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FOCUS ISSUE: ASPIRIN: STATE-OF-THE-ART PAPER

Aspirin, But Not Clopidogrel, Reduces Collateral Conductance in a Rabbit Model of Femoral Artery Occlusion

Imo E. Hoefer, MD, PhD^_*,,,_*, Sebastian Grundmann, MD^_*,, Stephan Schirmer, MD^_*,, Niels van Royen, MD, PhD, Benjamin Meder, MD^_*, Christoph Bode, MD^_*, Jan J. Piek, MD, PhD and Ivo R. Buschmann, MD^_*,||

^_* Research Group for Arteriogenesis, Department of Cardiology, University of Freiburg, Freiburg, Germany
Perfusion Technologies GmbH, Freiburg, Germany
Department of Experimental Cardiology, UMC, University of Utrecht, Utrecht, the Netherlands
Department of Cardiology, AMC, University of Amsterdam, Amsterdam, the Netherlands
^|| Humboldt University, Center for Cardiovascular Research, Charité, Berlin, Germany.

Manuscript received August 4, 2004; revised manuscript received January 20, 2005, accepted February 14, 2005.

^_* Reprint requests and correspondence: Dr. Imo E. Hoefer, UMC Utrecht, G02.523, Heidelberglaan 100, NL-3584 CX Utrecht, the Netherlands. (Email: i.hoefer{at}azu.nl).

OBJECTIVES: The objective of this study was to test the potential of aspirin and clopidogrel to influence collateral artery growth (arteriogenesis).

BACKGROUND: Aspirin and clopidogrel are antiplatelet agents commonly used in the treatment of ischemic cardiovascular disease. Both inhibit platelet aggregation; however, they differ mechanistically because aspirin acts via cyclooxygenase (COX) inhibition, while clopidogrel noncompetitively antagonizes the P2Y₁₂ adenosine diphosphate receptor. We hypothesized that aspirin, due to its anti-inflammatory effects through inhibition of COX activity could inhibit arteriogenesis. Given that clopidogrel does not affect COX activity, it would be less likely to interfere with collateral artery growth.

METHODS: Fifty-four New Zealand White rabbits received either saline, aspirin (10 mg/kg), or clopidogrel (10 mg/kg) for seven days after femoral artery ligation. Maximal collateral conductance was assessed with fluorescent microspheres under maximal vasodilation; cellular migration and proliferation (Ki-67) was evaluated by quantitative immunohistology.

RESULTS: Collateral conductance was significantly reduced by aspirin treatment, whereas clopidogrel had a neutral effect (saline: 0.94 ± 0.04; clopidogrel: 0.94 ± 0.05; aspirin: 0.64 ± 0.03 ml·min^–1·100 mm Hg^–1·g^–1; p < 0.001). Ki-67 proliferation indexes were consistent with these results (saline: 23.1 ± 2.9%; clopidogrel: 23.5 ± 1.1%; aspirin: 19.2 ± 1.1% Ki-67–positive cells). Immunohistochemistry showed COX expression in collateral arteries and a significantly decreased monocyte/macrophage accumulation in the perivascular tissue after aspirin treatment. Cell adhesion molecule expression on monocytes after activation was significantly reduced by aspirin, which might explain the reduced migratory ability.

CONCLUSIONS: In summary, clopidogrel had a neutral effect on natural arteriogenesis. Aspirin significantly inhibited collateral artery growth, probably due to its anti-inflammatory effect. Additional studies are needed to substantiate these results before translation into clinical practice.

Abbreviations and Acronyms   ADP = adenosine diphosphate   COX = cyclooxygenase   Mac-1 = membrane attack complex-1   LPS = lipopolysaccharide   LFA-1 = leukocyte functional antigen-1   MCP = monocyte chemoattractant protein   NSAID = non-steroidal anti-inflammatory drug

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