grantor:
University of TorontoRupture and repair of an abdominal aortic aneurysm, a combination of hemorrhagic shock and lower torso ischemia, is associated with a 50-70% mortality. Since myocardial dysfunction may contribute to the high mortality rate following aneurysm repair, the purpose of this thesis was to determine whether ruptured abdominal aortic aneurysm repair results in cardiac dysfunction, mediated by tumour necrosis factor-Ã (TNF-Ã). We modeled aortic rupture and repair in the rat by inducing hemorrhagic shock to a mean blood pressure of 50 mmHg for 1 hour followed by supramesenteric clamping of the aorta for 45 minutes. After 90 minutes of reperfusion, cardiac contractile function was assessed using an isolated heart perfusion apparatus. Myocardial TNF-Ã levels, myocardial energy stores (ATP and CP), neutrophil sequestration, markers of oxidant stress (F2-isoprostanes) and necrosis were measured. Cardiac function in the combined shock and clamp rats was significantly depressed compared to sham operated control rats, but was similar to that noted in animals subjected to shock alone. Myocardial TNF-Ã concentrations increased 10-fold in the combined shock and clamp rats compared to shams while there was no difference in myocardial ATP, CP, F2-isoprostanes and necrosis. Administration of a neutralizing anti-TNF-Ã antibody prior to shock improved cardiac function by 50% in the combined shock and clamp rats. Thus, Hemorrhagic shock is the primary insult inducing cardiac dysfunction in this model of ruptured abdominal aortic aneurysm repair and no synergistic effect between shock and aortic clamping was noted. An improvement in cardiac contractile function following immunoneutralization of TNF-Ã indicates that TNF-Ã mediates a significant portion of the myocardial dysfunction in this model.M.Sc
