididididididenenenenenenencecececececece o o f f f ff f f
ensionnnnnnn 2020202020202007070707070707:1:1:1:1:1:1:1 2222222
ndstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS. Relations
rum uric acid to longitudinal blood pressure tracking and hypertension incidence
p
m
ndstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS. Relations
rum uric acid to longitudinal blood pressure tracking and hypertension incidence
pertension. 2005;45:28-33.
mita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y, Odaka M,
by guest on April 27, 2018
http://circheartfailure.ahajournals.org/D
ownloaded from
Gout and CHF Eswar Krishnan
44. Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be
beneficial in heart failure. Eur J Heart Fail. 2005;7:461-467.
45. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De Faire U, Fyhrquist
F, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik
P, Oparil S, Wedel H, Chen C, Dahlof B. The impact of serum uric acid on
cardiovascular outcomes in the LIFE study. Kidney Int. 2004;65:1041-1049.
46. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler
G, Coats AJ, Anker SD, Hambrecht R. Effects of xanthine oxidase inhibition with
allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients
with chronic heart failure: results from 2 placebo-controlled studies. Circulation.
2002;105:2619-2624.
47. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM.
Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a
retrospective cohort study. Heart. 2002;87:229-234.
48. Cingolani HE, Plastino JA, Escudero EM, Mangal B, Brown J, Perez NG. The effect of
xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study.
J Card Fail. 2006;12:491-498.
49. Cleland JG, Coletta AP, Clark AL. Clinical trials update from the Heart Failure Society of
America meeting: FIX-CHF-4, selective cardiac myosin activator and OPT-CHF. Eur J
Heart Fail. 2006;8:764-766.
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udies CiCiCiCiCiCiCircrcrcrcrcrcculululululululatatatatatatatioioioioioioionnnnnnn
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uthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM
e
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02;105:2619-2624.
uthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM
ect of allopurinol on mortality and hospitalisations in chronic heart failure: a
rospective cohort study. Heart. 2002;87:229-234.
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Legend:
Figure 1. Potential epidemiological pathways linking hyperuricemia and heart failure can
be direct, mediated through risk factors such as hypertension, confounded by medication use,
or a combination of these.
Figure 2. Kaplan-Meier estimates for heart failure-free follow-up among the 4989
participants of the Framingham Offspring Study by quartiles of serum uric acid. For this survival
model, the observation started at the first study visit and ended at the time of incident heart
failure (n=201). Note that the Y axis scale is adjusted for the sake of clarity.
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Table 1. Framingham criteria for heart failure used for case definition in this study20, 21.
A definite diagnosis of congestive heart failure requires that a minimum of two major or one major and
two minor criteria be present concurrently. The presence of other conditions capable of producing the
symptoms and signs were considered in evaluating the findings.
Major Criteria:
1) Paroxysmal nocturnal dyspnea or orthopnea;
2) Distended neck veins (in other than the supine position);
3) Rales;
4) Increasing heart size by chest radiograph
5) Acute pulmonary edema on chest radiograph
6) Ventricular S(3) gallop;
7) Increased venous pressure > 16 cm water;
8) Hepatojugular reflux;
9) Pulmonary edema, visceral congestion, or cardiomegaly shown on autopsy;
10) Weight loss of 10 lb over 5 days on CHF treatment
Minor criteria:
1) Bilateral ankle edema;
2) Night cough;
3) Dyspnea on ordinary exertion;
4) Hepatomegaly;
5) Pleural effusion by chest radiograph
6) Decrease in vital capacity by one-third from maximum record;
7) Tachycardia (120 beats per minute or more);
8) Pulmonary vascular engorgement on chest radiograph
ed venous pressure > 16 cm water;
j
h
i
ed venous pressure > 16 cm water;
ugular reflux;
ary edema, visceral congestion, or cardiomegaly shown on autopsy;
ht loss of 10 lb over 5 days on CHF treatment
ia:
Bilateral ankle edema;
Night cough;
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Table 2 Baseline characteristics of Framingham Offspring Study participants according to serum uric acid concentrations (n=4912) Quartile 1 Quartile 2 Quartile 3 Quartile 4 p value for trend Metric 1.2-4.34 mg/dl 4.35-5.2 mg/dl 5.3-6.2 mg/dl 6.3-13.7 mg/dl Number of participants 1164 1194 1227 1329 Age in years ( mean ± SD) 34± 10 36± 10 36±11 38± 11 <0.001 Proportion of men % 5 30 65 88 <0.001 Body mass index in kg/m2 ( mean ± SD) 23±3 25±4 26±4 28±4 <0.001 Alcohol use % 81 84 85 90 <0.001 Proportion of current smokers % 60 65 62 68 <0.001 Diuretic users % 2 3 4 6 <0.001 Systolic blood pressure in mm Hg ( mean ± SD) 114±13 119±15 123±15 129±17 <0.001 Diastolic blood pressure in mm Hg (mean ± SD) 73±9 77±10 79±10 84±11 <0.001 Fasting glucose (mg/dl) (mean ± SD) 93±17 99±23 104±33 108±32 <0.001 Total Cholesterol (mg/dl) (mean ± SD) 187±37 191±38 199±41 205±40 <0.001 LDL cholesterol (mg//dl) (mean ± SD) 115±33 121±35 130±36 131±35 <0.001 HDL cholesterol (mg/dl) (mean ± SD) 57±14 53±15 48±13 45±13 <0.001 Triglycerides (mg/dl) (mean ± SD) 101±69 112±73 131±107 163±162 <0.001 Serum uric acid (mg/dl) (mean ± SD) 3.7±0.5 4.8±0.3 5.7±0.3 7.2±0.8 Valvular heart disease % 8.3 7.7 6.0 7.0 0.16 History of gout at baseline % 0.1 0.6 0.3 6.9 <0.001 History of diabetes at baseline % 0.9 1.8 2.7 2.3 0.008 Valvular heart disease was defined for this study as presence of cardiac murmur at baseline. Gout was determined based on physician diagnosis. Diabetes was defined using the American Diabetes Association Criteria and/or use of anti-diabetes medications.
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85858585858585 62626262626262
%% 2 3 4( mean ± SD) 114±13 119±15 123±15(mean ± SD) 73±9 77±10 79±10 (mean ± SD) 93±17 99±23 104±33 (mean ± SD) 187±37 191±38 199±41 (mean ± SD) 115±33 121±35 130±36
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Table 3 : Incident heart failure according to baseline uric acid quartiles in Framingham Offspring Cohort (n=4912)
Characteristic 1.2-4.34 mg/dl
(n=1164)
4.35-5.2 mg/dl
(n=1193 )
5.3-6.2 mg/dl
(n=1227 )
6.3-13.7 mg/dl
(n=1328)
P value
for trend
Number of incident heart failure 13 36 57 90
Rate per 10,000 person years (95% CI) 3.9(2.3-6.8) 10.8(1.8-15.0) 17.3(13.4-22.4) 25.8(21.0-
31.7) <0.001*
Unadjusted hazard ratio 1.00 2.8(1.5-5.3) 4.5(2.5-8.3) 7.0(3.9-12.4) <0.001
Age-sex adjusted hazard ratio 1.00 1.9(1.0-3.7) 2.6(1.3-4.9) 3.3(1.7-6.3) <0.001
Model 1: Multivariable-adjusted hazard
ratio with baseline values of covariates1.00 1.6(0.8-3.2) 1.7(0.9-3.3) 2.1(1.0-4.2) 0.007
Model 2: Multivariable-adjusted hazard
ratio with time-varying values of
covariates
1.00 1.6(0.7-3.5) 2.1(0.9-4.0) 2.3(1.0-5.1) † <0.01
Model 3: Multivariable-adjusted hazard
ratio with time-varying values of
covariates among the sub group without
metabolic syndrome
1.00 1.5(0.6-3.5) 2.0(0.8-4.8) 2.5(1.0-6.2) ‡ <0.01
CI: Confidence interval ;Multivariable models were adjusted for : sex, baseline values of age , smoking systolic blood pressure serum total cholesterol: high density lipoprotein ratio, alcohol use renal dysfunction, coronary artery disease, valvular heart disease, diuretic use and non-diuretic blood pressure medications * Age-sex adjusted trend confidence interval †(1.01-5.10) ; ‡confidence interval (1.04-6.18)
Page 22
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Table 4. Multivariable adjusted risk of heart failure among various sub-groups of the Framingham Offspring Cohort
Number of participants
in the model
Hazard ratio for each mg/dl increase in serum uric acid
95% confidence interval
No renal dysfunction anytime during the observation 3587 1.3 1.10-1.50
Non-uses of any non-diuretic blood pressure medications 3677 1.20 1.01-1.44
Non-users of diuretics 3639 1.20 1.00-1.41*
Non diabetics 3517 1.28 1.01-1.52
No metabolic syndrome at study end-date 3765 1.26 1.07-1.47
* p=0.048. Unless specified otherwise, multivariable models were adjusted for : sex, time varying measures of age , smoking systolic blood pressure serum total cholesterol: high density lipoprotein ratio, alcohol use renal dysfunction, coronary artery disease, valvular heart disease, diuretic use and non-diuretic blood pressure medications
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tivariable models were adjusted for : sex, time varying measures of agrotein ratio, alcohol use renal dysfunction, coronary artery disease, va
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0.90
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1.2-4.4 4.5-5.3
5.3-6.2 6.3-13.7
Baseline serum uric acid (mg/dl)
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Eswar KrishnanHyperuricemia and Incident Heart Failure
Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2009 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online August 6, 2009;Circ Heart Fail.
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