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EPA and DHA - Essential Omega-3 Fatty Acids
By Yousry Naguib, Ph.D.
Vitamin Retailer magazine

            On October 31, 2000, The Food and Drug Administration announced that supplement manufacturers could make a health claim regarding heart disease for products containing omega-3 polyunsaturated fatty acids. The claim should include that consumption of omega-3 fatty acids from all sources should not exceed two grams per day. The following claim is considered appropriate by the agency: “The scientific evidence about whether omega-3 fatty acids may reduce the risk of coronary heart disease (CHD) is suggestive, and not conclusive. Studies in the general population have looked at diets containing fish and it is not known whether diets or omega-3 fatty acids in fish may have a possible effect on a reduced risk of CHD. It is not known what effect omega-3 fatty acids may or may not have on the risk of CHD in the general population”.
This FDA announcement is in line with various studies, which started with the observation that Greenland Eskimos, whose food intake comprises mainly of fish, exhibited low incidences of cardiovascular diseases. The health benefit of fish was attributed to the presence of substantial amounts of the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil. 
            Fatty acids, usually present as their glycerides, can either be saturated, mono- or polyunsaturated. Polyunsaturated fatty acids such as EPA and DHA are usually referred to as 20:5n-3 and 22:6n-3, respectively; where the n-3 designation means that the first double bond begins at the third carbon counting from the methyl end of the carbon chain, usually referred to as omega-3. In the number:number designation, the first number indicates the length of the carbon chain, and the second number indicates how many double bonds are present. For EPA, 20:5 indicates twenty carbons and five double bonds; and for DHA, 22:6 indicates twenty-two carbons and six double bonds. Linolenic acid (18:3n-3) is also an omega-3 fatty acid.
Arachidonic acid is designated as 20:4n-6, indicating an omega-6 acid (the first double bond begins at the sixth carbon from the methyl end of the chain). linoleic acid (18:2n-6) is an omega-6 fatty acid.

            Long chain polyunsaturated fatty acids, including EPA and DHA, are essential components of all tissues and serve as precursors of a group of chemical messengers known as eicosanoids (eye-cos-an-oids). Eicosanoids regulate cell functions, and they include protaglandins, thromboxanes (potent platelet aggregator and vasoconstrictor), and leukotrienes (pro-inflammatory) [1]. Eicosanoids can either be anti-inflammatory (series-1 and series-3) or pro-inflammatory (series-2).
Series-2 eicosanoids stimulate vasoconstriction, platelet aggregation, tissue repair, clot formation, allergic responses, immune suppression, and insulin release inhibition.
            Series-1 and series-3 eicosanoids are vaso-dilative, allergic response inhibiting, nerve function improving, and immune function enhancing.
            In order to understand how can diet affect the eicosanoids status in our body, we need to know the biochemical pathways of their formation. The pathway to series-1 and series-2 begins with linoleic acid (LA), while that to series-3 begins with alpha-linolenic acid (ALA). LA is the major omega-6 fatty acid, and ALA is the major omega-3 fatty acid in the human diet. Omega-6 and omega-3 are not inter-convertible in the body. Eicosanoids derived from omega-6 acids are metabolically and functionally distinct from those derived from omega-3 acids. A balanced intake of both omega-3 and –6 is essential for health.
            In the body, LA with the help of Delta-6-Desaturase enzyme is converted to gamma-linolenic acid (GLA). GLA is found in borage oil, evening primrose oil, black currant oil, pumpkin and mother’s milk. With the help of the Elongase enzyme, GLA is converted to dihomo-gamma-linolenic acid (DGLA). DGLA produces series-1 eicosanoids. The Delta-5-Desaturase enzyme converts DGLA into arachidonic acid (AA). AA with the help of the Cycloxygenase enzyme produces series-2 eicosanoids (prostaglandins and thromboxanes). AA with the help of lipoxygenase is converted to hydroperoxy-eicosatetraenoic acid, and leukotrienes. These eicosanoids are also pro-inflammatory [2].
Alpha-linolenic acid (ALA), mainly found in green leafy vegetables, flax seeds, wheat germ, soy beans and walnuts, de-saturates and elongates in the human body to EPA and DHA, which are the precursors to series-3 eicosanoids. DHA is an essential compound in cell membranes and occurs in particularly high concentration in the retina and brain. EPA and DHA also displace arachidonic acid, reduce demand for cholesterol synthesis, stimulate metabolism of fat stores, activate T-lymphocytes, and enhance the action of insulin. Series-3 eicosanoids are found to be low in diabetics, people with coronary heart disease, people suffering from depression, and alcoholics.
            GLA, EPA, DHA, and AA are all available in our diet. AA comes mostly from red meat. DHA and EPA are commonly referred to as marine oil, or fish oil. EPA and DHA are also found in mother’s milk, algae and some seed oils. Flax seed oil contains both omega-3 and omega-6. Evening primrose, corn, safflower, and sunflower are rich in omega-6, linoleic acid. Elongation and de-saturation of 11 grams of ALA gives 1 gram EPA [3].

Heart Diseases

(a) Epidemiological Studies
In the epidemiological studies, investigators look for association between fish intake and heart disease. The first evidence of the effect of the intake of omega-3 fatty acids in preventing heart diseases came from the observation that Eskimos, with a relatively large intake of fish omega-3 acids in their traditional diet, had virtually no heart diseases [4]. Since then, several other studies revealed that populations with a high intake of fish or fish oil have a low incidence of death from heart attack.
The populations of Crete in Greece and Kohama Island in Japan have the longest life expectancy in the world and the lowest coronary heart disease mortality rate. The two populations are reported to have high dietary intake of omega-3 alpha-linolenic acid (ALA). In Japan, the dietary sources of ALA are mainly canola and soybean oils [5]. ALA in the Cretan diet comes from walnuts and green leafy plants [6].
In the Chicago Western Electric Study involving 1,931 men, an inverse association was found between fish consumption and coronary heart disease mortality during 25 years of follow-up [7].
In a study of lifestyle changes designed to reduce coronary diseases among high risk U.S. men, mortality from all cardiovascular diseases was higher among men with lower intakes of omega-3 fatty acids [8].
A 20-year prospective study of 852 men from the Netherlands showed that mortality from heart diseases was more than 50 % lower among those who consumed a fish meal twice a week [9]. Another recent study with 17 years of follow-up in the Netherlands also reached the same conclusion [10].
A study on 120 Japanese men enrolled in the Honolulu Heart Program reported that fish intake of two or more servings per week associated with 65 % reduction in heart diseases [11].
Intake of high amounts of fish did not score well in epidemiological studies. No association between fish intake and coronary mortality in a Norwegian population with a relatively high fish intake during 14 years follow-up [12]. A recent study of 45,000 male U.S. health professionals also found no significant association between dietary intake of omega-3 fatty acids or fish and the risk of coronary diseases. The study concluded that increasing fish intake from one or two servings per week to five or six servings per week does not substantially reduce the risk of heart diseases [13]. The study was criticized for a number of issues including relatively short period of observation.
In general, epidemiological studies showed an association between consumption of fish, two to three meals per week, and lower risk of heart diseases.

(b) Intervention Studies
In the intervention trial a change is made in the diet of a group of people, and compared with a similar group with no change in their diet.
Singh et al. reported an intervention trial involving patients who survived heart attacks. Patients were given 6 grams of fish oil daily, providing 2 grams of EPA and DHA. After one year, the rate of death from heart attacks was about half in the fish group compared to that in the placebo group. The fish oil group also showed significant less arrhythmia than in the placebo group [14].
Recently, an Italian study (GISSI) has shown a 20 % reduction among 12, 000 survivors of a heart attack given one gram of fish oil containing 85 % EPA and DHA. The trial lasted over three years [15].
A two-year intervention study by Burr et al, called the Diet and Re-infarction Trial (DART), involving 2,033 men who had recovered from heart attack, found that men who ate 3 fish meals per week, wherein the estimated dose of EPA was 0.3 gram per day, had 29 % lower death rate than the control group [16].
In another intervention trial on six hundreds five patients who had survived first myocardial infarctions (myocardial infarction is irreversible damage due to the lack of oxygen in the heart muscle) were assigned to either Mediterranean diet (containing alpha-linolenic acid, omega-3) or conventional diet. After 27 months of follow-up the Mediterranean group had 73 % lower death and heart attacks than the control group [17]. A similar study, known as The Lyon Diet Heart Study, which lasted for four years also showed a 70 % reduction in heart diseases mortality in people on Mediterranean diet, the estimated intake of alpha-linolenic acid was 2 grams per day [18]. Experiments showed that intake of 3 to 4 grams ALA / day is equivalent to 0.3 grams EPA / day with respect to the effect on the EPA content of plasma phospholipids [3].

(c) Anti-Blood Clotting Studies
            In myocardial infarction (heart attack), a blood clot large enough to completely block off blood flow in the coronary arteries is formed. Clumping or aggregation of blood cells, called platelets, initiates the formation of a blood clot. Therefore, preventing platelet aggregation may reduce the risk of a heart attack [19]. A study found that omega-3 fatty acids consumed in the diet reduced the production of a substance called thromboxane A2 which is responsible for platelet aggregation [20].
            A recent study from Harvard Medical School revealed a relationship between consumption of fish and risk of thrombotic stroke, which is caused by the build-up of clots on the brain artery wall, blocking blood flow. The 14-year study found that out of 79,939 U.S. women, a total of 574 suffered strokes. Women who ate more fish were less likely to suffer a stroke. Women who ate fish once a month had a 7 percent lower risk than those who ate less. This number rose to 52 percent less risk for women who ate fish five or more times a week [21].

(d) Lipids Lowering Studies
            High serum levels of total cholesterol, especially low-density lipoprotein (LDL), and triglycerides have been linked to increased risk of heart diseases [22]. Studies demonstrated that omega-3 fatty acid supplementation lowers blood triglycerides both in patients with high triglycerides and in people with normal triglycerides levels. A reduction in triglycerides has also been demonstrated in response to consumption of three fish meals per week. Therefore, supplementation with fish oil is beneficial for people with hypertriglyceridemia [23].
A four-week placebo-controlled, double-blind trial on 36 postmenopausal women showed that daily supplementation with fish oil concentrate reduced blood levels of triglycerides by 28 percent, and decreased the ratio of high-density lipoprotein (HDL) cholesterol to triglycerides in women receiving and not receiving hormone replacement therapy. The fish oil concentrate provided 2.4 grams EPA plus 1.6 gram DHA daily. The study concluded that fish oil could potentially reduce the risk of coronary heart disease by 27% in postmenopausal women [24].

(e) Cardiac Arrhythmia Studies
Cardiac arrhythmia (irregular heart beat) is believed to be one of the major causes of sudden death in patients with coronary heart disease. In the United States, sudden death due to ventricular arrhythmia accounts for 50 % of mortality from acute myocardial infarction and causes a quarter of million deaths per year. The dietary intervention study of Burr et al. supports the role of fish oil in decreasing mortality and sudden death in patients with one episode of myocardial infarction [16]. The estimated dose of EPA is 0.3 gram per day.
An observational study in humans showed that an intake of 5.5 grams omega-3 fatty acids per month (equivalent to one meal of fatty fish per week) was associated with 50 % reduction in the risk of a sudden death; this further supports the anti-arrhythmic effects of fish omega-3 fatty acids [25].
A pilot clinical trial with 19 subjects showed reduction in ventricular arrhythmia (VA) in subjects who received omega-3 acids at a dose of 5.2 grams per day (4.3 g of EPA and DHA) [26]. VA is an abnormal rapid heart rhythms (arrhythmia) that originates in the lower chambers of the heart (ventricles).
Sellmayer et al found a 44 % reduction in abnormal heart beats in a group of 34 patients given fish oil, with daily dose of 0.9 gram EPA and 1.5 gram of DHA or 5 grams of LA for 16 weeks, compared with only a 15 % reduction in a similar group given sunflower oil [27].

 (f) Restinosis Studies
Restinosis is the occurrence of obstruction after coronary angioplasty (dilatation to open the artery). A meta-analysis (combined statistical analysis) of seven clinical trials revealed that omega-3 acid supplementation significantly reduced restinosis [28].
In a recent study, 610 patients who had undergone coronary artery bypass grafting surgery were randomly assigned to fish oil (4 grams/day) or to a control group. All patients received blood thinners, aspirin or warfarin. After one year, the omega-3 fatty acids supplementation significantly reduced the incidence of vein graft occlusion as compared to the control group [29].
However, a recent large clinical trial (1999) known as Coronary Angioplasty Restenosis Trial (CART) showed no beneficial effect of a high dose, 7 grams/day, of omega-3 acids after 6 months. Taking omega-3 fish oil was not better than taking corn oil to prevent obstructions or recurrence of treated obstructions [30]. The study was criticized for the variability in quality and composition of the active ingredients EPA and DHA from one fish capsule to another. The study was also criticized for using corn oil as placebo treatment. Corn oil contains linoleic acid and may help prevent arterial obstruction, and therefore may be effective in preventing restinosis. 

Infants’ Development
            Sixty percent of the human brain is fat, 25% of which is DHA. DHA is also abundant in the retina of the eye, and an essential nutrient for eye and brain development in infants. Infants get their DHA from their mother’s milk, which is rich in DHA, or the diet. Premature infants often have low levels of DHA and are at higher-than-average risk of neurological disorders. Children with hyperactivity or attention deficit disorder also tend to have low levels of DHA [31].
            A study in the Lancet (a prestigious Medical Journal) reported that infants given a DHA-enriched formula had better problem-solving ability at 10 months compared with infants who had a standard low-DHA diet [32]. It was suggested that higher problem solving scores in infancy is related to higher childhood IQ.
            Clinical studies have shown that dietary supplementation with omega-3 fatty acids results in an improvement in visual function in formula-fed premature infants to match that of human milk-fed infants. In a randomized, double-blind trial, infants were supplemented with DHA (0.35 %) and AA (0.75 %) in a formula designed to closely match that of mothers’ milk. Infants in the supplemented group showed a significant increase in the Mental Development Index after 18 months [33], and an improvement in the visual performance at 12 months of age [34].

Rheumatoid Arthritis
            Fish oil EPA and DHA in a dose of 3 grams daily have been shown to reduce joint tenderness and the morning stiffness, and to reduce the dose of non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis [35].
Another study also reported that the use of omega-3 supplements, 360 mg / day of EPA and 240 mg / day of DHA, appeared to decrease production of pro-inflammatory prostaglandin E2 in bone, and significantly stopped bone loss [35a]. It was proposed that a high dose of EPA and DHA is associated with a significant reduction the release of pro-inflammatory eicosanoides prostaglandin (PGE2) and leukotriene (LB4). EPA can act as a competitive inhibitor of arachidonic acid conversion to PGE2 and LB4. Fish oil was also shown to inhibit production of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin 1beta. Flax seed oil was also found to reduce the production of these cytokines [36]. Flax seed oil contains alpha linolenic acid (omega-3), which can be converted after ingestion to EPA.
            In a most recent double-blind, placebo-controlled study at the University of Newcastle in Australia [37], 50 people with rheumatoid arthritis (RA) were randomly assigned to take either 40 mg / kg body weight of fish oil containing 60 percent omega-3 fatty acids, or placebo daily for 15 weeks. At 15 weeks, the fish oil group showed modest improvement in RA symptoms (joint stiffness, and soreness).

Other Health Benefits
            A population-based case-control study in New Zealand during 1996-1997, involving 317 prostate cancer cases and 480 age-matched controls, revealed an association between reduced prostate cancer risk and high levels of EPA and DHA in erythrocyte biomarkers [38].
            A recent Australian study on 3,654 people aged 49 years or older revealed that a higher frequency of fish consumption, more than once per week, decreased late age-related maculopathy [39].
            Deficiencies of DHA have been linked to memory loss and depression. In a 1994 multi-center European study, 494 elderly people supplemented with 90mg DHA (contained in 300 mg bovine phosphatidyl serine) daily for six months showed improvement in apathy and social withdrawal symptoms [40].  
            A 1999 double-blind, placebo-controlled study involving 30 manic-depressive patients showed that sixty-four percent of those who took 10 grams of fish oil per day for four months reported a marked improvement in their symptoms, as compared to only 19 percent in the control group [41].

            Fish oil has a reasonable safety record. There has been no case of bleeding, even in patients undergoing angioplasty, while on fish oil supplements.

In Summary, the available evidence from studies in human populations generally indicates that the risk of death from coronary diseases is lower among people who ate some fish than among those who avoid it. EPA and DHA, the most prominent long chain omega-3 fatty acids in fish oils, promote overall heart health by lowering blood triglycerides, reducing the tendency of blood clot and lowering the risk of cardiac arrhythmia. Many doctors are now recommending fish oils to patients with coronary artery diseases. Data also supports the importance of omega-3 fatty acids, in particular DHA (which is also obtained from algae, such as the product Neuromin) in the development of brain and eyes in infants, and in reducing the release of pro-inflammatory molecules in rheumatoid arthritis patients. EPA and DHA have also recently been shown to improve symptoms of depression.

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