AHA hyperuricemia and heart failure 2009

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 Off

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Eswar Krishnan

Hyperuricemia and Incident Heart Failure

75231

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX

Circulation: Heart Failure

doi: 10.1161/CIRCHEARTFAILURE.108.797662 2009;2:556-562; originally published online August 6, 2009;

Circ Heart Fail

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Eswar Krishnan, MD, MPhil

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 (n ⫽4912; mean baseline age, 36 years; 52% women) By 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 antihypertensive medications The incidence rates of heart failure were

⬇6-fold higher among those at the highest quartile of serum uric acid (⬎6.3 mg/dL) compared with those at the lowest quartile ( ⬍3.4 mg/dL) The adjusted hazard ratio for the highest quartile of serum uric acid compared with the lowest was 2.1 (1.04 to 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 (Circ Heart Fail 2009;2:556-562.)

Key Words: heart failure 䡲 risk 䡲 uric acid 䡲 incidence 䡲 hyperuricemia 䡲 prospective studies 䡲 biological markers

N early 5 million Americans currently suffer from heart

failure, and ⬇550 000 new cases of heart failure are

now diagnosed each year.1 Heart failure is associated with

high risk of morbidity, mortality, and hospital utilization in

the United States.2 The established risk factors for heart

failure include male sex, hypertension, valvular heart disease,

coronary artery disease, and obesity.3 Despite 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.

Clinical Perspective on p 562

Earlier studies have shown that heart failure is often

associated with hyperuricemia.4,5 Hyperuricemia is

associ-ated with worse hemodynamic measures such as increased

left atrial pressure and decreased cardiac index among

pa-tients with primary pulmonary hypertension, cor pulmonale,

and dilated cardiomyopathy in a small case series.6Among

those with established heart failure, hyperuricemia is a risk

factor for adverse outcomes, including mortality.5,7–15

Serum uric acid may be useful for prognostication among

those with preexisting heart failure.5,10 –15Hyperuricemia can

predict heart failure among those with preexisting

hyperten-sion.16 There have not been any studies that examined

hyperuricemia as an independent risk factor 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 increased risk for death from heart failure.17

Hyperuricemia can be easily detected in routine medical care.

If indeed presence of hyperuricemia provides additional infor-mation 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.

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 spouses.18All participants of the Framingham Offspring cohort that began in 1971 were eligible to be included in this study The data for our analyses were obtained from the National Heart, Lung, and Blood Institute 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 4 years by study visits that included medical review, physical examination, and laboratory testing In the current analyses, we used data collected from the first through seventh study visit The exact number of days from baseline

to each study visit or outcome event was used in our analyses The

Received June 9, 2008; accepted July 22, 2009

From the Department of Medicine, Stanford University School of Medicine, Stanford, Calif

Correspondence to Eswar Krishnan, MD, 1000 Welch Rd, Suite 203, Stanford, CA 94304 E-mail e.krishnan@stanford.edu

Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.108.797662

556 by guest on November 13, 2013 http://circheartfailure.ahajournals.org/

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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

indi-vidual 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

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 (ie, transition

probability) for each of the uric acid stratum Because 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

antidiabetic medication use was available at all visits Detailed

information on individuals’ diabetes and hypertension medications

such as name, dosage, and 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 was 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 ECG

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 diagnosis of definite gouty arthritis by the study

physician.19

Outcome Assessment

Heart Failure

Heart failure events (both hospitalized and nonhospitalized) were

adjudicated by a study physician panel according to the

predeter-mined Framingham criteria shown in Table 1.20,21Heart failure was

considered to be present if 2 major or 1 major and 2 minor criteria

were present in the absence of alternative explanation for the clinical

picture (please see Table 1 for further details) There were no

participants with heart failure at baseline

Statistical Analysis

Risk Factors for Heart Failure

Our primary analyses addressed the following question: Does

ele-vated 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

cardio-vascular risk factors is complex (Figure 1) because hyperuricemia is

a risk factor for kidney disease, hypertension, and atherosclerotic

cardiovascular diseases.22–27Changes 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 for those who

did not meet the adult treatment panel criteria for metabolic syndrome baseline,28who died of any cause during the follow-up, and those who survived until the cutoff 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 were more likely to be older, men, 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) During the follow-up period, the cumulative incidence of gout was 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 asso-ciated with increased risk for heart failure in unadjusted and age-sex–adjusted models (Table 3) In multivariable

regres-Table 1 Framingham Criteria for Heart Failure Used for Case Definition in this Study

A definite diagnosis of congestive heart failure requires that a minimum of 2 major or 1 major and 2 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 Paroxysmal nocturnal dyspnea or orthopnea Distended neck veins (in other than the supine position) Rales

Increasing heart size by chest radiograph Acute pulmonary edema on chest radiograph Ventricular S(3) gallop

Increased venous pressure⬎16 cm water Hepatojugular reflux

Pulmonary edema, visceral congestion, or cardiomegaly shown on autopsy

Weight loss ofⱖ10 lb over 5 d on CHF treatment Minor criteria

Bilateral ankle edema Night cough Dyspnea on ordinary exertion Hepatomegaly

Pleural effusion by chest radiograph Decrease in vital capacity by one third from maximum record Tachycardia (120 bpm or more)

Pulmonary vascular engorgement on chest radiograph CHF indicates congestive heart failure

Krishnan Hyperuricemia and Heart Failure 557

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sions, 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, interquartile range 28 to 44), the prevalence of

documented coronary artery disease at baseline was

infre-quent (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, nondiabetics; those who did not de-velop 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 until the seventh visit, each

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

Table 2 Baseline Characteristics of Framingham Offspring Study Participants According to Serum Uric Acid Concentrations

(n ⴝ4912)

Quartile 1 (1.2 to 4.34 mg/dL)

P

(for Trend)

Systolic blood pressure, mm Hg 114⫾13 119⫾15 123⫾15 129⫾17 ⬍0.001 Diastolic blood pressure, mm Hg 73⫾9 77⫾10 79⫾10 84⫾11 ⬍0.001 Fasting glucose, mg/dL 93⫾17 99⫾23 104⫾33 108⫾32 ⬍0.001 Total cholesterol, mg/dL 187⫾37 191⫾38 199⫾41 205⫾40 ⬍0.001 LDL cholesterol, mg/dL 115⫾33 121⫾35 130⫾36 131⫾35 ⬍0.001 HDL cholesterol, mg/dL 57⫾14 53⫾15 48⫾13 45⫾13 ⬍0.001 Triglycerides, mg/dL 101⫾69 112⫾73 131⫾107 163⫾162 ⬍0.001 Serum uric acid, mg/dL 3.7⫾0.5 4.8⫾0.3 5.7⫾0.3 7.2⫾0.8

Data are presented as mean⫾SD or % 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 or use of antidiabetes medications LDL indicates low-density lipoprotein; HDL, high-density lipoprotein

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unit increase in serum uric acid increased the risk for incident

heart failure for the deceased (n ⫽125; hazard ratio, 1.2 [0.9 to

1.5]) and survivors (n ⫽76; hazard ratio, 1.1 [0.9 to 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) Furthermore, when data were

ana-lyzed for men and women separately, the risk estimates were

greater than unity but not statistically significant in both

groups because of 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 cutoff point close to the solubility of urate in the normal human body.17

Our observation is not unexpected given the knowledge about the significance of hyperuricemia as a marker of abnormal oxidative metabolism.29Serum uric acid level is an index of oxidative stress in the human body.30Serum uric acid is known to contribute to endothelial dysfunction by impairing nitric oxide production.31Serum uric acid has also been shown to be inversely correlated with the measures of functional capacity and maximal oxygen intake.5 Among patients with chronic heart failure, serum uric acid concen-trations are associated with greater activity of superoxide dismutase and endothelium-dependent vasodilatation.32

Another potential pathophysiological link between hyper-uricemia and heart failure might be through inflammation Asymptomatic hyperuricemia is a proinflammatory state

0.90

0.92

0.94

0.96

0.98

1.00

Follow-up in years

1.2-4.4 4.5-5.3 5.3-6.2 6.3-13.7 Baseline serum uric acid (mg/dl)

Figure 2 Kaplan-Meier estimates for heart

failure-free follow-up among the 4912 par-ticipants 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⫽196)

Note that the y axis scale is adjusted for

the sake of clarity

Table 3 Incident Heart Failure According to Baseline Uric Acid Quartiles in Framingham Offspring Cohort (n ⴝ4912)

Characteristic

1.2 to 4.34 mg/dL (n⫽1164)

4.35 to 5.2 mg/dL (n⫽1193)

5.3 to 6.2 mg/dL (n⫽1227)

6.3 to 13.7 mg/dL (n⫽1328)

P

(for Trend)

Rate per 10 000 person-years (95% CI) 3.9 (2.3 to 6.8) 10.8 (1.8 to 15.0) 17.3 (13.4 to 22.4) 25.8 (21.0 to 31.7) ⬍0.001* Unadjusted hazard ratio 1.00 2.8 (1.5 to 5.3) 4.5 (2.5 to 8.3) 7.0 (3.9 to 12.4) ⬍0.001 Age-sex–adjusted hazard ratio 1.00 1.9 (1.0 to 3.7) 2.6 (1.3 to 4.9) 3.3 (1.7 to 6.3) ⬍0.001 Model 1: multivariable-adjusted hazard ratio

with baseline values of covariates

1.00 1.6 (0.8 to 3.2) 1.7 (0.9 to 3.3) 2.1 (1.0 to 4.2) 0.007 Model 2: multivariable-adjusted hazard ratio

with time-varying values of covariates

1.00 1.6 (0.7 to 3.5) 2.1 (0.9 to 4.0) 2.3 (1.0 to 5.1)† ⬍0.01 Model 3: multivariable-adjusted hazard ratio

with time-varying values of covariates among the

subgroup without metabolic syndrome

1.00 1.5 (0.6 to 3.5) 2.0 (0.8 to 4.8) 2.5 (1.0 to 6.2)‡ ⬍0.01

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 nondiuretic blood pressure medications CI indicates confidence interval

*Age-sex–adjusted trend

†95% CI, 1.01 to 5.10

‡95% CI, 1.04 to 6.18

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associated with higher levels of serum markers of

inflamma-tion, such as C-reactive protein, interleukin-6, and neutrophil

count.31,33,34 Among patients with heart failure,

hyperurice-mia is associated with higher levels of markers of endothelial

activation, such as the soluble intercellular adhesion

molecule-1, and inflammatory markers such as interleukin-6,

tumor necrosis factor- ␣, and its receptors.12Similar

observa-tions have been made in other population-based studies35and

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.36Locally, even when there is no

active arthritis, the synovial fluid of patients with gout shows

low-grade inflammatory activity.37

Increased levels of serum uric acid among normal

individ-uals predict hypertension,27,38renal dysfunction,25and

coro-nary artery disease22and portend reduced life expectancy.39

Lowering of serum uric acid with allopurinol can reduce

blood pressure among hypertensives.40,41 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 (a) in time-varying Cox models

in which 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 Although

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

measur-able clinical benefit among those with established heart

failure.42,43Some even argue that increased serum uric acid

caused by diuretic use might have a beneficial role in itself.43

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

hyper-trophy in the Losartan Intervention For Endpoint reduction in

hypertension (LIFE) study.44 The putative mechanisms by

which uric acid reduction treatments have shown benefit are

also unclear Specifically, it is unclear whether the observed

benefit from the use of xanthine oxidase inhibitors is

medi-ated through reduction in serum uric acid levels or some other mechanism Inhibition of xanthine oxidase enzyme by allo-purinol has beneficial effects in terms of improved peripheral vasodilator capacity, systemic blood flow, and clinical out-comes.45,46 Randomized controlled studies have also been unclear about the putative benefit of allopurinol or its metabolite oxypurinol on established heart failure Although

La Plata study showed improvement in left ventricular ejection fraction with the use of allopurinol,47the Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) study did not show an overall benefit.48In 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 a meaningful comparison If indeed allopurinol is protec-tive 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 In addition, 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 was different, the former having higher concentra-tions Thus, the lowest quartile of the pooled data was constituted mainly by women and the highest quartile by men The sex-uric acid statistical interaction was insignifi-cant, but limitations in statistical power precluded a more detailed analysis.

In summary, this large prospective study found that hyper-uricemia 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 serious health impact of heart failure, even such small clinical benefit can translate into substantial public health benefit.

Sources of Funding

The Framingham Offspring Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the Framingham Offspring Study Investigators This research was sup-ported in part by grant KL2 RR024154-01 from the National Center for Research Resources, a component of the National Institutes of

Table 4 Multivariable Adjusted Risk of Heart Failure Among Various Subgroups of the Framingham

Offspring Cohort

No of Participants

in Model

Hazard Ratio for Each 1-mg/dL Increase in Serum Uric Acid 95% CI

No of renal dysfunction anytime during the observation 3587 1.3 1.10 to 1.50

Nonusers of any nondiuretic blood pressure medications 3677 1.20 1.01 to 1.44

No metabolic syndrome at study end date 3765 1.26 1.07 to 1.47

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 nondiuretic blood pressure medications

*P⫽0.048

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Health, and National Institutes of Health Roadmap for Medical

Research Its contents are solely the responsibility of the authors and

do not necessarily represent the official view of the National Center

for Research Resources, the National Heart, Lung, and Blood

Institute, or the National Institutes of Health Information on the

National Center for Research Resources is available at http://

www.ncrr.nih.gov Information on Reengineering the Clinical

Re-search Enterprise is available at 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

Pharmaceuti-cals of North America, Inc, Deerfield, Ill (formerly TAP

Pharma-ceutical Products, Inc) and has held stock in Savient

Pharmaceuti-cals He has served as an advisor/consultant for both these

companies Proprietary products manufactured by these companies

are not named or discussed in this manuscript This manuscript was

prepared using a limited access dataset that Dr Krishnan obtained

from the National Heart, Lung, and Blood Institute and does not

necessarily reflect the opinions or views of the Framingham

Off-spring Study or the National Heart, Lung, and Blood Institute He

conceived the manuscript idea, designed the analysis plan, performed

statistical analysis, interpreted the results, drafted the manuscript,

and will serve as the guarantor

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CLINICAL PERSPECTIVE

Heart failure is an incurable condition that is responsible for at least 287 000 deaths annually Heart failure is the most common reason for hospitalization among people on Medicare, and the number of hospitalizations has been increasing over time We propose that hyperuricemia is a useful biomarker for estimating risk for heart failure and tested this hypothesis using the data from Framingham Offspring Study We observed that the incidence of heart failure among those with serum uric acid concentrations ⬎6.3 mg/dL was 6-fold higher than that among participants with serum uric acid ⬍3.4 mg/dL The adjusted risk for heart failure was double among those with hyperuricemia Our findings have implications for early identification of those at risk for heart failure and put forward a new target for intervention.

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