EDITORIAL COMMENT
Omega-3 Fatty Acids: The "Japanese" Factor?*
William Harris, PhD*
Sanford Research/USD, Metabolism and Nutrition Research Center, Sioux Falls, South Dakota
* Reprint requests and correspondence: Dr. William Harris, Sanford Research/USD, 1100 East 21st Street, Suite 700, Sioux Falls, South Dakota 57105. (Email: bill.harris{at}usd.edu).
A massive natural experiment is under way in Japan that may generate important information regarding the relationships between life-style factors—diet, smoking, stress—and cardiovascular disease (1). Since the end of World War II, a generation of Japanese men and women who have been assimilating a more Western dietary pattern is reaching the age where, at least in the West, coronary heart disease (CHD) typically begins to take its toll. Is the adoption of a higher-fat, higher-calorie Western diet going to result in a greater prevalence of classic CHD risk factors, such as increased serum cholesterol and blood pressure, in Japan? Is CHD going to precipitously rise in Japan? A cohort of post-World War II Japanese men have been followed by Sekikawa et al. (2) and have been found to have similar lifetime cholesterol and blood pressure levels as white men in the U.S., along with a greater rate of smoking and prevalence of diabetes. So, the stage appears to be set. However, to date, CHD rates in Japan remain less than one-half of those in the U.S. (3). This unexpected finding has stimulated the search for a factor or factors in the Japanese diet or life-style that have the power to withstand the onslaught of advancing risk factors. In this issue of the Journal, Sekikawa et al. (4) tested a hypothesis that is gaining traction around the world, one that might find its most compelling confirmation in Japan: could the factor be omega-3 fatty acids?
Sekikawa et al. (4) measured serum omega-3 fatty acids levels, carotid intimal-medial thickness (IMT), and coronary artery calcium (CAC) burden in approximately 900 men; one-third were Japanese men living in Japan (JiJ), one-third were Japanese-American men living in Honolulu (JiA), and the final one-third were white men residing in the U.S. (W). The researchers made several observations. First, serum omega-3 levels were 45% to 80% greater in JiJ than in JiA or W, respectively, indicating that the diet of the JiA cohort had, like their ancestors, migrated east. Second, both carotid IMT and CAC were reduced in the JiJ compared with both the W and the JiA groups but, unexpectedly, common carotid plaque burden was similar in the former 2 groups but increased in the latter. This finding illustrates how carotid plaque burden and carotid IMT can dissociate. In the 2 low-omega-3 populations (W and JiA), there were no relationships between any vascular measure and serum omega-3 fatty acid levels but, in the JiJ group (where the omega-3 range was the greatest), there was a significant inverse relationship between carotid IMT and serum omega-3 levels. However, CAC burdens were not related to omega-3 status in any cohort (another disconnect between these 2 surrogates of atherosclerosis). Finally, the differences between carotid IMT and CAC in the JiJ and the W populations (which persisted after adjustment for classical CHD risk factors) disappeared when adjusted for serum omega-3 content. This observation suggests that low omega-3 levels may be in the causal pathway for carotid IMT and CAC. The authors conclude that "very high intake of marine-derived n-3 fatty acids has antiatherosclerotic effects." The Japanese consume between 8 and 15 times more eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than typical Westerners (0.8 to 1.5 g/day) (5,6). Although there are other factors in the Japanese diet that could play a role in this phenomenon (e.g., low-fat diets, soy proteins, and/or isoflavones), the power of omega-3 levels to eliminate cross-population disparities suggests that these may be responsible.
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Inuit experience
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But is a "very high intake of n-3 fatty acids" always cardioprotective? Can these findings be generalized to others? Omega-3 intakes in Japan are only one-quarter of those in Eskimos (7), the population that birthed the omega-3 hypothesis. More than 30 years ago, Dyerberg and Bang (8) reported, despite the consumption of a diet very low in fruits, vegetables, and complex carbohydrates and high in fat and cholesterol, that serum cholesterol and triglycerides were lower in Greenland Inuit than in age-matched Danes. Kromann and Green (9) reported that acute myocardial infarction rates in this same population were markedly lower than those in Denmark. Through a series of now-classic investigations, the "Eskimo factor" that apparently protected them from the ravages of CHD was proposed to be the omega-3 fatty acids (EPA and DHA) (10) provided by the whale, seal, and fish consumed as part of their traditional diet. The seeds planted by these investigators took many years to germinate, sprout, and grow and are finally coming into full bloom. Seminal randomized clinical trials such as the 1989 Diet and Reinfarction Trial (11), the 1999 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) Prevenzione study (12), and the 2007 Japan EPA Lipid Intervention Study (13) have all confirmed that increased intakes of EPA alone or EPA + DHA reduce the risk for CHD. More and more, national and international health organizations are establishing recommendations for both primary and secondary prevention of CHD that include EPA and DHA (14).
But all is not well in the far north. Although some investigators continue to report that Inuit consuming traditional diets have lower CHD rates (15–17), others are questioning this dogma (18). Recent evidence from the GOCADAN (Genetics of Coronary Artery Disease in Alaska Natives) study indicates that carotid atherosclerosis is not only unrelated to omega-3 fatty acid intakes in this cohort (19) but, surprisingly, its prevalence is now greater than that in U.S. white populations (20). At least part of the problem in Alaska appears to be not a lack of omega-3 but the introduction of massive amounts of shortenings and other saturated fats into their Westernizing diet (18). Saturated and monounsaturated fat intakes in GOCADAN are approximately 12% and 15% of energy, whereas in a similar age group in Japan, intakes are 8% and 9.4% of energy, respectively (6). This difference may be critical.
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Norway?
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The Inuit population is not the only one consuming relatively high amounts of omega-3 fatty acids that still develops CHD. The prevalence of carotid plaque and intimal thickening is at "Western" levels in Norway as well (21), a country where the omega-3 intake is approximately 1 g/day in men (22), which is similar to that in Japan. Supplementation of elderly, hyperlipidemic Norwegian men with omega-3 fatty acids (2.4 g/day) did not reduce carotid plaque burden or carotid IMT over the course of 3 years, but it did improve pulse wave velocity, a marker of arterial elasticity (23). Interestingly, the fat intake of Norwegian coronary patients (13% energy saturated and 12% monounsaturated fatty acids) (22) is reminiscent of the Inuit intake and considerably greater than that in Japan.
The Japanese experience, when contrasted to that of the Inuit and the Norwegians, suggests that the cardioprotective punch of the long chain omega-3 fatty acids may be no match for diets high in fat, particularly saturated fat. Even higher-than-Inuit intakes of omega-3 have been tested for their ability to slow or reverse coronary artery atherosclerosis and were found wanting. Sacks et al. (24) randomized 59 patients in the U.S. to 6 g of EPA + DHA and followed them for 28 months and found no evidence for slowed progression measured by quantitative coronary angiography. On the other hand, a prolonged (lifetime?) above-average dietary intake of omega-3 FAs may be able to accomplish what a relatively short-term high-dose intervention could not. In 233 women participating in the Estrogen Replacement and Atherosclerosis study, those with higher than the median levels of DHA in serum phospholipids experienced a slower progression of coronary artery disease over 3.2 years than women with lower levels (25). These findings suggest the not unreasonable hypothesis that decades of a moderately high omega-3 dietary intake may be the best way to slow atherosclerosis. The observations of Sekikawa et al. (4) harmonize with this view and strongly suggest that the "Japanese factor" is likely to be omega-3 fatty acids. Only time will tell how this natural experiment will turn out, but with the incessant intrusion of Western dietary ways into Japan, one cannot be particularly optimistic.
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Footnotes
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Dr. Harris is a scientific advisor and speaker for GlaxoSmithKline (who now market Lovaza, the prescription omega-3), and he is an advisor to and grant recipient from Monsanto, Co., which is currently developing a soybean-based omega-3-enriched oil. In other words, his generally kind words for the "omega-3 hypothesis," which he believes to be evidence-based, could be construed as being conditioned by his relations with these companies.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Sekikawa A, Horiuchi BY, Edmundowicz D, et al. A "natural experiment" in cardiovascular epidemiology in the early 21st century Heart 2003;89:255-257.[Abstract/Free Full Text]2. Sekikawa A, Kuller LH, Ueshima H, et al. Coronary heart disease mortality trends in men in the post World War II birth cohorts aged 35-44 in Japan, South Korea and Taiwan compared with the United States Int J Epidemiol 1999;28:1044-1049.[Abstract/Free Full Text] 3. Sekikawa A, Ueshima H, Kadowaki T, et al. Less subclinical atherosclerosis in Japanese men in Japan than in White men in the United States in the post-World War II birth cohort Am J Epidemiol 2007;165:617-624.[Abstract/Free Full Text] 4. Sekikawa A, Curb JD, Ueshima H, et al. ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study J Am Coll Cardiol 2008;52:417-424.[Abstract/Free Full Text] 5. Kobayashi M, Sasaki S, Kawabata T, Hasegawa K, Tsugane S. Validity of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I to assess fatty acid intake: comparison with dietary records and serum phospholipid level J Epidemiol 2003;13:S64-S81.[Web of Science][Medline] 6. Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I Circulation 2006;113:195-202.[Abstract/Free Full Text] 7. Ebbesson SO, Risica PM, Ebbesson LO, Kennish JM. Eskimos have CHD despite high consumption of omega-3 fatty acids: the Alaska Siberia project Int J Circumpolar Health 2005;64:387-395.[Medline] 8. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-Coast Eskimos Lancet 1971;1:1143-1146.[Web of Science][Medline] 9. Kromann N, Green A. Epidemiological studies in the Upernavik District, Greenland Acta Med Scand 1980;208:401-406.[Web of Science][Medline] 10. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet 1978;2:117-119.[CrossRef][Web of Science][Medline] 11. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART) Lancet 1989;2:757-761.[Web of Science][Medline] 12. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione Circulation 2002;105:1897-1903.[Abstract/Free Full Text] 13. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis Lancet 2007;369:1090-1098.[CrossRef][Web of Science][Medline] 14. Harris WS. International recommendations for consumption of long-chain omega-3 fatty acids J Cardiovasc Med 2007;8(Suppl 1):S50-S52.[Web of Science] 15. Dewailly E, Blanchet C, Lemieux S, et al. n-3 fatty acids and cardiovascular disease risk factors among the Inuit of Nunavik Am J Clin Nutr 2001;74:464-473.[Abstract/Free Full Text] 16. Davidson M, Bulkow LR, Gellin BG. Cardiac mortality in Alaska's indigenous and non-Native residents Int J Epidemiol 1993;22:62-71.[Abstract/Free Full Text] 17. McLaughlin J, Middaugh J, Boudreau D, et al. Adipose tissue triglyceride fatty acids and atherosclerosis in Alaska Natives and non-Natives Atherosclerosis 2005;181:353-362.[CrossRef][Medline] 18. Bjerregaard P, Young TK, Hegele RA. Low incidence of cardiovascular disease among the Inuit—what is the evidence? Atherosclerosis 2003;166:351-357.[CrossRef][Web of Science][Medline] 19. Ebbesson SO, Roman MJ, Devereux RB, et al. Consumption of omega-3 fatty acids is not associated with a reduction in carotid atherosclerosis: the Genetics of Coronary Artery Disease in Alaska Natives study Atherosclerosis 2008In press. 20. Cutchins A, Roman MJ, Devereux RB, et al. Prevalence and correlates of subclinical atherosclerosis in Alaska Eskimos: the GOCADAN Study Stroke 2008In press. 21. Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Age and sex differences in the distribution and ultrasound morphology of carotid atherosclerosis: the Tromso Study Arterioscler Thromb Vasc Biol 1999;19:3007-3013.[Abstract/Free Full Text] 22. Andersen LF, Solvoll K, Drevon CA. Very-long-chain n-3 fatty acids as biomarkers for intake of fish and n-3 fatty acid concentrates Am J Clin Nutr 1996;64:305-311.[Abstract/Free Full Text] 23. Hjerkinn EM, Abdelnoor M, Breivik L, et al. Effect of diet or very long chain omega-3 fatty acids on progression of atherosclerosis, evaluated by carotid plaques, intima-media thickness and by pulse wave propagation in elderly men with hypercholesterolaemia Eur J Cardiovasc Prev Rehabil 2006;13:325-333.[CrossRef][Web of Science][Medline] 24. Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B, Pasternak RC. Controlled trial of fish oil for regression of human coronary atherosclerosis J Am Coll Cardiol 1995;25:1492-1498.[Abstract] 25. Erkkila AT, Matthan NR, Herrington DM, Lichtenstein AH. Higher plasma docosahexaenoic acid is associated with reduced progression of coronary-artery atherosclerosis in women with established coronary artery disease J Lipid Res 2006;47:2814-2819.[Abstract/Free Full Text]
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Inuit experience
Norway?