Abstract 17361: An Optimized Human Apyrase Substantially Decreases Infarct Size Without Bleeding Time Prolongation after Coronary Fibrinolysis in Dogs and Coronary Ligation and Release in Mice
Introduction: Early coronary reperfusion by percutaneous coronary intervention or pharmacologic fibrinolysis attenuates myocardial infarction, but thrombotic reocclusion and reperfusion injury limit the benefits of intervention. Standard-of-care conjunctive agents including aspirin, heparin and clopidogrel increase bleeding, and have unproven benefit in attenuating reperfusion injury.
Objectives: This study tested whether an optimized human recombinant apyrase (APT102), which degrades circulating ATP and ADP causing inhibition of platelet activation and generation of cardioprotective adenosine, will more effectively and safely decrease infarction.
Methods: Conscious dogs had coronary thrombotic occlusion induced by electrical current and fibrinolysis with IV rt-PA (Activase, 1 mg/kg) an average of 91min after ischemia; while anesthetized C57BL/6J mice had coronary ligation followed by release of ligation after 60 min. Animals received either clopidogrel (4-10 mg/kg, PO) or IV APT102 (1.0 mg/kg) 45-50 min after ischemia with heparin and aspirin, or saline as the control in dogs and mice, respectively. Bleeding times were measured serially by precision cuts to the inner lip for dogs and by immersing the incised tip of the tail in saline for mice. Ischemic ‘risk’ zone (Evan's blue perfusion) and infarcted myocardial tissue (TTC staining) were quantified after 24 h by planimetry of transverse heart sections.
Results: Reocclusion occurred in all clopidogrel-treated dogs (n=6), but was universally prevented in dogs given APT102 (n=6, p<0.05). All groups had similar ischemic risk zones, but infarction as a percent of the risk zone was 23 ±4% for clopidogrel-treated compared to 3 ± 2% for APT102-treated dogs (p<0.05). Infarction was decreased by 50% in mice given APT102, but was not affected by clopidogrel pretreatment. Bleeding times were increased significantly by clopidogrel compared with APT102. In mice given APT102 after clopidogrel, the bleeding time prolongation was decreased significantly.
Conclusions: APT102 prevents reocclusion and decreases infarct size after coronary fibrinolysis and/or reperfusion without increasing bleeding. APT102 warrants further study as a conjunctive agent to optimize reperfusion therapy.
- © 2011 by American Heart Association, Inc.