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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Local Cytokine Concentrations and Oxygen Pressure Are Related to Maturation of the Collateral Circulation in Humans

Stephan H. Schirmer, MD, PhD^_*,, Niels van Royen, MD, PhD^_*,_*, Perry D. Moerland, PhD, Joost O. Fledderus, PhD, José P. Henriques, MD, PhD^_*, René J. van der Schaaf, MD^_*, Marije M. Vis, MD^_*, Jan Baan, Jr, MD, PhD^_*, Karel T. Koch, MD, PhD^_*, Anton J.G. Horrevoets, PhD, Imo E. Hoefer, MD, PhD^|| and Jan J. Piek, MD, PhD^_*

^_* Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
^|| Department of Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands

Manuscript received September 2, 2008; revised manuscript received January 6, 2009, accepted February 16, 2009.

^_* Reprint requests and correspondence: Dr. Niels van Royen, Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (Email: n.vanroyen{at}amc.uva.nl).

Objectives: Our aim was to determine cytokine and oxygen gradients over the collateral circulation in humans.

Background: The molecular background of the maturation of the collateral circulation in response to coronary narrowing is poorly understood in humans, partly because of difficulties in obtaining local samples from the human collateral circulation.

Methods: Coronary collateral blood was sampled in 60 patients with nontotal (n = 25) or total coronary occlusions (n = 35) using a special wide-lumen catheter. Coronary collateral flow index (CFI) was assessed by intracoronary pressure measurements. Oxygenation and lactate content was measured as well as 30 cytokines potentially involved in collateral artery growth, using a custom-made multiplex assay.

Results: No rise in lactate or change in pH was found in collateral blood. Oxygen gradient between coronary and collateral arterial blood correlated inversely with CFI (r = –0.61, p < 0.001). Locally increased plasma levels were found for basic fibroblast growth factor, eotaxin, macrophage migration inflammatory factor, monocyte chemoattractant protein-1, and transforming growth factor-beta, while stem cell factor and stem cell growth factor-beta were significantly decreased. The highest cytokine gradients were found in patients with the least developed collateral circulation. The majority of cytokines correlated more strongly with the pO₂ gradient across the collateral bed than with CFI.

Conclusions: Intravascular ischemia during brief balloon coronary occlusion is absent in human coronary collateral arteries. The oxygen gradient found over the collateral circulation is increased in patients with a less matured collateral circulation and relates to local levels of several known pro-arteriogenic cytokines. In case of a more developed collateral circulation, relatively low levels of cytokines are present, suggesting that growth factor therapy might be beneficial at this stage.

Key Words: arteriogenesis • collateral circulation • growth substances • hemodynamics • molecular biology

Abbreviations and Acronyms   bFGF = basic fibroblast growth factor   CAD = coronary artery disease   CFI = collateral flow index   CTO = chronic total occlusion   CVP = central venous pressure   ELISA = enzyme-linked immunosorbent assay   GM-CSF = granulocyte-macrophage colony-stimulating factor   HGF = hepatocyte growth factor   IL = interleukin   MCP = monocyte chemoattractant protein   MIF = macrophage migration inflammatory factor   MIP = macrophage inflammatory protein   TGF = transforming growth factor   TNF = tumor necrosis factor

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