AHA hyperuricemia and heart failure 2009

Hyperuricemia and Incident Heart Failure
Eswar Krishnan
Circ Heart Fail. 2009;2:556-562; originally published online August 6, 2009;
doi: 10.1161/CIRCHEARTFAILURE.108.797662
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Hyperuricemia and Incident Heart Failure
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 (nϭ4912; 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
Ϸ6-fold higher among those at the highest quartile of serum uric acid (Ͼ6.3 mg/dL) compared with those at the lowest
quartile (Ͻ3.4 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 Ⅲ risk Ⅲ uric acid Ⅲ incidence Ⅲ hyperuricemia Ⅲ prospective studies Ⅲ biological markers

N

early 5 million Americans currently suffer from heart
failure, and Ϸ550 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 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 series.6 Among
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 –15 Hyperuricemia can
predict heart failure among those with preexisting hypertension.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 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.

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.18 All 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
© 2009 American Heart Association, Inc.
Circ Heart Fail is available at

DOI: 10.1161/CIRCHEARTFAILURE.108.797662

556
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Krishnan
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.

Hyperuricemia and Heart Failure

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

Measurement of Covariates

Distended neck veins (in other than the supine position)

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 Ϸ20%, 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

Rales

Outcome Assessment
Heart Failure
Heart failure events (both hospitalized and nonhospitalized) were
adjudicated by a study physician panel according to the predetermined Framingham criteria shown in Table 1.20,21 Heart 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 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 is complex (Figure 1) because hyperuricemia is
a risk factor for kidney disease, hypertension, and atherosclerotic
cardiovascular diseases.22–27 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 for those who

557

Increasing heart size by chest radiograph
Acute pulmonary edema on chest radiograph
Ventricular S(3) gallop
Increased venous pressure Ͼ16 cm water
Hepatojugular reflux
Pulmonary edema, visceral congestion, or cardiomegaly shown on
autopsy
Weight loss of Ն10 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.

did not meet the adult treatment panel criteria for metabolic
syndrome baseline,28 who 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% (nϭ171) and 4.5% (nϭ192) among heart
failure and no heart failure groups, respectively (PϽ0.001).
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 regres-

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November 2009

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.

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 infrequent (nϭ6), 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 subgroups: participants who did not use diuretics, any blood

pressure medications, nondiabetics; those 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 until the seventh visit, each

Table 2. Baseline Characteristics of Framingham Offspring Study Participants According to Serum Uric Acid Concentrations
(n‫؍‬4912)
Quartile 1
(1.2 to 4.34 mg/dL)
No. of participants

1164

Age, y

34Ϯ10

Proportion of men

5

Quartile 2
(4.35 to 5.2 mg/dL)
1194
36Ϯ10

Quartile 3
(5.3 to 6.2 mg/dL)
1227
36Ϯ11

Quartile 4
(6.3 to 13.7 mg/dL)

P

(for Trend)

1329
38Ϯ11

Ͻ0.001
Ͻ0.001

30

65

88

Body mass index, kg/m2

23Ϯ3

25Ϯ4

26Ϯ4

28Ϯ4

Ͻ0.001

Alcohol use

81

84

85

90

Ͻ0.001

Proportion of current smokers

60

65

62

68

Ͻ0.001

2

3

4

6

Ͻ0.001

Systolic blood pressure, mm Hg

114Ϯ13

119Ϯ15

123Ϯ15

129Ϯ17

Ͻ0.001

Diastolic blood pressure, mm Hg

73Ϯ9

77Ϯ10

79Ϯ10

84Ϯ11

Ͻ0.001

Fasting glucose, mg/dL

93Ϯ17

99Ϯ23

104Ϯ33

108Ϯ32

Ͻ0.001

Total cholesterol, mg/dL

187Ϯ37

191Ϯ38

199Ϯ41

205Ϯ40

Ͻ0.001

LDL cholesterol, mg/dL

115Ϯ33

121Ϯ35

130Ϯ36

131Ϯ35

Ͻ0.001

HDL cholesterol, mg/dL

57Ϯ14

53Ϯ15

48Ϯ13

45Ϯ13

Ͻ0.001

Triglycerides, mg/dL

101Ϯ69

112Ϯ73

131Ϯ107

163Ϯ162

Ͻ0.001

Serum uric acid, mg/dL

7.2Ϯ0.8

Diuretic users

3.7Ϯ0.5

4.8Ϯ0.3

5.7Ϯ0.3

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

Ͻ0.001

History of diabetes at baseline

0.9

1.8

2.7

2.3

0.008

Data are presented as meanϮSD 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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Hyperuricemia and Heart Failure

559

Proportion without heart failure

1.00

0.98

Figure 2. Kaplan-Meier estimates for heart
failure-free follow-up among the 4912 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 (nϭ196).
Note that the y axis scale is adjusted for
the sake of clarity.

0.96

0.94

0.92
Baseline serum uric acid (mg/dl)

0.90
0

1.2-4.4

4.5-5.3

5.3-6.2

6.3-13.7

5

10

15

20

25

30

Follow-up in years

unit increase in serum uric acid increased the risk for incident
heart failure for the deceased (nϭ125; hazard ratio, 1.2 [0.9 to
1.5]) and survivors (nϭ76; 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 (Pϭ0.21). Furthermore, when data were analyzed 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 communitydwelling population. Similar to the Vorarlberg study, this risk
Table 3.

was most evident at serum uric acid levels greater than Ϸ6

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.29 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 production.31 Serum 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 concentrations are associated with greater activity of superoxide
dismutase and endothelium-dependent vasodilatation.32
Another potential pathophysiological link between hyperuricemia and heart failure might be through inflammation.
Asymptomatic hyperuricemia is a proinflammatory state

Incident Heart Failure According to Baseline Uric Acid Quartiles in Framingham Offspring Cohort (n‫؍‬4912)
1.2 to 4.34 mg/dL
(nϭ1164)

Characteristic
No. of incident heart failure

13

4.35 to 5.2 mg/dL
(nϭ1193)

5.3 to 6.2 mg/dL
(nϭ1227)

6.3 to 13.7 mg/dL
(nϭ1328)

P
(for Trend)

36

57

90

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)

Ͻ0.001*

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)

Ͻ0.001

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)

Ͻ0.001

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)†

Ͻ0.01

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)‡

Ͻ0.01

Rate per 10 000 person-years (95% CI)

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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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

Nonusers of diuretics

3639

1.20

1.00 to 1.41*

Nondiabetics

3517

1.28

1.01 to 1.52

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.
*Pϭ0.048.

associated with higher levels of serum markers of inflammation, such as C-reactive protein, interleukin-6, and neutrophil
count.31,33,34 Among patients with heart failure, hyperuricemia 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.12 Similar observations have been made in other population-based studies35 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 shows
low-grade inflammatory activity.37
Increased levels of serum uric acid among normal individuals predict hypertension,27,38 renal dysfunction,25 and coronary artery disease22 and 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 measurable clinical benefit among those with established heart
failure.42,43 Some 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 hypertrophy 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 allopurinol has beneficial effects in terms of improved peripheral
vasodilator capacity, systemic blood flow, and clinical outcomes.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,47 the Oxypurinol
Therapy for Congestive Heart Failure (OPT-CHF) study did
not show an overall benefit.48 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 a 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. In addition, the long interval
between follow-up visits (Ϸ4 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 concentrations. 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 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 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 supported in part by grant KL2 RR024154-01 from the National Center
for Research Resources, a component of the National Institutes of

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Krishnan
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 Research Enterprise is available at />clinicalresearch/overview-translational.asp. No commercial products
are discussed in this manuscript.

15.

16.

17.

Disclosures
Dr Krishnan has received grant support from Takeda Pharmaceuticals of North America, Inc, Deerfield, Ill (formerly TAP Pharmaceutical Products, Inc) and has 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 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 Offspring 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 Ͼ6.3 mg/dL was 6-fold higher than that among participants with serum uric acid Ͻ3.4 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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