Study population
The study (ClinicalTrials.gov Identifier: NCT03616769) was a multi-center prospective Cohort Study. The first cross-sectional survey was conducted in 2011. The eligible participants were followed up from November 2011 to June 2018 (mean follow-up month was 68.71±11.35). During the followup time, 147subjects had missing data and 126 had no compliance. Thus, the study sample actually comprised 3,640 valid participants (1927 male, 1713 female), whose age older than or equal to 35 years (mean age 60.2±10.4 years) were followed up. A total of hospitalized subjects were consecutively enrolled from the cardiology departments of Beijing university affiliated hospitals and Shanghai Tongji university affiliated hospitals. All subjects are under treatment because of cardiovascular diseases. The inclusion criteria were with HAR patients. The exclusion criteria were severe congestive heart failure and severe renal failure subjects. Severe congestive heart failure was defined that above or equal to cardiac functional classify 3 formulated by the New York Heart Association (NYHA). Severe renal failure was defined as an estimated glomerular filtration rate <30 ml/min/1.73m2 (Figure1). All participants gave written informed consent to this study, which was approved by the ethics committee of Tongji University.
Cardiovascular events definitions
Hospitalized myocardial infarction was classified as definite or probable based on chest pain symptoms, cardiac enzyme levels, and electrocardiographic findings, or angioplasty. Coronary heart disease was determined to be present if there was (1) electrocardiographic (ECG) evidence of a prior myocardial infarction, (2) prior coronary artery bypass surgery or angioplasty, (3) Coronary angiography show coronary heart disease, (4) have symptoms of angina and ECG revealed myocardial ischemia performance or laboratory tests showed cardiac enzymes increased and exclude other types of disease, (5) a self-reported history of a physician-diagnosed heart attack. CAD death was classified as “definite” based on chest pain symptoms, hospital records, and medical history.
Assessment of cardiovascular events and Identification of Death from All-Causes and CVD
Cardiovascular events are composed of cardiac including non-fatal myocardial infarction, unstable angina, and coronary revascularization procedures during follow-up time. Exclusion criteria were stale angina (>6 months), revascularization procedure for CAD (>6 months) and myocardial infarction(>6 months).
In this study, the cardiovascular death was only cardiac event death. Medical records and death certificates of all patients who had an event were obtained and validated by cardiologist. Death was confirmed from hospital records or by contact with participants and their families. All materials were reviewed independently by five senior physicians of the cohort study to confirm the cause of death.
Hyperuricemia and Hyporuricemia definitions
Hyperuricemia refers to undertake normal purpurine diet, twice results of determination in different days, SUA ≥ 420 μmol/L or 7mg/dl (male), ≥ 357 μmol/L or 6mg/dl (female) 15. Hyporuricemia refers to undertake normal purpurine diet, twice results of determination in different days, SUA ≤ 178μmol/L or ≤ 3 mg/dl(male), SUA ≤ 149μmol/L or ≤ 2.5 mg/dl (female)26,27.
Framingham Risk Score and High Atherosclerosis Risk
The Framingham risk score (FRS) was calculated based on coronary risk factors, including age, gender, total cholesterol, LDL-C, hypertension and smoking status according to the National Cholesterol Education Program-Adult Treatment Panel III algorithm17. The calculated total scores were used to estimate the 10-year coronary heart disease risk in participants without previous CVD, and when FRS more than 20% or among 10% and 20% was considered HAR27.
Framingham Risk Factors
Diagnostic criteria of hypertension was receiving antihypertensive medication or systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg (1 mm Hg = 133 kPa) as well as both have. The criterion for hypertension refers to patients who have single hypertension disease.
Similarly, the criterion of dyslipidemia also refers to patients who have single dyslipidemia disease. The definition of dyslipidemias is that abnormalities in the serum levels of lipids, including overproduction or deficiency. Abnormal serum lipid profiles include high total cholesterol, high triglycerides, low HDL-C, and elevated LDL-C.
Measurement of Ankle and Arm Blood Pressures
Qualified ultrasonographers measured ankle and brachial systolic blood pressures. Doppler ultrasound (Nicolet Vascular, Elite 100R, USA) was used to measure systolic blood pressure (SBP) in the bilateral brachial, tibial and dorsal pedal arteries. ABI has been shown to be a powerful independent marker of cardiovascular risk, and predictive ability similar to the Framingham criteria29, 30.
A questionnaire was designed to collect information about general characteristics, diagnosis, medical history and relation factors, medical treatment and biochemical examination in all participants.
Baseline measurements
Variables were obtained in all subjects, which include daily habits, medical histories, and blood samples. These samples are measured of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), serum creatinine (Cr), serum uric acid (SUA), glucose and FPG. Blood samples were drawn from an antecubital vein with a 19-gauge needle in a vacutainer system and their serum concentrations were assessed with commercially available kits. Glomerular filtration rate (GFR) was calculated as GFR (ml/min/1.73m2)= 186×creatinine- 1.154× age- 0.203 and GFR (ml/min/1.73m2) =142× creatinine- 1.154 ×age-0.203 in males and females, respectively. Glucose was measured on a Hitachi 717 analyzer (Roche) using enzymatic reagents also from Roche. Presence of symptomatic peripheral arterial disease was evaluated by the Rose questionnaire31. A previous myocardial infarction or ischemic stroke was documented by hospital records. Physical examination data include Body-Mass index (BMI), blood pressure and ABI. Severe congestive heart failure was defined that above or equal to cardiac functional classify 3 formulated by New York Heart Association (NYHA). Severe renal failure was defined as an estimated glomerular filtration rate <30 ml/ min/1.73m2.
Follow-up methods
Follow-up participants were contacted by physicians of the cohort study at annual intervals. Outcomes were obtained during annual phone interviews, 6-yearly follow-up examinations, hospital records, and death records. The primary clinical event endpoints of this study were estimated with all-cause mortality and cardiovascularmortality. The secondary endpoints were examined coronary heart disease (CHD) and CHD risk equivale, including peripheral arterial disease (PAD), stroke, DM, cardiovascular disease incident. Follow-up time was the number of years from the baseline first visit to every participant. For subjects who had more than one event, all the clinical events were considered for the analysis.
Statistical Analysis
All analyses were performed using the R statistical package (version 3.6.2) (http://www.r-project.org32). Continuous variables are expressed as the mean ± SD, and categorical variables as percentage. Continuous and categorical variables differences comparison was made by Independent samples ANOVA (analysis of variance) and the Chi-square test, as appropriate. Kruskal-Wallis test for non-normally distributed continuous variables. A p-value < 0.05 was considered statistically significant. Due to skewed distribution, TC, TG, HDL-C, LDL-C, Cr, SUA were logarithm-transformed (log) in analyses. Crude deaths from all-cause and CVD were examined by SUA stratification. Cumulative event rates were estimated with Kaplan-Meier survival curves, and probability values were calculated with the log-rank test. Cox proportional hazard analyses were performed to test the association of the SUA and deaths from all-causes or CVD. Cox regression model was adjusted for potential confounders, including age, gender, duration of hypertension, smoking state, dyslipidemia history, chronic renal insufficiency history, diabetes mellitus (DM) history, percutaneouscoronary angioplasty ( PTCA) history, coronary artery bypass grafting ( CABG ) history, PAD history, myocardial infarction (MI) history, ischemic stroke history, hypertension, ABI, FRS, eGFR, use diuretics, center, year of screening examination. Potential confounding variables with P < 0.10 were adjusted for multivariate analysis. Restricted cubic splines with knots were used to further explore theshape of the dose-response relationship between the SUA levels and the HR of all-cause mortality and CVD mortality. Knots were at the 5th, 95th, and quartile of SUA distribution. Missing values were handled by K-means clustering imputation. All data P values were 2-tailed, and less than 0.05 were considered significant.
Table 1
Comparison of Subjects’ Baseline Characteristics of Gender Categories According to Serum Uric Acid Levels.
|
Male
|
Female
|
characteristics
|
quartile of SUA levels, umol / L
|
quartile of SUA levels, umol / L
|
0-242.0
|
242.1-312.0
|
312.1-386.75
|
>386.75
|
P value
|
0-242.0
|
242.1-312.0
|
312.1-386.75
|
>386.75
|
P value
|
Age( years)
|
67.3±11.3
|
65.8±11.7
|
65.7±11.8
|
68.0±11.5
|
0.002
|
65.6±10.8
|
67.3±10.5
|
67.7±9.7
|
70.4±9.9
|
<0.001
|
Diabetes , N (%)
|
198(41.8%)
|
174(35.9%)
|
154(31.8%)
|
159(32.9%)
|
0.006
|
310(43.7%)
|
189(42.3%)
|
134(45.1%)
|
99(38.2%)
|
0.372
|
DM duration(years)
|
2.8±5.0
|
3.0±6.0
|
2.3±4.8
|
2.5±5.0
|
0.173
|
3.6±6.1
|
3.8±6.4
|
3.8±7.1
|
3.6±6.9
|
0.925
|
Hypertension, N (%)
|
309(65.2%)
|
324(66.8%)
|
343(70.7%)
|
380(78.7%)
|
<0.001
|
479(78.7%)
|
347(78.7%)
|
252(84.8%)
|
216(83.4)
|
<0.001
|
HT duration(years )
|
8.5±11.5
|
8.9±11.2
|
9.7±12.2
|
10.8±11.3
|
0.012
|
8.3±10.8
|
10.5±11.6
|
12.1±11.8
|
12.6±13.1
|
<0.001
|
Dyslipidemia, N (%)
|
134(34.6%)
|
152(38.0%)
|
185(46.7%)
|
171(40.8%)
|
0.005
|
271(46.5%)
|
161(42.5%)
|
117(50.0%)
|
98(44.1%)
|
0.297
|
DL duration( years )
|
1.3±0.31
|
1.8±0.45
|
1.8±0.41
|
2.1±0.46
|
0.069
|
1.9±0.39
|
1.9±0.43
|
2.0±0.42
|
1.6±0.34
|
0.532
|
Smoking, N (%)
|
310(65.4%)
|
307(63.3%)
|
325(67.0%)
|
320(66.3%)
|
0.648
|
57(8.0%)
|
48(10.7%)
|
27(9.1%)
|
29(11.2%)
|
0.318
|
Smoking duration( years )
|
20.7±1.86
|
20.0±1.81
|
21.4±1.85
|
21.3±1.91
|
0.552
|
2.7±1.02
|
3.4±1.08
|
2.7±0.97
|
4.3±1.32
|
0.218
|
MI History, N (%)
|
87(18.4%)
|
83(17.1%)
|
94(19.4%)
|
102(21.1%)
|
0.439
|
60(8.5%)
|
51(11.4%)
|
34(11.4%)
|
27(10.4%)
|
0.307
|
Diuretics, N (%)
|
105(22.2%)
|
100(20.7%)
|
132(27.2%)
|
195(40.5%)
|
<0.001
|
140(19.8%)
|
116(26.0%)
|
106(35.8%)
|
111(43.0%)
|
<0.001
|
PTCA History, N (%)
|
56(11.8%)
|
70(14.4%)
|
69(14.2%)
|
64(13.3%)
|
0.631
|
59(8.3%)
|
42(9.4%)
|
24(8.1%)
|
18(6.9%)
|
0.721
|
CABG History, N (%)
|
18(3.8%)
|
16(3.3%)
|
19(3.9%)
|
20(4.1%)
|
0.918
|
9(1.3%)
|
7(1.6%)
|
7(2.4%)
|
5(1.9%)
|
0.634
|
IS History, N (%)
|
182(38.4%)
|
163(33.6%)
|
161(33.2%)
|
167(34.6%)
|
0.315
|
212(29.9%)
|
139(31.1%)
|
83(27.9%)
|
83(32.0%)
|
0.719
|
CRI History, N (%)
|
31(6.8%)
|
29(6.3%)
|
38(8.1%)
|
83(17.6%)
|
<0.001
|
56(8.1%)
|
29(6.6%)
|
32(11.0%)
|
53(21.1%)
|
<0.001
|
TG, mmol/L
|
1.4±0.80
|
1.5±0.90
|
1.6±1.00
|
1.8±1.50
|
<0.001
|
1.6±1.10
|
1.8±1.3 0
|
2.0±1.40
|
2.0±1.20
|
<0.001
|
HDL-c, mmol/L
|
1.2±0.40
|
1.2±0.3 0
|
1.1±0.40
|
1.1±0.50
|
0.106
|
1.3±0.40
|
1.2±0.30
|
1.3±0.40
|
1.2±0.40
|
0.001
|
LDL-c, mmol/L
|
2.5±0.80
|
2.7±0.80
|
2.7±0.90
|
2.6±0.80
|
<0.001
|
2.8±0.90
|
2.9±0.80
|
3.0±0.90
|
2.8±1.00
|
0.052
|
CRE
|
93.6±7.39
|
103.2±8.06
|
109.2±8.55
|
138.2±13.17
|
<0.001
|
79.0±6.73
|
84.9±6.83
|
91.2±6.53
|
143.0±15.9.0
|
<0.001
|
Blood glucose
|
6.8±0.30
|
6.4±0.27
|
6.0±0.24
|
6.1±0.26
|
<0.001
|
6.7±0.32
|
6.6±0.28
|
6.6±0.28
|
6.6±0.32
|
0.816
|
BMI, kg/m2
|
23.2±3.4
|
24.7±3.3
|
24.6±3.4
|
24.9±3.7
|
<0.001
|
23.8±3.6
|
24.3±3.8
|
25.1±3.5
|
24.9±4.0
|
<0.001
|
ABI
|
1.01±0.20
|
1.02±0.20
|
0.99±0.20
|
0.99±0.20
|
0.066
|
0.99±0.20
|
0.97±0.20
|
0.95±0.20
|
0.91±0.30
|
<0.001
|
FRS†
|
454(24.7%)
|
459(25.5%)
|
461(25.3%)
|
462(25.1%)
|
0.910
|
408(21.9%)
|
446(24.8%)
|
296(16.7%)
|
258(13.6%)
|
<0.001
|
FRS††
|
357(24.1%)
|
379(25.5%)
|
375(25.3%)
|
373(25.1%)
|
0.647
|
488(27.2%)
|
424(23.1%)
|
287(15.6%)
|
247(12.4%)
|
<0.001
|
systolic blood pressure (SBP), diastolic blood pressure (DBP ), Hypertension (HT), BMI (body mass index.), Total cholesterol (TC), Triglycerides (TG), Fasting plasma glucose (FPG), high density lipoprotein (HDL-c), low density lipoprotein (LDL-c), serum creatinine (Cr),serum uric acid (SUA), diabetes mellitus (DM), myocardial infarction (MI), Ischemic Stroke (IS), chronic renal insufficiency (CRI), Dyslipidemia (DL), cardiovascular disease (CVD), Peripheral arterial disease (PAD), ankle-rachial index (ABI), percutaneouscoronary angioplasty (PTCA), Hazard risk (HR), coronary artery bypass grafting (CABG), Framingham Risk Score (FRS), FRS† Analysis participants with Framingham risk score 10%-20%, FRS†† Analysis participants with Framingham risk score > 20% were identified as at high risks for 10-year coronary heart disease. |
Table 2
Adjusted Hazards Risks for All-cause Mortality and cardiovascular disease (CVD) Mortality By Cox Regression Models According to Serum Uric Acid Levels.
Variable
|
|
SUA
|
|
|
P for difference
|
Characteristic
SUA level, μmol/L
|
Quartile 1
|
Quartile 2
|
Quartile 3
|
Quartile 4
|
|
0-242.0
|
242.0<SUA≤312.0
|
312.0<SUA≤386.75
|
386.75<SUA
|
|
All-causemortality
|
973
|
789
|
672
|
613
|
|
Number of deaths
|
238(24.5%)
|
151(19.1%)
|
154(22.9%)
|
220(35.9%)
|
|
Multivariableadjustment
|
|
|
|
|
|
Model1
|
2.13(1.45-3.09)
|
1
|
1.94(1.23-2.92)
|
2.20(1.73-3.17)
|
<0.001
|
Model 2
|
2.10(1.21-3.12)
|
1
|
1.90(1.19-2.98)
|
2.17(1.70-3.09)
|
<0.001
|
Model 3
|
2.06(1.35-2.90)
|
1
|
1.86(1.54-2.89)
|
2.12(1.63-3.17)
|
<0.001
|
Model 4
|
2.05(1.35-2.90)
|
1
|
1.85(1.54-2.76)
|
2.11(1.59-3.07)
|
<0.001
|
CV mortality
|
973
|
789
|
672
|
613
|
|
Number of deaths
|
119(12.2%)
|
85(10.8%)
|
90(13.4%)
|
112(18.3%)
|
|
Multivariableadjustment
|
|
|
|
|
|
Model1
|
2.21(1.32-3.04)
|
1
|
1.82(1.36-2.94)
|
2.57(1.77-3.32)
|
<0.001
|
Model 2
|
2.18(1.43-2.97)
|
1
|
1.81(1.32-2.93)
|
2.53(1.71-3.30)
|
<0.001
|
Model 3
|
1.98(1.32-2.94)
|
1
|
1.71(1.08-2.85)
|
2.45(1.67-3.22)
|
<0.001
|
Model 4
|
1.95(1.29-2.90)
|
1
|
1.70(1.05-2.81)
|
2.42(1.61-3.12)
|
<0.001
|
Model 1 was adjusted for age and gender, eGFR (estimated glomerular filtration rate), use diuretics
Model 2 was adjusted for model 1 covariates and smoking, alcohol drinking, use of diuretics, a history of heart failure,a history of diabetes, a history of renal insufficiency, a history of metabolic syndrome and a history of stroke
Model 3 was adjusted for model 2 covariates ABI (ankle - brachial index), FRS (Framingham risk score)
Model 4 was adjusted for model 3 covariates central effect, year of screening examination
|