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Heart. Aug 2004; 90(8): 945–946.
PMCID: PMC1768377
Coronary collateral flow and peripheral blood monocyte concentration in patients treated with granulocyte–macrophage colony stimulating factor
R Zbinden, R Vogel, B Meier, and C Seiler
Department of Cardiology, University Hospital Bern, Switzerland
Correspondence to:
Professor Christian Seiler
University Hospital Bern, Freiburgstrasse Bern, CH-3010, Switzerland; christian.seiler/at/insel.ch
Accepted November 28, 2003.
Keywords: arteriogenesis, coronary collateral flow, granulocyte–macrophage colony stimulating factor, monocytes
Established options for revascularisation of coronary artery disease (CAD) are angioplasty or bypass surgery, both of which are unsuitable in about one in five patients because of the severity of atherosclerosis, co-morbidities, or both. An alternative therapeutic option is to promote the endogenous development of collateral vessels.
There are three principle ways in which vessel growth can occur: (1) vasculogenesis—this occurs primarily during embryonic development by differentiation of haematopoietic stem cells; (2) angiogenesis—this is the sprouting of new vessels out of existing ones, occurring during embryonic development and under certain conditions in the adult; (3) arteriogenesis—pre-existing collateral arterioles transform into arteries by dilatation, smooth muscle cells and endothelial cells proliferate, and consecutively acquire a typical arterial structure.1 Angiogenesis is induced by various cytokines, is dependant on ischaemia, and mainly results in high resistance capillaries; true collateral artery growth is temporally and spatially dissociated from ischaemia and results in large interconnecting arterioles which are required for the salvage of myocardium.2
Aside from their role in defending the host against invading pathogens, monocytes play an important role in building collateral arteries during arteriogenesis. Arteriogenesis is initiated by increased shear forces in pre-existing arterioles (due to an occlusion or narrowing of the main vessel) with subsequent upregulation of adhesion molecules and cytokine production by endothelial cells. Circulating monocytes adhere and migrate into deeper parts of the vessel wall and stimulate vessel growth by releasing cytokines, growth factors, and enzymes such as metalloproteinases.3
Previous studies, in a model of acute ligation of the femoral artery in mice and rabbits, showed stimulation of arteriogenesis by increased concentrations of blood monocytes and inhibition of collateral artery growth with selective depletion of peripheral blood monocytes. The negative effect was reversed when monocyte depletion was compensated for by an injection of purified monocytes.4
The purpose of this study was to elucidate whether there is an association between the amount of collateral flow change in response to granulocyte–macrophage colony stimulating factor (GM-CSF) treatment5 and blood monocyte concentration.
Twenty one patients (mean (SD) age 75 (10) years, 10 men and 11 women) with extensive CAD not eligible for, or unwilling to undergo, coronary artery bypass surgery, and with at least one stenotic lesion suitable for percutaneous coronary intervention (PCI), were included in the study. Patients were randomly assigned to a two week, double blind protocol of intracoronary followed by subcutaneous GM-CSF (Molgramostim) (n  = 10) or placebo (n  = 11). Collateral flow index (CFI) was assessed invasively during balloon occlusion at inclusion and after two weeks. CFI was determined by simultaneous measurement of mean aortic pressure (Pao) obtained via the guiding catheter, distal coronary artery pressure during balloon occlusion (Poccl) obtained via a 0.014 inch pressure monitoring guidewire, and central venous pressure (CVP). CFI was calculated as (Poccl – CVP) divided by (Pao – CVP).
A complete white blood cell count of all patients at inclusion and at follow up was performed.
Mean (SD) increase in total leucocytes (7.23 (6.63) × 109/l, p  = 0.007), neutrophils (6.25 (6.24) × 109/l, p  = 0.01), and eosinophils (1.03 (1.29) × 109/l, p  = 0.04) was significant after GM-CSF treatment; increases in monocytes (0.45 (0.68) × 109/l, p  = 0.079), lymphocytes (0.16 (0.80) × 109/l, p  = NS), and basophils (0.01 (0.08) × 109/l, p  = NS) did not reach significance. There was a significant correlation between peripheral blood monocyte concentration and invasively assessed CFI (fig 11).). There was no association between the increase in CFI and total peripheral leucocyte, granulocyte, or lymphocyte concentration.
Figure 1
Figure 1
 Regression plot of patients receiving GM-CSF (baseline and follow up measurements).
There was no correlation between peripheral monocyte count and CFI in the placebo group.
Heil and colleagues showed, in an ischaemic hindlimb model in rabbits and mice, the critical role of monocytes in collateral vessel development.4 Our study demonstrates a direct association between peripheral blood monocyte count in humans treated with GM-CSF and invasively assessed CFI. This underlines the importance of monocytes and their inflammatory response in the vessel wall during arteriogenesis because GM-CSF prolongs survival of monocytes/macrophages and protects a high number of attracted monocytes from apoptosis, therefore enhancing their arteriogenic potential. Additionally, the recruitment of monocytes from bone marrow, which increases the number in peripheral blood, seems to be important. Conversely, there is no association between increased total leucocyte, lymphocyte or granulocyte count, although the number of these cells is equally elevated after GM-CSF treatment; this would indicate a minor involvement of these cells in arteriogenesis or no involvement at all.
Abbreviations
  • CAD, coronary artery disease
  • CFI, collateral flow index
  • CVP, central venous pressure
  • GM-CSF, granulocyte–macrophage colony stimulating factor
  • PCI, percutaneous coronary intervention
1. Carmeliet P . Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000;6:389–95. [PubMed]
2. Buschmann I , Schaper W. Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. News Physiol Sci 1999;14:121–5. [PubMed]
3. Arras M , Ito WD, Scholz D, et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998;101:40–50. [PMC free article] [PubMed]
4. Heil M , Ziegelhoeffer T, Pipp F, et al. Blood monocyte concentration is critical for the enhancement of collateral artery growth (arteriogenesis). Am J Physiol Heart Circ Physiol 2002;3:H2411–9.
5. Seiler C , Pohl T, Wustmann K, et al. Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation 2001;104:2012–7. [PubMed]
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