Annotated References

Decreasing excessive omega-6 eicosanoid action can reduce the risk of ischemic heart disease (IHD) as demonstrated in the Physicians Health Study, the Antiplatelet Trial Collaboration, and the Thrombosis Prevention Trial.
    • Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989; 321: 129-135.
    •Ridker, P.M., Manson, J.E., Buring, J.E., Goldhaber, S.Z. and Hennekens, C.H. The effect of chronic platelet inhibition with low-dose aspirin on atherosclerotic progression and acute thrombosis: clinical evidence from the Physicians Health Study. Am Heart J 1991; 122: 1588-1592.
    • Collaborative overview of randomised trials of antiplatelet therapy: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Brit Med J 1994; 308: 81-106.
    •MRC General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet 1998; 351: 233-241.
Decreasing ischemic heart disease by increasing dietary omega-3 fats was shown in two recent large secondary prevention trials, the Lyon Diet Heart Study and the GISSI-Prevenzione trial, that confirmed results of the earlier DART trial.
    •Michael deLogeril et al, The Final Report of the Lyon Diet Heart Study. Circulation 1999; 99: 779-785.
    •Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial Lancet 354: 447-455, 1999 plus an editorial by Morris Brown, Lancet 1999; 354: 441-442.
    •Burr ML; Fehily AM; Rogers S; Welsby E; King S; Sandham S. Diet and reinfarction trial (DART): design, recruitment, and compliance. Eur Heart J 1989; 10(6): 558-567.
Agreement that consumption of omega-3 fatty acids may reduce the risk of coronary heart disease came from an expert workshop convened in Europe.
    •de Deckere E.A.M., Korver O., Verschuren P.M., Katan M.B. Health aspects of fish and n-3 polyunsaturated fatty acids from plant and marine origin. Eur J Clin Nutr 1998; 52: (10) 749-753.
Similar agreement was published from another expert workshop addressing Adequate Intakes of essential fatty acids.
    •Simopoulos AP; Leaf A; Salem N Jr. Workshop on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids. J Am Coll Nutr 1999; 18 (5):487-489.
Both expert group reports (above) recommended separate attention to four types of dietary fatty acid: 18-carbon omega-3, 18-carbon omega-6, 20- and 22-carbon omega-3, and 20- and 22-carbon omega-6 fatty acids because these four types interact in a well-documented hyperbolic, competitive metabolism that maintains essential fatty acids in tissue lipids.
    •Mohrhauer, H, Holman, RT, Effect of linolenic acid upon the metabolism of linoleic acid, J. Nutr. 1963; 81: 67-74.
    •Mohrhauer, H, Holman, RT, The effect of dose level of essential fatty acids upon fatty acid composition of the rat liver, J. Lipid Res.1963; 4: 151-159.
Possibly one-half of sudden deaths from coronary heart disease have detectable thrombi, but the other half may be due to unstable electrical patterns of the heart leading to ventricular fibrillation.
    •Nair, S.S.D., Leitch, J.W., Falconer, J. and Garg, M.L. Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action. J. Nutr.1997; 127: 383-393.
Dietary fish oil (but not corn oil) significantly reduced myocardial ischemic damage and decreased cardiac inotropic response to a-adrenergic agonists.
    •Hock, C.E., Holahan, M.A. and Reibel, D.K. Effect of dietary fish oil on myocardial phospholipids and myocardial ischemic damage. Am. J. Physiol. 1987; 252: H554-H560 Reibel, D.K., Holahan, M.A., and Hock, C.E. Effects of dietary fish oil on cardiac responsiveness to adrenoceptor stimulation. Am. J. Physiol.1987; 254: H494-H499.
Both omega-3 and omega-6 types of non-esterified polyunsaturated acids are anti-arrhythmic by inhibiting channel conduction of voltage-dependent L-type Ca2+ currents, but the omega-6 acid, arachidonate, can be arrhythmogenic by forming omega-6 eicosanoids. Thus, omega-6 eicosanoids (but NOT omega-3 eicosanoids) exacerbate arrhythmogenic events.
    •Kang, J.X. and Leaf, A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocyte. Proc. Natl. Acad. Sci., USA 1994; 91: 9886-9890. Xiao, Y-F., Gomez, A.M., Morgan, J.P., Lederer, W.J. and Leaf, A. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Nat Acad Sci, USA 1997; 94: 4182-4187.
A useful surrogate clinical index is the proportion of omega-6 acids among the 20- and 22-carbon highly unsaturated fatty acids (HUFA) in tissues. It helps interpret the impact of average daily dietary intakes of omega-3 and omega-6 nutrients upon thromboxane generation, and occurrence of fatal ischemic heart disease among Americans, Japanese, and Greenlanders.
    •Lands, W.E.M., Libelt, B., Morris, A., Kramer, N.C., Prewitt, T.E., Bowen, P., Schmeisser, D., Davidson, M.H., and Burns, J.H. Maintenance of lower proportions of n-6 eicosanoid precursors in phospholipids of human plasma in response to added dietary n-3 fatty acids. Biochem. Biophys. Acta 1992; 1180:147-162. Lands WEM. Long-term fat intake and biomarkers. Am. J. Clin. Nutr. 1995; 61(suppl):721-725S.
The usual care cohort of the MRFIT trial provided a prospective primary prevention study in which those in the upper quintile of long-chain omega-3 intake (an intake near the lower quintiles for Japanese) had an observed 0.6 relative risk of mortality from cardiovascular disease.
    •Dolecek, T.A., Grandits, G. In World Review of Nutrition and Diet (AP Simopoulos, RE Kifer, RR Martin, SE Barlow, eds.) 1991; 66: 205-216. Karger, Basel.
The US Physicians Health Study reported that consumption of fish at least once per week may reduce the risk of sudden cardiac death in men.
    •Albert CM; Hennekens CH; O'Donnell CJ; Ajani UA; Carey VJ; Willett WC; Ruskin JN; Manson JE. Fish consumption and risk of sudden cardiac death. JAMA 1998; 279(1): 23-28. NF Sheard. Fish consumption and risk of sudden cardiac death. Nutrition Reviews 1998; 56: 177-179.
Japanese in Brazil and USA who eat foods that have less omega-3 fats and maintain the surrogate clinical marker in tissues near 75% (rather than below 50% for those in Japan) and have correspondingly greater cardiovascular death rates.
    •Mizushima S, Moriguchi EH, Nakada Y, Biosca MDG, Nara Y, Murakami K, Horie R, Moriguchi Y, Mimura G, Yamori Y. (1992) The relationship of dietary factors to cardiovascular diseases among Japanese in Okinawa and Japanese immigrants, originally from Okinawa, in Brazil. Hypertension Res 1992;15: 45-55.     •Iso H; Sato S; Folsom AR; Shimamoto T; Terao A; Munger RG; Kitamura A; Konishi M; Iida M; Komachi Y. Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men. Int J Epidemiol 1989; 18(2): 374-381.
Fish meals that provided an average of 3.6 g/d of omega 3-fatty acids (close to the historic average daily intake for Japanese) reduced platelet aggregation and platelet thromboxane B2 responses.
    •Mori TA; Beilin LJ; Burke V; Morris J; Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17(2):279-286.
Significant decreases in platelet sensitivity to collagen, serum TXB2 levels, and urinary TXB2 metabolites were observed following omega-3 PUFA treatment.
    •Prisco D; Filippini M; Francalanci I; Paniccia R; Gensini GF; Serneri GG. Effect of n-3 fatty acid ethyl ester supplementation on fatty acid composition of the single platelet phospholipids and on platelet functions. Metabolism 1995; 44(5): 562-569.
Eicosapentaenoate supplementation decreased synthesis of the omega-6 platelet agonist thromboxane A2 coincident with formation of the inactive omega-3 form, thromboxane A3.
    •Knapp HR; Reilly IA; Alessandrini P; FitzGerald GA. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis. N Engl J Med 1986; 10;314(15):937-942.     •Needleman, P., Raz, A., Minkes, M.S., Ferendelli, J.A. and Sprecher, H. Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Nat Acad Sci, USA 1979; 76: 944-948.
A longitudinal study with forty individuals showed graphically how an inappropriate linear analyses of the hyperbolic data on thromboxane formation and aggregation can obscure the powerful action of dietary omega-3 fats in diminishing platelet function.
    •Lands, W.E.M., Culp, B.R., Hirai, A. and Gorman, R. Relationship of Thromboxane Generation to the Aggregation of Platelets from Humans: Effects of Eicosapentaenoic Acid. Prostaglandins 1985; 30, 819-825.
With about 20 to 40% of human body mass being fat and 15-20% of body fat being 18:2n-6, an adult American may have more than 3 kg of 18:2n-6. This large reservoir of omega-6 may need three years to equilibrate with dietary lipids.
    •Dayton, S., Hashimoto, S., Dixon, W., Pearce, M.L. Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat. J Lipid Res 1966; 7: 103-111.