Effective antithrombotic therapy for acute ischemic cardiac disease has been precluded largely because of our incomplete understanding of the pathogenesis of thrombosis and the absence of suitable laboratory models. Utilizing NADH autofluorescence photography, we have developed a new model which permits high resolution of ischemic zones (plus and minus 50 microns) in an isolated perfused rabbit heart; intracoronary activation of hemostatic elements; and the selective manipulation of platelets, clotting proteins, and endothelial cells to determine the relative contribution of each to the thrombotic process. In addition to fluorophotography, cardiac ischemia will be assessed where appropriate by direct measurement of coronary flow, determinations of lactate levels, EKG changes, and intracellular concentrations of NADH and NAD. We intend to evaluate the ability of normal and cholesterol-loaded human platelets, devoid of clotting proteins, to induce significant global and segmental cardiac ischemia following intracoronary activation with thrombin, ADP, arachidonic acid, and epinephrine. By measuring thromboxane B2, platelet factor 4, and N-acetyl glucosaminidase in the cardiac effluent, we plan to assess the extent and relative importance of the platelet release reaction to the ensuing ischemic insult. Utilizing endotoxin and collagenase, endothelial cells will be altered and the affinity of the exposed subendothelium for platelets assessed. By measuring 6 ket0-PGF1yield plasminogen activator, and fibronectin in the cardiac effluent, the degree of endothelial cell stimulation/damage and the role of the endothelial cell during a thrombotic stress will be studied. Ultrastructural analyses to detect intravascular thrombosis and endothelial damage will be performed as well. The contribution of thrombosis to infarct extension will be determined. The presumed adverse effects of certain dietary lipids, hypertension, and high dose aspirin on the vascular endothelium will be explored. Finally, representative agents of each of the four broad categories of antiplatelet drugs will be compared to anticoagulation and tested for their ability to preserve coronary flow during a global thrombotic challenge. The role of antiplatelet therapy in infarct modification will be assessed as will the antithrombotic efficacy of a new prostacyclin analogue ZK 36374. We believe the proposed research plan will provide new insights and, ultimately, therapy for such diverse thromboembolic events as perioperative and acute myocardial infarction and sudden death.
Showing the most recent 10 out of 11 publications
