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Macrophage colony stimulating factor (MCSF) is a haematopoietic growth factor released by the injured endothelium and can stimulate proliferation, differentiation, and maturation of monocytes and macrophages.1 MCSF stimulates the synthesis of monocyte chemotactic protein 1 and increases the adhesion of monocytes to endothelium. In addition, MCSF has been located in atherosclerotic lesions of humans and it has been proposed that it may contribute to the progression of atherosclerosis.
Elevation of MCSF has also been reported in unstable angina but few data exist regarding the prognostic value.2 In the present study we evaluated whether admission concentrations of MCSF can predict prognosis in patients hospitalised with unstable angina.
We studied 122 patients (96 men and 26 women) aged 59 (10) years (range 38–75 years) admitted to our coronary care unit with severe unstable angina. Inclusion criteria were angina at rest with at least two attacks or one episode lasting > 20 minutes in the previous 24 hours with newly developed ⩾ 0.1 mV ST segment depression in two or more contiguous leads. There was no elevation of creatine kinase (CK) on admission or six hours later. Exclusion criteria were recent myocardial infarction (< 3 months), coronary artery bypass graft, age > 75 years, left bundle branch block, and inflammatory disease.
Venous blood samples were obtained on admission for assessment of MCSF, interleukin 6 (IL-6), and C-reactive protein (CRP). CK was measured on admission and six hours later and those with increased concentrations were excluded. CK was also determined 12 hours after admission and then every day during hospitalisation to identify those with myocardial necrosis.
All patients received intravenous heparin, nitrates, aspirin, and a combination of β blockers and calcium antagonists according to the severity of symptoms. Patients were divided into two groups according to in-hospital outcome: group A comprised 70 patients with an eventful course, and group B comprised 52 patients without an event. An event was defined as the occurrence of death, non-fatal acute myocardial infarction, and the recurrence of angina requiring further titration of anti-ischaemic medication or early revascularisation.
Serum MCSF concentration was measured by quantitative sandwich enzyme immunoassay technique (R & D Systems) with a range from 31.2–2000 pg/ml. IL-6 was measured with high sensitivity enzyme linked immunoassay (R & D Systems) with a range from 0.156–10 pg/ml. CRP was assayed by particle enhanced immunonephelometry (N Latex CRP mono, Dade-Behring) with a range from 0.175–1100 mg/l. The intra-assay and inter-assay coefficient of variation for MCSF and CRP measurements was < 5% and for IL-6 measurements < 12%.
MCSF, IL-6, and CRP values which were not normally distributed were expressed as medians. Differences between groups were analysed by Mann-Whitney U test. Spearman's rank correlation test was used for correlations. A logistic regression model was applied using outcome as dependent variable and MCSF, IL-6, CRP, age, sex, diabetes mellitus, hypertension, smoking, and body mass index as predictor variables. In this model logarithmic transformation was made on MCSF, IL-6, and CRP concentrations. A probability value of p < 0.05 was considered significant.
The two groups did not differ significantly with regard to age, sex, and risk factor distribution. During hospitalisation 70 of 122 patients (57.4%) had an eventful in-hospital course (group A). Of these, two died, 12 developed a myocardial infarction, and 56 had a recurrence of angina which in 31 patients did not respond to maximal medical treatment followed by urgent coronary angiogram. Fifty two of 122 patients (42.6%) responded entirely to medical treatment (group B).
MCSF, IL-6, and CRP concentrations were higher in group A compared to group B (table 1). MCSF concentrations were the most powerful predictor of outcome with an adjusted odds ratio for event during hospitalisation of 6.3 (95% confidence interval (CI) 1.9 to 21.2, p = 0.003). There was also a positive correlation between MCSF with IL-6 (r = 0.37, p = 0.0001) and CRP (r = 0.52, p = 0.0001) concentrations.
This study is the first to report that patients with unstable angina and clinical in-hospital deterioration have higher MCSF concentrations on admission than those with an uneventful course. In addition, MCSF concentrations were the most powerful predictor for short term prognosis. Recently, Saitoh and colleagues2 showed that high MCSF concentrations predict cardiac events during a follow up period of 14 months in patients with stable and unstable angina.
Unstable angina is associated with an exaggerated inflammatory reaction and is characterised by a significantly larger amount of macrophage-rich plaques compared to stable angina. It has also been reported that MCSF is higher in patients with unstable than stable angina. These increased MCSF concentrations may not represent an epiphenomenon but may play a substantial role in activation and proliferation of macrophages. The precise signal of MSCF production in acute coronary syndromes is unknown. In vitro studies showed that minimally modified low density lipoprotein (LDL) induces the expression of MCSF,3 and therefore oxidised LDL could be a candidate inducer of MCSF production. It has also been postulated that MCSF may initiate and prolong ischaemic episodes by increasing coronary tone, impairing vasodilatation, and promoting the formation of microthrombi.4 Therefore, the higher MCSF concentrations which predicted worse short term prognosis in our study may not only be a marker of ischaemia but may also play a role in triggering or worsening the ischaemia.
In our study admission IL-6 and CRP concentrations were also higher in patients with a complicated in-hospital course which is in line with previous studies.5 We also found a positive correlation of MCSF with IL-6 and CRP. The underlying mechanism of the interaction among MCSF, IL-6, and CRP is unclear. It is tempting to speculate that MCSF activated macrophages produce increased amounts of IL-6 which may lead to CRP production by hepatocytes.
This study suggests that increased admission concentrations of MCSF predict a worse short term prognosis in patients with unstable angina. MCSF may therefore play an active role in acute coronary events.