Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an antiapoptotic soluble receptor considered to play an important role in immune modulation and has pro-inflammatory functions. This study was designed to test whether circulating DcR3 levels are associated with coronary artery disease (CAD) severity and predict future major adverse cardiovascular events (MACEs) in patients with CAD. Circulating DcR3 levels and the Syntax score (SXscore) were determined in patients with multivessel CAD. The primary end point was the MACE within 12 months. In total, 152 consecutive patients with angiographically confirmed multivessel CAD who had received percutaneous coronary intervention were enrolled and were divided into 3 groups according to CAD lesion severity. Group 1 was defined as low SXscore (≤13), group 2 as intermediate SXscore (>13 and ≤22), and group 3 as high SXscore (>22). DcR3 levels were significantly higher in the high SXscore group than the other 2 groups (13,602 ± 7,256 vs 8,025 ± 7,789 vs 4,637 ± 4,403 pg/ml, p <0.001). By multivariate analysis, circulating DcR3 levels were identified as an independent predictor for high SXscore (adjusted odds ratio 1.15, 95% confidence interval 1.09 to 1.21; p <0.001). The Kaplan-Meier analysis showed that increased circulating DcR3 levels are associated with enhanced 1-year MACE in patients with multivessel CAD (log-rank p <0.001). In conclusion, increased circulating DcR3 levels are associated with CAD severity and predict future MACE in patients with multivessel CAD.
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor superfamily (TNFRSF) 6b, is a soluble receptor and is considered an immune modulator, based on its neutralizing effects on Fas ligand (FasL), LIGHT, and TNF-like cytokine 1A (TL1A). Recent study has suggested that DcR3 can increase monocyte adhesion to endothelial cells and reduce phagocytic activity of macrophages toward apoptotic bodies and immune complexes. The impaired phagocytosis of apoptotic cells by macrophages may lead to the progression of atherosclerosis in human atherosclerotic plaques. Kidney function as measured by glomerular filtration rate was found to be inversely correlated with the complexity and severity of CAD, which could be quantified by Syntax score (SXscore), a comprehensive anatomic scoring system based on the coronary angiogram. Recent study has shown that DcR3 levels can independently predict cardiovascular and all-cause mortality in patients with end-stage renal disease, who are prone to develop more advanced atherosclerotic CAD. However, whether circulating DcR3 level is associated with coronary atherosclerotic lesion severity and predicts future cardiovascular events in patients with advanced atherosclerotic CAD who underwent percutaneous coronary intervention (PCI) has not been explored. Based on these findings, we conducted a longitudinal analysis to test the hypothesis that DcR3 levels are associated with the severity of CAD and predict future cardiovascular events in patients with multivessel CAD who underwent PCI.
Methods
This study enrolled consecutive patients who were admitted to a tertiary medical referral center for PCI from 2012 to June 2013, with stable CAD and angiographically confirmed multivessel disease, defined as stenosis of ≥50% in ≥2 major epicardial vessels involving ≥2 separate coronary artery territories. Before enrollment, a detailed review of each patient’s chart was conducted to gather data on medications, smoking status, and risk factors for CAD, such as age, hypertension, diabetes mellitus (DM), dyslipidemia, chronic kidney disease (CKD), and other co-morbidities. Smokers were classified as former only if they had successfully abstained for >6 months. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or use of antihypertensive treatment. DM was defined as fasting plasma glucose ≥126 mg/dl or use of hypoglycemic agents. CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m 2 . Patients were excluded if the coronary anatomy was not suitable for PCI or if emergent coronary artery bypass grafting (CABG) surgery was required. Patients with acute coronary syndrome or acute myocardial infarction (MI) who required primary PCI were also excluded. The study was approved by the research ethics committee of Taipei Veterans General Hospital (VGHIRB No.: 2012-03-001AC and 2014-04-005CC), and all participants provided their written informed consent.
After an overnight fast ≥8 hours, blood samples were obtained from all patients. Serum levels of creatinine and lipid profiles including triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured using a Hitachi 7600 autoanalyzer (Hitachi Ltd, Tokyo, Japan). Serum levels of DcR3 (Biovendor, Modrice, Czech Republic) were measured using commercially available enzyme-linked immunosorbent assay (ELISA, BioLegend Inc, San Diego, CA) kits according to the manufacturer’s instructions. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured using an immunoturbidimetric assay and rate nephelometry (IMMAGE; Beckman Coulter, Galway, Ireland).
Two expert angiographers, blind to the patient’s clinical and laboratory data, independently reviewed the coronary angiography. Each coronary lesion with a diameter stenosis of ≥50%, in vessels of ≥1.5 mm, was scored. The latest updated version of the calculation algorithm found online was used for the calculation of the SXscore ( http://www.Syntaxscore.com ). The patients were then divided into different groups according to their SXscore.
All patients were stratified into 3 groups according to their SXscore values in tertile. Patients with SXscore >22 (highest tertile) were defined as the high SXscore group (n = 50, 33%), those with SXscore ≤13 (lowest tertile) as the low SXscore group (n = 51, 34%), and those with SXscore >13 and ≤22 as the intermediate-SXscore group (n = 51, 34%).
All patients included in the study were followed up for 12 months or until the occurrence of a major adverse cardiovascular event (MACE). The study end point was the MACE, defined by a composite of clinical events including death, fatal or nonfatal MI, ischemic stroke, and target vessel revascularization (TVR). All participants were contacted by telephone periodically and their medical records were followed up regularly. No patients dropped out of the study, and all occurrences of adverse events were recorded. Nonfatal MI was defined as an increase of cardiac troponin I with ischemic symptoms and/or characteristic electrocardiographic changes. Ischemic stroke was defined as the presence of a new neurologic deficit lasting for ≥24 hours with definite evidence of a cerebrovascular accident verified by either magnetic resonance imaging or computed tomography. TVR was defined as any clinically driven repeat PCI of the target lesion or CABG surgery of the target vessel that was performed for a clinical indication.
Data were expressed as the mean ± SD for numeric variables and as the number (%) for categorical variables. Comparisons of continuous variables between groups were performed by the Student’s t test or 1-way analysis of variance test. Subgroup comparisons of categorical variables were assessed by the chi-square or Fisher’s exact test. Survival curves were generated by the Kaplan-Meier method, and survival was compared between groups using the log-rank test. Significant variables associated with the presence of high SXscore in univariate analysis were entered into the multivariate regression model. Multivariate logistic regression analysis was performed to determine the independent predictors of high SXscore. To determine the independent predictors of MACE, multivariate Cox regression analysis was performed by adjusting for variables significantly associated with clinical outcomes (including traditional risk factors, SXscore, serum DcR3, and hs-CRP levels). Data were analyzed using SPSS software (version 20; SPSS, Chicago, Illinois). A p value <0.05 was considered to indicate statistical significance.
Results
During a 12-month follow-up period to June 2014, 152 patients (110 men and 42 women; mean age 72.5 ± 11.7 years) were enrolled for analysis. Based on coronary angiography, 83 patients had 2-vessel CAD, 69 patients had 3-vessel CAD, and 23 patients were found to have left main disease (the presence of ≥50% stenosis in left main coronary artery).
All study subjects were divided into 3 groups ( Table 1 ). Group 1 was defined as high SXscore (>22), group 2 as intermediate SXscore (>13 and ≤22), and group 3 was defined as low SXscore (≤13). The baseline characteristics of the 3 groups are listed in Table 1 . There were no significant differences in baseline characteristics among the 3 groups except there were more patients with previous MI in group 3 than in groups 1 and 2 (p <0.05). Additionally, DcR3 levels were significantly higher in the high SXscore group than in the intermediate and low SXscore group (13,602 ± 7,256 vs 8,025 ± 7,789 vs 4,637 ± 4,403 pg/ml, p <0.001; Figure 1 ). By multivariate analysis, circulating DcR3 levels were identified as an independent predictor for high SXscore (adjusted odds ratio 1.15; 95% confidence interval 1.09 to 1.21; p <0.001; Table 2 ).
| Variables | Syntax Score | P value | ||
|---|---|---|---|---|
| ≤13 (n = 51) | >13 and ≤22 (n = 51) | >22 (n = 50) | ||
| Age (years) | 72.0 ± 10.4 | 72.9 ± 13.0 | 72.7 ± 11.8 | 0.933 |
| Male | 37 (73%) | 37 (73%) | 36 (72%) | 0.997 |
| Smoker | 12 (24%) | 12 (24%) | 10 (20%) | 0.887 |
| Hypertension | 39 (77%) | 40 (78%) | 35 (70%) | 0.593 |
| Diabetes mellitus | 26 (51%) | 24 (47%) | 31 (62%) | 0.297 |
| Previous MI | 10 (20%) | 25 (49%) | 20 (40%) | 0.007 |
| Previous CVA | 9 (18%) | 7 (14%) | 9 (18%) | 0.812 |
| Heart failure | 23 (45%) | 19 (37%) | 23 (46%) | 0.619 |
| Atrial fibrillation | 10 (20%) | 9 (18%) | 13 (26%) | 0.561 |
| Chronic kidney disease | 24 (47%) | 26 (51%) | 25 (50%) | 0.919 |
| Lipid profiles (mg/dl) | ||||
| Triglycerides | 118.9 ± 61.1 | 107.6 ± 48.9 | 118.3 ± 72.0 | 0.599 |
| Total cholesterol | 148.3 ± 54.5 | 153.4 ± 54.4 | 167.9 ± 45.9 | 0.147 |
| HDL-C | 40.1 ± 10.9 | 40.8 ± 12.5 | 45.1 ± 11.7 | 0.089 |
| LDL-C | 80.9 ± 43.4 | 85.2 ± 53.4 | 98.7 ± 46.9 | 0.158 |
| Creatinine (mg/dl) | 1.56 ± 1.32 | 2.04 ± 2.25 | 1.99 ± 2.42 | 0.431 |
| DcR3 levels (pg/dL) | 4637 ± 4403 | 8025 ± 7789 | 13602 ± 7256 | <0.001 |
| Syntax score | 9.4 ± 8.5 | 18.0 ± 2.6 | 30.1 ± 5.9 | <0.001 |
| Hs-CRP (mg/L) | 0.85 ± 1.75 | 1.62 ± 2.39 | 1.59 ± 3.56 | 0.261 |
| Variables | Unadjusted OR | 95% CI | P value | Adjusted ∗ OR | 95% CI | P value |
|---|---|---|---|---|---|---|
| Age: per 1 year | 1.01 | 0.98-1.04 | 0.625 | 1.01 | 0.97-1.04 | 0.775 |
| Male: male vs. female | 0.97 | 0.46-2.07 | 0.943 | 1.29 | 0.51-3.24 | 0.588 |
| Smoking: smokers vs. non-smokers | 1.04 | 0.53-2.06 | 0.902 | |||
| Hypertension: hypertension vs. non-hypertension | 1.47 | 0.69-3.16 | 0.320 | 1.42 | 0.58-3.45 | 0.441 |
| Diabetes: diabetes vs. non-diabetes | 1.70 | 0.85-3.39 | 0.133 | 1.81 | 0.77-4.22 | 0.172 |
| CKD: CKD vs. non-CKD | 1.04 | 0.53-2.05 | 0.910 | |||
| Previous MI: MI vs. non-MI | 1.28 | 0.64-2.57 | 0.493 | |||
| LDL-C: per 1 mg/dL | 1.01 | 1.00-1.01 | 0.161 | 1.00 | 0.99-1.01 | 0.715 |
| Creatinine: per 1 mg/dL | 1.06 | 0.91-1.25 | 0.458 | |||
| Hs-CRP: per 1 mg/L | 1.07 | 0.95-1.20 | 0.254 | 1.10 | 0.96-1.27 | 0.163 |
| Serum DcR3: per 1,000 pg/mL | 1.14 | 1.08-1.20 | <0.001 | 1.15 | 1.09-1.21 | <0.001 |
∗ Adjusted for age, gender, hypertension, diabetes, plasma LDL-C, hs-CRP and DcR3 levels.
During the post-PCI follow-up period of 12 months, 40 patients (26%) reached the study end points (MACE), including 12 death, 22 fatal or nonfatal MI events, and 29 TVR events but no event of ischemic stroke. The Kaplan-Meier analysis demonstrated a significant difference in 12-month cardiovascular events between subjects with high DcR3 levels (>11,866 pg/ml, the highest tertile), intermediate levels (>2,975, and ≤11,866 pg/ml, the second tertile), and low levels (≤2,975 pg/ml, the lowest tertile; log-rank test p <0.001). Patients in the high DcR3 group had a significantly lower MACE-free survival rate ( Figure 2 ). Moreover, a divergence of effect before and after the 3-month time point was observed in the survival curves. Within the first 3 months of follow-up, the intermediate and high DcR3 groups had a similar incidence of cardiovascular events and the low DcR3 group demonstrated a lower incidence of MACE compared with intermediate and high DcR3 groups. After 3 months of PCI, the high DcR3 group showed a higher incidence of MACE compared with the intermediate DcR3 group, whereas the low and intermediate DcR3 groups had a similar incidence of cardiovascular events during this period. The Kaplan-Meier analysis also demonstrated a significant difference in the 12-month MACE among high, intermediate, and low-SXscore groups (p <0.001; Figure 3 ).
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