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Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia

José A. Barrabés, MD^*, David Garcia-Dorado, MD, FACC^*,*, Maribel Mirabet, PhD^*, Javier Inserte, PhD^*, Luis Agulló, PhD^*, Bernat Soriano, PharmD, Anna Massaguer, PhD, Ferran Padilla, MD^*, Rosa-Maria Lidón, MD^* and Jordi Soler-Soler, MD, FACC^*

^* Department of Cardiología, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Department of Medicina Nuclear, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Department of Immunology Unit, IDIBAPS, Barcelona, Spain

Manuscript received July 13, 2004; accepted September 28, 2004.

^* Reprint requests and correspondence: Dr. David Garcia-Dorado, Servicio de Cardiología, Hospital Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain (Email: dgdorado{at}vhebron.net).

OBJECTIVES: The goal of this study was to assess whether selectin blockade reduces myocardial platelet deposition and platelet-mediated injury after transient ischemia.

BACKGROUND: Selectins participate in platelet adhesion to reperfused endothelium.

METHODS: Thiopental-anesthetized, open-chest pigs were subjected to mechanical injury of the left anterior descending coronary artery followed by a 48-min occlusion and 2 (n = 20) or 4 (n = 16) h of reperfusion. Fifteen minutes before occlusion, animals were blindly allocated to receive a continuous intravenous infusion of the selectin blocker fucoidan (30 µg/kg/min, plus a 1-mg/kg bolus in the latter group) or saline. In isolated rat hearts infused with thrombin-activated platelets, the effects of fucoidan (30 µg/ml) administered during reperfusion after 40 min of global ischemia were also analyzed.

RESULTS: Fucoidan did not prevent the development of cyclic reductions in coronary flow, but reduced the content of ^99mTc-labeled platelets in reperfused myocardium after 2 h of reperfusion (23.4 ± 3.3 vs. 42.1 ± 8.3 x 10⁶ platelets/g in treated and untreated animals, p = 0.03) and attenuated the impairment in the coronary flow reserve and reduced infarct size after 4 h (53 ± 2% vs. 73 ± 5% of the ischemic region, respectively, p = 0.003). Treated animals showed a trend toward less neutrophil infiltration early after reperfusion, but not after 4 h. In isolated hearts, fucoidan improved functional recovery and reduced coronary resistance and lactate dehydrogenase release, lacking any beneficial effects if given in the absence of platelets.

CONCLUSIONS: The results suggest that selectin-dependent adhesion is a prominent mechanism of platelet deposition in reperfused cardiac microvessels and highlight its potential as a therapeutic target in patients with acute myocardial infarction.

Abbreviations and Acronyms   CFR = cyclic flow reduction   GP = glycoprotein   LAD = left anterior descending coronary artery   LDH = lactate dehydrogenase   LVEDP = left ventricular end-diastolic pressure   MPO = myeloperoxidase   VF = ventricular fibrillation

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