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Long term treatment with enalapril reduces plasma concentrations of macrophage colony stimulating factor in patients with coronary artery disease
  1. KENJI SADAMATSU,
  2. HIROAKI SHIMOKAWA*,
  3. HIDEKI TASHIRO,
  4. KUNIHIKO YAMAMOTO
  1. Division of Cardiology
  2. St Mary's Hospital
  3. Kurume, Japan
  4. *Department of Cardiovascular Medicine
  5. Kyushu University
  6. Graduate School of Medical Sciences
  7. Fukuoka, Japan
  1. Dr Hiroaki Shimokawa, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;shimo{at}cardiol.med.kyushu-u.ac.jp

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Previous studies both in vivo and in vitro showed that angiotensin converting enzyme (ACE) inhibitors exert antiatherogenic effects. Long term blockade of ACE significantly reduces atherosclerosis related events in patients with coronary artery disease.1 These results suggest that this class of drugs may present antiatherogenic properties; however, the mechanism for it remains to be fully elucidated. Macrophage colony stimulating factor (M-CSF, one of the major inflammatory cytokines) and transforming growth factor β (TGF-β, one of the major anti-inflammatory cytokines) have been shown to play a key role in the pathogenesis of atherosclerosis. Indeed, we and others have previously shown that plasma concentrations of M-CSF are increased while those of TGF-β are decreased in patients with coronary artery disease, and that the ratio of plasma concentrations of M-CSF and those of TGF-β well correlates with the severity of coronary atherosclerosis.2 3However, no study has ever examined the effect of ACE inhibitors on the cytokine system in patients with coronary artery disease. We thus examined whether or not long term blockade of ACE improves the altered plasma concentrations of M-CSF and those of TGF-β.

This study was approved by the human research committee of our institute. Informed consent to participate in this study was obtained from all patients. Thirty consecutive patients were randomly divided into two groups; one group received 2.5 mg/day of enalapril for the first eight weeks, followed by 5.0 mg/day for the next eight weeks, while another group served as a control. All patients were proved to have significant coronary artery disease by coronary angiography. Exclusion criteria included acute coronary events, recent coronary angioplasty or bypass surgery within three months, renal or liver diseases, any malignant tumours, or any inflammatory diseases. There was no significant difference in the prevalence of coronary risk factors or that of medications, including aspirin (table 1). Blood pressure was fairly controlled with other medications in both groups before the enalapril treatment, and there was no significant difference in systolic blood pressure between the two groups, while diastolic blood pressure was significantly higher in the enalapril group than in the control group. However, enalapril did not significantly lower blood pressure in both groups (table 1). Fasting venous blood samples were collected before treatment, and eight and 16 weeks after in the treated group, and before and 16 weeks after the observation period in the control group. Plasma concentrations of M-CSF and TGF-β were measured by an enzyme linked immunosorbent assay.2

Table 1

Patient demographics

In the enalapril group, mean (SEM) plasma concentrations of M-CSF tended to decrease at the 2.5 mg dose (from 361.9 (46.4) pg/ml at baseline to 316.7 (50.6) pg/ml) and were significantly decreased at the 5.0 mg dose (284.3 (39.5) pg/ml, p < 0.01), whereas they remained unchanged in the control group (361.4 (40.1) pg/ml at baseline and 393.7 (39.8) pg/ml at 16 weeks) (fig 1). By contrast, plasma concentrations of TGF-β remained unchanged in both groups: 6.6 (0.5), 6.8 (0.6), and 6.3 (0.8) pg/ml at baseline, eight, and 16 weeks in the enalapril group, respectively, and 7.2 (1.2) and 7.7 (1.3) pg/ml at baseline and 16 weeks in the control group, respectively.

Figure 1

Reduction of plasma concentrations of M-CSF by long term treatment with enalapril. The long term treatment with enalapril (2.5 mg daily for the first eight weeks and 5.0 mg daily for the next eight weeks) significantly reduced plasma concentrations of M-CSF in the treated group but not in the control group. Results are presented as mean (SEM). *p < 0.05 v 0 week, †p < 0.01 v control group (by Wilcoxon matched pairs, signed ranks test).

Macrophages synthesise and release various cytokines that influence vascular tone, plaque stability, and thrombogenesis. M-CSF is a multifunctional inflammatory cytokine that regulates differentiation, proliferation, and survival of monocytes and macrophages. Furthermore, M-CSF deficiency significantly reduces atherogenesis in a mouse model of atherosclerosis,4 whereas its overexpression accelerates atherogenesis caused by increased monocyte recruitment and enhanced smooth muscle migration and proliferation.5 Thus, it is highly possible that the decrease in M-CSF plasma concentrations by long term blockade of ACE may suppress the progression of atherosclerosis, thus contributing, at least in part, to the reduction of cardiovascular events in patients with coronary artery disease.1 By contrast, plasma concentrations of TGF-β was not significantly changed by the long term blockade of ACE, suggesting that this anti-inflammatory cytokine may not play a major role in the antiatherogenic effect of ACE inhibitors.

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