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Omega-3 Fish Oils: The Greatest Nutritional Health Discovery Since Vitamins
Part 4: The Major Studies, An Interview with Professor Jørn Dyerberg, M.D.
By Richard A. Passwater, Ph.D.
In the introduction to our chat with Jørn Dyerberg, M.D., I briefly mentioned a few of the reasons why readers should be interested in learning more about fish oil. Dr. Dyerberg’s discoveries led to our understanding of why the long-chain omega-3 fatty acids, EPA and DHA, are so important to our health.
In Part One, I called your attention to the following: “Reduce your chance of dying a sudden death by 45% (1, 2)! Reduce your risk of dying from sudden cardiac death by 90% (3). Reduce your chance of developing Alzheimer’s disease by 45–50% (4). Stay younger longer (5, 6)! Reduce the inflammation and pain of rheumatoid arthritis and the pain of osteoarthritis arthritis and other inflammatory diseases (7, 8). The litany of health benefits from omega-3s goes on, but hopefully, these are enough to get your attention so that you will read on about this miraculous dietary supplement. We will discuss the details of these studies in a later installment of this series.
“Recently, a low level of long-chain omega-3 fatty acids had been purposed as a risk factor for heart disease. The new risk factor is based on measuring the fatty acids in red blood cells, and is expressed as a percentage of EPA + DHA of total fatty acids. An omega-3 index of >8% is associated with 90% less risk for sudden cardiac death, as compared to an omega-3 index of <4% (9).”
In Part 2, I noted another important large multi-year study in which Dutch researchers reported a 62% lower risk of fatal heart attack in people consuming a modest amount of EPA and DHA (approximately 230 mg/day) from fish as compared with those consuming small amounts (approximately 40 mg/day of EPA and DHA) (10).
This month we will chat with Dr. Dyerberg about the details and meaning of these studies.
Jørn Dyerberg, M.D., professor and Dr. Med. Sc., has made several discoveries that elucidate many of the health benefits of omega-3 fish oils. Dr. Dyerberg made five scientific expeditions to Northwest Greenland in the 1970s examining the association between fish oil intake and coronary heart diseases in Eskimos. Dr. Dyerberg, who is Danish, hypothesized that the rarity of coronary heart disease among the Inuit could be due to the omega-3 fatty acids in their diet consisting largely of seal and cold-water oily fish. Together with his fellow researchers, he went on to elucidate the unique physiological effects of these fatty acids. His research opened new fields leading to thousands of health studies by many. His own research encompasses more than 350 scientific publications primarily concerning blood lipids, atherosclerosis, the blood coagulation system, omega-3 polyunsaturated fatty acids, trans-fatty acids and prostaglandins.
In 2007, Dr. Dyerberg was honored by the American Heart Association in “Recognition of Outstanding Scientific Contribution for the Advancement of Heart Health Worldwide.” In 2008, he received the American Dietetic Association Foundation’s Edna and Robert Langholtz International Nutrition Award.
Passwater: Dr. Dyerberg, there are so many important studies that show the health benefits of fish oil. It’s hard to pick just a few to chat about, but let’s start with one of my favorites: The 1999 GISSI Study (1). This study caught the attention of many clinical researchers and influenced the thinking of “official” organizations that make dietary recommendations. The GISSI study used supplements of 850 mg/day of total EPA and DHA.
Dr. Dyerberg, what is important about the GISSI Study? What is the take home message for us?
Dyerberg: The GISSI study was the second large clinical trial examining the effect of an increased intake of EPA and DHA on coronary heart disease. The first was the Diet and Reinfarction Trial (DART) (11). The DART study (published in 1989) involved 2,033 men recovering from myocardial infarction. They were randomly allocated to receive advice or to receive no advice on each of three dietary factors: an increase in fatty fish intake, a reduction in intake of certain fats (saturated fat) with an increase in others (polyunsaturated fatty acids, PUFAs) or an increased intake of cereal fiber. The men advised to eat more fatty fish had 29% lower two-year all-cause mortality; the other forms of advice did not have any significant effects (12).
The Italian GISSI-Prevenzione trial (published in 1999) was even bigger, involving 11,300 persons! The trial showed that three-year treatment with low-dose omega-3 PUFAs (850 mg/day) was associated with a significant total mortality reduction of 21% in patients who survived a recent myocardial infarction or heart attack (starting treatment within three months from symptom onset). An analysis of the causes of death showed that among all cardiac causes, sudden cardiac death was the most affected by n-3 PUFA, which was reduced by 45%!
Passwater: I like to use slides based on three studies in my lectures. The most important message that I see in these studies is that those persons in the highest quartile of EPA and DHA combined intake have only about 10% of the cardiac risks of persons in the lowest quartile of EPA and DHA intake. The data from Dr. D.S. Siscovick and colleagues looked at a patient cohort nested within the famous Physicians Health Study and found that those persons in the highest quartile of EPA and DHA intake had only 10% of the risk of sudden cardiac death of normal people (90% reduction in risk of sudden cardiac death) (14). We haven’t even discussed the importance of EPA and DHA in normalizing heart rhythm and preventing abnormal heart rhythms that can lead to sudden heart death (3).
Figures 1–3 are based on these three studies and I think they present compelling graphics that should get everyone’s attention.
Dr. Dyerberg, these three studies add considerably to the body of science that shows that EPA and DHA reduce the risk of death from cardiovascular disease. We owe you a lot for your pioneering research and further elucidation of the science that has led to these studies. What should people conclude from these and similar studies?
Figure 1: The odds ratio (relative risk) of having an acute coronary syndrome is inversely associated with the combined EPA and DHA content of the blood. Acute coronary syndrome is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischemia. Acute myocardial ischemia is chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease (also called coronary heart disease). This content can be conveniently expressed as the percentage of EPA and DHA in the total blood cell membrane fatty acids. This percentage is referred to by Dr. W.S. Harris et al. as the “Omega-3 Index.” Figure 1 charts the EPA and DHA intake as three groupings: low (<4%), intermediate (4–8%) and high (>8%). The odds ratios were calculated to include possible confounding factors including age, race, sex, diabetes, hypertension, family history and various serum lipids. Data are from R.C. Block et al. (13).
Figure 2: Relationship between total EPA and DHA content (expressed as the Omega-3 Index) and the risk for primary cardiac death. Primary cardiac death is the sudden cessation of heartbeat and cardiac function, resulting in the loss of effective circulation. It is also called primary cardiac arrest or sudden cardiac death. Data are from Dr. D.S. Siscovick and colleagues (14).
Figure 3: Relationship between the total EPA and DHA (expressed as the Omega-3 Index) and sudden cardiac death. Data are from Dr. C.M. Albert and colleagues (2).
Dyerberg: There are several conclusions, but to me the most obvious is that we are in a nutritional deficiency of long- chained omega-3 fatty acids. In the United States, the average daily intake of EPA plus DHA is 100–200 mg. In 20% of U.S. citizens, the intake is close to zero! The recommended intake is 400–600 mg/day, and in pregnancy and lactation, women should consume 300 mg of DHA/day.
Passwater: Wow! The intake of EPA and DHA is close to zero in 20% of U.S. citizens! Holy smoke! And, the U. S. Daily average is about 100–200 mg, instead of the recommended 400–600 mg! On average, U.S. citizens are getting only a third to a sixth of the recommended amounts, and I feel that the 600 mg recommendation should be higher. We seek optimal health, not average health. I personally lean more toward the 1,000-mg level for healthy persons and more for those with health problems. This is still far short of the 14,000 mg you found in the Eskimo diet (15).
Let’s turn to another critical health problem. Dementia and Alzheimer’s disease may become the most important health problem as the population ages. There have been studies showing that EPA and DHA may become more important to counter these problems. I mentioned the study by Dr. E.J. Schaefer and colleagues in the introduction (4).
Dr. Dyerberg, what does this study suggest to you?
Dyerberg: That the field of long-chained omega-3 fatty acids in human nutrition is broadening rapidly. The necessity of a sufficient daily intake of EPA plus DHA is maybe even more convincing when considering brain health, that with respect to heart health! Several studies have reported that the risk of developing dementia—as Alzheimer’s disease—is inversely related to the intake of long-chain omega-3 fatty acids. This is maybe most convincingly shown in the Framingham study finding that a mean DHA intake of 180 mg/d was associated with a significant 47% reduction in the risk of developing all-cause dementia (4). Studies from the Netherlands, France and Italy find the same relations.
In one study, researchers examined omega-3 fatty acid erythrocyte membrane content and cognitive variation in late adulthood (16). Dr. L.J. Whalley and colleagues found that total omega-3 PUFA and DHA concentrations in erythrocytes were associated with benefits for cognition in persons aged 64 to 68 years.
There are 5.2 million people in the United States living with Alzheimer’s. Alzheimer’s is the seventh-leading cause of death. The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion each year.
Passwater: Our goal is to help people not just live longer, but to live better longer. I mentioned two studies that may impact on just this very idea—living better longer. In the studies that I mentioned in the introduction to this series, it was found that fish oils protected telomeres from shortening. A telomere is a region of repetitive DNA at the end of a chromosome that protects the chromosome from deterioration. Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality.
Dr. Dyerberg, do you see fish oil as improving our general health beyond reducing the risk of overt diseases, but also in helping us live better longer?
Dyerberg: Results from New Zealand illustrates that an increased intake of long-chained omega-3 fatty acids may help us not just to live longer, but to live better longer. In the New Zealand Adolescents and Adults study of 2,416 persons above 15 years of age, researchers found that there was a significant positive trend in mental well-being across the quintiles of the ratio of EPA to AA in serum phospholipids (17). The longevity issue is convincingly illustrated by the findings that those in the highest quartile of omega-3 fatty acid blood levels experienced the slowest rate of telomere shortening. But, other studies have also found similar relations.
In a Norwegian randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk, they observed a tendency toward reduction in all-cause mortality in the n-3 PUFA groups that, despite a low number of participants, reached borderline statistical significance (18).
In The Heart and Soul Study, blood n-3 FA levels were inversely associated with total mortality independent of standard and emerging risk factors, suggesting that reduced tissue n-3 FA levels may adversely impact metabolism (19).
Passwater: Research soon took us from primarily cardiovascular studies to protection against the inflammatory diseases. I mentioned two studies related to arthritis in the introduction (7, 8).
Dr. Dyerberg, how do you see the role of EPA and DHA in reducing inflammation?
Dyerberg: The omega-3 polyunsaturated fatty acids possess potent anti-inflammatory activities. Some of the effects of omega-3 PUFAs are brought about by a modulation in the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases.
Passwater: Well, your pioneering research certainly has extended into many areas of health for all people. It seems as if there are new studies about the benefits of EPA and DHA being published nearly every week. They extend the role of these long-chain omega-3 fatty acids from artery health (20) to cancer prevention (21–26). Dr. Emily White and her colleagues at the Fred Hutchinson Cancer Research Center studies 35,016 postmenopausal women who did not have a history of breast cancer for six years and found those who regularly used fish oil supplements had a 32% reduced risk of ductal breast cancer. They concluded, “Fish oil may be inversely associated with breast cancer risk.”(26)
There are so many thousands of research articles published now that I bet it is difficult for even you to keep track of all of the published articles.
Dyerberg: The number of scientific publications on the health effects of EPA and DHA has increased enormously since our original publications in the 1970s, and the number of human studies is now above 9,000! This is of course nearly impossible to keep check on—my own database has now reached number 2,846 and is still growing. I consider myself privileged to have been a co-initiator of such an important science.
Passwater: On behalf of myself and our thousands of readers, I thank you for your time and patience in chatting with us over these past four months. It’s been a remarkable and truly enjoyable experience. Your explanations as well as your research will help countless millions of people. WF
1. Dietary Supplementation With N-3 Polyunsaturated Fatty Acids And Vitamin E After Myocardial Infarction: Results Of The GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (1999).
2. C.M. Albert, et al., “Blood Levels of Long-Chain N-3 Fatty Acids and the Risk of Sudden Death,” N. Engl. J. Med. 346 (15), 1113–1118 (2002).
3. H. Leon, et al., “Effect of Fish Oil on Arrhythmias and Mortality: Systematic Review,” BMJ 337, a2931 (2008).
4. E.J. Schaefer, et al., “Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease: The Framingham Heart Study,” Arch. Neurol. 63 (11), 1545-1550 (2006).
5. R. Farzaneh-Far, et al., “Association of Marine Omega-3 Fatty Acid Levels with Telomeric Aging in Patients with Coronary Heart Disease,” JAMA 303 (3), 250–257.
6. R. Farzaneh-Far, et al., “Telomere Length Trajectory and its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study,” PLoS One 5 (1), e8612.
7. B. Galarraga, et al., “Cod Liver Oil (N-3 Fatty Acids) as a Non-Steroidal Anti-Inflammatory Drug Sparing Agent in Rheumatoid Arthritis,” Rheumatol (Oxford) 47, 665–669 (2008).
8. D. Fritsch, et al., “A Multicenter Study of the Effect of Dietary Supplementation with Fish Oil Omega-3 Fatty Acids on Carprofen Dosage in Dogs with Osteoarthritis,” J. Amer. Veterinary Medical Assoc. 236 (5), 535–539 (2010).
9. W.S. Harris, “The Omega-3 Index as a Risk Factor for Coronary Heart Disease,” Am. J. Clin. Nutr. 87 (6), 1997S–2002S (2008).
10. J. de Goede and J.M. Geleijnse, et al., “Marine (n-3) Fatty Acids, Fish Consumption, and the 10-Year Risk of Fatal and Nonfatal Coronary Heart Disease in a Large Population of Dutch Adults with Low Fish Intake,” J. Nutr. 140 (5), 1023–1028 (2010).
11. M.L. Burr, et al., “Diet and Reinfarction Trial (DART): Design, Recruitment, and Compliance,” Eur. Heart J. 10 (6), 558–567 (1989).
12. M.L. Burr, et al., “Effects of Changes in Fat, Fish, and Fibre Intakes on Death and Myocardial Reinfarction: Diet and Reinfarction Trial (DART),” The Lancet, 2 (8666), 757–761 (1989).
13. R.C. Block, et al., “EPA and DHA in Blood Cell Membranes from Acute Coronary Syndrome Patients and controls,” Atherosclerosis 197 (2), 821–828 (2008).
14. D.S. Siscovick, et al., ”Dietary Intake and Cell Membrane Levels of Long-Chain n-3 Polyunsaturated Fatty Acids and the Risk of Primary Cardiac Arrest,” JAMA 274 (17), 1363-1367 (1995).
15. T.A. Dolecek and G. Grandits, “Dietary Polyunsaturated Fatty Acids and Mortality in the Multiple Risk Factor Intervention Trial (MRFIT),” in: Health Effects of w3 Polyunsaturated Fatty Acids in Seafood, Vol. 66 Eds. A.P. Simopoulos, et al., (Karger, Basel, Switzerland, 1991), 205–216.
16. L.K. Whalley, et al., “n-3 Fatty Acid Erythrocyte Membrane Content, APOE Varepsilon4, and Cognitive Variation: An Observational Follow-Up Study in Late Adulthood,” Am. J. Clin. Nutr. 87 (2), 449–454 2008).
17. F.L. Crowe, et al., “Serum Phospholipid n 3 Long-Chain Polyunsaturated Fatty Acids and Physical and Mental Health in a Population-Based Survey of New Zealand Adolescents and Adults,” Am. J. Clin. Nutr. 86 (5), 1278–1285 (2007).
18. G. Einvik, et al., “A Randomized Clinical Trial on n-3 Polyunsaturated Fatty Acids Supplementation and All-Cause Mortality in Elderly Men at High Cardiovascular Risk,” Eur. J. Cardiovasc. Prev. Rehabil. 2010 Apr 10. [Epub ahead of print].
19. J.V. Pottala, et al., “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 Jun 15. [Epub ahead of print].
20. C.A. Fahs, et al., “The Effect of Acute Fish Oil Supplementation on Endothelial Function and Arterial Stiffness Following a High-Fat Meal,” Appl. Physiol. Nutr. Metab. 35(3), 294–302 (2010).
21. M. Ligo, T. Nakagawa and Y. Iwahori, “Inhibitory Effects of Docosahexaenoic Acid on Colon Carcinoma Metastasis to the Lung,” Br. J. Cancer 75 (5), 650–655 (1997).
22. J. Kim, et al., “Fatty Fish and Fish Omega-3 Fatty Acid Intakes Decrease the Breast Cancer Risk: A Case-Control Study,” BMC Cancer 9, 216 (2009).
23. E.J. Ramos, et al., “Effects of Omega-3 Fatty Acid Supplementation on Tumor-Bearing Rats,” J. Am. Coll. Surg. 199 (5), 716–723 (2004).
24. H. Toriyama-Baba, et al., “Organotropic Chemoprevention Effects of n-3 Unsaturated Fatty Acids in a Rat Multi-Organ Carcinogenesis Model,” Jpn. J. Cancer Res. 92 (11), 1175–1183 (2001).
25. A. Wolk, et al., “Long-Term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women,” JAMA 296 (11) 1371–1376 (2006).
26. Brasky, T. M., Lampe, J. W., Potter, J. D., et al. Specialty Supplements and Breast Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev 19(7); 1696-1708 (2010).