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Asymptomatic hyperuricemia and incident congestive heart failure in elderly patients without comorbidities
Journal Pre-proof Asymptomatic hyperuricemia and incident congestive heart failure in elderly patients without comorbidities Xianfeng Wu, Guihua Jian, Yuezhong Tang, Huan Cheng, Niansong Wang, Junnan Wu PII:
S0939-4753(19)30457-0
DOI:
https://doi.org/10.1016/j.numecd.2019.12.008
Reference:
NUMECD 2199
To appear in:
Nutrition, Metabolism and Cardiovascular Diseases
Received Date: 7 October 2019 Revised Date:
25 November 2019
Accepted Date: 13 December 2019
Please cite this article as: Wu X, Jian G, Tang Y, Cheng H, Wang N, Wu J, Asymptomatic hyperuricemia and incident congestive heart failure in elderly patients without comorbidities, Nutrition, Metabolism and Cardiovascular Diseases, https://doi.org/10.1016/j.numecd.2019.12.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.
1
Asymptomatic hyperuricemia and incident congestive heart failure in elderly
2
patients without comorbidities
3 4
Xianfeng Wua*, Guihua Jiana*, Yuezhong Tangb, Huan Chengb, Niansong Wanga,
5
Junnan Wua
6 7
a
8
University, Shanghai, China.
9
b
Department of Nephrology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong
Kangjian Community Health Center, Xuhui District, Shanghai, China.
10 11
*These authors contributed equally to this work.
12 13
Correspondence: Niansong Wang, Email: [email protected]; Junnan Wu,
14
Email: [email protected]. Department of Nephrology, Affiliated Sixth People's
15
Hospital, Shanghai Jiao Tong University, No. 600 Yi Shan Road, Shanghai, China
16 17 18 19 20 21 22 1
1
Abstract
2
Background and Aims: Although hyperuricemia is associated with congestive heart
3
failure (CHF), hyperuricemic patients frequently have other comorbidities. Thus, it is
4
difficult to distinguish the role of hyperuricemia from that of other comorbid
5
conditions in CHF. The aim of this study was to evaluate the association between
6
hyperuricemia and CHF in elderly patients without comorbidities.
7
Methods: Subjects aged ≥65 years were analyzed at enrollment (2009-2012) and
8
during the 4-year follow-up period at the Kangjian Community Health Center of
9
Shanghai. Subjects were excluded if they had hypertension, diabetes mellitus,
10
preexisting cardiovascular disease, hyperlipidemia, overweight or obesity, a history of
11
gout or hyperuricemia and were taking medication for their condition, or chronic
12
kidney disease. The primary outcome of this study was to investigate the impact of
13
asymptomatic hyperuricemia on incident CHF. We used Cox regression to estimate
14
the hazard ratio (HR) for incident CHF events between hyperuricemic (defined as an
15
SUA level >7 mg/dL in men and ≥6 mg/dL in women) and normouricemic subjects.
16
Results: A total of 2749 subjects (70.9±6.0 years) were followed for 47.4±3.6 months.
17
Asymptomatic hyperuricemia was associated with an increased cumulative incidence
18
of incident CHF events (6.5% versus 3.1%, odds ratio [OR]=2.15, 95% confidence
19
index [CI] 1.39-3.33, p=0.001). After adjusting for confounding factors, including
20
baseline eGFR, hyperuricemia independently predicted the risk of incident CHF
21
events (HR=2.34, 95% CI 1.50-3.63, p<0.001).
22
Conclusion: Asymptomatic hyperuricemia was a valuable biomarker for predicting 2
1
the development of incident CHF in elderly patients without comorbidities.
2
Keywords: Congestive heart failure, elderly, hyperuricemia
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 3
1
Introduction
2
The relationship between serum uric acid (SUA) and cardiovascular disease (CVD)
3
has received much attention for the past few years. Congestive heart failure (CHF)
4
afflicts 1-2% of the adult population in developed countries [1]. As CHF is the end
5
stage of most CVDs, SUA may play a vital role in CHF [2]. A number of studies and a
6
previous meta-analysis have assessed the association between SUA and subsequent
7
CHF risk, demonstrating that elevated SUA could be a risk factor for incident CHF
8
events [3-8]. However, because many individuals with hyperuricemia have
9
comorbidities such as obesity, diabetes mellitus (DM), hypertension and chronic
10
kidney disease (CKD) [9], it can be difficult to differentiate the role of SUA from that
11
of other comorbid conditions in CHF. Although multivariable analysis can be used to
12
control for these other conditions, multivariable analysis can be misleading if the
13
associated risk factors are causally linked. The limitations associated with
14
multivariable analysis as a means for determining causation are well known [9-11].
15
Therefore, an alternative approach is needed to limit the subjects of a study to only
16
those with hyperuricemia who do not have any other cardiovascular, cerebrovascular,
17
metabolic or renal risk factors. Therefore, in this study, we investigated whether
18
asymptomatic hyperuricemia was associated with an increased risk for CHF in elderly
19
subjects without comorbidities.
20 21 22 4
1
Methods
2
Study design and study subjects
3
This study was a large-scale, longitudinal cohort study. The study population was an
4
apparently healthy population recruited during annual routine health check-up visits at
5
Kangjian Community Health Center. The subjects also provided a general history of
6
their comorbidities. No patients were involved in setting the research question or
7
outcome measures or were involved in the design or implementation of the study. This
8
study was conducted according to the principles expressed in the Declaration of
9
Helsinki. The Ethics Committees of Kangjian Community Health Center approved the
10
protocol of this observational study and waived the need for written informed consent
11
because the data were analyzed anonymously.
12
We enrolled study subjects aged ≥65 years between January 1, 2009, and December
13
31, 2012. We excluded subjects with hypertension, DM, preexisting CVD,
14
hyperlipidemia, CKD (reduced estimated glomerular filtration rate (eGFR) of <60
15
mL/min per 1.73 m2), overweight or obesity (body mass index (BMI) of ≥25 kg/m2),
16
or hyperuricemia or gout who were taking medication for the condition. Baseline
17
demographic and clinical data were collected at the initiation of this study. We used
18
the baseline SUA measurement as the study entry date. Eligible subjects visited the
19
center once every 12 months and were followed until death, loss to follow-up, or for 4
20
years from the initiation of this study. Indications for uric acid-lowering drugs were
21
determined by each patient’s physician during the observation period.
22 5
1
Primary outcome and definitions
2
The end point for this study was incident CHF events. End point criteria included
3
incident CHF events diagnosed by a physician and the patient receiving medical
4
treatment for CHF and 1) pulmonary edema/congestion by chest X-ray and/or 2)
5
dilated ventricle or poor LV function by echocardiography or ventriculography or
6
evidence of LV diastolic dysfunction [12]. If the patients developed CHF events at
7
any hospital, the hospital and physician records were referred to for the diagnosis of
8
CHF events, and if CHF events occurred outside a hospital, the experts reached a
9
consensus regarding the diagnosis of CHF events after a comprehensive consideration
10
of the history, recent situations, signs, and symptoms before and after the CHF events
11
from the patient’s medical records at our center and descriptions provided by family
12
members.
13
Hyperuricemia was defined as >7.0 mg/dL of SUA in men and ≥6.0 mg/dL in women
14
as the standard definition for most studies [3-8]. Blood pressure (BP) and pulse rate
15
readings were obtained using an automatic brachial sphygmomanometer (OMRON
16
Corporation, Kyoto, Japan). Two BP examinations were taken after subjects had been
17
seated and were resting quietly for >5 minutes with their feet on the ground and their
18
backs supported. The mean systolic and diastolic BP of each of the subjects was
19
calculated from the recorded measurements [13]. BMI was calculated as BMI=weight
20
(kg)/height2 (m2) from the weight measured to the nearest 0.5 kg and the height
21
measured to the nearest 0.1 cm. Hypertension was defined as systolic BP ≥140 mmHg
22
and/or diastolic BP ≥90 mmHg and/or the use of antihypertensive medications. DM 6
1
was defined as fasting glucose 126 mg/dL or the use of hypoglycemic medication [12].
2
We defined preexisting CVD as a history of coronary heart disease, CHF, stroke, or
3
peripheral vascular disease. Hyperlipidemia was defined by serum concentrations of
4
cholesterol ≥5.7 mmol/L, triglyceride ≥1.7 mmol/L, low density lipoprotein (LDL)
5
levels ≥3.6 mmol/L, or as patients who were currently undergoing treatment with
6
lipid-lowering agents [14]. The eGFR levels were calculated by the simplified
7
Modification of Diet in Renal Disease equation. CKD was defined as having an eGFR
8
of <60 mL/min per 1.73 m2 [15]. Individuals who reported smoking at least one
9
cigarette per day during the year before the examination were classified as having a
10
smoking habit. Individuals who reported consuming more than 20 g/day of ethanol
11
during the same time period were classified as having a drinking habit.
12
Baseline biochemical parameters, including SUA, hemoglobin, total protein, serum
13
albumin, serum creatinine, total cholesterol, triglycerides, low-density lipoprotein
14
(LDL) and high-density lipoprotein (HDL), were collected every 12 months after this
15
study was initiated.
16
Statistical analysis
17
We divided the eligible subjects into hyperuricemia and normouricemia groups using
18
baseline SUA levels. Data are expressed as the mean±standard derivation (SD) or as
19
percent frequency, unless otherwise specified. Comparisons between two groups were
20
performed with t tests for normally distributed variables and χ2 tests for categorical
21
data. Survival was calculated using the Kaplan-Meier method, and differences
22
between distributions of survival were assessed with a log-rank test. We analyzed the 7
1
hazard ratio (HR) of risk for incident CHF events using multivariable Cox regression
2
models. We compared cumulative incidences of incident CHF events over 4 years
3
between subjects with hyperuricemia and those with normouricemia and calculated
4
the HR for incident CHF events by crude analysis and after adjusting for age, sex,
5
smoking status and drinking status (Model 1); with the addition of baseline BMI,
6
systolic and diastolic BP (Model 2); and with the addition of baseline eGFR, total
7
cholesterol, triglycerides, LDL and HDL (Model 3). In addition, because the
8
distribution of SUA differed between male and female subjects, multivariable
9
regression analyses were also stratified by sex. Furthermore, we calculated cumulative
10
incidences of incident CHF events over 4 years for sex-specific quartiles by their SUA
11
levels at baseline (<4.6, 4.6 to 5.1, 5.2 to 6.2, and ≥6.3 mg/dL in males and <4.6, 4.6
12
to 5.2, 5.3 to 5.8, and ≥5.9 mg/dL in females). The statistically significant level was
13
set at α=0.05, and all statistical analyses were 2-sided. All statistical analyses were
14
performed with GraphPad Software (version 8).
15
Sensitivity analysis
16
To reduce selection bias, propensity score matching (PSM) was applied to select the
17
two groups with and without hyperuricemia at a 1:1 ratio [16]. The propensity score
18
was calculated using logistic regression to estimate the probability of the
19
hyperuricemia assignment based on all baseline variables. We re-estimated the odds
20
ratio [OR] of incident CHF events between the PSM-derived groups.
21 22 8
1
Results
2
Patient characteristics at baseline
3
There were 9637 subjects aged ≥65 years who underwent annual medical
4
examinations at the health center both in 2009 and 2012. Of the 9637 subjects, we
5
excluded 6888 subjects with comorbidities at baseline: 1416 had hypertension, 1019
6
had preexisting CVD, 1194 had DM, 865 had CKD, 1198 had hyperlipidemia, 879
7
were overweight/obese, and 317 had hyperuricemia or gout and were taking
8
medication for their condition (Figure 1). Thus, 2749 patients were enrolled in this
9
study (mean age of 70.9±6.0 years, 1457 men, 53.0%) with a mean follow-up of
10
47.4±3.6 months.
11
SUA concentrations showed an approximate Gaussian distribution (range, 2.3-15.7
12
mg/dL; mean±SD, 5.5±1.4 mg/dL). The baseline demographic and clinical
13
characteristics of this study are shown in Table 1 and are categorized according to sex
14
and SUA concentration. The hyperuricemic subjects showed mild but significant
15
differences in systolic BP and eGFR from the normouricemic subjects, although both
16
groups had values within the normal range. Hyperuricemic subjects more frequently
17
had smoking and drinking habits and presented with higher hemoglobin, total protein,
18
albumin, serum creatinine, total cholesterol, triglyceride and LDL levels but with a
19
lower eGFR and HDL level than normouricemic subjects in the cohort. Similar
20
differences in baseline characteristics were also observed between male and female
21
subjects, except for serum albumin.
22
Incidence of incident CHF events 9
1
During follow-up, 297 (10.8%) deaths occurred, including 163 (54.9%) CVD deaths.
2
Of those CVD deaths, 69 (42.3%) were due to CHF events. In addition, 55 (2.0%)
3
patients were lost to follow-up in the study population. A total of 129 CHF events
4
occurred in this population, of which 102 (3.7%) were incident CHF events. We
5
compared the incidence of incident CHF events in subjects with hyperuricemia to
6
those with normouricemia (Figure 2) and found that the hyperuricemic subjects
7
showed a significantly higher incidence of incident CHF events than did the
8
normouricemic subjects (6.5% versus 3.1%, OR=2.15, 95% confidence index [CI]
9
1.39-3.33, p=0.001). We also compared the incidences for incident CHF events
10
between hyperuricemia and normouricemia by sex. In males, the hyperuricemic
11
subjects showed a significantly higher incidence of incident CHF events than did the
12
normouricemic subjects (6.9% versus 3.4%, OR=2.10, 95% CI 1.19-3.71, p=0.014).
13
In females, the hyperuricemic subjects showed a significantly higher incidence of
14
incident CHF events than did the normouricemic subjects (6.0% versus 2.8%,
15
OR=2.19, 95% CI 1.10-4.33, p=0.031). In the cohort study, there were no sex
16
differences in terms of CHF incidence (OR=0.82, 95% CI 0.55-1.21, p=0.363). In
17
addition, in the hyperuricemic and normouricemic subjects, there were no sex
18
differences in terms of the incident CHF risk (OR=0.86, 95% CI 0.40-1.83, p=0.849,
19
and OR=0.82, 95% CI 0.51-1.32, p=0.473, respectively).
20
Association of hyperuricemia and incident CHF events using multivariable Cox
21
regression
22
According to the crude analysis, hyperuricemia was a risk factor for incident CHF 10
1
events in this study population (HR=2.12; 95% CI, 1.38-3.24, p=0.001, Table 2). After
2
adjustment, including baseline eGFR, hyperuricemia became an independent risk
3
factor for incident CHF events (HR=2.34, 95% CI 1.50-3.63, p<0.001, total, Model 3;
4
Table 2). When analysis was restricted to males, hyperuricemia remained an
5
independent risk factor for incident CHF events (HR=2.45; 95% CI, 1.35–4.42,
6
p=0.003; male sex, Model 3; Table 2). When the analysis was restricted to females,
7
hyperuricemia also remained an independent risk factor for incident CHF events
8
(HR=2.14; 95% CI, 1.10–4.18, p=0.024; female sex, Model 3; Table 2).
9
Cumulative incidence of incident CHF events between hyperuricemic and
10
normouricemic subjects
11
Compared with normouricemic subjects, hyperuricemic subjects had an increased risk
12
of incident CHF events based on Kaplan-Meier curves (Figure 3). In the cohort study,
13
according to the crude analysis of the risk of incident CHF events, the cumulative risk
14
was significantly higher in the hyperuricemic subjects (HR=2.57, 95% CI 1.52-4.34,
15
p<0.001) than in the normouricemic subjects. Male and female hyperuricemic
16
subjects also had higher cumulative incident CHF risk than their normouricemic
17
counterparts (HR=2.46, 95% CI 1.28-4.81, p=0.009 and HR=2.66, 95% CI 1.16-6.10,
18
p=0.021; Figure 3, respectively).
19
Analysis of incidence of incident CHF events by sex for SUA quartiles
20
We calculated the incidences of incident CHF events by sex for the quartile ranges of
21
SUA, including <4.6, 4.6 to 5.1, 5.2 to 6.2, and ≥6.3 mg/dL in males and <4.6, 4.6 to
22
5.2, 5.3 to 5.8, and ≥5.9 mg/dL in females (Figure 4 and Figure 5, respectively). The 11
1
incidences of incident CHF events were 2.6%, 3.3%, 3.9%, and 6.1%, respectively, in
2
male subjects and 2.4%, 2.8%, 4.0%, and 4.9%, respectively, in female subjects. The
3
results showed that individuals with higher baseline SUA levels had a higher
4
incidence of incident CHF events across both sexes.
5
Sensitivity analysis
6
PSM analysis was performed using logistic regression analysis to create a propensity
7
score for the hyperuricemic and normouricemic groups with a logistic regression
8
model. The following variables were entered into the propensity model: age, sex, BMI,
9
systolic BP, diastolic BP, current smoking habit, drinking habit, albumin, total
10
cholesterol, and eGFR. One-to-one matching without replacement was performed
11
with a 0.1 caliper width. PSM matching was successfully applied to 375 pairs of
12
patients. As expected, baseline characteristics were well balanced in the matched
13
group (Table 3). After PSM, the hyperuricemic subjects showed a significantly higher
14
incidence of incident CHF than the normouricemic subjects in the cohort study (6.6%
15
versus 3.2%, OR=2.13, 95% CI 1.36-3.34, p<0.001). Similarly, in males,
16
hyperuricemic subjects showed a significantly higher incidence of incident CHF
17
events than their normouricemic counterparts (6.8% versus 3.5%, OR=2.07, 95% CI
18
1.19-3.70, p=0.016). This trend was also found for females, with hyperuricemic
19
subjects showing a significantly higher incidence of incident CHF events than their
20
normouricemic counterparts (5.9% versus 2.7%, OR=2.17, 95% CI 1.14-4.19,
21
p=0.020).
22 12
1
Discussion
2
Our primary finding was that asymptomatic hyperuricemic subjects without
3
comorbidities had a significantly increased (2.34-fold) risk for developing incident
4
CHF events. In addition, there was no sex differences between hyperuricemic and
5
normouricemic subjects regarding CHF risk.
6
CHF is a major health problem, and the considerable morbidity and mortality
7
burden attributable to this disease continues to increase as the population ages [17]. In
8
CHF, SUA levels may rise due to increased purine catabolism resulting from tissue
9
hypoxia, apoptosis, and/or enhanced or unregulated xanthine oxidase receptor activity
10
[18]. In a large prospective cohort study, CHF decompensation was independently
11
associated with hyperuricemia in men with a high cardiovascular risk profile [19]. A
12
previous study with 83683 Austrian men across a wide age range found that men with
13
baseline SUA values >6.7 mg/dL had a 50% greater risk for fatal CHF than did those
14
with SUA concentrations ≤4.6 mg/dL during a median of 13.6 years of follow-up [20].
15
In a prospective cohort study of 41879 Chinese men and 48514 women,
16
hyperuricemia (SUA level >7 mg/dL) was an independent risk factor for CHF
17
mortality; CHF mortality increased 13% for every 1 mg/dL increase in the level of
18
SUA [21]. In the Apolipoprotein Mortality Risk study, moderate levels of SUA appear
19
to be associated with an increased incidence of CHF in middle-aged subjects without
20
prior CVD. These associations seem to increase gradually from lower to higher levels
21
of SUA [22]. Although they comprised a large number of subjects, the studies by
22
Strasak et al. did not report on risk associations between SUA and nonfatal CHF [23]. 13
1
In the study reporting on a 29-year follow-up of 2321 middle-aged men, SUA was no
2
longer found to be a significant risk factor for CHF when adjusted for established risk
3
factors [23]. Nonetheless, it is worth noting that SUA is inversely proportional to
4
estimated stroke volume and cardiac output in apparently healthy subjects from Italy.
5
Researchers selected 734 adult subjects who were not taking antihypertensive,
6
antidiabetic, lipid-lowering, or uric acid-lowering drugs, which may reduce selection
7
bias and help exclude the role of SUA in their findings from that of other comorbid
8
conditions [24].
9
SUA is also known to be associated with other important risk factors of CHD, so its
10
independent relationship with CHD has been questioned [25]. Known risk factors, and
11
other potential confounding factors may contribute to an under- or overestimation of
12
the association between hyperuricemia and the risk of related CHF events. Most
13
previous studies recruited eligible subjects with hyperuricemia, of which the majority
14
already carry cardiometabolic comorbidities [26]. Thus, an alternative approach to
15
studying the relationship between hyperuricemia and CHF events was to limit the
16
study population to only subjects with hyperuricemia who do not have other
17
cardiovascular, metabolic or renal risk factors. The importance of our study was that
18
we evaluated subjects with asymptomatic hyperuricemia who did not exhibit cardiac
19
or metabolic risk factors to determine whether they were still at risk for CHF. Indeed,
20
we found that the presence of hyperuricemia was an independent risk factor for
21
incident CHF events in elderly subjects without comorbidities. The results of the
22
present study may help to distinguish the role of hyperuricemia from that of other 14
1
comorbid conditions in incident CHF events. In the present study, there were no sex
2
differences in cumulative CHF incidence. The changing association between elderly
3
men and postmenopausal women suggests that there may be an interaction with sex
4
hormones [27]. Notably, in our study, subjects with hyperuricemia had a higher
5
prevalence of smoking and alcohol consumption, leading to an increase in metabolic
6
abnormalities, including increased levels of triglycerides and LDL cholesterol, which
7
might explain the presence of hyperuricemia. As is well known, smoking, drinking,
8
and elevated levels of triglycerides and LDL cholesterol increase one’s risk of chronic
9
heart failure. Therefore, to reduce selection bias and make baseline characteristics
10
comparable, we performed sensitivity analysis using PSM, which was applied to
11
select the two groups with and without hyperuricemia at a 1:1 ratio; and then, baseline
12
characteristics were well balanced between matched subjects, and similar trends were
13
observed between two matched groups. It is no doubt that smoking cessation, alcohol
14
withdrawal and management of dyslipidemia are beneficial for alleviating
15
hyperuricemia, thereby reducing the incidence of chronic heart failure. Thus, to
16
further identify these findings in the present study, we should perform a prospective
17
study involving those subjects with comparable baseline characteristics.
18
The strength of our study lies in our separation of subjects into subsets, including a
19
subset of subjects who were normotensive, without other comorbidities. While the
20
results of this study are likely true for elderly populations, the application of these
21
findings to younger populations remains to be elucidated. In addition, as it was an
22
observational design, subjects were not randomly assigned, and thus, causality could 15
1
not be assessed. PSM is not a substitute for randomization, and despite the application
2
of analytical tools to reduce bias by indication, residual confounding or reverse
3
causality phenomena cannot be completely ruled out [28]. We failed to exclude
4
subjects whose eGFR was 60 to 75 mL/min per 1.73 m2, which qualifies as abnormal
5
renal function but is not defined as CKD. Failure to exclude these subjects may
6
interfere with the analysis of the association between SUA and incident CHF events.
7
Meanwhile, subjects with hyperuricemia may have an increase in metabolic
8
abnormalities, including higher levels of blood glucose, triglycerides or LDL.
9
Unfortunately, blood glucose levels were not measured in these subjects in the present
10
study, which may lead to increase selection bias in our study. Moreover, our analysis
11
used only baseline data, which did not cover the change in SUA levels during the
12
observation period. Finally, the results of our study may not be generalizable to other
13
ethnic populations, as all patients were recruited from China.
14
In conclusion, the presence of hyperuricemia in elderly adults without comorbidities
15
carried a 2.34-fold risk for developing incident CHF events within 4 years, and there
16
were no sex differences in terms of cumulative CHF incidence. Asymptomatic
17
hyperuricemia was a valuable biomarker for predicting the development of incident
18
CHF events. Further prospective research is needed to evaluate whether strategies to
19
reduce SUA over time can prevent this condition.
20 21 22 16
1
Acknowledgments
2
We express our gratitude to all patients who participated in the study.
3 4
Declaration of conflicting interests
5
The authors declare that they have no potential conflicts of interest with respect to the
6
research, authorship and/or publication of this article.
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 17
1
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14
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Methylenetetrahydrofolate
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[15] Ito H, Abe M, Mifune M, Oshikiri K, Antoku S, Takeuchi Y, et al. Hyperuricemia
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patients with type 2 diabetes mellitus. PloS one. 2011;6:e27817.
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[16] LS P. SUGI 29: Performing a 1: N Case-Control Match on Propensity Score. The
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Allopurinol improves myocardial efficiency in patients with idiopathic dilated
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cardiomyopathy. Circulation. 2001;104:2407-11.
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[19] Misra D, Zhu Y, Zhang Y, Choi HK. The independent impact of congestive heart
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rheumatism. 2011;41:471-6.
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[20] Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, et al. Serum uric
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acid and risk of cardiovascular mortality: a prospective long-term study of 83,683
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Austrian men. Clinical chemistry. 2008;54:273-84.
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[21] Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an 20
1
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Chinese cohort study. Arthritis and rheumatism. 2009;61:225-32.
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[22] Holme I, Aastveit AH, Hammar N, Jungner I, Walldius G. Uric acid and risk of
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myocardial infarction, stroke and congestive heart failure in 417,734 men and women
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in the Apolipoprotein MOrtality RISk study (AMORIS). Journal of internal medicine.
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[23] Ingelsson E, Arnlov J, Sundstrom J, Zethelius B, Vessby B, Lind L. Novel
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metabolic risk factors for heart failure. Journal of the American College of Cardiology.
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2005;46:2054-60.
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[24] Cicero AF, Rosticci M, Parini A, Baronio C, D'Addato S, Borghi C. Serum uric
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acid is inversely proportional to estimated stroke volume and cardiac output in a large
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sample of pharmacologically untreated subjects: data from the Brisighella Heart Study.
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Intern Emerg Med. 2014;9:655-60.
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[25] Lippi G, Montagnana M, Franchini M, Favaloro EJ, Targher G. The paradoxical
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relationship between serum uric acid and cardiovascular disease. Clinica chimica acta;
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international journal of clinical chemistry. 2008;392:1-7.
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[26] Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US
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general population: NHANES 2007-2008. The American journal of medicine.
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2012;125:679-87 e1.
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[27] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the
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NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition
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Examination Survey. Jama. 2000;283:2404-10. 21
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[28] Maduell F, Varas J, Ramos R, Martin-Malo A, Perez-Garcia R, Berdud I, et al.
2
Hemodiafiltration Reduces All-Cause and Cardiovascular Mortality in Incident
3
Hemodialysis Patients: A Propensity-Matched Cohort Study. American journal of
4
nephrology. 2017;46:288-97.
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 22
1
Figure legends
2
Figure 1. Flow diagram of study enrollment.
3
CHF: congestive heart failure; CVD: cardiovascular disease; CKD: chronic kidney
4
disease; BMI: body mass index; SUA: serum uric acid.
5 6
Figure 2. The incidence of incident CHF events between hyperuricemic and
7
normouricemic subjects.
8
CHF: congestive heart failure.
9 10
Figure 3. The cumulative incidence of incident CHF events between hyperuricemic
11
and normouricemic subjects.
12
CHF: congestive heart failure; HR: hazard ratio; CI: confidence index.
13 14
Figure 4. Incidence of incident CHF events in SUA quartiles in male subjects.
15
CHF: congestive heart failure; SUA: serum uric acid.
16 17
Figure 5. Incidence of incident CHF events in quartiles of SUA in female subjects.
18
CHF: congestive heart failure; SUA: serum uric acid.
19 20
23
Table 1. Baseline characteristics of study subjects stratified by serum SUA. Total (n=2749)
Male (n=1457)
Normouricemia
Hyperuricemia
p-value
Number of subjects
2289
460
Male sex
52.3%
56.5%
0.097
Age, years
70.9±6.0
70.7±5.8
BMI, kg/m2
22.4±1.6
Pulse rate, bpm
Normouricemia Hyperuricemia
Female (n=1292) p-value
Normouricemia
Hyperuricemia
1092
200
p-value
1197
260
0.414
71.4±6.1
71.0±6.0
0.384
70.5±5.9
70.3±5.4
0.669
22.3±1.6
0.242
22.4±1.6
22.3±1.6
0.197
22.5±1.6
22.4±1.6
0.819
73.0±11.0
73.9±9.1
0.145
72.6±10.6
74.2±8.7
0.022
73.3±11.4
73.4±9.8
0.942
Systolic BP, mmHg
120.4±10.8
121.9±8.9
0.005
120.2±11.0
121.9±8.9
0.009
120.6±10.6
121.9±9.0
0.064
Diastolic BP, mmHg
73.5±7.6
74.0±7.1
0.239
73.3±7.6
74.2±7.0
0.097
73.7±7.6
73.7±7.2
0.959
Current smoking habit
28.7%
57.6%
<0.001
53.9%
63.1%
<0.001
14.6%
26.8%
<0.001
Drinking habit
37.1%
69.4%
<0.001
60.4%
70.2%
<0.001
13.9%
29.7%
<0.001
13.4±1.3
14.3±1.2
<0.001
13.4±1.3
14.3±1.2
<0.001
13.5±1.3
14.3±1.2
<0.001
Hemoglobin (g/dL)
24
Total protein, g/dL
7.2±0.5
7.3±0.6
<0.001
7.2±0.5
7.3±0.5
0.005
7.2±0.5
7.4±0.6
<0.001
Albumin, g/dL
4.3±0.4
4.4±0.4
0.001
4.3±0.4
4.4±0.4
0.484
4.3±0.4
4.5±0.4
<0.001
Total cholesterol (mmol/L)
5.1±1.1
5.3±1.2
<0.001
5.1±1.1
5.3±1.0
0.007
5.1±1.1
5.4±1.2
0.005
Triglycerides (mmol/L)
1.5±0.9
1.6±1.0
<0.001
1.5±1.0
1.6±1.0
<0.001
1.5±0.8
1.6±1.0
<0.001
HDL (mmol/L)
1.7±0.5
1.5±0.4
<0.001
1.7±0.4
1.5±0.3
<0.001
1.8±0.5
1.5±0.4
<0.001
LDL (mmol/L)
3.3±0.9
3.5±0.9
<0.001
3.3±0.9
3.5±0.8
<0.001
3.3±0.9
3.5±1.0
0.001
87.7±12.3
83.6±11.2
<0.001
85.1±11.7
81.5±10.8
<0.001
89.6±12.1
85.2±11.5
<0.001
0.8±0.1
0.9±0.1
<0.001
0.8±0.1
0.9±0.1
<0.001
0.7±0.1
0.8±0.1
<0.001
eGFR, mL/min per 1.73 m2 Serum creatinine, mg/dL
SUA: serum uric acid; BMI: body mass index; BP: blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.
25
Table 2. Association between hyperuricemia and quartiles of serum uric acid and incident CHF events Crude
Model 1
Model 2
Model 3
HR
95% CI
p-value
HR
95% CI
p-value
HR
95% CI
p-value
HR
95% CI
p-value
2.12
1.38-3.24
0.001
2.31
1.50-3.53
<0.001
2.30
1.50-3.53
<0.001
2.34
1.50-3.63
<0.001
Hyperuricemia
2.08
1.19-3.60
0.010
2.51
1.44-4.38
0.001
2.51
1.44-4.38
0.001
2.45
1.36-4.42
0.003
SUA (<4.6 mg/dL)
Reference
SUA (4.6-5.1 mg/dL)
1.19
1.09-3.21
0.013
1.18
1.09-3.38
0.021
1.16
1.10-3.36
0.023
1.13
1.07-3.45
0.030
SUA (5.2-6.2 mg/dL)
1.37
1.10-3.36
0.001
1.31
1.10-3.37
0.002
1.27
1.11-3.45
0.007
1.24
1.10-3.41
0.012
SUA (≥6.3 mg/dL)
2.23
1.39-4.78
<0.001
2.22
1.38-4.76
<0.001
2.18
1.40-4.78
<0.001
2.15
1.39-4.78
0.001
2.15
1.10-4.19
0.024
2.15
1.10-4.19
0.024
2.15
1.10-4.18
0.024
2.14
1.10-4.18
0.024
Total=2749 Hyperuricemia Male sex=1457
Female sex=1292 Hyperuricemia
26
SUA (<4.6 mg/dL)
Reference
SUA (4.6-5.2 mg/dL)
1.17
1.07-3.41
0.011
1.16
1.07-3.46
0.014
1.13
1.07-3.47
0.017
1.10
1.06-3.39
0.028
SUA (5.3-5.8 mg/dL)
1.28
1.12-3.37
0.001
1.25
1.12-3.37
0.005
1.20
1.11-3.39
0.009
1.17
1.10-3.41
0.013
SUA (≥5.9 mg/dL)
2.36
1.21-4.61
<0.001
2.35
1.21-4.62
<0.001
2.31
1.20-4.62
<0.001
2.25
1.21-4.65
0.001
CHF: congestive heart failure; SUA: serum uric acid; HR: hazard ratio; CI: confidence index.
27
Table 3. Baseline characteristics of study subjects stratified by serum SUA with propensity score matching. Normouricemia
Hyperuricemia
375
375
53.4%
53.7%
0.568
Age, years
71.3±6.1
71.5±6.1
0.714
BMI, kg/m2
22.6±1.6
22.3±1.6
0.826
Pulse rate, bpm
73.2±8.6
73.6±8.7
0.439
Systolic BP, mmHg
120.5±9.0
120.8±8.9
0.139
Diastolic BP, mmHg
73.9±7.1
74.2±7.0
0.284
Current smoking habit
56.4%
56.7%
0.497
Drinking habit
64.6%
64.8%
0.376
Hemoglobin (g/dL)
13.7±1.2
13.8±1.2
0.496
Total protein, g/dL
7.2±0.5
7.2±0.6
0.738
Number of subjects Male sex
28
p-value
Albumin, g/dL
4.4±0.4
4.4±0.4
0.694
Total cholesterol (mmol/L)
5.2±1.1
5.2±1.2
0.561
Triglycerides (mmol/L)
1.6±0.9
1.6±1.0
0.723
HDL (mmol/L)
1.6±0.5
1.6±0.4
0.715
LDL (mmol/L)
3.5±1.0
3.5±1.0
0.133
83.7±11.2
83.5±11.1
0.371
0.8±0.1
0.8±0.1
0.684
eGFR, mL/min per 1.73 m2 Serum creatinine, mg/dL
SUA: serum uric acid; BMI: body mass index; BP: blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.
29
Highlights · Asymptomatic hyperuricemia was associated with incident congestive heart failure (CHF) in elderly patients without comorbidities. · Male and female hyperuricemic subjects also had higher cumulative incident CHF risk than their counterparts, respectively. · There was no sex difference in the cumulative CHF incidence.
S0939-4753(19)30457-0
DOI:
https://doi.org/10.1016/j.numecd.2019.12.008
Reference:
NUMECD 2199
To appear in:
Nutrition, Metabolism and Cardiovascular Diseases
Received Date: 7 October 2019 Revised Date:
25 November 2019
Accepted Date: 13 December 2019
Please cite this article as: Wu X, Jian G, Tang Y, Cheng H, Wang N, Wu J, Asymptomatic hyperuricemia and incident congestive heart failure in elderly patients without comorbidities, Nutrition, Metabolism and Cardiovascular Diseases, https://doi.org/10.1016/j.numecd.2019.12.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.
1
Asymptomatic hyperuricemia and incident congestive heart failure in elderly
2
patients without comorbidities
3 4
Xianfeng Wua*, Guihua Jiana*, Yuezhong Tangb, Huan Chengb, Niansong Wanga,
5
Junnan Wua
6 7
a
8
University, Shanghai, China.
9
b
Department of Nephrology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong
Kangjian Community Health Center, Xuhui District, Shanghai, China.
10 11
*These authors contributed equally to this work.
12 13
Correspondence: Niansong Wang, Email: [email protected]; Junnan Wu,
14
Email: [email protected]. Department of Nephrology, Affiliated Sixth People's
15
Hospital, Shanghai Jiao Tong University, No. 600 Yi Shan Road, Shanghai, China
16 17 18 19 20 21 22 1
1
Abstract
2
Background and Aims: Although hyperuricemia is associated with congestive heart
3
failure (CHF), hyperuricemic patients frequently have other comorbidities. Thus, it is
4
difficult to distinguish the role of hyperuricemia from that of other comorbid
5
conditions in CHF. The aim of this study was to evaluate the association between
6
hyperuricemia and CHF in elderly patients without comorbidities.
7
Methods: Subjects aged ≥65 years were analyzed at enrollment (2009-2012) and
8
during the 4-year follow-up period at the Kangjian Community Health Center of
9
Shanghai. Subjects were excluded if they had hypertension, diabetes mellitus,
10
preexisting cardiovascular disease, hyperlipidemia, overweight or obesity, a history of
11
gout or hyperuricemia and were taking medication for their condition, or chronic
12
kidney disease. The primary outcome of this study was to investigate the impact of
13
asymptomatic hyperuricemia on incident CHF. We used Cox regression to estimate
14
the hazard ratio (HR) for incident CHF events between hyperuricemic (defined as an
15
SUA level >7 mg/dL in men and ≥6 mg/dL in women) and normouricemic subjects.
16
Results: A total of 2749 subjects (70.9±6.0 years) were followed for 47.4±3.6 months.
17
Asymptomatic hyperuricemia was associated with an increased cumulative incidence
18
of incident CHF events (6.5% versus 3.1%, odds ratio [OR]=2.15, 95% confidence
19
index [CI] 1.39-3.33, p=0.001). After adjusting for confounding factors, including
20
baseline eGFR, hyperuricemia independently predicted the risk of incident CHF
21
events (HR=2.34, 95% CI 1.50-3.63, p<0.001).
22
Conclusion: Asymptomatic hyperuricemia was a valuable biomarker for predicting 2
1
the development of incident CHF in elderly patients without comorbidities.
2
Keywords: Congestive heart failure, elderly, hyperuricemia
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 3
1
Introduction
2
The relationship between serum uric acid (SUA) and cardiovascular disease (CVD)
3
has received much attention for the past few years. Congestive heart failure (CHF)
4
afflicts 1-2% of the adult population in developed countries [1]. As CHF is the end
5
stage of most CVDs, SUA may play a vital role in CHF [2]. A number of studies and a
6
previous meta-analysis have assessed the association between SUA and subsequent
7
CHF risk, demonstrating that elevated SUA could be a risk factor for incident CHF
8
events [3-8]. However, because many individuals with hyperuricemia have
9
comorbidities such as obesity, diabetes mellitus (DM), hypertension and chronic
10
kidney disease (CKD) [9], it can be difficult to differentiate the role of SUA from that
11
of other comorbid conditions in CHF. Although multivariable analysis can be used to
12
control for these other conditions, multivariable analysis can be misleading if the
13
associated risk factors are causally linked. The limitations associated with
14
multivariable analysis as a means for determining causation are well known [9-11].
15
Therefore, an alternative approach is needed to limit the subjects of a study to only
16
those with hyperuricemia who do not have any other cardiovascular, cerebrovascular,
17
metabolic or renal risk factors. Therefore, in this study, we investigated whether
18
asymptomatic hyperuricemia was associated with an increased risk for CHF in elderly
19
subjects without comorbidities.
20 21 22 4
1
Methods
2
Study design and study subjects
3
This study was a large-scale, longitudinal cohort study. The study population was an
4
apparently healthy population recruited during annual routine health check-up visits at
5
Kangjian Community Health Center. The subjects also provided a general history of
6
their comorbidities. No patients were involved in setting the research question or
7
outcome measures or were involved in the design or implementation of the study. This
8
study was conducted according to the principles expressed in the Declaration of
9
Helsinki. The Ethics Committees of Kangjian Community Health Center approved the
10
protocol of this observational study and waived the need for written informed consent
11
because the data were analyzed anonymously.
12
We enrolled study subjects aged ≥65 years between January 1, 2009, and December
13
31, 2012. We excluded subjects with hypertension, DM, preexisting CVD,
14
hyperlipidemia, CKD (reduced estimated glomerular filtration rate (eGFR) of <60
15
mL/min per 1.73 m2), overweight or obesity (body mass index (BMI) of ≥25 kg/m2),
16
or hyperuricemia or gout who were taking medication for the condition. Baseline
17
demographic and clinical data were collected at the initiation of this study. We used
18
the baseline SUA measurement as the study entry date. Eligible subjects visited the
19
center once every 12 months and were followed until death, loss to follow-up, or for 4
20
years from the initiation of this study. Indications for uric acid-lowering drugs were
21
determined by each patient’s physician during the observation period.
22 5
1
Primary outcome and definitions
2
The end point for this study was incident CHF events. End point criteria included
3
incident CHF events diagnosed by a physician and the patient receiving medical
4
treatment for CHF and 1) pulmonary edema/congestion by chest X-ray and/or 2)
5
dilated ventricle or poor LV function by echocardiography or ventriculography or
6
evidence of LV diastolic dysfunction [12]. If the patients developed CHF events at
7
any hospital, the hospital and physician records were referred to for the diagnosis of
8
CHF events, and if CHF events occurred outside a hospital, the experts reached a
9
consensus regarding the diagnosis of CHF events after a comprehensive consideration
10
of the history, recent situations, signs, and symptoms before and after the CHF events
11
from the patient’s medical records at our center and descriptions provided by family
12
members.
13
Hyperuricemia was defined as >7.0 mg/dL of SUA in men and ≥6.0 mg/dL in women
14
as the standard definition for most studies [3-8]. Blood pressure (BP) and pulse rate
15
readings were obtained using an automatic brachial sphygmomanometer (OMRON
16
Corporation, Kyoto, Japan). Two BP examinations were taken after subjects had been
17
seated and were resting quietly for >5 minutes with their feet on the ground and their
18
backs supported. The mean systolic and diastolic BP of each of the subjects was
19
calculated from the recorded measurements [13]. BMI was calculated as BMI=weight
20
(kg)/height2 (m2) from the weight measured to the nearest 0.5 kg and the height
21
measured to the nearest 0.1 cm. Hypertension was defined as systolic BP ≥140 mmHg
22
and/or diastolic BP ≥90 mmHg and/or the use of antihypertensive medications. DM 6
1
was defined as fasting glucose 126 mg/dL or the use of hypoglycemic medication [12].
2
We defined preexisting CVD as a history of coronary heart disease, CHF, stroke, or
3
peripheral vascular disease. Hyperlipidemia was defined by serum concentrations of
4
cholesterol ≥5.7 mmol/L, triglyceride ≥1.7 mmol/L, low density lipoprotein (LDL)
5
levels ≥3.6 mmol/L, or as patients who were currently undergoing treatment with
6
lipid-lowering agents [14]. The eGFR levels were calculated by the simplified
7
Modification of Diet in Renal Disease equation. CKD was defined as having an eGFR
8
of <60 mL/min per 1.73 m2 [15]. Individuals who reported smoking at least one
9
cigarette per day during the year before the examination were classified as having a
10
smoking habit. Individuals who reported consuming more than 20 g/day of ethanol
11
during the same time period were classified as having a drinking habit.
12
Baseline biochemical parameters, including SUA, hemoglobin, total protein, serum
13
albumin, serum creatinine, total cholesterol, triglycerides, low-density lipoprotein
14
(LDL) and high-density lipoprotein (HDL), were collected every 12 months after this
15
study was initiated.
16
Statistical analysis
17
We divided the eligible subjects into hyperuricemia and normouricemia groups using
18
baseline SUA levels. Data are expressed as the mean±standard derivation (SD) or as
19
percent frequency, unless otherwise specified. Comparisons between two groups were
20
performed with t tests for normally distributed variables and χ2 tests for categorical
21
data. Survival was calculated using the Kaplan-Meier method, and differences
22
between distributions of survival were assessed with a log-rank test. We analyzed the 7
1
hazard ratio (HR) of risk for incident CHF events using multivariable Cox regression
2
models. We compared cumulative incidences of incident CHF events over 4 years
3
between subjects with hyperuricemia and those with normouricemia and calculated
4
the HR for incident CHF events by crude analysis and after adjusting for age, sex,
5
smoking status and drinking status (Model 1); with the addition of baseline BMI,
6
systolic and diastolic BP (Model 2); and with the addition of baseline eGFR, total
7
cholesterol, triglycerides, LDL and HDL (Model 3). In addition, because the
8
distribution of SUA differed between male and female subjects, multivariable
9
regression analyses were also stratified by sex. Furthermore, we calculated cumulative
10
incidences of incident CHF events over 4 years for sex-specific quartiles by their SUA
11
levels at baseline (<4.6, 4.6 to 5.1, 5.2 to 6.2, and ≥6.3 mg/dL in males and <4.6, 4.6
12
to 5.2, 5.3 to 5.8, and ≥5.9 mg/dL in females). The statistically significant level was
13
set at α=0.05, and all statistical analyses were 2-sided. All statistical analyses were
14
performed with GraphPad Software (version 8).
15
Sensitivity analysis
16
To reduce selection bias, propensity score matching (PSM) was applied to select the
17
two groups with and without hyperuricemia at a 1:1 ratio [16]. The propensity score
18
was calculated using logistic regression to estimate the probability of the
19
hyperuricemia assignment based on all baseline variables. We re-estimated the odds
20
ratio [OR] of incident CHF events between the PSM-derived groups.
21 22 8
1
Results
2
Patient characteristics at baseline
3
There were 9637 subjects aged ≥65 years who underwent annual medical
4
examinations at the health center both in 2009 and 2012. Of the 9637 subjects, we
5
excluded 6888 subjects with comorbidities at baseline: 1416 had hypertension, 1019
6
had preexisting CVD, 1194 had DM, 865 had CKD, 1198 had hyperlipidemia, 879
7
were overweight/obese, and 317 had hyperuricemia or gout and were taking
8
medication for their condition (Figure 1). Thus, 2749 patients were enrolled in this
9
study (mean age of 70.9±6.0 years, 1457 men, 53.0%) with a mean follow-up of
10
47.4±3.6 months.
11
SUA concentrations showed an approximate Gaussian distribution (range, 2.3-15.7
12
mg/dL; mean±SD, 5.5±1.4 mg/dL). The baseline demographic and clinical
13
characteristics of this study are shown in Table 1 and are categorized according to sex
14
and SUA concentration. The hyperuricemic subjects showed mild but significant
15
differences in systolic BP and eGFR from the normouricemic subjects, although both
16
groups had values within the normal range. Hyperuricemic subjects more frequently
17
had smoking and drinking habits and presented with higher hemoglobin, total protein,
18
albumin, serum creatinine, total cholesterol, triglyceride and LDL levels but with a
19
lower eGFR and HDL level than normouricemic subjects in the cohort. Similar
20
differences in baseline characteristics were also observed between male and female
21
subjects, except for serum albumin.
22
Incidence of incident CHF events 9
1
During follow-up, 297 (10.8%) deaths occurred, including 163 (54.9%) CVD deaths.
2
Of those CVD deaths, 69 (42.3%) were due to CHF events. In addition, 55 (2.0%)
3
patients were lost to follow-up in the study population. A total of 129 CHF events
4
occurred in this population, of which 102 (3.7%) were incident CHF events. We
5
compared the incidence of incident CHF events in subjects with hyperuricemia to
6
those with normouricemia (Figure 2) and found that the hyperuricemic subjects
7
showed a significantly higher incidence of incident CHF events than did the
8
normouricemic subjects (6.5% versus 3.1%, OR=2.15, 95% confidence index [CI]
9
1.39-3.33, p=0.001). We also compared the incidences for incident CHF events
10
between hyperuricemia and normouricemia by sex. In males, the hyperuricemic
11
subjects showed a significantly higher incidence of incident CHF events than did the
12
normouricemic subjects (6.9% versus 3.4%, OR=2.10, 95% CI 1.19-3.71, p=0.014).
13
In females, the hyperuricemic subjects showed a significantly higher incidence of
14
incident CHF events than did the normouricemic subjects (6.0% versus 2.8%,
15
OR=2.19, 95% CI 1.10-4.33, p=0.031). In the cohort study, there were no sex
16
differences in terms of CHF incidence (OR=0.82, 95% CI 0.55-1.21, p=0.363). In
17
addition, in the hyperuricemic and normouricemic subjects, there were no sex
18
differences in terms of the incident CHF risk (OR=0.86, 95% CI 0.40-1.83, p=0.849,
19
and OR=0.82, 95% CI 0.51-1.32, p=0.473, respectively).
20
Association of hyperuricemia and incident CHF events using multivariable Cox
21
regression
22
According to the crude analysis, hyperuricemia was a risk factor for incident CHF 10
1
events in this study population (HR=2.12; 95% CI, 1.38-3.24, p=0.001, Table 2). After
2
adjustment, including baseline eGFR, hyperuricemia became an independent risk
3
factor for incident CHF events (HR=2.34, 95% CI 1.50-3.63, p<0.001, total, Model 3;
4
Table 2). When analysis was restricted to males, hyperuricemia remained an
5
independent risk factor for incident CHF events (HR=2.45; 95% CI, 1.35–4.42,
6
p=0.003; male sex, Model 3; Table 2). When the analysis was restricted to females,
7
hyperuricemia also remained an independent risk factor for incident CHF events
8
(HR=2.14; 95% CI, 1.10–4.18, p=0.024; female sex, Model 3; Table 2).
9
Cumulative incidence of incident CHF events between hyperuricemic and
10
normouricemic subjects
11
Compared with normouricemic subjects, hyperuricemic subjects had an increased risk
12
of incident CHF events based on Kaplan-Meier curves (Figure 3). In the cohort study,
13
according to the crude analysis of the risk of incident CHF events, the cumulative risk
14
was significantly higher in the hyperuricemic subjects (HR=2.57, 95% CI 1.52-4.34,
15
p<0.001) than in the normouricemic subjects. Male and female hyperuricemic
16
subjects also had higher cumulative incident CHF risk than their normouricemic
17
counterparts (HR=2.46, 95% CI 1.28-4.81, p=0.009 and HR=2.66, 95% CI 1.16-6.10,
18
p=0.021; Figure 3, respectively).
19
Analysis of incidence of incident CHF events by sex for SUA quartiles
20
We calculated the incidences of incident CHF events by sex for the quartile ranges of
21
SUA, including <4.6, 4.6 to 5.1, 5.2 to 6.2, and ≥6.3 mg/dL in males and <4.6, 4.6 to
22
5.2, 5.3 to 5.8, and ≥5.9 mg/dL in females (Figure 4 and Figure 5, respectively). The 11
1
incidences of incident CHF events were 2.6%, 3.3%, 3.9%, and 6.1%, respectively, in
2
male subjects and 2.4%, 2.8%, 4.0%, and 4.9%, respectively, in female subjects. The
3
results showed that individuals with higher baseline SUA levels had a higher
4
incidence of incident CHF events across both sexes.
5
Sensitivity analysis
6
PSM analysis was performed using logistic regression analysis to create a propensity
7
score for the hyperuricemic and normouricemic groups with a logistic regression
8
model. The following variables were entered into the propensity model: age, sex, BMI,
9
systolic BP, diastolic BP, current smoking habit, drinking habit, albumin, total
10
cholesterol, and eGFR. One-to-one matching without replacement was performed
11
with a 0.1 caliper width. PSM matching was successfully applied to 375 pairs of
12
patients. As expected, baseline characteristics were well balanced in the matched
13
group (Table 3). After PSM, the hyperuricemic subjects showed a significantly higher
14
incidence of incident CHF than the normouricemic subjects in the cohort study (6.6%
15
versus 3.2%, OR=2.13, 95% CI 1.36-3.34, p<0.001). Similarly, in males,
16
hyperuricemic subjects showed a significantly higher incidence of incident CHF
17
events than their normouricemic counterparts (6.8% versus 3.5%, OR=2.07, 95% CI
18
1.19-3.70, p=0.016). This trend was also found for females, with hyperuricemic
19
subjects showing a significantly higher incidence of incident CHF events than their
20
normouricemic counterparts (5.9% versus 2.7%, OR=2.17, 95% CI 1.14-4.19,
21
p=0.020).
22 12
1
Discussion
2
Our primary finding was that asymptomatic hyperuricemic subjects without
3
comorbidities had a significantly increased (2.34-fold) risk for developing incident
4
CHF events. In addition, there was no sex differences between hyperuricemic and
5
normouricemic subjects regarding CHF risk.
6
CHF is a major health problem, and the considerable morbidity and mortality
7
burden attributable to this disease continues to increase as the population ages [17]. In
8
CHF, SUA levels may rise due to increased purine catabolism resulting from tissue
9
hypoxia, apoptosis, and/or enhanced or unregulated xanthine oxidase receptor activity
10
[18]. In a large prospective cohort study, CHF decompensation was independently
11
associated with hyperuricemia in men with a high cardiovascular risk profile [19]. A
12
previous study with 83683 Austrian men across a wide age range found that men with
13
baseline SUA values >6.7 mg/dL had a 50% greater risk for fatal CHF than did those
14
with SUA concentrations ≤4.6 mg/dL during a median of 13.6 years of follow-up [20].
15
In a prospective cohort study of 41879 Chinese men and 48514 women,
16
hyperuricemia (SUA level >7 mg/dL) was an independent risk factor for CHF
17
mortality; CHF mortality increased 13% for every 1 mg/dL increase in the level of
18
SUA [21]. In the Apolipoprotein Mortality Risk study, moderate levels of SUA appear
19
to be associated with an increased incidence of CHF in middle-aged subjects without
20
prior CVD. These associations seem to increase gradually from lower to higher levels
21
of SUA [22]. Although they comprised a large number of subjects, the studies by
22
Strasak et al. did not report on risk associations between SUA and nonfatal CHF [23]. 13
1
In the study reporting on a 29-year follow-up of 2321 middle-aged men, SUA was no
2
longer found to be a significant risk factor for CHF when adjusted for established risk
3
factors [23]. Nonetheless, it is worth noting that SUA is inversely proportional to
4
estimated stroke volume and cardiac output in apparently healthy subjects from Italy.
5
Researchers selected 734 adult subjects who were not taking antihypertensive,
6
antidiabetic, lipid-lowering, or uric acid-lowering drugs, which may reduce selection
7
bias and help exclude the role of SUA in their findings from that of other comorbid
8
conditions [24].
9
SUA is also known to be associated with other important risk factors of CHD, so its
10
independent relationship with CHD has been questioned [25]. Known risk factors, and
11
other potential confounding factors may contribute to an under- or overestimation of
12
the association between hyperuricemia and the risk of related CHF events. Most
13
previous studies recruited eligible subjects with hyperuricemia, of which the majority
14
already carry cardiometabolic comorbidities [26]. Thus, an alternative approach to
15
studying the relationship between hyperuricemia and CHF events was to limit the
16
study population to only subjects with hyperuricemia who do not have other
17
cardiovascular, metabolic or renal risk factors. The importance of our study was that
18
we evaluated subjects with asymptomatic hyperuricemia who did not exhibit cardiac
19
or metabolic risk factors to determine whether they were still at risk for CHF. Indeed,
20
we found that the presence of hyperuricemia was an independent risk factor for
21
incident CHF events in elderly subjects without comorbidities. The results of the
22
present study may help to distinguish the role of hyperuricemia from that of other 14
1
comorbid conditions in incident CHF events. In the present study, there were no sex
2
differences in cumulative CHF incidence. The changing association between elderly
3
men and postmenopausal women suggests that there may be an interaction with sex
4
hormones [27]. Notably, in our study, subjects with hyperuricemia had a higher
5
prevalence of smoking and alcohol consumption, leading to an increase in metabolic
6
abnormalities, including increased levels of triglycerides and LDL cholesterol, which
7
might explain the presence of hyperuricemia. As is well known, smoking, drinking,
8
and elevated levels of triglycerides and LDL cholesterol increase one’s risk of chronic
9
heart failure. Therefore, to reduce selection bias and make baseline characteristics
10
comparable, we performed sensitivity analysis using PSM, which was applied to
11
select the two groups with and without hyperuricemia at a 1:1 ratio; and then, baseline
12
characteristics were well balanced between matched subjects, and similar trends were
13
observed between two matched groups. It is no doubt that smoking cessation, alcohol
14
withdrawal and management of dyslipidemia are beneficial for alleviating
15
hyperuricemia, thereby reducing the incidence of chronic heart failure. Thus, to
16
further identify these findings in the present study, we should perform a prospective
17
study involving those subjects with comparable baseline characteristics.
18
The strength of our study lies in our separation of subjects into subsets, including a
19
subset of subjects who were normotensive, without other comorbidities. While the
20
results of this study are likely true for elderly populations, the application of these
21
findings to younger populations remains to be elucidated. In addition, as it was an
22
observational design, subjects were not randomly assigned, and thus, causality could 15
1
not be assessed. PSM is not a substitute for randomization, and despite the application
2
of analytical tools to reduce bias by indication, residual confounding or reverse
3
causality phenomena cannot be completely ruled out [28]. We failed to exclude
4
subjects whose eGFR was 60 to 75 mL/min per 1.73 m2, which qualifies as abnormal
5
renal function but is not defined as CKD. Failure to exclude these subjects may
6
interfere with the analysis of the association between SUA and incident CHF events.
7
Meanwhile, subjects with hyperuricemia may have an increase in metabolic
8
abnormalities, including higher levels of blood glucose, triglycerides or LDL.
9
Unfortunately, blood glucose levels were not measured in these subjects in the present
10
study, which may lead to increase selection bias in our study. Moreover, our analysis
11
used only baseline data, which did not cover the change in SUA levels during the
12
observation period. Finally, the results of our study may not be generalizable to other
13
ethnic populations, as all patients were recruited from China.
14
In conclusion, the presence of hyperuricemia in elderly adults without comorbidities
15
carried a 2.34-fold risk for developing incident CHF events within 4 years, and there
16
were no sex differences in terms of cumulative CHF incidence. Asymptomatic
17
hyperuricemia was a valuable biomarker for predicting the development of incident
18
CHF events. Further prospective research is needed to evaluate whether strategies to
19
reduce SUA over time can prevent this condition.
20 21 22 16
1
Acknowledgments
2
We express our gratitude to all patients who participated in the study.
3 4
Declaration of conflicting interests
5
The authors declare that they have no potential conflicts of interest with respect to the
6
research, authorship and/or publication of this article.
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 17
1
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5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 22
1
Figure legends
2
Figure 1. Flow diagram of study enrollment.
3
CHF: congestive heart failure; CVD: cardiovascular disease; CKD: chronic kidney
4
disease; BMI: body mass index; SUA: serum uric acid.
5 6
Figure 2. The incidence of incident CHF events between hyperuricemic and
7
normouricemic subjects.
8
CHF: congestive heart failure.
9 10
Figure 3. The cumulative incidence of incident CHF events between hyperuricemic
11
and normouricemic subjects.
12
CHF: congestive heart failure; HR: hazard ratio; CI: confidence index.
13 14
Figure 4. Incidence of incident CHF events in SUA quartiles in male subjects.
15
CHF: congestive heart failure; SUA: serum uric acid.
16 17
Figure 5. Incidence of incident CHF events in quartiles of SUA in female subjects.
18
CHF: congestive heart failure; SUA: serum uric acid.
19 20
23
Table 1. Baseline characteristics of study subjects stratified by serum SUA. Total (n=2749)
Male (n=1457)
Normouricemia
Hyperuricemia
p-value
Number of subjects
2289
460
Male sex
52.3%
56.5%
0.097
Age, years
70.9±6.0
70.7±5.8
BMI, kg/m2
22.4±1.6
Pulse rate, bpm
Normouricemia Hyperuricemia
Female (n=1292) p-value
Normouricemia
Hyperuricemia
1092
200
p-value
1197
260
0.414
71.4±6.1
71.0±6.0
0.384
70.5±5.9
70.3±5.4
0.669
22.3±1.6
0.242
22.4±1.6
22.3±1.6
0.197
22.5±1.6
22.4±1.6
0.819
73.0±11.0
73.9±9.1
0.145
72.6±10.6
74.2±8.7
0.022
73.3±11.4
73.4±9.8
0.942
Systolic BP, mmHg
120.4±10.8
121.9±8.9
0.005
120.2±11.0
121.9±8.9
0.009
120.6±10.6
121.9±9.0
0.064
Diastolic BP, mmHg
73.5±7.6
74.0±7.1
0.239
73.3±7.6
74.2±7.0
0.097
73.7±7.6
73.7±7.2
0.959
Current smoking habit
28.7%
57.6%
<0.001
53.9%
63.1%
<0.001
14.6%
26.8%
<0.001
Drinking habit
37.1%
69.4%
<0.001
60.4%
70.2%
<0.001
13.9%
29.7%
<0.001
13.4±1.3
14.3±1.2
<0.001
13.4±1.3
14.3±1.2
<0.001
13.5±1.3
14.3±1.2
<0.001
Hemoglobin (g/dL)
24
Total protein, g/dL
7.2±0.5
7.3±0.6
<0.001
7.2±0.5
7.3±0.5
0.005
7.2±0.5
7.4±0.6
<0.001
Albumin, g/dL
4.3±0.4
4.4±0.4
0.001
4.3±0.4
4.4±0.4
0.484
4.3±0.4
4.5±0.4
<0.001
Total cholesterol (mmol/L)
5.1±1.1
5.3±1.2
<0.001
5.1±1.1
5.3±1.0
0.007
5.1±1.1
5.4±1.2
0.005
Triglycerides (mmol/L)
1.5±0.9
1.6±1.0
<0.001
1.5±1.0
1.6±1.0
<0.001
1.5±0.8
1.6±1.0
<0.001
HDL (mmol/L)
1.7±0.5
1.5±0.4
<0.001
1.7±0.4
1.5±0.3
<0.001
1.8±0.5
1.5±0.4
<0.001
LDL (mmol/L)
3.3±0.9
3.5±0.9
<0.001
3.3±0.9
3.5±0.8
<0.001
3.3±0.9
3.5±1.0
0.001
87.7±12.3
83.6±11.2
<0.001
85.1±11.7
81.5±10.8
<0.001
89.6±12.1
85.2±11.5
<0.001
0.8±0.1
0.9±0.1
<0.001
0.8±0.1
0.9±0.1
<0.001
0.7±0.1
0.8±0.1
<0.001
eGFR, mL/min per 1.73 m2 Serum creatinine, mg/dL
SUA: serum uric acid; BMI: body mass index; BP: blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.
25
Table 2. Association between hyperuricemia and quartiles of serum uric acid and incident CHF events Crude
Model 1
Model 2
Model 3
HR
95% CI
p-value
HR
95% CI
p-value
HR
95% CI
p-value
HR
95% CI
p-value
2.12
1.38-3.24
0.001
2.31
1.50-3.53
<0.001
2.30
1.50-3.53
<0.001
2.34
1.50-3.63
<0.001
Hyperuricemia
2.08
1.19-3.60
0.010
2.51
1.44-4.38
0.001
2.51
1.44-4.38
0.001
2.45
1.36-4.42
0.003
SUA (<4.6 mg/dL)
Reference
SUA (4.6-5.1 mg/dL)
1.19
1.09-3.21
0.013
1.18
1.09-3.38
0.021
1.16
1.10-3.36
0.023
1.13
1.07-3.45
0.030
SUA (5.2-6.2 mg/dL)
1.37
1.10-3.36
0.001
1.31
1.10-3.37
0.002
1.27
1.11-3.45
0.007
1.24
1.10-3.41
0.012
SUA (≥6.3 mg/dL)
2.23
1.39-4.78
<0.001
2.22
1.38-4.76
<0.001
2.18
1.40-4.78
<0.001
2.15
1.39-4.78
0.001
2.15
1.10-4.19
0.024
2.15
1.10-4.19
0.024
2.15
1.10-4.18
0.024
2.14
1.10-4.18
0.024
Total=2749 Hyperuricemia Male sex=1457
Female sex=1292 Hyperuricemia
26
SUA (<4.6 mg/dL)
Reference
SUA (4.6-5.2 mg/dL)
1.17
1.07-3.41
0.011
1.16
1.07-3.46
0.014
1.13
1.07-3.47
0.017
1.10
1.06-3.39
0.028
SUA (5.3-5.8 mg/dL)
1.28
1.12-3.37
0.001
1.25
1.12-3.37
0.005
1.20
1.11-3.39
0.009
1.17
1.10-3.41
0.013
SUA (≥5.9 mg/dL)
2.36
1.21-4.61
<0.001
2.35
1.21-4.62
<0.001
2.31
1.20-4.62
<0.001
2.25
1.21-4.65
0.001
CHF: congestive heart failure; SUA: serum uric acid; HR: hazard ratio; CI: confidence index.
27
Table 3. Baseline characteristics of study subjects stratified by serum SUA with propensity score matching. Normouricemia
Hyperuricemia
375
375
53.4%
53.7%
0.568
Age, years
71.3±6.1
71.5±6.1
0.714
BMI, kg/m2
22.6±1.6
22.3±1.6
0.826
Pulse rate, bpm
73.2±8.6
73.6±8.7
0.439
Systolic BP, mmHg
120.5±9.0
120.8±8.9
0.139
Diastolic BP, mmHg
73.9±7.1
74.2±7.0
0.284
Current smoking habit
56.4%
56.7%
0.497
Drinking habit
64.6%
64.8%
0.376
Hemoglobin (g/dL)
13.7±1.2
13.8±1.2
0.496
Total protein, g/dL
7.2±0.5
7.2±0.6
0.738
Number of subjects Male sex
28
p-value
Albumin, g/dL
4.4±0.4
4.4±0.4
0.694
Total cholesterol (mmol/L)
5.2±1.1
5.2±1.2
0.561
Triglycerides (mmol/L)
1.6±0.9
1.6±1.0
0.723
HDL (mmol/L)
1.6±0.5
1.6±0.4
0.715
LDL (mmol/L)
3.5±1.0
3.5±1.0
0.133
83.7±11.2
83.5±11.1
0.371
0.8±0.1
0.8±0.1
0.684
eGFR, mL/min per 1.73 m2 Serum creatinine, mg/dL
SUA: serum uric acid; BMI: body mass index; BP: blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate.
29
Highlights · Asymptomatic hyperuricemia was associated with incident congestive heart failure (CHF) in elderly patients without comorbidities. · Male and female hyperuricemic subjects also had higher cumulative incident CHF risk than their counterparts, respectively. · There was no sex difference in the cumulative CHF incidence.