907-105 Selectin Blockade as an Adjunct to Thrombolytic Therapy Successfully Reduces Infarct Size Following Reperfusion in the Electrolytic Canine Coronary Artery Model

Abstract

Adhesion between neutrophils and endothelial cells has been demonstrated to be a requisite event for neutrophil migration into injured tissue. The selectins mediate transient, reversible adhesion of neutrophils to endothelial cells after ischemia reperfusion, and thus may facilitate neutrophil-mediated tissue damage. We tested the hypothesis that administration of an oligosaccharide analog of Sialyl Lewis- X (CY 1503), a known counter receptor for the selectins, may limit infarct size when given during coronary thrombolysis. A thrombus was formed in the circumflex (Cx) coronary artery of 20 dogs using electrolytic injury. Coronary blood flow was monitored with a Doppler flow probe, and continuous ECG monitoring was performed. After at least 1 hour of occlusion (mean ± SD; 80 ± 20 min), thrombolysis was induced in a random fashion with t-PA (1 mg/kg) given over 20 min with either placebo (n = 10) or CY 1503 given as a single bolus of 40 mg/kg (n = 10). At the onset of reflow each dog received a continuous infusion of t-PA (20 /μg/kg/min) to maintain reperfusion for 60 minutes. The heart was then explanted and perfused with Evan's blue and triphenyl tetrazolium chloride dyes to define the coronary distribution and regions of myocardial necrosis. Sections of myocardium from the area at risk were assayed for myeloperoxidase (MPO) content, an index of neutrophil infiltration. No hemodynamic or adverse effects were noted in the CY 1503 treated dogs. Infarct size, expressed as a percent of the area at risk was reduced by 68% in CY 1503 treated dogs (p = 0.007). MPO content in the ischemic Cx territory was also markedly reduced in the CY 1503 group (p = 0.02). We conclude that inhibition of neutrophil-endothelial cell adhesion by CY 1503 reduces infarct size well beyond thrombolytic-mediated reperfusion, and is a highly attractive strategy for future clinical investigation.