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Editorial |
1 From the Division of Endocrinology, Diabetes, and Clinical Nutrition, the Department of Medicine, Oregon Health & Science University, Portland.
See corresponding article on page 464.
2 Supported by the Oregon Health & Science University Foundation and the General Clinical Research Centers Program (RR-59) of the Division of Research Resources of the National Institutes of Health.
3 Address reprint requests to WE Connor, Department of Medicine, L465, Oregon Health & Science University, Portland, OR 97201. E-mail: connorw{at}ohsu.edu.
The steps in the development of important medical discoveries rest first on intuition and then on associations of a certain factor with a disease, followed by scientifically designed experiments. The history of the importance of the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) illustrates this point beautifully. Early Arctic explorers commented on the rarity of coronary artery disease in Eskimos despite their consumption of a very-high-fat, high-cholesterol diet. This finding was indeed a paradox until it was resolved by 2 Danish scientists, Bang and Dyerberg (1). When these investigators looked at the coronary mortality statistics in Greenland Eskimos and in Danish persons living in Greenland but having a vastly different lifestyle, they found few deaths from coronary artery disease in Greenland Eskimos but many deaths in Danes. The answer to this riddle came from an analysis of the diet of the Eskimos compared with that of the Danes (1). The latter group ate a diet high in saturated fat and cholesterol from meat and dairy products similar to the diet eaten in the homeland of Denmark. The Eskimos, on the other hand, ate seal, whale, and fish, all of which are extremely rich in EPA and DHA. This was in contrast with the lower n-3 fatty acid content of the typical Danish diet. In the Greenland Eskimos also, the content of these same n-3 fatty acids in the blood was high (2), and the tendency of the blood to form thrombi was lessened because the n-3 fatty acids were taken up by the blood platelets (3).
The same situation prevails in present-day Eskimos, as illustrated by the study by Dewailly et al (4) in this issue of the Journal. The Nunavik Inuit of Quebec, despite some Westernization, still partly consume the diet of their ancestors, which is rich in fish and marine mammals. Mortality from coronary artery disease in the Inuit is 50% less than that in the Quebec province as a whole. The Inuit's high blood content of EPA and DHA reflects their consumption of these foods from the sea.
Why the n-3 fatty acids from fish and marine oils prevent coronary artery disease has now been delineated in hundreds of experiments in animals and tissue culture cells and in population and clinical trials (5). Of the nutritional modalities thought to prevent heart disease, the evidence for the efficacy of n-3 fatty acids is strong. This evidence may be best summarized in Table 1
and by answering the following question: have other population studies and clinical trials shown that fish consumption is associated with a lowered incidence of coronary artery disease? Japanese, Dutch, and US studies indicate that deaths from coronary artery disease are reduced by 
50% by the consumption of 1–2 fish meals/wk (6–8). The most important finding is of a reduction in sudden death from ventricular fibrillation and tachycardia. About 300000 such deaths occur in the United States each year. Direct clinical trials of fish and fish oil have also shown a striking reduction in sudden deaths (9, 10); these findings have great public health significance. Furthermore, animal studies and experiments in isolated myocytes showed that ventricular arrhythmias are inhibited by EPA, which affects sodium and calcium ion channels in the heart (11).
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The EPA and DHA contained in fish oil inhibit the development of atherosclerosis. There is evidence in both pigs and monkeys that dietary fish oil prevents atherosclerosis by actions other than the lowering of plasma cholesterol concentrations (14). These actions may be associated with the inhibition of monocyte migration into the plaque, with less cytokine and interleukin 1
production, and with stimulation of the endothelial production of nitric oxide.
Dyerberg and Bang also found that the blood of Greenland Eskimos had lower triacylglycerol and cholesterol concentrations, particularly triacylglycerol, than the blood of Danes (2). Dewailly et at (4) found that n-3 fatty acids in the plasma phospholipids of Nunavik Inuit were positively associated with HDL-cholesterol concentrations and inversely associated with plasma triacylglycerol and the ratio of total to HDL cholesterol. These Inuit had higher n-3 fatty acid (EPA+DHA) concentrations in their plasma phospholipids proportional to the intakes of typical Eskimo marine foods. However, plasma total and LDL-cholesterol concentrations correlated positively with n-3 fatty acid concentrations. The divergent effects of n-3 fatty acids to reduce plasma triacylglycerol and elevate LDL may be explained by a dietary background high in cholesterol and saturated fat as well as in n-3 fatty acids. The 2 situations are completely compatible. In a feeding experiment by Nordoy et al (15), a diet high in n-3 fatty acids but also high in cholesterol and saturated fat decreased plasma triacylglycerol and VLDL and at the same time increased plasma LDL. The optimal diet would be one high in n-3 fatty acids and low in cholesterol and saturated fat, thus reducing both triacylglycerol and LDL concentrations in the plasma.
This pronounced effect of fish oil on hyperlipidemia is especially well documented by precise dietary studies in which a diet rich in salmon oil was fed and contrasted with a vegetable oil diet and a diet high in saturated fat (16). Fish oil lowers plasma triacylglycerol concentrations by inhibiting the synthesis of triacylglycerol and VLDL in the liver. Apolipoprotein B production is lower after consumption of fish oil than after consumption of vegetable oils such as safflower or olive oil. This mechanism of action is further substantiated by cultures of rabbit and rat hepatocytes in which EPA, for example, in contrast with oleic acid, inhibited triacylglycerol synthesis and stimulated the synthesis of membrane phospholipid.
Pronounced postprandial lipemia occurs after the absoprtion of fat from diets with high fat contents. Postprandial lipoproteins are known to be atherogenic. They are also thrombogenic because postprandial lipemia increases activated factor VII, a procoagulant. Pretreatment with fish oil greatly lessens postprandial lipemia (17), and this effect should be considered both anti-atherogenic and anti-thrombotic.
The emphasis on fish and fish oil for coronary prevention does not mean that vegetarians could not benefit from the consumption of n-3 fatty acids. The precursor to EPA and DHA in the n-3 fatty acid synthetic pathway is -linolenic acid (18:3n-3), which is especially rich in certain vegetable oils such as canola, soy, flaxseed, and walnut oils. In the Lyon Heart Study, which emphasized linolenic acid consumption from canola margarine, blood EPA concentrations increased and the death rate from coronary artery disease was reduced by 70% with a concomitant reduction in sudden death (18). A vegetarian diet, then, can still benefit from an increased n-3 fatty acid content.
In summary, n-3 fatty acids from fish and fish oil are natural food substances that prevent coronary artery disease and sudden death. Physicians should become acquainted with the powerful therapeutic potential of these fatty acids. n-3 Fatty acids have immense public health significance for the control of the current coronary epidemic.
REFERENCES
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  J. M. McKenney and D. Sica Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia Am. J. Health Syst. Pharm., March 15, 2007; 64(6): 595 - 605. [Abstract] [Full Text] [PDF]
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 A. A Welch, S. A Bingham, J. Ive, M. D Friesen, N. J Wareham, E. Riboli, and K. Khaw Dietary fish intake and plasma phospholipid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1330 - 1339. [Abstract] [Full Text] [PDF]
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 A. M. Perez-Granados, M. P. Vaquero, and M. P. Navarro Comparative Effects of the Fat Extracted from Raw and Fried Sardines Upon Rat Growth and Zinc Bioavailability Food Science and Technology International, August 1, 2003; 9(4): 285 - 293. [Abstract] [PDF]
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C. H Halsted Dietary supplements and functional foods: 2 sides of a coin? Am. J. Clinical Nutrition, April 1, 2003; 77(4): 1001S - 1007. [Abstract] [Full Text] [PDF]
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