Although monocyte chemoattractant protein-1 (MCP-1) levels are increased in patients with ST-segment elevation myocardial infarction, the prognostic value of MCP-1 in primary percutaneous coronary intervention (pPCI) is not clear. The goal of the present study was to investigate the association of MCP-1 levels with myocardial perfusion and prognosis in patients with ST-segment elevation myocardial infarction undergoing pPCI. Consecutive pPCI patients (n = 192) were assigned to tertiles according to their admission serum MCP-1 levels. Angiographic no-reflow, Thrombolysis In Myocardial Infarction flow grade, myocardial blush grade, and ST-segment resolution were assessed. Mortality and major adverse cardiac events were evaluated during hospitalization and at the 3-year clinical follow-up visit. Failure of ST resolution was associated with greater admission MCP-1 levels. The risk of no-reflow (Thrombolysis In Myocardial Infarction flow ≤2 or Thrombolysis In Myocardial Infarction flow 3 with final myocardial blush grade ≤2 after pPCI and ST resolution <30%) increased as the admission MCP-1 increased. The 3-year mortality increased as the MCP-1 level increased (8% vs 22% vs 28% for the 3 tertiles, p <0.01). Multivariate logistic regression analysis demonstrated that MCP-1 levels at admission are a significant independent correlate of 3-year mortality in patients with no-reflow as detected by myocardial blush grade. A receiver operating characteristics analysis identified an optimum cut point of ≥254 pg/ml, which was associated with a negative predictive value of 95% in association with 1-year mortality. In conclusion, the plasma MCP-1 levels at admission are independently associated with the development of no-reflow and 3-year mortality in patients with ST-segment elevation myocardial infarction undergoing pPCI.
Inflammation plays a crucial role in the initiation and progression of atherosclerotic disease. Monocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family that is produced by monocytes or macrophages, smooth muscle cells, and endothelial cells within atherosclerotic plaques. In addition to its established role in the pathogenesis of atherosclerotic disease progression and plaque rupture, MCP-1 is also involved in the reparative response, such as arteriolar remodeling and restenosis after an acute coronary event. The no-reflow phenomenon is associated with a poor prognosis after acute myocardial infarction. Inflammation has been implicated in the pathophysiology of no-reflow, and MCP-1 might, therefore, be associated with the development of no-reflow. In acute coronary syndromes, in general, elevated baseline MCP-1 levels have been associated with an increased risk of death and recurrent ischemic events, independent of standard risk factors. Although it has been demonstrated that MCP-1 levels are increased in patients with ST-segment elevation myocardial infarction (STEMI), the prognostic value of MCP-1 in patients with STEMI treated with primary percutaneous coronary intervention (pPCI) is not clear. The goal of the present study was to investigate the association of MCP-1 levels with immediate myocardial perfusion and prognosis in patients with STEMI undergoing pPCI.
Methods
The initial study population was composed of 228 consecutive patients with STEMI who had been admitted within 12 hours of symptom onset. Patients with cardiogenic shock within the first 24 hours were also included. The diagnosis of STEMI was established by the presence of either of the following 2 criteria: (1) persistent anginal chest pain lasting for ≥20 minutes and ST-segment elevation of >1 mm in ≥2 standard leads or ≥2 mm in ≥2 contiguous precordial leads, or (2) the presence of a new left bundle branch block. PCI was preferred as the primary strategy for reperfusion in all the patients because of its ready availability in the study center and its superiority to fibrinolytic therapy. The Thrombolysis In Myocardial Infarction (TIMI) risk score was determined in all patients.
Patients with a culprit lesion in the left main coronary artery or a left main stenosis >50%, those who had previously undergone coronary artery bypass surgery, those with end-stage renal failure (creatinine clearance <15 ml/min), hematologic disorders, active hepatobiliary disease, active infections, neoplastic diseases, recent major surgical procedure or trauma, and patients with lacking sufficient data were excluded from the present study. The final study population consisted of 192 patients with STEMI. A local ethics committee approved the study, and all subjects provided written informed consent.
A venous blood sample was obtained on admission before pPCI. The serum MCP-1 levels were measured using an enzyme-linked immunosorbent assay by a ready commercial kit (RayBiotech, Norcross, Georgia). High-sensitivity C-reactive protein levels were measured using an immunonepholometric method (Image Immunochemistry System; Beckman Coulter, Fullerton, California). Other biochemical parameters, including lipid profiles, were analyzed using commercially available methods and kits.
Coronary angiography was performed using standard projections, and the injections were recorded using digital media for later off-line quantitative analysis (Digital Imaging and Communications in Medicine viewer; MedCom GmbH, Darmstadt, Germany). All patients were administered a 300-mg loading dose of acetylsalicylic acid, a 600-mg loading dose of clopidogrel before the intervention, and unfractioned heparin during the intervention. Bare metal stents were implanted. Administration of glycoprotein IIb/IIIa receptor blockers was at the operator’s discretion. Each patient was treated with a maintenance dose of clopidogrel therapy at a dose of 75 mg/day for ≥1 month after coronary stent implantation.
The coronary angiograms were analyzed by 2 independent and experienced interventional cardiologists who were unaware of the study details. Coronary blood flow before and after pPCI was evaluated using the TIMI flow grade classification scheme, and the myocardial blush grade (MBG) was assessed using the technique of Van’t Hof et al. As in previous studies, the angiographic no-reflow phenomenon was defined as a coronary TIMI flow grade of ≤2 after vessel recanalization or a TIMI flow grade of 3 with a final MBG of ≤2.
All patients underwent a complete 2-dimensional echocardiographic evaluation, and left ventricular ejection fraction was assessed using the modified Simpson method by observers who were unware of all clinical and angiographic data.
The clinical follow-up data were obtained through outpatient examination or telephone interviews a median of 38 months (interquartile range [IQR] 36 to 40) after pPCI. The primary end points were all-cause mortality and major adverse cardiovascular events, a composite end point of death, nonfatal reinfarction, target vessel revascularization, and new-onset congestive heart failure during hospitalization or follow-up. In-hospital reinfarction was defined as recurrent chest pain lasting for >30 minutes, associated with new Q waves or recurrent ST-segment elevation ≥0.1 mV in standard leads and a re-elevation of creatine kinase-MB isoform to at least twice the upper limit of normal and/or >50% greater than the previous value after the index procedure. Data regarding reinfarction and target vessel revascularization after hospital discharge was obtained during outpatient clinical visits and telephone interviews. New-onset heart failure was defined as New York Heart Association class III to IV symptoms >24 hours after the index event. Target vessel revascularization was defined as PCI to, or surgical bypass grafting of, any segment of the target vessel (i.e., the entire coronary artery proximal and distal to the index lesion, including any branch and the index lesion itself) after the primary intervention.
Statistical analyses were done using the Statistical Package for Social Sciences software, version 15.0 (SPSS, Chicago, Illinois). Continuous data are reported as the median and IQR or mean ± SD. The study population was divided into tertiles on the basis of serum MCP-1 levels on admission. The mean values were compared using the Kruskal-Wallis test or analysis of variance, as appropriate. Continuous variables were tested to determine whether they displayed normal distribution using a Kolmogorov-Smirnov test. Categorical variables are reported as percentages and were compared using the chi-square test. The Spearman rank correlation coefficient was used to evaluate the association between 2 continuous variables. The independent association of admission MCP-1 levels with the no-reflow phenomenon was analyzed using multivariate logistic regression. Any variable that demonstrated a significant correlation with the no-reflow phenomenon on univariate analysis was included in the model. All variables listed in Table 1 were assessed in the univariate analyses.
| Variable | Tertile 1 (n = 64) | Tertile 2 (n = 64) | Tertile 3 (n = 64) | p Value |
|---|---|---|---|---|
| MCP-1 (pg/ml) | 186 (168–201) | 252 (226–262) | 287 (277–314) | |
| Age (yrs) | 61.3 ± 9.6 | 60.8 ± 9.1 | 61.1 ± 9.0 | 0.51 |
| Gender | 0.58 | |||
| Women | 11 | 11 | 15 | |
| Men | 53 | 53 | 49 | |
| Cigarette smoker | 40 (63%) | 45 (70%) | 39 (61%) | 0.49 |
| Systemic hypertension | 14 (22%) | 16 (25%) | 16 (25%) | 0.89 |
| Diabetes mellitus | 8 (13%) | 12 (19%) | 8 (13%) | 0.51 |
| Creatinine (mg/dl) | 0.83 (0.6–1.25) | 0.80 (0.6–0.99) | 0.80 (0.6–1.01) | 0.77 |
| hs-CRP (mg/dl) | 1.36 (1.22–2.31) | 2.79 (1.34–3.01) | 3.06 (2.80–3.34) | <0.01 |
| Previous MI | 8 (13%) | 11 (17%) | 9 (14%) | 0.74 |
| Previous aspirin use | 13 (20%) | 12 (19%) | 16 (25%) | 0.66 |
| Previous ACE inhibitor use | 10 (16%) | 9 (14%) | 7 (11%) | 0.73 |
| Previous β-blocker use | 6 (8%) | 8 (12%) | 2 (3%) | 0.12 |
| Previous statin use | 14 (22%) | 12 (19%) | 15 (23%) | 0.80 |
| Peak CK-MB (ng/ml) | 331 (179–452) | 287 (218–397) | 235 (153–305) | 0.11 |
| Peak troponin I (ng/ml) | 66 (32–96) | 55 (33–95) | 47 (28–96) | 0.17 |
| TIMI risk score | 2 (1–5) | 2 (1–4) | 2 (1–5) | 0.29 |
| LVEF (%) | 44.6 ± 5.4 | 42.9 ± 5.7 | 40.9 ± 6.4 | 0.01 |
Multivariate Cox regression analysis was used to evaluate the correlates of mortality and major adverse cardiovascular events at 1 year. The Cox model included the variables that were significant (p <0.1) in the univariate analyses. The analysis was performed using 2 methods. In the first model, admission MCP-1 was evaluated as a continuous variable, and in the second model, admission MCP-1 was evaluated as a categorical variable. The Kaplan-Meier method was used to demonstrate the timing of events during long-term follow-up in relation to the admission MCP-1, and the log-rank test was applied. The receiver operating characteristics curve analysis was used to identify a potential cut point to segregate patients with and without an event.
Results
The study enrolled 192 consecutive subjects with STEMI and divided them into tertiles according to the admission MCP-1 ratio as follows: patients with a ratio <214 were assigned to the first tertile; those with a ratio of 214 to 269 were assigned to the second tertile; and those with a ratio >269 were assigned to the third tertile. The baseline characteristics of the subjects are listed in Table 1 .
Of the 192 patients, 33 (17%) had TIMI flow grade ≤2 and 159 (83%) had TIMI flow grade 3 after PCI. TIMI flow grade ≤2 after PCI was associated with a greater MCP-1 level on admission compared with patients with TIMI flow grade 3 (271 pg/ml, IQR 228 to 313, vs 241 pg/ml, IQR 194 to 273, p <0.001; Figure 1 ). TIMI flow grade 3 with a final MBG of ≤2 was observed in 61 subjects (32%). MBG of ≤2 after PCI was associated with greater admission MCP-1 compared with MBG 3 (273 pg/ml, IQR 223 to 303, vs 228 pg/ml IQR 187 to 267, p <0.001; Figure 1 ).
In a multivariate logistic regression model with no-reflow as the dependent variable, high-sensitivity C-reactive protein (odds ratio 1.04, 95% confidence interval 1.01 to 1.07, p = 0.03), TIMI risk score (odds ratio 1.30, 95% confidence interval 1.20 to 1.56, p <0.01), and MCP-1 on admission (odds ratio 1.05, 95% confidence interval = 1.03 to 1.09, p = 0.01) were the only significant independent correlates of the no-reflow phenomenon.
Death during 1 year of follow-up was associated with greater median MCP-1 levels compared with survival (270 pg/ml, IQR 258 to 328, vs 229 pg/ml, IQR 194 to 273, p <0.001; Figure 1 ). Likewise, the 3-year mortality and major adverse cardiovascular events were associated with significant increases in MCP-1 ( Table 2 ).
| Variable | Tertile 1 (n = 64) | Tertile 2 (n = 64) | Tertile 3 (n = 64) | p Value |
|---|---|---|---|---|
| MCP-1 (pg/ml) | 186 (168–201) | 252 (226–262) | 287 (277–314) | |
| IRA | ||||
| LAD | 24 (38%) | 22 (34%) | 25 (39%) | 0.76 |
| Right | 31 (47%) | 34 (53%) | 27 (42%) | 0.46 |
| LCx | 10 (15%) | 8 (13%) | 12 (19%) | 0.62 |
| Multivessel coronary disease | 16 (25%) | 17 (27%) | 15 (23%) | 0.41 |
| Door to balloon time (min) | 29 ± 4 | 27 ± 4 | 32 ± 5 | 0.41 |
| PCI success rate (%) | 97% | 96% | 95% | 0.66 |
| Pain to reperfusion (h) | 3 (2–6) | 3 (2–4) | 3 (2–4) | 0.21 |
| Stent use | 100% | 100% | 100% | 1 |
| Tirofiban administration | 25 (39%) | 22 (34%) | 26 (41%) | 0.75 |
| Use of thrombus aspiration device | 4 (6%) | 6 (9%) | 5 (8%) | 0.80 |
| Stent diameter (mm) | 3.2 ± 0.4 | 3.1 ± 0.5 | 3.3 ± 0.4 | 0.21 |
| Stent length (mm) | 18.0 ± 3.0 | 18.9 ± 3.0 | 18.5 ± 3.1 | 0.23 |
| Angiographic data | ||||
| Final TIMI flow grade (after PCI) <3 | 5 (8%) | 12 (19%) | 16 (25%) | 0.03 |
| Final MBG (after PCI) <3 | 11 (17%) | 18 (28%) | 32 (50%) | <0.01 |
| In-hospital | ||||
| Deaths | 0 (0%) | 3 (5%) | 6 (9%) | 0.04 |
| MACE | 1 (2%) | 6 (9%) | 10 (16%) | 0.02 |
| At 3-yr follow-up | ||||
| Deaths | 5 (8%) | 14 (22%) | 18 (28%) | 0.01 |
| MACE | 9 (14%) | 20 (31%) | 32 (50%) | <0.01 |
The receiver operating characteristics curves of MCP-1 and high-sensitivity C-reactive protein for predicting 3-year mortality are shown in Figure 2 . A MCP-1 >254 pg/ml predicted 3-year mortality with 86% sensitivity and 62% specificity. A high-sensitivity C-reactive protein level >2.7 mg/dl had 78% sensitivity and 53% specificity in its association with 3-year mortality. Figures 3 and 4 depict the Kaplan-Meier curves for 3-year mortality and major adverse cardiovascular events in patients with high MCP-1 (≥254 pg/ml) compared with those with low MCP-1 (<254 pg/ml). Pearson’s correlation analysis demonstrated that MCP-1 correlated positively with high-sensitivity C-reactive protein (r = 0.71, p <0.01; Figure 5 ).
