Review supports benefits of omega-3 fatty acids for prevention of heart disease
ATLANTA, GEORGIA. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to lower mortality from coronary heart disease (CHD) in several, but not all, observational studies on the topic. Prevention trials of n-3 PUFAs have also supported a role in CHD prevention, but several different varieties of n-3 PUFAs were used.

Now, researchers from Emory University School of Medicine have reviewed the data from randomized controlled clinical trials on n-3 PUFAs and CHD. The studies were divided into those using plant-based n-3 PUFAs (alpha-linolenic acid, ALA), fish-based n-3 PUFAs (eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA), and fish consumption in the diet. Fourteen randomized clinical trials were included in the review, six of which were of fish oil, including one large trial of 10,000 participants. The researchers report a clear trend suggesting that there are important differences in CHD outcomes when using fish-based EPA or DHA compared with plant-based ALA. Most of the fish oil trials suggest a significant reduction in total mortality and CHD deaths and a possible strong antiarrhythmic effect. The dietary fish trials also suggest a reduction in mortality and reduced arrhythmia, supporting the theory that fish-based n-3 PUFAs may impart their cardioprotective effect by acting as an antiarrhythmic agent. They may do so by stabilizing the electrical activity of heart muscle cells or by decreasing the heart rate. The trials of ALA supplements and ALA-enriched diets, including walnut, soybean, or flaxseed oil, were less reliable, but showed possible benefits in reducing mortality.

The review concludes that the evidence suggests a role for fish oil (EPA, DHA) or fish in secondary prevention, as clinical trial data demonstrate a significant reduction in total mortality, coronary heart disease death, and sudden death. However the data on ALA is limited by studies of limited quality. Several previous studies have suggested that n-3 PUFAs reduce heart attack risk through benefiting endothelial function (cells of blood vessel walls), reducing inflammation, and the risk of thrombosis (blood clotting). The American Heart Association has published guidelines for patients with CHD recommending a consumption of fish and fish oil, totaling 1g/day of EPA and DHA.
Harper, C.R. and Jacobson, T.A. Usefulness of Omega-3 Fatty Acids and the Prevention of Coronary Heart Disease. American Journal of Cardiology, Vol. 96, December 2005, pp. 1521-29

Omega-3 fatty acids may reduce mortality from heart disease
BASEL, SWITZERLAND. Hyperlipidemia, or excess levels of fats in the blood, is associated with increased risk of cardiovascular disease. Many lipid-lowering agents exist for both primary and secondary prevention of cardiovascular disease.

To determine the overall benefit of these agents on mortality, a group of researchers at the University Hospital Basel reviewed the most reliable published studies. They searched for good- quality randomized, controlled trials between 1965 and 2003, comparing lipid-lowering drugs or dietary interventions against placebo. This process left them with 35 trials on statins, 17 on fibrates, 8 on resins, 2 on niacin, 14 on omega-3 fatty acids, and 17 on other dietary interventions. This produced a total of 137,140 participants in treatments groups and 138,976 in control groups.

A combined analysis showed that treatment with omega-3 fatty acids (fish and flaxseed oils) reduced overall risk of death by 23 per cent as compared to placebo. Treatment with statin drugs, on the other hand, only reduced overall mortality by 13 per cent as compared to placebo. Fibrates (gemfibrozil, fenofibrates), bile acid resins (cholestyramine, colestipol), niacin and dietary interventions showed no statistically significant differences from results obtained in the control groups.

Deaths from cardiovascular causes were 32 per cent lower in the omega-3 fatty acid groups than in control (placebo) groups. Statin drugs reduced cardiovascular mortality by 22 per cent and the use of bile acid resins were associated with a 30 per cent decline in cardiovascular mortality. When death from non-cardiovascular causes was considered, none of the interventions were significantly linked to reduced mortality. However, fibrates were linked to a 13 per cent increased risk of death.

The effects on mortality tended to be more pronounced in longer studies and those with patients whose cardiovascular disease was well established, say the authors. Regarding n-3 fatty acids, they speculate that the reduction in mortality risk does not occur through a reduction in cholesterol but by other means, possibly antiarrhythmic, antithrombotic or anti-inflammatory effects.

The trials of n-3 fatty acids used different dietary and supplement sources; nevertheless, the authors conclude that this study adds to the positive evidence for n-3 fatty acids. They suggest that further trials be carried out to examine the effects of combined treatment with n-3 fatty acids and statins.
Studer, M., et al. Effect of different antilipidemic agents and diets on mortality. Archives of Internal Medicine, Vol. 165, April 2005, pp. 725-30

Eating fish may lower inflammation in the blood vessels
ATHENS, GREECE. Consuming fish has long been thought to help protect against heart disease, possibly through reducing inflammation in blood vessels. However, study results on the effects of fish on inflammatory markers are mixed, so a team of researchers from Harokopio University set out to examine the relationship in a population-based group of men and women free of heart disease.

They gathered data on 1,514 men and 1,528 women aged 18 to 89, taking part in the ongoing ATTICA study into the benefits of a Mediterranean diet on heart health. Compared to those who did not eat fish, those who ate the most (10.5 ounces per week or more) had an average 33 per cent lower level of C-reactive protein, a widely-used marker for inflammation. They also had a 33 per cent lower level of interleukin-6, another inflammatory marker found in the plasma. This group had 21 per cent lower tumor necrosis factor-alpha, which affects lipid metabolism, coagulation, and insulin resistance, and 28 per cent lower serum amyloid A, a blood protein increased by inflammation. Significantly lower levels of these markers were also found in people who ate about 5 to 10 ounces of fish per week.

This clear and strong inverse association between fish consumption and inflammatory markers may help explain why people who eat fish tend to have lower rates of heart disease, say the authors. The benefits remained once many risk factors were taken into account and were observed even in people with high blood pressure or diabetes, but not high cholesterol. Nevertheless, it was a cross-sectional study which did not follow people over time, so cannot prove causation.

These results support recommendations that people eat more fish, the authors write, particularly oily fish with their high levels of omega-3 fatty acids. One or two portions per week may be sufficient, but the fish should not be fried. In some cases, omega-3 fatty acid supplements may be appropriate to achieve an optimal intake of 0.6 grams of omega-3 fatty acids per day.
Zampelas, A. et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: The ATTICA Study. Journal of the American College of Cardiology, Vol. 46, July 2005, pp. 120-24

Polyunsaturated fatty acids don’t compete over benefits
BOSTON, MASSACHUSETTS. Polyunsaturated fatty acids (PUFAs) are effective at reducing heart disease risk, but fears have been raised that n-6 PUFAs may interfere with the metabolism of n-3 PUFAs. However, new evidence from Harvard Medical School will help put these fears to rest.

Researchers studied the links between various PUFA intakes and the incidence of coronary heart disease (CHD) in 45,722 men enrolled in the Health Professionals Follow-up Study. A reliable food-frequency questionnaire was given at the start and completed every four years to determine PUFA intakes. During the 14 years of follow-up, there were 218 sudden deaths, 1,521 nonfatal myocardial infarctions (MIs) and 2,306 total CHD events (combined sudden death, other CHD deaths, and nonfatal MI) among the participants. Dietary analysis showed that both seafood-derived long-chain and plant-derived intermediate-chain n-3 PUFA intakes were linked to a reduced CHD risk, regardless of n-6 PUFA intake. Men who consumed more than 250 mg seafood-based n-3 PUFA per day had a 40-50 per cent lower risk of CHD.

The researchers also looked at the relationship between seafood-based n-3 PUFAs and plant-based n-3 PUFAs. They found that when seafood-based n-3 PUFA intake is low (less than 100 mg per day), plant- based n-3 PUFAs are particularly effective at reducing CHD risk. For every additional 1 g of plant-based n-3 PUFA per day, MI risk was reduced by 58 per cent and total CHD risk was reduced by 47 per cent. Contrary to previous findings, this study found no links between overall CHD risk and intake of n-6 PUFAs. The results suggest that a modest dietary intake of seafood (250 mg, equaling around 1-2 oily fish meals a week) may lower the risk of CHD, irrespective of n-6 PUFA intake. The authors concluded that plant sources of PUFAs are especially important in populations with limited access to, or consumption of seafood.
Mozaffarian D et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation, Vol. 111, January 2005, pp.157-164

Fish oils and atrial fibrillation
AARHUS, DENMARK. There is impressive evidence that fish oils (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) can materially reduce the risk of sudden cardiac death (cardiac arrest). Researchers at the University of Washington found that men and women who consumed fatty fish just once a week reduced their risk of cardiac arrest by 50%. They believe that fatty fish consumption increases the levels of EPA and DHA in the membranes of red blood cells, which in turn, reduces platelet aggregation and the risk of fatal ventricular arrhythmias. Other researchers have confirmed the protective effect of fish oils against ventricular fibrillation, but very few, if any, studies have investigated the association between fish/fish oil intake and the development of atrial fibrillation.

A group of Danish researchers recently set out to fill in this gap in our knowledge. Their study included 22,528 men and 25,421 women (average age of 56 years) who were free of endocrine and cardiovascular diseases at baseline. All participants completed a detailed semi-quantitative food- and drink-frequency questionnaire and were then followed for an average of 5.7 years. At the end of the follow-up period 374 men (1.7%) and 182 women (0.7%) had been diagnosed with either atrial fibrillation or atrial flutter. About 10% of all participants were being treated for hypertension. Somewhat surprisingly, the researchers found that participants with a high consumption of fatty fish (herring, mackerel, sardines, trout, and salmon) had a significantly higher incidence of new-onset atrial fibrillation than did participants who rarely or never ate oily fish. After adjusting for age, gender, height, BMI, smoking, alcohol consumption, total daily energy intake, systolic blood pressure, treatment for hypertension, cholesterol level, and level of education, the researchers concluded that participants whose daily fish oil intake averaged 1290 mg had a 34% greater risk of developing AF than did those whose intake averaged only 160 mg/day. The difference was statistically significant (p=0.006). The researchers point out that the lack of an observed beneficial effect could have been because the consumption of fish oil was insufficient to prevent arrhythmias. They also say, "We cannot exclude the possibilities that fish oil may prevent the development of atrial fibrillation in patients with symptomatic heart disease or that fish oil may prevent relapses of atrial fibrillation in patients with paroxysmal atrial fibrillation."

Finally, they point out that they did not collect information regarding the use of fish oil supplements and also emphasize that they do not know whether fish oil would have a protective effect against the development of AF in populations with a low intake of fatty fish (such as the United States). Their overall conclusion was that, "Consumption of omega-3 fatty acids from fish is not associated with a reduction in the risk of developing atrial fibrillation or flutter."
Frost, L and Vestergaard, P. n-3 fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. American Journal of Clinical Nutrition, Vol. 81, January 2005, pp. 5-54

Editor's comment: The conclusions of the Danish study are fully in line with the results of the two LAF surveys, which investigated the association between afib severity and fish oil intake. None of our surveys have ever found that a high fish oil intake is associated with fewer or shorter episodes. This, as pointed out by the Danish researchers, could be due to the fact that the fish oil intake was not high enough to provide a benefit. However, this would seem unlikely since the highest intakes were well above those required to provide excellent protection against ventricular fibrillation. The finding that heavy fish consumers have a statistically significant 34% greater risk of developing atrial fibrillation or flutter is worth noting. It is possible that this could be due to the higher mercury intake associated with higher fish consumption. Several studies have shown that people with a high consumption of certain fish have higher mercury levels in their blood and toenails. The lesson here is that the safest way to obtain a high intake of EPA and DHA is through the consumption of a high quality, molecular distilled fish oil supplement. In conclusion then, even though there may be no scientific evidence that fish oils can prevent the development of AF, there are still numerous reasons for ensuring an adequate intake (1-2 grams/day). The evidence that they help prevent cardiac arrest, reduce triglyceride levels, combat inflammation, and help prevent stroke and heart attack makes fish oils a must supplement for all, whether an afibber or not.

Determination of omega-3 fatty acids in heart tissue
KANSAS CITY, MISSOURI. There is overwhelming evidence that omega-3 fatty acids or, more specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the main components of fish oils, are highly effective in preventing sudden cardiac death, death from heart disease, and certain arrhythmias. Investigations involving individual heart cells have shown that EPA + DHA prolong the refractory state of the cells by interacting with fast-acting sodium channels and L-type calcium channels. It is thus clear that the cardioprotective effect of EPA + DHA is intimately associated with the degree to which these two fatty acids are actually incorporated into the heart tissue (myocardium). The ultimate test of the extent of incorporation is, of course, analysis of the heart tissue itself; however this, for obvious reasons, is not terribly practical.

Researchers at the Mid America Heart Institute now report that the EPA + DHA content of red blood cells (RBCs) almost exactly mirrors the concentration in the myocardium. Their study involved 20 heart transplant patients whose EPA + DHA level was measured in heart tissue and red blood cells. The researchers found an almost perfect correlation (r = 0.82) between the content in cardiac tissue and the content of RBCs.

In a subsequent experiment involving 25 heart transplant patients, the researchers measured EPA + DHA in biopsied myocardial tissue, plasma lipids, cells scraped from the cheek (buccal tissue), and red blood cells before and after 6 months of supplementation with 300 mg EPA + 200 mg DHA. The supplementation resulted in a 272% increase in EPA and a 94% increase in DHA in the heart tissue itself. The corresponding increases in plasma lipids, buccal tissue, and RBCs were 365% and 104%, 124% and 95%, and 279% and 84% respectively. The best correlation was between myocardial tissue and RBCs followed by myocardial tissue and buccal tissue. The researchers conclude that EPA and DHA levels in RBCs give an accurate indication of the content in heart cells. Buccal tissue is also a good indicator, but more cumbersome and exacting to obtain than a blood sample. The researchers also point out that RBC content is a good indicator of long-term intake, whereas plasma lipids vary depending on the food consumed on the day immediately preceding the test.
Harris, WS, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation, Vol. 110, September 21, 2004, pp. 1645- 49

Fish oils benefit patients with lupus
BELFAST, NORTHERN IRELAND. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease. It can manifest itself via a photosensitive facial rash, fatigue, anorexia, weight loss, and night sweats and can progress to life-threatening involvement of the heart, lungs, kidneys or central nervous system. Flare-ups of SLE are typically followed by periods of clinical remission. Fish oils and copper have both been found useful in the treatment of other inflammatory diseases, so researchers at the University of Ulster decided to see if supplementation with one or both of these would help alleviate SLE symptoms.

Their clinical trial involved 52 SLE patients who were randomly assigned to receive 3 grams/day of fish oil providing 540 mg/day of EPA (eicosapentaenoic acid) and 360 mg/day of DHA (docosahexaenoic acid), 3 mg/day of copper in the form of a copper di-glycinate amino acid complex, both fish oil and copper, or a placebo. The study lasted 24 weeks and participants were assessed at baseline, 6, 12 and 24 weeks.

The researchers found that disease activity at 24 weeks, as measured by the SLAM-R score, was significantly less in the groups that had supplemented with fish oil than in the placebo and copper only groups. They conclude that supplementation with fish oil may be effective in favourably modifying the symptomatic disease activity in SLE.
Duffy, EM, et al. The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. Journal of Rheumatology, Vol. 31, August 2004, pp. 1551-56

Fish oils help prevent prostate cancer
BETHESDA, MARYLAND. Alpha-linolenic acid (ALA) is a major component of flax seed oil and has been associated with significant cardiovascular benefits. Some studies, however, have shown that a high intake of ALA is associated with an increased risk of prostate cancer. A prestigious team of researchers from the National Cancer Institute, the Harvard Medical School, the Harvard School of Public Health, and the Karolinska Institutet in Stockholm has just released the results of a study aimed at settling the controversy as to whether or not ALA is detrimental when it comes to prostate cancer. The researchers also determined the effect of other fatty acids, including fish oils, on prostate cancer risk.

The study involved 47,866 male American health professionals who were followed over a 14-year period beginning in 1986. The participants completed detailed food frequency questionnaires in 1986, 1990 and 1994. By the year 2000, 2965 new cases of prostate cancer had been reported with 448 of these being advanced (metastasized) or fatal. The overall incidence of new prostate cancer detected over the 14-year period was 0.5% per year.

The researchers found no correlation between ALA intake and overall prostate cancer risk, but did observe a strong association between a high ALA intake and the risk of advanced prostate cancer. Men with a high ALA intake (greater than 0.58% of energy or about 1.3 grams/day) were twice as likely to develop advanced prostate cancer as were men with a lower intake (less than 0.37% of energy or about 0.8 grams/day) even after adjusting for all other known variables that could affect the risk. The risk was slightly higher for ALA from non-animal sources than for ALA from meat and dairy sources. There was a trend for red meat, mayonnaise and salad dressings to be associated with a higher risk. The intake of two other abundant fatty acids, linoleic acid and arachidonic acid, was not related to prostate cancer risk.

The team of researchers found a protective effect associated with a high intake of fish oils - eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Men with a daily intake of more than 0.214% of daily energy (about 470 mg/day) were 11% less likely to develop prostate cancer than were men with an intake less than 0.057% of energy (about 125 mg/day). The beneficial effect of EPA plus DHA was particularly pronounced in regard to the incidence of advanced prostate cancer. Fish oil supplements were slightly less effective than fish oils from fatty fish perhaps indicating that vitamin D and vitamin A are necessary to obtain the maximum benefit.
Leitzmann, MF, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. American Journal of Clinical Nutrition, Vol. 80, July 2004, pp. 204-16

Fish oils in cancer prevention

STOCKHOLM, SWEDEN. Several test tube (in vitro) and animal experiments have clearly shown that the long-chain omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the main components of fish oil, help inhibit the promotion and progression of cancer. Their beneficial effect is particularly pronounced in hormone-dependent cancers such as breast and prostate cancer. Some, but not all, epidemiologic studies have also found a beneficial effect.

Researchers at Sweden’s famous Karolinska Institutet have just published a comprehensive review of the current knowledge regarding the role of PUFAs in carcinogenesis. They conclude that omega-3 PUFAs are protective against cancer progression, while omega-6 PUFAs, notably arachidonic acid and its derivatives, help promote the growth of cancer. They believe the n-3 PUFAs exert their beneficial effects in several different ways:

They suppress the synthesis of pro-inflammatory eicosanoids from arachidonic acid and thus produce an overall anti-inflammatory effect.
They positively affect gene expression or the activities of signal transduction molecules involved in the control of cell growth, differentiation apoptosis, angiogenesis and metastasis.
They suppress excessive production of nitrogen oxide (NO) during chronic inflammation and thereby help prevent DNA damage and impaired DNA repair.
They decrease estrogen production and thus reduce the estrogen-stimulated growth of hormone-dependent cancer cells.
Fish oils improve insulin sensitivity and cell membrane fluidity and may help prevent metastasis through these effects.
Free radicals and reactive oxygen species produced in cells may attack PUFAs resulting in the formation of more free radicals, specifically hydroperoxides. The hydroperoxides, in turn, may damage DNA ultimately leading to cancer. These effects have indeed been observed in some in vitro experiments, but not in actual human beings. Many studies have shown that fish oils actually retard aging and suppress so-called free radical diseases such as atherosclerosis and cancer. Other studies have shown that a daily EPA + DHA intake in excess of 2.3 grams decreases the production of superoxide, a potent cancer promoter. At least one in vitro and one animal experiment have observed that EPA + DHA kill human breast cancer cells via the formation of hydroperoxides, but that this effect is strongly inhibited by vitamin E. Thus, at this point, it is not entirely clear whether EPA + DHA exert part of their beneficial effect through an increase or a decrease in the production of free radicals and reactive oxygen species. The researchers recommend more work in this area, but emphasize that the major benefits of fish oils probably are associated with their ability to inhibit the synthesis of arachidonic acid-derived, pro-inflammatory eicosanoids. The Swedish researchers also confirm that fatty, cold-water fish are the best sources of EPA and DHA and that the conversion rate of alpha- linolenic acid (flaxseed oil) to EPA is very low, even in healthy humans – probably in the order of 2-5%.
Larsson, SC, et al. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. American Journal of Clinical Nutrition, Vol. 79, June 2004, pp. 935-45