Skip to main content
1004-2012, 1004-2013, 1005-2016, 1006-2026
class com.aha.ucm.component.cis.TagListPageData=[,docNativeURL=null,docName=UCM_501197,docStatus=RELEASED,dOutDate=null,docSSFileName=UCM_501197_Omega-3-Fatty-Acids-and-Coronary-Heart-Disease-A-Very-Fishy-Story.jsp,docTitle=Omega-3 Fatty Acids and Coronary Heart Disease: A Very Fishy Story,xWebsites=professional,dDocAuthor=stacy.ragsdale,xNextReviewDate=09/21/2016 5:30 PM,xTier1=36,xFeaturedItem=No,xElectronicRegistration=No,UserLocale=null,xSubCategory=,dpEvent=null,xComments=Author: Lewis H. Kuller, MD, DrPH | The new American Heart Association (AHA) Science Advisory, ?Seafood long chain n-3 PUFAs and cardiovascular disease? recommends one to two seafood meals per week to reduce risk of heart failure (HF), CHD, ischemic stroke, and cardiac death, especially when seafood replaces less healthy foods. It is unclear why one to two servings were selected.,NoHttpHeaders=null,UserTimeZone=null,xRegionDefinition=GENERIC_RD_COL_1,xVideoRenditions=,xSnippetItem=,xNotes=,UserDateFormat=null,encodeDocUrl=null,isDocProfileDone=null,xKeywords=diet; fatty acids, unsaturated; seafood,xTier2=,refreshSubMonikers=null,xEditorStepReassignedUsers=null,xLinkTextToDisplay=,dDocAccount=WCM/SOP/SMD,xEndDateTime=null,xClbraAliasList=null,ClientEncoding=null,xCpdIsLocked=0,xUsageRightsDate=null,xModifyDate=05/16/2018 9:47 PM,xTier3=,xEventDate=null,dSubscriptionType=null,xCopyright=No,xPackagedConversions=,dSubscriptionAlias=null,xStorageRule=,dpName=null,xDepartment=Science Operations,dStatus=RELEASED,dPublishType=,xCopyrightDetails=,xSubType=64,isDocProfileUsed=null,xWebsiteObjectType=Data File,xWebFlag=,xSeeAlsoLinks=,xClbraUserList=null,xPartitionId=,xCpdIsTemplateEnabled=0,xLinkWebAddress=,xDontShowInListsForWebsites=,xStartDateTime=null,dInDate=05/17/2018 9:00 AM,xWebsiteSection=professional:1463,dDocName=UCM_501197,dpAction=null,dRevLabel=1,dSecurityGroup=AHAMAH-Public,xCategory=,refreshMonikers=null,xDamConversionType=,dDocFormats=null,xAssociatedImage=,dDocType=SingleColumn,xBusinessOwner=Business Owner,xUploadDate=null,xDiscussionCount=0,xMainFlowEntryCriteria=True,xItemInformation=,xUsageRights=,xDiscussionType=N/A,xRecipeTaxonomy=,dSubscriptionID=null,dOriginalName=UCM_501197.xml,xProfileTrigger=SingleColumn,dLocation=,dRevisionID=1,dPublishState=,dReleaseState=Y,xTrashDeleter=null,dMessage=,dWebExtension=xml,dExtension=xml,dProcessingState=Y,xTrashDeleteName=null,dIsCheckedOut=0,xForceFolderSecurity=null,dRevClassID=501197,dIsPrimary=1,dFileSize=55348,dIndexerState=,dFlag1=,xviaAddNewContentService=,dIsWebFormat=0,xCollectionID=null,dRevRank=0,xReadOnly=null,dCheckoutUser=,dFormat=Application/xml,dWorkflowState=,dDocID=1842409,dRendition2=,dRendition1=,xInhibitUpdate=null,dReleaseDate=05/17/2018 9:00 AM,xTrashDeleteLoc=null,dCreateDate=05/16/2018 9:47 PM,xHidden=null,labelTier1=ScienceNews,labelTier2=,labelTier3=,labelTier4=,mobileNavURL=DEFAULT2_VALUE_FROM_getDataForAdvanceSearch,xContactPhoneNumber=,xContactEmailAddress=,xContactName=,xATGRolesDisciplines=,xPublishDate=05/17/2018 9:00 AM,xRobotParameter=,xCommunities=1004-2012, 1004-2013, 1005-2016, 1006-2026,xMembershipLevel=,rsCalories=null,rsSodium=null,rsRecipeTaxonomy=null,rsServings=null,rsTotalTime=null,rsTotalFat=null,rsTotalCarbs=null,rsFeaturedImage=null,xDisplayComments=

Omega-3 Fatty Acids and Coronary Heart Disease: A Very Fishy Story

Disclosure: None
Pub Date: Thursday, May 17, 2018
Author: Lewis H. Kuller, MD, DrPH
Affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh

View the full Science News coverage for Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease


Rimm EB, Appel LJ, Chiuve SE, Djoussé L, Engler MB, Kris-Etherton PM, Mozaffarian D, Siscovick DS, Lichtenstein AH; on behalf of the American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association [published online ahead of print May 17, 2018]. Circulation. DOI: 10.1161/CIR.0000000000000574.

Article Text

The new American Heart Association (AHA) Science Advisory, “Seafood long chain n-3 PUFAs and cardiovascular disease”1 recommends one to two seafood meals per week to reduce risk of heart failure (HF), CHD, ischemic stroke, and cardiac death, especially when seafood replaces less healthy foods. It is unclear why one to two servings were selected. Twenty years ago, Connor2 recommended two to three servings per week. The successful DASH diet recommended .5 servings per day or about three to four servings per week.3

The critical questions are whether this is the proper dose? Should recommended dose vary by host genetic susceptibility? Will this dose raise n-3 PUFAs levels in blood similar to those of low risk Japanese population? What is the effect of adding fish oil in a typical high fat, higher saturated fat US diet as compared to countries with high intake of n-3 PUFAs but also lower intake of saturated fat?

The authors of this statement and the recent previous reports of 2002 and 20164,5 were influenced by the results from clinical trials of n-3 PUFAs and supplements, especially in the US as compared to the ecological evidence based on much lower CHD rates in Japan with five or more times higher intake of n-3 PUFAs6. CVD rates are also low in other populations consuming higher amounts of n-3 PUFAs.

An important question is why is there such a discrepancy between both strong ecological inverse associations of high population dietary consumption of n-3 PUFAs and CHD incidence and mortality and the results of clinical trials.4,6-11 Numerous, but not all, epidemiological studies have supported the benefit of fish consumption to reduce CHD/CVD death, except for fried fish.2,12-18 Blood and tissue levels of n-3 PUFAs19-25 are linked to lower risk of coronary artery disease (CAD). Clinical and laboratory feeding experiments have also found consistent positive benefits of n-3 PUFA consumption in relationship to inflammation, cardiac arrhythmias, left ventricular function, thrombosis, and plaque stability.26-31 Pathology studies have also noted a low prevalence of atherosclerotic plaque associated with higher n-3 PUFAs.32,33

The difference between the results of clinical trials and the ecological, epidemiological, and laboratory studies, on the benefits of n-3 PUFAs is far more than of academic interest having very substantial public health implications. The Seven Countries Study 34 as well as previous studies of populations in Greenland that consume large amounts of fish oils documented the low mortality from CAD. The Japanese consume about 1 g/day of n-3 PUFAs as compared to 100-200 mg/day in the US.22,35 Plasma phospholipid-measured n-3 PUFA levels in the blood are much higher in the Japanese than in the US.22,36 The key public health question is whether the recommended intake of seafood in the US should be to reach the same levels of n-3 PUFAs in blood as in Japan, about 9% of total fatty acids in blood versus 4% in the US. The addition of two servings of seafood per week might increase consumption of n-3 PUFAs by about 500 mg.20

The most recent (2013) CHD age-adjusted death rates for Japanese men age 35-74 was 44/100,000 as compared to 128/100,000 for US men and for women, 12 versus 49/100,000, an over 4-fold difference.10 Endemic CHD in the US might practically disappear if consuming one g/day of fish oil, as is done in Japan, resulted in death rates in the US similar to Japan. There would be a substantial increase in life expectancy and likely decrease in health care utilization and costs for treatment of CVD. The low rates in Japan are not primarily due to genetic differences because migration of Japanese to the US or Brazil, for example, resulted in increase in CHD rates within a single generation associated with decline in n-3 PUFA intake.37

Studies of post-World War II birth cohorts in Japan as compared to the US have documented higher blood pressure, cigarette smoking, and similar cholesterol levels in Japanese and US white men but much lower CHD rates and extent of coronary atherosclerotic disease, as measured by coronary computed tomography (CT). The slopes of the risk of CHD by risk factor are similar but at any level of CHD incidence was much lower in Japan.38

Studies have consistently shown very low rates of CHD in southern Europe and in France7,10,39 attributed to differences in diet, including higher intake of n-3 PUFAs, alpha linolenic acid, lower intake of saturated fat and higher fish intake and higher intake of specific monounsaturated fatty acids, i.e. olive oil, nuts, Mediterranean diet. 40-45 The evidence strongly suggests that there is a protective effect in the diet that is associated with lower risk of CHD at similar levels of risk factors such as low-density lipoprotein cholesterol (LDL-C), Apolipoprotein-B, triglycerides, obesity. This contrasts with lower CHD rates among vegans due to lower intake of saturated fat and lower blood LDL-C levels.46 Furthermore, the lower prevalence of atherosclerotic plaque and coronary artery calcium by CT in Japan versus the US would be consistent with an effect on development of atherosclerotic plaques rather than later effects primarily on thrombosis, fibrinolysis. However, the specific benefits, if any, of n-3 PUFAs is still unsubstantiated in clinical trials.

Nutritional epidemiology is an example of a common source epidemic similar to a population consuming a common food contaminated with a bacteria leading to cases of gastrointestinal disease.47 The determinants of the epidemic include first, identifying the individuals who consume the specific common source; second, the dose of the agent; third, the likelihood of disease given the exposure, e.g. virulence; fourth, measures of host susceptibility, including genetics and other factors that either increase or decrease the likelihood of both disease and severity of disease given exposure; and fifth, the time between the exposure and the disease, the incubation period. In common source epidemics, it is often feasible to identify the specific common agent but very difficult to identify the differences in dose of exposure for those who did and did not develop the disease. This is especially true when many of the individuals may have subclinical disease, e.g. subclinical atherosclerosis.

Further investigation of n-3 PUFAs, therefore, as a common source exposure may improve our understanding of relationship to CHD:

  1. The first issue is dose of exposure to the agent. The levels of triglycerides in Japan are similar to those in the US, even in the younger age groups in spite of the fact that the Japanese are much thinner than the US population. Substantial effects of n-3 PUFAs on triglyceride levels usually require doses higher than in the general population as noted, perhaps 2-5 g/day. Most clinical trials in the US except those treating hypertriglyceridemia include a maximum of only about 1 g/day, the average in Japan, or even lower doses. The dose in many of the trials may be too low to modify risk of CHD, especially in secondary prevention. Therefore, much higher dose of n-3 PUFAs clinical trials may be required.48 There is little evidence that there are differences in blood fatty acid changes after consuming similar doses of n-3 PUFAs from fatty fish versus capsules containing fish oils.20
  2. Are there other dietary sources that impact the association of n-3 PUFAs with CHD risk? Countries with low incidence of CHD, such as Japan as well as in southern Europe, also generally consume lower amounts of animal products, especially beef, and have lower saturated fat intake.49,50 The virulence, e.g. the development of atherosclerosis and clinical CVD, may be a function of both the amount of consumption of saturated fat and other nutrients in animal products as well as the amount of n-3 PUFAs and other poly- and monounsaturated fatty acids in the diet.51,52 The amount of n-3 PUFAs in diet or supplements to reduce atherosclerosis and CVD may have to be much higher if the saturated fat intake of the population is also very high, e.g. higher than it is in Japan. For example, feeding studies many years ago from the Cleveland Clinic and others showed that the amount of polyunsaturated fatty acids necessary to reduce LDL-C was a function of the amount of saturated fat and polyunsaturated fat at the current levels of 10-15% of saturated fat, polyunsaturated fat had to increase to 12-15% or more to have a major beneficial effect on the LDL-C levels and probably the reduction of CHD, much higher than were used in some of the trials and much higher than the intake of n-3 PUFAs in the US population.53 It is of great relevance possibly that two major trials of Mediterranean diet and n-3 PUFAs (Japan EPA Lipid lowering Interventions Study [JELIS]) were carried out in low CHD risk populations, e.g. Spain and Japan. Neither trial, however, was double blinded and limits the interpretation of results.44,54 The JELIS trial used higher doses of n-3 PUFAs in a population with higher intake of n-3 PUFAs and the PREDIMED trial (Prevención con Dieta Mediterránea) provided both olive oil and nuts to intervention group. Would either of the trials had the same benefit effect if tested in a population consuming a typical higher saturated fat and protein, low polyunsaturated fat diet, e.g. in the US? Would increases in alpha linolenic acid n-3 PUFA from vegetable sources reduce CHD incidence if just added to a usual US diet?55,56 There is, for example, suggestion that benefit of alpha linolenic acid (vegetable source) may be a function of levels of arachidonic acid (animal source polyunsaturated fat).57 Future clinical trials and feeding studies in the US should evaluate the effects of very high n-3 PUFA intake and lower saturated fat intake, e.g. similar to Japan, France, or higher monounsaturated fat, e.g. southern Europe. The key limiting variable may be the amount of saturated fat in the diet.
  3. Is the incubation period for n-3 PUFAs exposure too short in most clinical trials? The Japanese and other populations with low CHD rates consume potentially beneficial high n-3 PUFA diets, etc. from a very early age. The prevention of CVD may depend on the effects on early stages of atherosclerotic development or the rate of progression of atherosclerosis. Feeding n-3 PUFAs in clinical trials to reduce CHD events among older participants with extensive atherosclerosis for 1, 2, or even 5 years may miss the need for long term interventions beginning possibly at earlier ages because of the long incubation period of atherosclerosis to clinical CAD.
  4. Host susceptibility may be an important determinant of benefits of n-3 PUFAs. The nutrients in the western diet, e.g. related to the high consumption of animal protein and saturated fat that may affect the gastrointestinal biology and metabolism and contribute to the high rates of CHD seen in the US and in many other countries. Differences in metabolism of nutrients may be affected both by differences in GI microflora among countries and interaction of genetic and unique environmental exposures, e.g. epigenetic effects. Further feeding studies could focus on n-3 PUFAs, phospholipid metabolism and relationship to atherosclerosis. 58-61

It is also possible that higher doses of n-3 PUFAs have a primary anti-inflammatory role in slowing the progression of atherosclerosis or possibly on thrombosis and fibrinolysis. Better short term feeding studies can now evaluate the effects of n-3 PUFAs on new measures of both adaptive and innate immunity and atherosclerosis.62-65 Similarly, ecological studies could evaluate the relationship of incident morbidity and mortality of other diseases related to inflammation, e.g. rheumatoid arthritis, other “autoimmune diseases,” COPD, etc. in relation to consumption of n-3 PUFAs.

The current design of clinical trials may have provided false-negative interpretation of the relationship between n-3 PUFAs and reduction of CHD incidence or mortality. On the other hand, it is possible that both the ecological and the clinical epidemiological studies may be incorrect, that the substantially lower CHD rate in Japan may be a function of their lower body weight, continued lower saturated fat intake, etc. or to other factors, such as the high intake of soy flavonoids. We also may be still observing a cohort effect and that the prior low levels of cholesterol, cigarette smoking, and saturated fat intake are still impacting on the population even these many years later.66-69 However, studies of birth cohorts in Japan born after World War II who had substantial changes in their risk factors early in life to levels similar to the US still consistently show both higher intake of n-3 PUFAs and substantially lower extent of atherosclerosis and CHD mortality.38,70-72

In summary, CHD is an example of a common source epidemic driven primarily by nutrients that account for the continued marked geographic variations in CHD in Japan, France, Israel, southern Europe. Genetic, host susceptibility, and other risk factors, i.e. smoking, elevated BP, physical activity, and obesity, obviously contribute to risk of CHD. Nutrients and their effect on lipoprotein metabolism, inflammation, and thrombosis is the driving force for this common source epidemic. Further nutrition research is important that could improve dietary guidelines and recommendations for seafood consumption in the US.

Better and longer feeding experiments with measures of intermediate endpoints should be considered. The choice of intermediate endpoints is problematic, lipoproteins, inflammation, thrombogenesis, vascular imaging. The availability of new technologies to measure intermediate endpoints may enhance nutrition feeding studies. The ideal clinical trial mimicking the experience in Japan would have to enroll young adults and follow them for at least 20-30 years. Such a trial is not feasible. Current trials may improve our understanding of effects of high doses of n-3 PUFAs in the short term, especially among individuals with atherosclerosis and/or CHD but will not resolve the issue of dose for public health prevention of CHD.

The increase in seafood or other sources of n-3 PUFAs may not be feasible at the population level without input from the food industry. Modern genetic technologies could result in foods with higher n-3 PUFAs content and reduction of saturated fat.

The marked geographic variations in CHD incidence and mortality, especially in Japan, France, and in southern Europe as compared to the US and other countries still persist. Reduction of CHD rates in the US to the low incidence and mortality countries like Japan would have, by far, the biggest impact on the CHD epidemic in the US.73-75 A common source epidemic cannot be controlled by individual-based interventions alone. It is perhaps unfortunate that after 50+ years of research, the best we can do is recommend one to two servings of seafood per week. A further substantial decline in incidence and mortality due to CVD is very likely to depend on modification of the common source diet.45


  1. Rimm EB, Appel LJ, Chiuve SE, Djoussé L, Engler MB, Kris-Etherton PM, Mozaffarian D, Siscovick DS, Lichtenstein AH; on behalf of the American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association [published online ahead of print May 17, 2018]. Circulation. DOI: 10.1161/CIR.0000000000000574.
  2. Connor SL, Connor WE. Are fish oils beneficial in the prevention and treatment of coronary artery disease? Am J Clin Nutr 1997;66:1020S-1031S.
  3. Stamler J. Improved Nutrition: Key to Solving the Populationwide Blood Pressure Problem. Nutritional and Metabolic Bases of Cardiovascular Disease. Hoboken, NJ: Wiley & Sons, Inc, 2010:303-320.
  4. Siscovick D. BTA, Fretts A. M., Wu J. H. Y., Lichtenstein A. H., Costello R. B., Kris-Etherton P. M., Jacobson T. A., Engler M. B, Alger H. M., Appel L. J., Mozaffarian D. . AHA Science Advisory: n-3 polyunsaturated fatty acid ("fish oil") supplementation and the prevention of clinical cardiovascular disease. 2016.
  5. Kris-Etherton PM, Harris WS, Appel LJ, American Heart Association. Nutrition C. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57.
  6. Kimura N, Keys A. Coronary heart disease in seven countries. X. Rural southern Japan. Circulation 1970;41:I101-12.
  7. Sans S, Kesteloot H, Kromhout D. The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe. Eur Heart J 1997;18:1231-48.
  8. 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;28:1044-9.
  9. Sekikawa A, Willcox BJ, Usui T et al. Do differences in risk factors explain the lower rates of coronary heart disease in Japanese versus U.S. women? J Womens Health (Larchmt) 2013;22:966-77.
  10. Writing Group M, Mozaffarian D, Benjamin EJ et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016;133:e38-360.
  11. Nestel P. Nutritional evidence still lacks consistency. Curr Opin Lipidol 2007;18:1-2.
  12. Albert CM, Hennekens CH, O'Donnell CJ et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:23-8.
  13. London B, Albert C, Anderson ME et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office Of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation 2007;116:e320-35.
  14. Belin RJ, Greenland P, Martin L et al. Fish intake and the risk of incident heart failure: the Women's Health Initiative. Circ Heart Fail 2011;4:404-13.
  15. Larsson SC, Orsini N, Wolk A. Long-chain omega-3 polyunsaturated fatty acids and risk of stroke: a meta-analysis. Eur J Epidemiol 2012;27:895-901.
  16. Breslow JL. n-3 fatty acids and cardiovascular disease. Am J Clin Nutr 2006;83:1477S-1482S.
  17. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 2006;296:1885-99.
  18. Engeset D, Braaten T, Teucher B et al. Fish consumption and mortality in the European Prospective Investigation into Cancer and Nutrition cohort. Eur J Epidemiol 2015;30:57-70.
  19. Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. J Lipid Res 1997;38:2012-22.
  20. Harris WS, Pottala JV, Sands SA, Jones PG. Comparison of the effects of fish and fish-oil capsules on the n 3 fatty acid content of blood cells and plasma phospholipids. Am J Clin Nutr 2007;86:1621-5.
  21. Pottala JV, Garg S, Cohen BE, Whooley MA, Harris WS. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: the Heart and Soul study. Circ Cardiovasc Qual Outcomes 2010;3:406-12.
  22. Sekikawa A, Curb JD, Ueshima H et al. Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study. J Am Coll Cardiol 2008;52:417-24.
  23. Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis 2007;193:1-10.
  24. Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr 2003;77:319-25.
  25. Siscovick DS, Raghunathan TE, King I et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995;274:1363-7.
  26. Cawood AL, Ding R, Napper FL et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis 2010;212:252-9.
  27. Gajos G, Zalewski J, Rostoff P, Nessler J, Piwowarska W, Undas A. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol 2011;31:1696-702.
  28. Farzaneh-Far R, Harris WS, Garg S, Na B, Whooley MA. Inverse association of erythrocyte n-3 fatty acid levels with inflammatory biomarkers in patients with stable coronary artery disease: The Heart and Soul Study. Atherosclerosis 2009;205:538-43.
  29. Heydari B, Abdullah S, Pottala JV et al. Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial. Circulation 2016;134:378-91.
  30. Lopez-Garcia E, Schulze MB, Manson JE et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr 2004;134:1806-11.
  31. Sekikawa A, Kadowaki T, Curb JD et al. Circulating levels of 8 cytokines and marine n-3 fatty acids and indices of obesity in Japanese, white, and Japanese American middle-aged men. J Interferon Cytokine Res 2010;30:541-8.
  32. Takei H, Strong JP, Yutani C, Malcom GT. Comparison of coronary and aortic atherosclerosis in youth from Japan and the USA. Atherosclerosis 2005;180:171-9.
  33. Shimamoto T, Sasaki T, Fujita T, Mukai N. The natural history of atherosclerosis. Comparison of aortic lesions in Tokyo, New Orleans, Guatemala and Costa Rica. J Atheroscler Res 1966;6:107-19.
  34. Menotti A, Lanti M, Kromhout D et al. Forty-year coronary mortality trends and changes in major risk factors in the first 10 years of follow-up in the seven countries study. Eur J Epidemiol 2007;22:747-54.
  35. Okuda N, Ueshima H, Okayama A et al. Relation of long chain n-3 polyunsaturated fatty acid intake to serum high density lipoprotein cholesterol among Japanese men in Japan and Japanese-American men in Hawaii: the INTERLIPID study. Atherosclerosis 2005;178:371-9.
  36. Sekikawa A, Steingrimsdottir L, Ueshima H et al. Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans--a descriptive epidemiologic study. Prostaglandins Leukot Essent Fatty Acids 2012;87:11-6.
  37. Iso H, Sato S, Folsom AR et al. Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men. Int J Epidemiol 1989;18:374-81.
  38. Sekikawa A, Doyle MF, Kuller LH. Recent findings of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on atherosclerosis and coronary heart disease (CHD) contrasting studies in Western countries to Japan. Trends Cardiovasc Med 2015;25:717-23.
  39. Ducimetiere P, Ruidavets JB, Montaye M, Haas B, Yarnell J, Group PS. Five-year incidence of angina pectoris and other forms of coronary heart disease in healthy men aged 50-59 in France and Northern Ireland: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study. Int J Epidemiol 2001;30:1057-62.
  40. de Lorgeril M, Salen P, Paillard F, Laporte F, Boucher F, de Leiris J. Mediterranean diet and the French paradox: two distinct biogeographic concepts for one consolidated scientific theory on the role of nutrition in coronary heart disease. Cardiovasc Res 2002;54:503-15.
  41. Zatonski W, Campos H, Willett W. Rapid declines in coronary heart disease mortality in Eastern Europe are associated with increased consumption of oils rich in alpha-linolenic acid. Eur J Epidemiol 2008;23:3-10.
  42. Campos H, Baylin A, Willett WC. Alpha-linolenic acid and risk of nonfatal acute myocardial infarction. Circulation 2008;118:339-45.
  43. Estruch R. Anti-inflammatory effects of the Mediterranean diet: the experience of the PREDIMED study. Proc Nutr Soc 2010;69:333-40.
  44. Estruch R, Ros E, Salas-Salvado J et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
  45. Stamler J. Toward a modern Mediterranean diet for the 21st century. Nutr Metab Cardiovasc Dis 2013;23:1159-62.
  46. Orlich MJ, Singh PN, Sabate J et al. Vegetarian dietary patterns and mortality in Adventist Health Study 2. N Engl J Med 2013;173:1230-8.
  47. Kuller LH, Orchard TJ. The epidemiology of atherosclerosis in 1987: unraveling a common-source epidemic. Clin Chem 1988;34:B40-8.
  48. Harris WS. International recommendations for consumption of long-chain omega-3 fatty acids. J Cardiovasc Med (Hagerstown) 2007;8 Suppl 1:S50-2.
  49. The World almanac and book of facts, 2010. Choice: Current Reviews for Academic Libraries 2010;47:1650-1651.
  50. Bernstein AM, Willett, W. C. Red meat intake and the risk of cardiovascular disease. Curr Cardiovasc Risk Rep 2011;5:145-148.
  51. Song M, Fung TT, Hu FB et al. Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality. N Engl J Med 2016;176:1453-1463.
  52. Mann J, Morenga LT, McLean R et al. Dietary guidelines on trial: the charges are not evidence based. Lancet 2016;388:851-3.
  53. Brown HB, Farrand M, Page IH. Design of practical fat-controlled diets. Foods, fat composition, and serum cholesterol content. JAMA 1966;196:205-13.
  54. 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;369:1090-8.
  55. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779-85.
  56. Mozaffarian D. JELIS, fish oil, and cardiac events. Lancet 2007;369:1062-3.
  57. Baylin A, Campos H. Arachidonic acid in adipose tissue is associated with nonfatal acute myocardial infarction in the central valley of Costa Rica. J Nutr 2004;134:3095-9.
  58. Tang WH, Wang Z, Fan Y et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014;64:1908-14.
  59. Hui DY. Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease. Curr Opin Lipidol 2016;27:507-12.
  60. Wang Z, Koonen D, Hofker M, Fu J. Gut microbiome and lipid metabolism: from associations to mechanisms. Curr Opin Lipidol 2016;27:216-24.
  61. Feldman SA, Ho KJ, Lewis LA, Mikkelson B, Taylor CB. Lipid and cholesterol metabolism in Alaskan Arctic Eskimos. Arch Pathol 1972;94:42-58.
  62. De Caterina R. n-3 fatty acids in cardiovascular disease. N Engl J Med 2011;364:2439-50.
  63. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010;376:540-50.
  64. Ferrucci L, Cherubini A, Bandinelli S et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006;91:439-46.
  65. Harris WS. Updating the cardiovascular benefits of n-3 fatty acids. The Lipid Spin. San Antonio, TX: National Lipid Foundation, 2005:1, 4-5.
  66. Wen CP, Gershoff SN. Changes in serum cholesterol and coronary heart disease mortality associated with changes in the postwar Japanese diet. Am J Clin Nutr 1973;26:616-9.
  67. Matsushita Y, Takahashi Y, Mizoue T et al. Overweight and obesity trends among Japanese adults: a 10-year follow-up of the JPHC Study. Int J Obes (Lond) 2008;32:1861-7.
  68. Ueshima H. Explanation for the Japanese paradox: prevention of increase in coronary heart disease and reduction in stroke. J Atheroscler Thromb 2007;14:278-86.
  69. Okayama A, Ueshima H, Marmot M, Elliott P, Choudhury SR, Kita Y. Generational and regional differences in trends of mortality from ischemic heart disease in Japan from 1969 to 1992. Am J Epidemiol 2001;153:1191-8.
  70. Ueshima H, Tatara K, Asakura S. Declining mortality from ischemic heart disease and changes in coronary risk factors in Japan, 1956-1980. Am J Epidemiol 1987;125:62-72.
  71. Sekikawa A, Miura K, Lee S et al. Long chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese men in Japan and white men in the USA: population based prospective cohort study. Heart 2014;100:569-73.
  72. Yamagishi K, Iso H, Date C et al. Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study. J Am Coll Cardiol 2008;52:988-96.
  73. Stanley JC, Elsom RL, Calder PC et al. UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. Br J Nutr 2007;98:1305-10.
  74. Hu FB, Manson JE. Omega-3 fatty acids and secondary prevention of cardiovascular disease-is it just a fish tale?: comment on "Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease". Arch Intern Med 2012;172:694-6.
  75. Seafood choices: balancing benefits and risks. Choice: Current Reviews for Academic Libraries 2007;45:133-133.

-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --