P-selectin inhibition prevents early neutrophil activation but provides only modest protection against myocardial injury in dogs with ischemia and forty-eight hours reperfusion

OBJECTIVES This study was designed to determine whether antibody neutraliza tion of the adhesion protein P-selectin would prevent neutrophil activation and reduce myocardial reperfusion injury. BACKGROUND Although inhibition of P-selectin markedly reduces short-term my ocardial injury after ischemia and reperfusion, it is unknown whether it ca n provide meaningful long-term protection and preserve left ventricular fun ction. METHODS Closed-chest dogs underwent 90 min left anterior descending coronar y artery occlusion and 48 h reperfusion, and were randomized to 1) a treatm ent group (n = 11) receiving 1 mg/kg of the blocking anti-P-selectin antibo dy PB1.3, or 2) a control group receiving 1 mg/kg PNB1.6 (nonblocking antib ody against P-selectin, n = 7) or an equivalent volume of saline (n = 2) 10 min before reperfusion. Infarct size was assessed postmortem by triphenyl tetrazolium chloride staining. Contrast left ventriculography was used to m easure left ventricular function. Activation of circulating polymorphonucle ar neutrophils (PMNs) was assessed by an increase in surface CD18 expressio n. RESULTS Neutrophil activation was observed at 30 min after reperfusion in t he control group, but was abolished in the treatment group. Infarct size wa s reduced about 25%, in the treatment group after controlling for variation s in ischemic blood flow (p = 0.003, by analysis of covariance). However, t his protective effect was not associated with preservation of blood flow to the ischemic-reperfused myocardium, nor with any improvement in global or regional left ventricular function. CONCLUSIONS The anti-P-selectin antibody PB1.3 prevented early PMN activati on, but had only a modest long-term infarct-limiting effect over 48 h reper fusion. Adhesion molecules other than P-selectin may mediate delayed PMN ac tivation and accumulation in reperfused myocardium. (C) 1999 by the America n College of Cardiology.