Coronary artery disease (CAD) is a major cause of mortality worldwide [
The risk factors for CAD in young patients are different from those in older patients [
The urokinase plasminogen activator receptor (uPAR) is a three-domain membrane-bound receptor [
The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Shunde Hospital, Southern Medical University, China. Written informed consent was obtained from all participants. In accordance with the previous reports, young patients with CAD were defined as those presenting with initial CAD symptoms at ≤55 years of age [
A total of 188 age-matched individuals with normal CAG or negative findings by ultrafast coronary computed tomography angiography (CCTA) were enrolled as controls. Coronary angiography or CCTA was performed because of chest discomfort with suspected ischemic findings, such as ST deviation in an electrocardiograph, regional dyskinesia by echocardiography, or difficulty in differential diagnosis. Patients with uncontrolled infectious diseases, autoimmune diseases, hormone replacement therapy after menopause, malignancy, severe renal dysfunction (creatinine ≥ 3 mg/dL), and psychiatric disorders were excluded.
Venous blood samples were collected after overnight fasting. Levels of fasting plasma glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and serum creatinine (SCr) were measured using an Olympus AU2700 automatic biochemical analyzer (Japan). Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald equation. We used the high-sensitivity nephelometric method to determine the levels of hs-CRP. After centrifugation at 1500 ×g for 10 min at 4°C, plasma samples were stored at −80°C for future measurements of levels of suPAR. Levels of suPAR were measured using the commercial ELISA suPARnostic kit (ViroGates, Copenhagen, Denmark) according to the manufacturer’s instructions. The interassay and intra-assay coefficients of variation were 6.2% and 4.3%, respectively. It has previously been shown that suPAR is highly stable throughout several freezing and thawing cycles [
Conventional CAD risk factors evaluated in this study included the following: (1) Positive family history of premature CAD was defined as a diagnosis of CAD in a first-degree male relative < 55 years old or first-degree female relative < 65 years old. (2) With regard to smoking status, participants were classified as current smokers if they reported smoking regularly during the preceding year. Subjects who had never smoked or had stopped smoking at least 1 year before enrollment were classified as nonsmokers. (3) Hypertension was defined as per the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VII guidelines [
Based on the conventional risk factors for CAD, we also calculated the absolute 10 year CAD event risk scores based on the FRS system modified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines [
All statistical analysis was performed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). Continuous variables are presented as median (interquartile range) or mean (standard deviation) as appropriate. Categorical variables are expressed as percentages. Continuous variables were compared using the Mann–Whitney
Multiple logistic regression analysis was performed to evaluate the risk factors for CAD. Age, smoking history, hypertension, DM, family history of CAD, BMI, TG, TC, HDL-C, LDL-C, hs-CRP, eGFR, and suPAR levels were set as independent variables in the regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
We screened 214 young patients diagnosed with CAD by CAG and 203 age-matched controls. Based on the predefined exclusion criteria, 17 patients and 15 controls were excluded (eight patients with CAD, five controls with severe renal dysfunction, two patients with CAD with severe hepatic insufficiency, six controls with a history of anxiety or depression, eight patients with CAD, and four controls with uncontrolled infectious diseases). Therefore, 196 young patients with CAD (142 men, 54 women) and 188 age-matched controls (101 men, 87 women) were ultimately enrolled. Of the young patients diagnosed with CAD, 48 were classified as having unstable angina, 86 as having ST-segment elevation myocardial infarction, and 62 as having non-ST-segment elevation myocardial infarction. Table
Demographic and clinical characteristics of CAD patients and controls.
CAD group ( |
Control group ( |
| |
---|---|---|---|
Age (years) | 48.3 ± 9.3 | 49.8 ± 10.4 | 0.14 |
Men ( |
142 (72.4%) | 92 (48.9%) | <0.0001 |
CAD family history ( |
15 (7.7%) | 11 (5.9%) | 0.55 |
Current smokers ( |
76 (38.8%) | 31 (16.5%) | <0.0001 |
Hypertension ( |
49 (25.0%) | 35 (18.6%) | 0.14 |
Systolic blood pressure (mmHg) | 124.1 ± 12.5 | 123.0 ± 12.8 | 0.39 |
Diastolic blood pressure (mmHg) | 73.2 ± 9.1 | 71.6 ± 8.8 | 0.08 |
Diabetes mellitus ( |
23 (11.7%) | 17 (9.0%) | 0.41 |
Fasting blood glucose (mg/dl) | 90.3 ± 17.8 | 92.3 ± 16.7 | 0.26 |
Dyslipidemia ( |
63 (32.1%) | 41 (21.8%) | 0.03 |
TC (mg/dl) | 189.0 ± 38.1 | 184.7 ± 39.5 | 0.28 |
LDL-C (mg/dl) | 129.3 ± 27.9 | 125.1 ± 26.0 | 0.13 |
HDL-C (mg/dl) | 41.5 ± 13.8 | 43.3 ± 13.5 | 0.14 |
TG (mg/dl) | 157.6 ± 29.4 | 146.5 ± 28.2 | 0.0002 |
Overweight/obesity ( |
61 (31.1%) | 40 (21.3%) | 0.04 |
Body mass index (kg/m2) | 24.8 ± 5.3 | 23.7 ± 4.6 | 0.03 |
eGFR (mL/min/1.73 m2) | 111.2 ± 35.0 | 115.4 ± 39.8 | 0.27 |
hs-CRP (mg/dl) | 5.36 (1.24–11.65) | 2.28 (0.75–7.21) | <0.0001 |
suPAR (ng/ml) | 5.8 (1.3–11.8) | 2.8 (1.0–6.5) | <0.0001 |
10-year CAD event risk (%) | 5.8 ± 4.7 | 5.0 ± 4.0 | 0.07 |
Data are presented as mean (±SD), median (interquartile range), or percentages. CAD: coronary artery disease; eGFR: estimated glomerular filtration rate; TC: total cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein-cholesterol; LDL-C: low-density lipoprotein-cholesterol; hs-CRP: high-sensitivity C-reactive protein; suPAR: soluble urokinase plasminogen activator receptor.
Compared with the control group, the CAD group had a higher proportion of smoking, overweight/obesity, and dyslipidemia (
Table
Correlation of suPAR and other cardiovascular risk factors.
Variables |
|
|
---|---|---|
Age | 0.20 | 0.04 |
Sex | −0.11 | 0.21 |
Smoking | 0.33 | 0.008 |
SBP | 0.09 | 0.78 |
DBP | 0.17 | 0.12 |
FPG | −0.10 | 0.56 |
TC | 0.15 | 0.11 |
LDL-C | 0.19 | 0.09 |
HDL-C | −0.14 | 0.08 |
TG | 0.18 | 0.12 |
BMI | 0.21 | 0.03 |
eGFR | 0.15 | 0.26 |
hs-CRP | 0.31 | 0.01 |
suPAR and hs-CRP were skewed variables and logarithmically transformed. suPAR: soluble urokinase plasminogen activator receptor; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting blood glucose; TC: total cholesterol; LDL-C: low-density lipoprotein-cholesterol; HDL-C: high-density lipoprotein-cholesterol; TG: triglyceride; BMI: body mass index; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitivity C-reactive protein.
Multivariate logistic regression analysis revealed that male sex (OR = 3.12, 95% CI = 1.18–8.25,
Risk factors for CAD in young patients in multivariate logistic regression analysis.
Risk factors | OR | 95% CI |
|
---|---|---|---|
Sex (male versus female) | 3.12 | 1.18–8.25 | 0.02 |
Age (per 10 years) | 1.32 | 0.85–2.05 | 0.22 |
Smoking (yes versus no) | 3.41 | 1.55–7.50 | 0.002 |
CAD family history (yes versus no) | 1.10 | 0.58–2.09 | 0.77 |
BMI (≥24 kg/m2 versus <24 kg/m2) | 1.34 | 0.97–1.85 | 0.08 |
DM (yes versus no) | 1.21 | 0.82–1.76 | 0.33 |
Hypertension (yes versus no) | 1.25 | 0.37–4.22 | 0.72 |
TG (≥1.7 mmol/L versus <1.7 mmol/L) | 1.89 | 1.10–3.25 | 0.02 |
TC (≥5.18 mmol/L versus <5.18 mmol/L) | 1.04 | 0.75–1.44 | 0.81 |
LDL-C (≥3.37 mmol/L versus <3.37 mmol/L) | 1.17 | 0.88–1.56 | 0.28 |
HDL-C (≥1.04 mmol/L versus <1.04 mmol/L) | 0.97 | 0.12–7.84 | 0.98 |
eGFR (per 10 mL/min/1.73 m2) | 1.58 | 0.42–5.94 | 0.50 |
Log hs-CRP (per SD) | 1.24 | 1.02–1.51 | 0.03 |
Log suPAR (per SD) | 1.37 | 1.09–1.72 | 0.007 |
BMI: body mass index; CAD: coronary artery disease; CHD: coronary heart disease; DM: diabetes mellitus; CI: confidence interval; eGFR: estimated glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; hs-CRP: high-sensitivity C-reactive protein; LDL-C: low-density lipoprotein cholesterol; OR: odds ratio; suPAR: soluble urokinase plasminogen activator receptor; TC: total cholesterol; TG: triglyceride.
To our knowledge, this is the first report of suPAR being an independent risk factor for CAD in young Chinese patients. This correlation was observed even after adjustment for traditional cardiovascular risk factors, including hypertension, smoking, DM, dyslipidemia, and hs-CRP levels.
The immune system plays an important role in the pathogenesis of atherosclerosis. Chronic low-grade inflammation is significantly associated with the risk of CVD, while hs-CRP is the most common recommended risk marker of inflammation in cardiovascular risk stratification and has been widely evaluated in epidemiological studies [
Compared with hs-CRP, suPAR may be a more reliable factor for evaluating the risk of CAD. First, the role of hs-CRP in inflammation is controversial and it has been suggested that hs-CRP is merely a passive risk marker rather than a risk factor [
The exact pathophysiological mechanisms underlying the association between suPAR and CAD are still unclear, but we suggest several possibilities. First, suPAR and its ligand are involved in many pathogenic pathways, including pericellular proteolysis and matrix degradation, plasminogen activation and fibrinolysis, cell adhesion, migration, and proliferation [
It has previously been reported that lifestyle modification, such as smoking cessation, and weight loss, would lower the levels of plasma suPAR [
The current study has some limitations. First, the case-control design of the study could not definitely evaluate a potential risk factor since reverse causality may exist. However, suPAR levels have been shown to be within minimal variation after acute myocardial infarction [
We report that suPAR, a novel inflammatory marker, is positively associated with the risk of CAD in young Chinese patients. Further studies to evaluate the effect of anti-inflammatory treatment on suPAR levels and the risk of CAD are needed.
The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Shunde Hospital, Southern Medical University. Written informed consent was obtained from all participants.
The funding source had no role in the study design, data collection, data analysis, data interpretation, or writing of the article.
The authors declare that they have no competing interests.
Yuli Huang is the first author and performed the data collection, data analysis, and manuscript preparation. Haobin Zhou and Yu Wu performed the data analysis and manuscript preparation. You Yang and Wensheng Li performed the data collection. Yuli Huang and Jianhua Lu are the principle investigators and are responsible for the study design, data collection, data analysis, and manuscript preparation. The manuscript was approved by all above authors.
This work is supported by the Key Specialist Department Training Project of Foshan City, Guangdong, China (FSPY3-2015034).