Epidemiologic studies, intervention studies in human volunteers, and experiments in animal models suggest a protectivve role for Omega-3 fatty acids in cardiovascular diseases. Eicosapentaenoic acid (C20:5 Omega-3) is transformed by specific cells alone in human to specific eicosanoids that are less thrombogenic and less proinflammatory than those derived from arachidonic acid. Thus far, effects of Omega-3 fatty acids have been ascribed to eicosapentaenoic acid. However, we recently published the first study, which demonstrated that docosahexaenoic acid (22:6Omega-3) has a platelet inhibitory effect of its own, when give in purified form to human volunteers. Therefore we plan to carry out the following studies 1) To further understand the metabolism of eicosapentaenoic acid in the eicosanoid system by more than one cell to metabolites that no cell alone can produce. Biologica effects of the resulting compounds and enzymatic apparatus necessary for their generation will be investigated. 2) Determine how docosahexaenoic acid exerts its antiplatelet effect. Dietary C22:6Omega-3 is incorporated into platelet phospholipids. However, it is not released upon stimulation. A mechanism for the action of C22:6Omega-3 remains to be defined. 3) Own recent studies suggest that fatty acid exchange between erythrocytes or platelets and the surrounding plasma milieu is very limited. Rather the fatty acid composition of these cells appears to be defined during cell maturation. These studies will be extended by studying phospholipid subclasses of other cell types. 4) Patients on long-term dialysis or type I diabetics are prone to rapid progression of atherosclerosis. In these patients, feasibility studies will be performed to evaluate the prophlactic potential of Omega-3 fatty acids. 5) Based on results from these studies and those reported in the literature, we plan to initiate a randomized, risk-stratified, double blind, placebo-controlled study in one group of these patients. All analytic techniques for these studies (TLC, GLC, HPLC, radiochemical procedures and ultracentrifugation) are operational in the laboratory of the Principal Investigator. We are experienced in conducting feasibility studies as well as studies as described under 5.
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