A novel sialyl LewisX analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion.

Abstract

Polymorphonuclear leukocytes (PMNs) have been shown to mediate coronary vascular and myocardial tissue injury after coronary artery ischemia and reperfusion. Previous studies using specific monoclonal antibodies directed against P-selectin and L-selectin have demonstrated the involvement of the selectin family of glycoproteins in the early phase of PMN-induced myocardial ischemia-reperfusion injury. We examined the effects of a novel oligosaccharide analog of sialyl LewisX (SLeX), which blocks both P-selectin and E-selectin in an acute canine model of myocardial ischemia and reperfusion. Anesthetized, open-chest dogs were subjected to 1.5 hours of left circumflex coronary artery (LCx) occlusion followed by 4.5 hours of reperfusion and randomly received the SLeX analog CY-1503 (5 mg/kg IV), the nonfucosylated analog of CY-1503, SLN (5 mg/kg IV), or saline 5 minutes before reperfusion. The investigators were blinded to the treatment until all the data analysis was completed. All three groups of dogs exhibited similar and severe reductions in transmural myocardial blood flow in the LCx region as well as pronounced myocardial contractile dysfunction during occlusion, suggesting comparable degrees of myocardial ischemia. After reperfusion, dogs receiving saline (n = 6) displayed an enhanced degree of myocardial injury that was evidenced by a dramatic elevation in plasma creatine kinase (CK) activity, PMN accumulation, and myocardial necrosis. Plasma CK activity increased from 1.9 +/- 0.5 IU/microgram protein at baseline to 73.0 +/- 11.0 IU/micrograms protein (P < .001) at 4.5 hours of reperfusion and myocardial PMN accumulation, as measured by cardiac myeloperoxidase (MPO) activity, and was significantly enhanced (P < .01) within the necrotic zone compared with the nonischemic zone (4.3 +/- 0.6 versus 0.7 +/- 0.1 U/100 mg tissue). After 4.5 hours of reperfusion, 36% of the myocardium within the ischemic zone and 17% of the left ventricle became necrotic in the dogs receiving saline. Treatment with CY-1503 (n = 6) significantly (P < .05) blunted plasma CK activity by more than 50% throughout the reperfusion period, reduced necrotic zone PMN accumulation by 63% (P < .05), and reduced myocardial necrosis in the area at risk by 65% (P < .01) and by 72% within the left ventricle (P < .01). In contrast, administration of the nonfucosylated analog of CY-1503, SLN (n = 6), failed to exert any detectable cardioprotective effects after myocardial ischemia and reperfusion. Our results provide strong evidence that treatment with a unique carbohydrate analog of SLeX, CY-1503, significantly reduces the degree of myocardial injury associated with coronary artery ischemia and reperfusion. The profound cardioprotection appears to be related to a reduction in PMN accumulation within the ischemic-reperfused myocardium. Additional studies investigating more-prolonged periods of reperfusion are required to determine whether CY-1503 treatment merely delays the onset or actually reduces the full extent of myocardial necrosis after ischemia and reperfusion.