Identification of a Time Window for Therapy to Reduce Experimental Canine Myocardial Injury: Suppression of Neutrophil Activation During 72 Hours of Reperfusion

The cardio-protective effects of neutrophil depletion or inhibition of neutrophil activation early hi the course of myocardial reperfusion has been established. Whether these treatments would be effective during extended periods of reperfusion has not been ascertained. Open-chest anesthetized dogs were subjected to left circumflex artery (LCX) occlusion for 90 minutes followed by 72 hours of reperfusion. Dogs were randomized into one of four groups1) control; 2) Ho-2 (iloprost 100 ng/kg/min administered via the left atrium beginning 10 minutes after LCX occlusion and continuing 2 hours into reperfusion); 3) Ilo-48 (iloprost 100 ng/kg/min administered as above until 1 hour after reperfusion then 25 ng/kg/min for 48 hours of reperfusion; or 4) antibody (neutrophil antibody administered before occlusion and 1/2 hourly for 2 hours of reperfusion and then every 24 hours). Myocardial infarct size, as a percentage of the area at risk assessed after 72 hours of reperfusion, was significantly smaller hi the antibody-treated group (32.1±5.0% mean±SEM) or Do-48 (22.6±4.0%) treatment group compared with control (48.7±5.6%) or Co-2 (57.6±5.2%) groups. Regional myocardial blood flow studies demonstrated that all groups developed similar degrees of ischemia. The iloprost-treated groups had lower mean arterial blood pressures during occlusion and reperfusion than groups 1 and 4 (p < 0.05). Circulating neutrophil counts were increased in groups 1 and 2 at 24 and 48 hours after reperfusion compared to groups 3 and 4 (p < 0.001). Analysis of histological sections demonstrated a direct association between the extent of inflammatory cell infiltration and the size of myocardial infarcts (p < 0.05). Thus, iloprost or neutrophil depletion effectively reduces ultimate myocardial infarct size detected after prolonged reperfusion, and there is a direct relation between infarct size and neutrophil accumulation within the myocardium risk region. In addition, a "time window for therapy" has been defined. Iloprost treatment during the first 2 hours of reperfusion reduces the infarct size that results after 6 hours of reperfusion, but not after 72 hours of reperfusion. However, iloprost treatment for 48 hours or prolonged neutrophil depletion reduces the ultimate extent of myocardial injury. The delayed development of myocardial injury after acute short term iloprost infusion suggests that therapeutic interventions with limited pharmacological half-lives should be administered up to 48 h