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.

1. 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

2. 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.

3. • 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

4. • 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.

5. 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

6. • 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.

7. • 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.

8. • 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.

9. • 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.

10. • 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.

11. 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.

13. • 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).

15. • 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).

22. 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.

23. • 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.

24. • 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.

25. • 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.

26. • 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.

27. • 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.

28. • 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

29. • 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.