gout and heart failurecircheartfailure.ahajournals.org/content/circhf/early/2009/08/06/... · gout...

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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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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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

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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

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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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(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

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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

ditions over time such as increased blood pressure and worse renal function ca by guest on April 27, 2018


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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

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.

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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

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ess, other studies have shown that hyperuricemia is an independent risk factor fo

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ses the possibility of the hyperuricemia-heart failure link being mediated by

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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

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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

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serious health impact of heart failure, even such small clinical benefit can translate into

substantial public health benefit.



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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.

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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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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.

clclclclclclclarararararararititititititity.y.y.y.y.y.y



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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.

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


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


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)

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1.00 1.6(0.8-3.2) 1.7(0.9-3.3) 2.1(1.

1.00 1.6(0.7-3.5) 2.1(0.9-4.0) 2.3(1.



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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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Eswar KrishnanHyperuricemia and Incident Heart Failure

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