A NOVEL SIALYL LEWIS(X) ANALOG ATTENUATES NEUTROPHIL ACCUMULATION ANDMYOCARDIAL NECROSIS AFTER ISCHEMIA AND REPERFUSION

Background Polymorphonuclear leukocytes (PMNs) have been shown to medi ate coronary vascular and myocardial tissue injury after coronary arte ry ischemia and reperfusion. Previous studies using specific monoclona l antibodies directed against P-selectin and L-selectin have demonstra ted the involvement of the selectin family of glycoproteins in the ear ly phase of PMN-induced myocardial ischemia-reperfusion injury. We exa mined the effects of a novel oligosaccharide analog of sialyl Lewis(x) (SLe(x)), which blocks both P-selectin and E-selectin in an acute can ine model of myocardial ischemia and reperfusion, Methods and Results Anesthetized, open-chest dogs were subjected to 1.5 hours of left circ umflex coronary artery (LCx) occlusion followed by 4.5 hours of reperf usion and randomly received the SLe(x) analog CY-1503 (5 mg/kg IV), th e nonfucosylated analog of CY-1503, SLN (5 mg/kg IV), or saline 5 minu tes before reperfusion. The investigators were blinded to the treatmen t 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 d ysfunction during occlusion, suggesting comparable degrees of myocardi al ischemia. After reperfusion, dogs receiving saline (n=6) displayed an enhanced degree of myocardial injury that was evidenced by a dramat ic elevation in plasma creatine kinase (CK) activity, PMN accumulation , and myocardial necrosis. Plasma CK activity increased from 1.9+/-0.5 IU/mu g protein at baseline to 73.0+/-11.0 IU/mu g protein (P<.001) a t 4.5 hours of reperfusion and myocardial PMN accumulation, as measure d by cardiac myeloperoxidase (MPO) activity, and was significantly enh anced (P<.01) within the necrotic zone compared with the nonischemic z one (4.3+/-0.6 versus 0.7+/-0.1 U/100 mg tissue). After 4.5 hours of r eperfusion, 36% of the myocardium within the ischemic zone and 17% of the left ventricle became necrotic in the dogs receiving saline. Treat ment with CY-1503 (n=6) significantly (P<.05) blunted plasma CK activi ty by more than 50% throughout the reperfusion period, reduced necroti c zone PMN accumulation by 63% (P<.05), and reduced myocardial necrosi s in the area at risk by 65% (P<.01) and by 72% within the left ventri cle (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. Conclusions Our re sults provide strong evidence that treatment with a unique carbohydrat e analog of SLe(x), CY-1503, significantly reduces the degree of myoca rdial 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. Additiona l studies investigating more-prolonged periods of reperfusion are requ ired to determine whether CY-1503 treatment merely delays the onset or actually reduces the full extent of myocardial necrosis after ischemi a and reperfusion.