Usefulness of Monocyte Chemoattractant Protein-1 to Predict No-Reflow and Three-Year Mortality in Patients

With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous

Coronary Intervention

Eyup Buyukkaya, MD, Fatih Poyraz, MD, Mehmet F. Karakas, MD, Mustafa Kurt, MD et al

Am J Cardiol 2013;112:187e193

Introduction

• 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, 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.

• 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 venous blood sample was obtained on admission before pPCI. The serum MCP-1 levels ,High-sensitivity C-reactive protein levels &Other biochemical parameters, including lipid profiles, were analyzed using commercially available methods and kits

• 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 ≥ 1month after coronary stent implantation.

• Coronary blood flow before and after pPCI was evaluated using the TIMI flow grade classification scheme, and the myocardial blush grade (MBG).

• 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.

• 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.

• The study population was divided into tertiles on the basis of serum MCP-1 levels on admission.

• The independent association of admission MCP-1 levels with the no-reflow phenomenon was analyzed using multivariate logistic regression.

• Multivariate Cox regression analysis was used to evaluate the correlates of mortality and major adverse cardiovascular events at 1 year.

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 pg/ml 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.

• 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).

Discussion

• According to our findings, the MCP-1 levels at admission were associated with both death and major adverse cardiovascular events (death, nonfatal reinfarction, target vessel revascularization, and new-onset congestive heart failure) independent of the TIMI risk score, MBG, left ventricular ejection fraction, and high-sensitivity C-reactive protein.

• The optimal cutoff point for segregating risk was a MCP-1 level of 254 pg/ml (86% sensitivity and 62% specificity).

• Although MCP-1 and high-sensitivity C-reactive protein levels correlated significantly with each other, the area under curve was stronger for MCP-1 (0.78) than for high-sensitivity C-reactive protein (0.70).

• Elevated MCP-1 levels were also independently associated with an increased risk of developing no-reflow when adjusted for potential confounders such as left ventricular ejection fraction, TIMI risk score, high-sensitivity C-reactive protein, and creatinine.

• Evidence supporting the role of MCP-1 in the development and progression of atherosclerotic disease is increasing, and this has led investigators to focus on the plasma levels of MCP-1 as a clinically relevant biomarker.

• The plasma MCP-1 levels are strongly associated with traditional atherosclerotic risk factors and subclinical atherosclerosis.

• Additionally, MCP-1 is associated with the healing response and adverse remodeling after reperfused myocardial infarction.

• MCP-1 is also associated with restenosis after PCI.• Taken together, these findings relating MCP-1 to the biology of

atherosclerosis suggest that MCP-1 might be associated with the cardiovascular prognosis. This hypothesis was tested in multiple studies conducted of heterogeneous patients with acute coronary syndrome, and increased levels of MCP-1 were independently associated with a poor prognosis at follow-up.

• The present study is the first to demonstrate the association of MCP-1 levels in patients with STEMI treated with pPCI with adverse outcomes.

• Several pathophysiologic mechanisms could be responsible for the association of MCP-1 with adverse clinical outcomes.

• First, the baseline elevation of plasma MCP-1 might reflect enhanced expression of the chemokine in atherosclerotic lesions, resulting in increased macrophage recruitment and more extensive atherosclerotic disease.

• Second, enhanced systemic activation of the MCP-1 axis might exert prothrombotic effects, resulting in recurrent coronary events.

• Third, enhanced elevation of plasma MCP-1 might identify patients who have a more intense cardiac inflammatory reaction after a coronary event. Enhanced inflammation after the acute event could result in adverse cardiac remodeling.

• The baseline levels of MCP-1 after an acute coronary event are independent of the extent of an injury.

• A study by de Lemos et al demonstrated that the prognostic association of MCP-1 is independent of the cardiac troponin levels. Similarly, in the present study, no significant difference was found in the peak troponin and creatine kinase-MB levels across the MCP-1 tertiles, although the left ventricular ejection fraction decreased and the prognosis worsened from the lowest to highest MCP-1 tertiles.

• Another potential pathophysiologic mechanism that might explain the association of MCP-1 with adverse clinical outcomes is the increased no-reflow ratio associated with elevated MCP-1 levels after pPCI.

• No-reflow after pPCI is a very well-known and strong risk factor for increased morbidity and mortality.

• Although the pathophysiology of no-reflow is not fully understood, it appears to be multifactorial.

• The role of inflammation in the pathophysiology of no-reflow was first demonstrated in animal models. Charron et al found that widespread activation of interacting inflammatory and coagulation pathways after microsphere embolization occurs before the onset of angiographic no reflow.

• This finding was further supported by the following clinical studies.

• Akpek et al, in a large cohort of patients with STEMI (418 consecutive patients) treated with pPCI, demonstrated that high-sensitivity C-reactive protein and the neutrophil/lymphocyte ratio were independent predictors of no-reflow.

• Similarly, in 192 consecutive patients with STEMI treated with pPCI, the present study demonstrated that high-sensitivity C-reactive protein and basal MCP-1 levels were independent predictors of no-reflow development.

• The present study is the first to demonstrate that the admission MCP-1 levels are independent correlates of no reflow in patients with STEMI treated with pPCI.

• The primary limitation of the present study was the evaluation of MCP-1 levels only once at admission.

• Additional studies with serial measurements during the course of acute myocardial infarction are required to determine the optimum timing of blood collection for the use of MCP-1 to predict the prognosis.

• This was a single-center experience and included a small number of patients. However, our study population contained homogeneous unselected patients with STEMI undergoing pPCI, mirroring the real-world scenario

• According to our findings, the plasma MCP-1 levels are associated with poor myocardial perfusion immediately after pPCI and poorer prognosis in the long term; thus, one can onsider that anti-inflammatory strategies targeting chemokines would be an attractive therapeutic target.

• Although increased levels of some chemokines have been associated with increased damage and correlated with increased infarct size, others take part in cardiac repair, and increased levels have been associated with improved myocardial function.

• Thus, additional research and carefully selected targets for anti-inflammatory therapies are required for future improvements in the prognosis of acute myocardial infarction.