MECHANISM OF DISEASE PREVENTION BY N 3 FATTY ACIDS

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Our broad, long term objective is to understand the mechanism(s) by which common dietary polyunsaturated fatty acids (PUFA) can prevent lethal cardiac tachyarrhythmias resulting from ischemic, toxic, hormonal, or neurohumoral stress, as we now have demonstrated. Of the dietary PUFAs two omega-3 (n-3) PUFA, eicosapentaenoic acid (C2O:5n-3, EPA) and docosahexaenoic (c22:6n-3) are the most potent in their antiarrhythmic effects, whereas arachidonic acid (C2O:4n-3, AA) is proarrhythmic if the heart cells are making ecoisanoids from AA. Our specific aims are: (1) To determine if the primary source of the free PUFA which prevents cardiac arrhythmias is that PUFA occupying the sn-2 position in membrane phospholipids or that in the nonesterified fatty acid pool. (2) To determine if there exists a relationship between the potent dysrhythmic effects of lysophosphatidylcholine and the prevention of that arrhythmia by PUFA (3) To determine which eicosanoid (oxidized metabolite) of AA is prodysrhythmic, i.e., an AA product of cyclooxygenase, lipoxygenase, or epoxygenase, and what is the mechanism of its arrhythmic effect. (4) To determine cytosolic free Ca2+ levels when PUFA inhibit dysrhythmias. (5) To determine by patch clamp which ion channel(s) is modulated to make the changes in excitability/automaticity which EPA and DHA produce in isolated heart cells. These changes, we now think, constitute the primary antiarrhythmic action of these PUFAs. The health relatedness of these studies is that they will increase our understanding of how these fatty acids, when ingested chronically in the diet or injected intraveneously just prior to an ischemic stress can prevent fatal arrhythmias. With some 60% of deaths (some 300,000 annually) from acute myocardial infarctions resulting from sudden cardiac death, i.e., ventricular tachyarrhythmias, in the U.S.A., the potential public health benefits of this knowledge may be considerable.