Myocardial infarction remains a major cause of morbidity and mortality in the United States. Therefore, any form of therapy directed towards reduction in infarct size has important clinical application. Perfluorochemicals (PFC) given intravenously have been shown to reduce infarct size in various animal models. However, large doses of PFC were used in these experiments. This proposal will define whether low-dose intracoronary PFC (Fluosol-DA) administration results in increased infarct size reduction and improved ventricular function compared to intravenous administration. In a closed-chest dog model Fluosol-DA or saline will be infused intracoronary (this model simulates reperfusion with fibrinolytic therapy) or intravenously at 15 ml/kg after 90 minutes of coronary occlusion. Ventricular function will be assessed with contrast ventriculography and the first derivative of change in pressure over time (dp/dt) at 3 hrs, 24 hrs, 3 weeks and 4 weeks post reperfusion. Infarct size will also be assessed in vivo using magnetic resonance imaging techniques and at sacrifice using the ratio of area of necrosis and area at risk. These studies will determine which route of administration of low-dose therapy results in greater myocardial salvage. The mechanisms through which PFC act to reduce infarct size are not well understood. PFC particles have been demonstrated in the endothelial cells of capillaries in the region of irreversible damage after permanent occlusion suggesting that one mechanism through which PFC may operate is by preserving structure and function of endothelial cells and flow through the microvascular circulation, thereby abolishing the """"""""no re-flow"""""""" phenomenon. To prove this hypothesis fluorescein dye will be injected after 60 minutes of left anterior descending artery occlusion and reperfusion with Fluosol-DA or saline. Capillaries receiving flow will fluoresce under ultraviolet light. The non-fluorescent area will define the area of """"""""no reflow"""""""" and this will be compared to the area at risk and area of necrosis. Should Fluosol preserve flow through the microcirculation, greater fluorescence will be present in the ischemic zone. The changes in flow will be correlated with ultrastructural changes in endothelial cells. Isolated and excised epicardial coronary arteries exposed in vivo to Fluosol-DA or saline will be assessed in vitro in tissue bath preparations for preservation of endothelial cell function using acetylcholine, ATP, and thrombin. These studies will provide the rationale for clinical use of perfluorochemicals in myocardial ischemia.
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