Engler MM, Engler MB. Effect of docosahexaenoic acid on lipoprotein subclasses in hyperlipidemic children (the EARLY study.American Journal of Cardiology, 2005;95(7):869-871

To test the hypothesis that a dietary omega-3 fatty acid, docosahexaenoic acid, improves the lipoprotein subclass profile of children who have hyperlipidemia, we conducted a randomized, double-blind, placebo-controlled study.

Children who had hyperlipidemia (n = 20) were stabilized on a low-fat diet for 6 weeks and then randomized to receive 1.2 g/day of docosahexaenoic acid for 6 weeks or placebo.

Supplementation with docosahexaenoic acid significantly increased low-density lipoprotein subclass 1 and high-density lipoprotein subclass 2 (large and buoyant; less atherogenic particles) by 91% and 14%, respectively, compared with the placebo phase.

Low-density lipoprotein subclass 3 (small and dense; more atherogenic particles) decreased by 48%.

Stark KD, Park EJ, Maines VA, Holub BJ. Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double blind trial. Am J Clin Nutr 2000;72(2):389-394.

BACKGROUND: Omega-3 fatty acid supplementation lowered serum triacylglycerol concentrations in studies in which most of the subjects were male. The effects of omega-3 fatty acid supplementation in postmenopausal women receiving and not receiving hormone replacement therapy (HRT) have received little attention. OBJECTIVE: We sought to determine the effects of a fish-oil-derived omega-3 fatty acid concentrate on serum lipid and lipoprotein risk factors for cardiovascular disease in postmenopausal women receiving and not receiving HRT, with an emphasis on serum triacylglycerol concentrations and the ratio of triacylglycerol to HDL cholesterol.

DESIGN: Postmenopausal women (n = 36) were grouped according to exogenous hormone use and were randomly allocated to receive 8 capsules/d of either placebo oil (control) or n-3 fatty acid-enriched oil (supplement). The supplement provided 2.4 g eicosapentaenoic acid (EPA) plus 1.6 g docosahexaenoic acid (DHA) daily. Serum lipids and the fatty acid composition of serum phospholipids were determined on days 0 and 28.

RESULTS: Supplementation with omega-3 fatty acids was associated with 26% lower serum triacylglycerol concentrations (P < 0.0001), a 28% lower overall ratio of serum triacylglycerol to HDL cholesterol (P < 0.01), and markedly greater EPA and DHA concentrations in serum phospholipids (P < 0.05).

CONCLUSIONS: These results show that supplementation with a fish-oil-derived concentrate can favorably influence selected cardiovascular disease risk factors, particularly by achieving marked reductions in serum triacylglycerol concentrations and triacylglycerol: HDL cholesterol in postmenopausal women receiving and not receiving HRT. This approach could potentially reduce the risk of coronary heart disease by 27% in postmenopausal women.

Maggie Laidlaw and Bruce J Holub. Effects of supplementation with fish oil derived n-3 fatty acids and gamma-linolenic acid on circulating plasma lipids and fatty acid profiles in women. Am J of Clinical Nutrition, 2003;77(1)37-42

Background:
Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA) have lipid-modifying and antiinflammatory properties. The effects of supplement mixtures of these fatty acids on plasma lipids and the fatty acid compositions of serum phospholipids have received little attention.

Objective:
The objective was to determine the effects of different levels of GLA supplementation together with a constant intake of EPA plus DHA on the triacylglycerol-lowering effect of EPA plus DHA alone and on the fatty acid patterns (eicosanoid precursors) of serum phospholipids.

Design:
Thirty-one women were assigned to 1 of 4 groups, equalized on the basis of their fasting triacylglycerol concentrations. They received supplements providing 4 g EPA+DHA (4:0, EPA+DHA:GLA; control group), 4 g EPA+DHA plus 1 g GLA (4:1), 2 g GLA (4:2), or 4 g GLA (4:4) daily for 28 d. Plasma lipids and fatty acids of serum phospholipids were measured on days 0 and 28.

Results:
Plasma triacylglycerol concentrations were significantly lower on day 28 than on day 0 in the 4:0, 4:1, and 4:2 groups. LDL cholesterol decreased significantly (by 11.3%) in the 4:2 group. Dihomo-gamma-linolenic acid increased significantly in serum phospholipids only in the 4:2 and 4:4 groups; however, total n-3 fatty acids increased in all 4 groups.

Conclusions:
A mixture of 4 g EPA+DHA and 2 g GLA favorably altered blood lipid and fatty acid profiles in healthy women.
On the basis of calculated PROCAM values, the 4:2 group was estimated to have a 43% reduction in the 10-y risk of myocardial infarction.

Sanders TA, Lewis F, et al. Effect of varying the ratio of n-6 to n-3 fatty acids by increasing the dietary intake of ALA, EPA and DHA, or both on fibrinogen & clotting factors VII and XII in persons aged 45-70 y. Am J Clin Nutr,2006;84:513-522.

Background:
Elevated fibrinogen, activated factor XII (FXIIa), and factor VII coagulant activity (FVIIc) are associated with higher risk of fatal ischemic heart disease. This study tested the hypothesis that lowering the dietary ratio of n-6 to n-3 polyunsaturated fatty acids (n-6:n-3) would modify these risk factors in older men and women.

Objective:
The objective of the study was to measure fasting hemostatic risk factors and postprandial changes in activated FVII (FVIIa) concentrations after a 6-mo alteration in dietary n-6:n-3.

Design:
In a randomized, parallel design in 258 subjects aged 45-70 y, we compared 4 diets providing 6% of energy as polyunsaturated fatty acids at an n-6:n-3 between 5:1 and 3:1 with a control diet that had an n-6:n-3 of 10:1. The diets were enriched in alpha-linolenic acid, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid, or both.

Results:
Fasting and 3-h plasma triacylglycerol concentrations were 11.1% and 7.2% lower with the diet that had an n-6:n-3 of 3:1 and that was enriched with EPA and DHA than with the other diets. Fasting fibrinogen, FXIIa, FVIIc, FVIIa, and FVII antigen and postprandial FVIIa were not influenced by the diets. Avoiding foods high in fat the day before measurement decreased FVIIc and FVIIa by 8% and 19.2%, respectively. A test meal containing 50 g fat resulted in a mean 47% (95% CI: 42%, 52%) increase in FVIIa 6 h later, but the response did not differ by n-6:n-3.

Conclusion:
Decreasing the n-6:n-3 to 3:1 by increasing the intake of EPA and DHA lowers fasting and postprandial plasma triacylglycerol concentrations in older persons but does not influence hemostatic risk factors.

Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nut 1991;54:438-463.

Several sources of information suggest that man evolved on a diet with a ratio of omega 6 to omega 3 fatty acids of approximately 1 whereas today this ratio is approximately 10:1 to 20-25:1, indicating that Western diets are deficient in omega 3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation.

In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega 3 fatty acids.

Many studies show that the effects of omega 3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant.
In patients with hyperlipidemia, omega 3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases.

The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis.

In various animal models omega 3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors.

Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants.

Because omega 3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans.

Omega-3 and omega 6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes.

Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake.

Hjerkinn EM, Seljeflot I, Ellingsen I, et al. Influence of long-term intervention with dietary counseling, long-chain n3 fatty acid supplements, or both on circulating markers of endothelial activation in men with lo

Background:
Dietary factors and very-long-chain n3 polyunsaturated fatty acids (n3 PUFAs) may influence the atherothrombotic process. Elevated concentrations of circulating cell adhesion molecules, thrombomodulin (TM), von Willebrand factor (vWF), and tissue-type plasminogen activator antigen (tPAag) are related to atherothrombotic cardiovascular disease.

Objective:
The randomized Diet and Omega-3 Intervention Trial (DOIT) targeted a comparison of the effect of 3-y dietary counseling, n3 PUFA supplementation (2.4 g/d), or both on circulating markers of endothelial activation.

Design:
The study included 563 elderly men with long-standing hyperlipidemia. The men were randomly assigned by factorial design into 4 groups: control (no dietary counseling and placebo capsules), dietary counseling (and placebo capsules), n3 PUFA supplementation (no dietary counseling), and dietary counseling and n3 PUFA supplementation.

Results:
Serum concentrations of fatty acids reflected good compliance. Dietary counseling was followed by significantly reduced concentrations of soluble intercellular adhesion molecule 1 (sICAM-1; P < 0.001), sTM (P = 0.004), and tPAag (P < 0.001) than in subjects without dietary counseling. After n?3 PUFA supplementation, significantly reduced concentrations of sICAM-1 (P < 0.001) and sTM (P = 0.006) were observed when compared with subjects receiving placebo capsules. An increase in tPAag was not significantly different from that observed in subjects receiving placebo capsules. For sICAM-1, a significant effect was observed for both interventions combined.

Conclusions:
Each intervention (dietary counseling or n?3 PUFA supplements) reduced sTM and sICAM-1 concentrations, indicating decreased endothelial activation. The tPAag increase in the groups not receiving dietary counseling (pooled), which indicates progression of atherosclerosis, was significantly counteracted by dietary counseling.

Omega-3 Fatty Acids and Hyperlipidemia
By David Kiefer, MD
Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson

A type of polyunsaturated fatty acid (PUFA), the omega-3 fatty acids (often abbreviated n-3) have attracted attention from the scientific community for about 30 years, ever since the discovery of low serum cholesterol, low low-density lipoprotein (LDL), and low triglycerides in the Greenland Inuit, who have a diet high in fish oils.(1) Other observations of a change in the ratio of omega-6 fatty acids to omega-3 fatty acids from approximately 1:1 in early human diets to approximately 10:1 to 20:1 with the development of the modern Western diet,(2) combined with an increase in incidence of coronary heart disease (CHD), led researchers to consider the cardioprotective effect of n-3 fatty acids and investigate the antihyperlipidemic effects of n-3 fatty acids.

This review will explore the evidence for the use of n-3 fatty acids for hyperlipidemia.

Source of Omega-3 Fatty Acids
Omega-3 fatty acids are either plant-based (a-linolenic acid, LNA), or marine animal-derived (eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). LNA is an essential fatty acid (as is a-linoleic acid, an omega-6 fatty acid), that is, it is required in the human diet, and is the most common omega-3 fatty acid in the American diet. LNA is found in flaxseed oil (8.5 g/Tbsp), flaxseeds (2.2 g/Tbsp), canola oil (1.3 g/Tbsp), soybean oil (0.9 g/Tbsp), English walnuts (0.7 g/Tbsp), and olive oil (0.1 g/Tbsp).(3) In the human body, one of LNA?s activities is to serve as a precursor primarily to EPA, but also to DHA, although the conversion to these longer-chain n-3 fatty acids is minimal.

Fish are the main dietary source of EPA and DHA; the concentration of EPA and DHA varies by the species of fish, the season harvested, the packaging and cooking methods, whether it was farm-raised or wild (though wild and farmed salmon appear to be similar in this regard), and the diet of the fish.(3) The highest n-3 concentrations appear to be in cold-water fish, such as (in order of decreasing EPA and DHA content) herring, sardines, salmon, mackerel, tuna, and halibut.(4) For example, 15 g of mackerel or herring provides about 400 mg of n-3 fatty acids.(5)

Mechanism of Action
There are many proposed mechanisms for the effects of n-3 fatty acids on the physiology of lipid metabolism. Researchers have shown that n-3 fatty acids inhibit hepatic triglyceride (TG) synthesis, such as through the inhibition of TG synthetic enzymes like diacylglycerol acyltransferase, resulting in a decreased rate of very low-density lipoprotein (VLDL)-TG secretion from the liver,(6-8) as well as decreased content of TG in VLDL particles.(9,10)

N-3 fatty acids also shift LDL subfractions to the less-atherogenic, larger, lighter particles. Changes in VLDL as mentioned above will lead to changes in LDL production, including which subfractions are made.(9) The VLDL created in these processes are favored precursors for LDL-C, perhaps explaining why LDL may increase with n-3 supplementation.

Other researchers have found that fish oil appears to inhibit VLDL triglyceride and apoB synthesis, but with different effects depending on the baseline TG levels; this may occur because of an underlying disturbance in LDL metabolism that affects the response of LDL to fish oil.(11) For example, people with normal TG levels are more likely to have decreased LDL apoB with fish oil supplementation through decreased apoB synthesis because VLDL is efficiently converted to LDL via delipidation.(11) Overall, it is possible that LDL responses to fish oil may be linked to underlying differences in LDL composition and LDL metabolic behavior. Some of these genetic nuances agree with animal studies: Strains of mice with different variations of human apolipoprotein B genes have different plasma TG and apoB responses to two weeks of fish oil supplementation.(8)

One human experiment illustrated more of the mechanism of action of n-3 fatty acids. Ten people with varied plasma TG levels were assigned to either a control diet consisting of 20% fat from cocoa butter and peanut oil or to a test diet of 10-17 g/d of n-3 fatty acids from fish oil.(6) The fish oil diet caused a decrease in the VLDL-TG synthetic rate, and increased the VLDL-TG catabolic rate, leading to a 66% reduction in plasma TG levels, mainly because of a 78% decrease in VLDL-TG. Total cholesterol also fell 26% (from 195 mg/dL to 144 mg/dL), LDL had an insignificant increase, and HDL fell 23% (from 31 mg/dL to 24 mg/dL). This shows a reduced rate of TG entering VLDL, and an increase in the rate of TG removal from VLDL. The increase in LDL only occurred in patients with TG > 350 mg/dL, otherwise there was a slight decrease in LDL for patients with normal TG levels. With high TG, fish oil may enhance the conversion of VLDL to LDL.

Clinical Studies
One review looked at all human placebo-controlled, crossover, or parallel-design studies, lasting at least two weeks, and with less than 7 g/d of n-3 fatty acids.(10) There were three studies using LNA; LNA causes lipid changes equivalent to omega-6 fatty acids, except when large amounts (38-60 g/d) of flaxseed oil are given, which then causes decreased plasma TG, a finding in line with other published research.(12) The review detailed 36 crossover (usually using MaxEPA(®) [n-3 4 g/d] vs. olive oil [usually 10 g/d] for 7-10 weeks) and 29 parallel design studies (usually MaxEPA [n-3 4 g/d] vs. olive oil for 7 weeks). The results of these trials showed that approximately 3 g/d of marine n-3 fatty acids do not affect total serum cholesterol, cause an increase in LDL (5% to 10%) and HDL (1% to 3%), and decrease serum TG (25% to 30%).

Since that review, clinical trials have further refined the effects of n-3 fatty acids. For example, 19 non-obese people with high TG levels were given two consecutive diets for three weeks each: a high-fat diet (providing 39% of the calories from fat and consisting of 1.6% n-3 marine fatty acids) vs. a low-fat diet (providing 28% of the calories from fat). The high-fat diet decreased TG (63%), total cholesterol (22%), VLDL (54%), and LDL (16%), while increasing HDL (8%).(13) The researchers were unable to comment on whether these effects would be observed if people only ate fish 3-4 times weekly, a more likely pattern of consumption.

In a double-blind, placebo-controlled crossover trial 16 people with non-insulin-dependent diabetes and hypertriglyceridemia were randomized to two consecutive six-month interventions: 15 g/d of either olive oil or fish oil.(14) The fish oil used was the brand Promega® and it provided 6 g/d of omega-3 fatty acids (4.1 g EPA, 1.9 g DHA). There was a decrease in TG (P = 0.0004), VLDL-cholesterol and VLDL-triglyceride (P = 0.0001), and LDL-cholesterol (P = 0.0003), but no change in total cholesterol or HDL-cholesterol. There was also no change in diabetic parameters, such as fasting glucose or hemoglobin A1C.

Another review investigated the use of n-3 fatty acids for primary and secondary prevention of CHD.(5) The authors found numerous clinical trials in hyperlipidemic subjects involving 4 g/d of n-3 fatty acids (often as Omacor® capsules containing 850-882 mg of EPA + DHA, and 4 mg alpha-tocopherol per capsule) alone vs. placebo or in combination with statin medications or estrogen. The range of results showed a decrease in serum TG between 20% and 37% with n-3 fatty acid treatment, and there was a further decrease in TG when n-3 fatty acids were added to simvastatin, including a suppression of postprandial hypertriglyceridemia. One of the studies reviewed included 59 patients with hypertriglyceridemia and CHD on 10-40 mg/d of simvastatin who were randomized to placebo or 2 g twice daily of Omacor for six months.(15) Serum TG and VLDL decreased by 20-30% (P < 0.005) and 30-40% (P < 0.005), respectively, in the Omacor group. There was no change in LDL or HDL between the two groups.

As mentioned above, there are differences in the responses to fish oil depending on the baseline lipid levels. One trial examined the effects of EPA and DHA on serum TG levels. People with normal TG and people with elevated TG given 3 g/d of EPA + DHA showed decreases in TG of 12% and 21%, respectively.(11)

As essential fatty acids, there is a need for both omega-6 and omega-3 fatty acids in the human diet. When examining the overall cardiovascular effect of omega-3 fatty acids, most research points to the importance of considering omega-3 fatty acid intake in the context of the omega-6 fatty acid consumption; although the absolute amount consumed is important, so is the ratio of omega-6 to omega-3 fatty acids.(16) The primary omega-6 fatty acid, linoleic acid, is associated with a lower cardiovascular risk, probably through its effects in lowering total and LDL-C cholesterol.(17) With this in mind, one recommendation is that for healthy adults, 5-8% of calories (or 11-20 g/d, based on a 2,000 kcal diet) should come from linoleic acid, a level that seems to convey cardiovascular benefits, allows for a positive interaction with omega-3 fatty acids, and yet is low enough not to contribute to increased inflammation.(17)

In the bigger picture of dietary changes that have clinical relevance, the recommendations to increase omega-3 fatty acid intake are most relevant when measured against the omega-6 intake (see above), and in relation to other components of the diet. For example, when any fats replace carbohydrates, there is an increase in HDL and LDL and a decrease in TG, in amounts that depend on the type of fat and the baseline diet.(18)

Other Clinical Effects
Epidemiological studies and randomized controlled trials have investigated the role of fish intake, fish oil, dietary LNA, or supplemental n-3 fatty acids in primary and secondary prevention of CHD, finding a decreased risk of sudden cardiac death and cardiac arrest, and a reduction in cardiac death,(3,5) the details of which go beyond the scope of this review. Research also seems to support an improvement in myocardial infarction risk and death from ischemic CHD in people with LNA in their diets,(3,18) as well as an inverse association between dietary fish intake and CHD risk, stronger for fatal CHD than nonfatal myocardial infarction (MI),18 and for populations with greater-than-average CHD risk.(18)

LNA also has cardiovascular effects such as decreased arrhythmias, inflammation, and thrombosis, whereas EPA + DHA improve vascular function and decrease thrombosis,(17) and might prevent or favorably influence coronary heart disease and stroke; Crohn?s disease; breast, colon, and prostate cancer; hypertension; and rheumatoid diseases.(12) Also, EPA and DHA decrease the risk of ischemic heart disease,(17) and supplementation with omega-3 fatty acids is thought to be anti-atherogenic and stabilize plaques via its anti-inflammatory properties.(19) There is also a slight hypotensive effect with omega-3 fatty acids.(3)

Dosages and Formulation
The dose of n-3 fatty acids necessary to achieve a reduction in plasma TG is approximately 3 g/d total of EPA + DHA. With 1 g fish oil capsules, which usually contain 180 mg EPA and 120 mg DHA,(2) it will be necessary to take approximately 10 capsules daily. To avoid the toxic effects of some of the environmental contaminants of fish (see below), it is important to choose supplements that have been tested and are free of methylmercury, polychlorinated biphenyls (PCBs), and dioxins. The dose of LNA necessary to achieve similar results is difficult to predict due to the incomplete conversion of LNA to EPA and DHA in the body. A review detailing the effect of LNA on plasma TG found that 60 g of flaxseed oil used daily, or 38 g of flaxseed oil substituted for 45 g of linoleic acid, could lead to plasma TG lowering.(10)

Adverse Effects, Contraindications, and Drug Interactions
N-3 fatty acids can cause an increase of approximately 5% in LDL cholesterol in some people. As mentioned above, the elevation in LDL appears to be most pronounced in people with elevated TG because fish oil may enhance the conversion of VLDL to LDL;(6) the LDL consists of the less-pathogenic, larger, less-dense LDL particles. Also, the effect of n-3 fatty acids is more pronounced in carriers of the apoE4 polymorphism, which confers a tendency to have higher baseline serum cholesterol and higher risk of CHD.(9)

There are concerns about the contamination of fish with methylmercury, PCBs, and dioxins.(2) Because of the dangers of these contaminants, the FDA and the Environmental Protection Agency recommend that women who might become pregnant, who are pregnant, or who are breastfeeding, and young children should not eat more highly contaminated fish species such as shark, swordfish, king mackerel, or tilefish, and should eat only 12 oz/wk of less contaminated fish species (canned light tuna, salmon, Pollock, catfish).(2,20) Of note, albacore (white) tuna is higher in mercury than canned light tuna, and only up to 6 oz should be consumed per week.

There are conflicting reports about whether n-3 fatty acids increase fasting glucose in people with diabetes. One randomized, double-blind trial investigated the use of 4 g/d of EPA, DHA, or olive oil placebo for six weeks in 59 people with Type 2 diabetes mellitus, and found a slight, but significant increase in fasting glucose of 1.40 and 0.98 mol/L in the EPA and DHA groups, respectively, when compared with placebo. There was no change in glycosylated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure.(21) This result is in contrast to other studies that have not found blood glucose elevations.(14)

There are also dose-dependent adverse effects of n-3 supplementation such as a fishy aftertaste, gastrointestinal disturbances, and increased bleeding time, though no clinically significant abnormal bleeding events have been documented in the medical literature.(2)

Cohort studies and some, but not all, epidemiological studies demonstrate an increased risk of prostate cancer with dietary consumption of LNA, an interesting finding given that EPA and DHA appear to be protective of prostate cancer and that LNA may be protective against breast cancer.(22,23) Some experts state that there is less of a prostate cancer risk, and maybe even a benefit, with the use of ground or whole flaxseeds due to the lignan content; lignans act as phytoestrogens and antioxidants, showing anticancer effects in animal models.(24,25)

Conclusion
The use of n-3 fatty acids, either as LNA or as EPA + DHA, has been studied extensively in both animals and humans, and been subject to numerous reviews examining their clinical effects. LNA has negligible effects on serum lipids, except for a modest decrease in serum TG when high doses of flaxseed oil that are difficult to achieve are consumed daily. The bulk of the convincing clinical effects have been from the use of supplemental EPA and DHA, the n-3 fatty acids from marine sources. Most research shows that 3-4 g/d of EPA + DHA can lead to a 25-30% decrease in TG, an effect more pronounced for people with higher serum TG. There are also variable effects on other serum lipids, such as a small increase in LDL (again, mainly in people with elevated TG) and HDL, the specifics of which depend on many factors, including genetic differences in LDL metabolism. Some of these effects can be achieved with dietary modifications that include daily fish consumption; it remains to be definitively proven whether the sporadic ingestion of n-3 fatty acids leads to similar clinical effects. The generally recommended dose is approximately 3 g/d of EPA + DHA, about 10 capsules daily of most commonly sold preparations. Some of the adverse effects mentioned in the medical literature include elevated LDL cholesterol, increased fasting glucose in people with diabetes, exposure to environmental contamination of fish (not usually a problem with tested supplements), aberrations of bleeding time, and an increased risk of prostate cancer with LNA consumption.

Recommendation
The n-3 fatty acids, LNA, EPA, and DHA, have documented beneficial effects on plasma TG, especially in people with elevated plasma TG. It is possible to lower TG with a supplement, most effectively by consuming approximately 3 g/d of EPA + DHA due to the inefficient conversion of ingested LNA to EPA and DHA, although regular daily consumption of LNA and/or fish also conveys some benefits. There are official warnings about fish consumption due to environmental contaminants, but these dangers can be avoided by consuming tested fish oil capsules or focusing on LNA ingestion. N-3 fatty acids are generally well-tolerated with minimal side effects, though n-3 fatty acids may affect other lipid parameters, such as causing an increase in LDL; it would be a good idea to monitor patients? lipid levels regularly to detect any undesirable abnormalities. The consumption of LNA oils or supplements should be avoided in people with prostate cancer, though flax seeds may be safe in reasonable doses; more research is needed to clarify this point.

References
1. Caron MF, White CM. Evaluation of the antihyperlipidemic properties of dietary supplements. Pharmacotherapy 2001;21:481-487.

2. Covington MB. Omega-3 fatty acids. Am Fam Physician 2004;70:133-140.

3. Kris-Etherton PM, et al. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.

4. USDA Nutrient Data Laboratory. Available at: www.nal.usda.gov/fnic/foodcomp/. Accessed May 5, 2005.

5. Weisman D, et al. Efficacy of omega-3 fatty acid supplementation in primary and secondary prevention of coronary heart disease. Isr Med Assoc J 2004; 6:227-232.

6. Harris WS, et al. Effects of fish oil on VLDL tri-glyceride kinetics in humans. J Lipid Res 1990;31: 1549-1558.

7. Nestel PJ, et al. Suppression by diets rich in fish oil of very low density lipoprotein production in man. J Clin Invest 1984;74:82-89.

8. Ko C, et al. A fish oil diet produces different degrees of suppression of apoB and triglyceride secretion in human apoB transgenic mouse strains. J Lipid Res 2003;44:1946-1955.

9. Griffin BA. The effect of n-3 fatty acids on low den- sity lipoprotein subfractions. Lipids 2001;36(Suppl): S91-S97.

10. Harris WS. n-3 Fatty acids and serum lipoproteins: Human studies. Am J Clin Nutr 1997;65(5 suppl): 1645S-1654S.

11. Schectman G, et al. Heterogeneity of low density lipoprotein responses to fish-oil supplementation in hypertriglyceridemic subjects. Arteriosclerosis 1989; 9:345-354.

12. Wahrburg U. What are the health effects of fat? Eur J Nutr 2004;43(Suppl 1):I/6-11.

13. Pieke B, et al. Treatment of hypertriglyceridemia by two diets rich either in unsaturated fatty acids or in carbohydrates: Effects on lipoprotein subclasses, lipolytic enzymes, lipid transfer proteins, insulin and leptin. Int J Obes Relat Metab Disord 2000;24: 1286-1296.

14. Connor WE, et al. The hypotriglyceridemic effect of fish oil in adult-onset diabetes without adverse glucose control. Ann N Y Acad Sci 1993;683:337-340.

15. Durrington PN, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 2001;85:544-548.

16. Simopoulos AP. Omega-3 fatty acids and antioxidants in edible wild plants. Biol Res 2004;37:263-277.

17. Wijendran V, Hayes KC. Dietary n-6 and n-3 fatty acid balance and cardiovascular health. Annu Rev Nutr 2004;24:597-615.

18. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA 2002;288:2569-2578.

19. Plotnikoff GA, et al. Prevention of Atherosclerosis. In: Rakel D, ed. Integrative Medicine. Philadelphia, PA: Saunders; 2003.

20. U.S. Department of Health and Human Services and U.S. Environmental Protection Agency. What You Need to Know About Mercury in Fish and Shellfish. March 19, 2004. Available at: www.cfsan.fda.gov/~dms/admehg3.html. Accessed May 5, 2005.

21. Woodman RJ, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr 2002;76:1007-1015.

22. Leitzmann MF, Et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 2004;80:204-216.

23. Astorg P. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: A review of epidemiological and experimental evidence. Cancer Causes Control 2004;15:367-386.

24. Chen J, et al. Dietary flaxseed enhances the inhibitory effect of tamoxifen on the growth of estrogen-dependent human breast cancer (mcf-7) in nude mice. Clin Cancer Res 2004;10:7703-7711.

25. Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncology 2002;3:364-373.

Source: Alternative Medicine Alert/American Health Consultants

Balk EM, Lichtenstein AH, Chung M, et al. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis,2006;189(1):19-30.

Greater fish oil consumption has been associated with reduced CVD risk, although the mechanisms are unclear. Plant-source oil omega-3 fatty acids (ALA) have also been studied regarding their cardiovascular effect.

We conducted a systematic review of randomized controlled trials that evaluated the effect of consumption of fish oil and ALA on commonly measured serum CVD risk factors, performing meta-analyses when appropriate.

Combining 21 trials evaluating lipid outcomes, fish oil consumption resulted in a summary net change in triglycerides of -27 (95% CI -33, -20)mg/dL, in HDL cholesterol of +1.6 (95% CI +0.8, +2.3)mg/dL, and in LDL cholesterol of +6 (95% CI +3, +8)mg/dL. There was no effect of fish oil on total cholesterol.

Across studies, higher fish oil dose and higher baseline levels were associated with greater reductions in serum triglycerides. Overall, the 27 fish oil trials evaluating Hgb A(1c) or FBS found small non-significant net increases compared to control oils. Five studies of ALA were inconsistent in their effects on lipids, Hgb A(1c) or FBS. Four studies investigating the effects of omega-3 fatty acids on hs-CRP were also inconsistent and non-significant.

The evidence supports a dose-dependent beneficial effect of fish oil on serum triglycerides, particularly among people with more elevated levels.

Fish oil consumption also modestly improves HDL cholesterol, increases LDL cholesterol levels, but does not appear to adversely affect glucose homeostasis. The evidence regarding the effects of omega-3 fatty acids on hs-CRP is inconclusive, as are data on ALA.

Lox CD. Effects of marine fish oil (omega-3 fatty acids) on lipid profiles in women. Gen Pharmacol,1990; 21(3):295-298.

Cycling women both taking or not taking oral contraceptives and menopausal women on replacement estrogen ingested 3 g daily of marine fish oil for 30 days. Triglycerides decreased in the contraceptive users, cholesterol and LDL increased in the non-contraceptive user; while LDL decreased in the menopausal women. After 14 days removal of the fish oil, lipid profiles generally returned to a pattern generally thought to be harmful. Fish oil appears to alter lipids favorably in women receiving exogenous estrogens compared to natural circulating estrogen.

Durrington P, Bhatnagar D, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease. Heart 2001; 85(5):544-548.

BACKGROUND: Omega-3 fatty acids, such as those present in fish oil, have been reported to prolong life in myocardial infarction survivors. These fatty acids can decrease serum triglyceride concentrations, but so far the doses used in trials examining their effects on coronary end points have had only minimal triglyceride lowering effects.

OBJECTIVE: To examine the triglyceride lowering effectiveness, safety, and tolerability of Omacor, a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil (84% of the total as opposed to an average of 35% in fish oil) over one year in patients with established coronary heart disease (CHD) and persisting hypertriglyceridaemia, despite receiving simvastatin in doses similar to those employed in the Scandinavian simvastatin survival study.

SUBJECTS AND METHODS: 59 patients with CHD, receiving simvastatin 10-40 mg daily with serum triglycerides > 2.3 mmol/l, were randomised to receive Omacor 2 g twice a day or placebo for 24 weeks in a double blind trial. Forty six patients accepted the offer of active treatment for a further 24 weeks in an open phase of the trial. RESULTS: There was a sustained significant decrease in serum triglycerides by 20-30% (p < 0.005) and in very low density lipoprotein (VLDL) cholesterol by 30-40% (p < 0.005) in patients receiving active Omacor at three, six, and 12 months compared either to baseline or placebo. Omacor did not have any deleterious effect on low density or high density lipoprotein cholesterol or on biochemical and haematological safety tests. There was no adverse effect on glycaemic control in patients with diabetes, who showed a decrease in serum triglyceride, which was at least as great as in non-diabetic patients. One patient receiving placebo died of acute myocardial infarction. Three patients withdrew from the trial (two on placebo and one on active treatment). Omacor was generally well tolerated.

CONCLUSION: Omacor was found to be a safe and effective means of lowering serum triglycerides over one year in patients with CHD and combined hyperlipidaemia, whose triglycerides remained elevated despite simvastatin treatment.

Varady KA, Jones PJH. Combination Diet and Exercise Interventions for the Treatment of Dyslipidemia: an Effective Preliminary Strategy to Lower Cholesterol Levels? J. Nutr, 2005; 135:1829-1835.

At present, dyslipidemia is most commonly treated with drug therapy. However, because safety concerns regarding the use of pharmaceutical agents have arisen, a need for alternative nonpharmacological therapies has become increasingly apparent.

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recommends lifestyle therapies, which include a combination of diet and exercise modifications, in place of drug treatment for patients who fall into an intermediate range of coronary heart disease (CHD) risk.

This review examined the cholesterol lowering efficacy of the following 2 NCEP-recommended combination therapies: 1) low saturated fat diets combined with exercise, and 2) nutritional supplementation, i.e., fish oil, oat bran, or plant sterol supplementation, combined with exercise, in the treatment of dyslipidemia.

Combination therapies are particularly advantageous because diet and exercise elicit complementary effects on lipid profiles.

More specifically, diet therapies, with some exceptions, lower total (TC) and LDL cholesterol (LDL-C) concentrations, whereas exercise interventions increase HDL cholesterol (HDL-C) while decreasing triglyceride (TG) levels.

With respect to specific interventions, low saturated fat diets combined with exercise lowered TC, LDL-C, and TG concentrations by 718, 715, and 418%, respectively, while increasing HDL-C levels by 514%.

Alternatively, nutritional supplements combined with exercise, decreased TC, LDL-C, and TG concentrations by 8.26, 8.30, and 12.39%, respectively, while increasing HDL-C levels by 2.8%.

These findings suggest that combination lifestyle therapies are an efficacious, preliminary means of improving cholesterol levels in those diagnosed with dyslipidemia, and should be implemented in place of drug therapy when cholesterol levels fall just above the normal range.

Damsgaard CT, Schack-Nielsen L, Michaelsen KF, et al. Fish Oil Affects Blood Pressure and the Plasma Lipid Profile in Healthy Danish Infants. J Nut.,2006;136:94-99.

Animal and epidemiologic studies indicate that early nutrition has lasting effects on metabolism and cardiovascular disease risk.

In adults, (n-3) long-chain PUFA (LCPUFA) from fish oils improve blood pressure, the lipid profile, and possibly cardiovascular disease mortality.

This randomized trial is the first to investigate the effects of fish oil on blood pressure and the lipid profile in infancy. Healthy term 9-mo old infants (n = 83) were randomly assigned to 5 mL fish oil daily or no fish oil for 3 mo and to 2 different milk types.

Before and after the intervention, blood pressure was measured with an oscillometric device, and blood was sampled for analysis of erythrocyte fatty acid composition and the plasma lipid profile. This paper examines the effects of the fish oil supplement, with adjustment for the effects of the milk intervention when relevant.

The fish oil intervention increased erythrocyte (n-3) LCPUFA content (P < 0.001). At 12 mo, infants administered fish oil had a lower systolic blood pressure [adjusted mean difference (95% CI)] 6.3 mm Hg (0.9, 11.7) (P = 0.02), a 0.51 mmol/L (0.07, 0.95) higher plasma total cholesterol (P = 0.02), and a 0.52 mmol/L (0.02,1.01) higher LDL cholesterol (P = 0.04) than infants not administered fish oil.

Plasma triacylglycerol was inversely associated with the erythrocyte content of eicosapentaenoic acid (r = 0.34, P < 0.01), a biomarker of fish oil dose.

The observed effects of fish oil are in accordance with findings in adults. The long-term health implications warrant further investigation.

Visioli F, Crawford MA, Cunnane S, et al. Lipid transport, dietary fats, and endogenous lipid synthesis: hypotheses on saturation and competition processes. Nutr Health,2006;18(2) :127-132.

Plasma lipid concentrations are the net result of the balance between two opposite processes: the loading, i.e. the entry of new lipids into the plasma compartment through the ingestion (diet) and/or endogenous synthesis, and the unloading, i.e. energy utilization, incorporation into cell membranes, and storage.

Even though many fatty acids are thought to be synthesized in the body, it appears as nearly all circulating fatty acids are, in fact, derived from the diet.

In view of the wide dietary availabilty of such nutrients, the need to conserve energy likely minimizes endogenous synthesis. Consequently, the possibility exists to alter circulating the profile of fatty acids, including the "non essential" ones by dietary manipulations.

In turn, a theory on the dietary vs endogenous contribution to circulating fatty acids, including those known as non-essential, is discussed based on critical interpretation of original data.

Polozova A, Gionfriddo E, Salem Jr. N. Effect of docosahexaenoic acid on tissue targeting and metabolism of plasma lipoproteins. Prostag Leukot Essent Fatty Acids,2006;75(3):183-190.

We examined the effect of the docosahexaenoic acid (DHA) content of lipoproteins on their metabolism in vivo by a radioisotope labeling and tracking method.

Purified HDL and LDL were labeled with (3)H-cholesteryl oleate tracer. To mimic dietary-related changes in fatty acid composition of lipoproteins, we incorporated lipids acylated with either DHA, arachidonic (AA) or oleic (OA) acid to phosphatidylcholine (didocosahexaenoylphosphatidylcholine (di22:6-PC), diarachidonoylphosphatidylcholine (di20:4-PC) and dioleoylphosphatidylcholine (di18:0-PC), respectively) into the purified particles.

The lipids, at the amount added, did not cause detectable alterations in the morphology of the lipoproteins. Levels of radiotracers in blood and in several target tissues such as brain, heart, liver, muscle and adipose were determined at 1.5, 3 and 24h after intravenous injection into C57Bl/6J mice.

No statistically significant differences were detected in the tissue distribution of tracers introduced into HDL enriched in DHA, compared to particles enriched with OA.

In contrast, we found a significantly higher proportion of radiolabel associated with LDL enriched in DHA in heart, brown adipose and brain tissues. The uptake of labels associated with DHA containing LDL nearly doubled for heart and brown adipose tissues at 1.5 and 3h, and it was 30% higher for brain tissues at 24h.

The tissue distribution of labels from the same particles enriched in AA or OA did not show a statistically significant difference from unaltered control lipoproteins.

These findings point to the possible role of DHA in the regulation of LDL metabolism and involvement of the lipoproteins in transport of n-3 PUFA to target organs.

Charman A, Muriithi EW, et al. Fish oil before cardiac surgery: neutrophil activation is unaffected but myocardial damage is moderated.
Prostaglandins Leukot Essent Fatty Acids, 2005; 72(4):257-265

Could pre-operative dietary intervention with fish oil reduce neutrophil activation and myocardial damage associated with cardiopulmonary bypass (CPB)

Patients were randomised to receive either 8 g/day fish oil (n=22) or placebo (n=18) for 6 weeks. Neutrophil activation, apoptosis and cardiac damage were measured. Demographics and operative variables were similar.

Fish oil diet decreased plasma VLDL from 0.69+/-0.34 to 0.51 +/-0.24 mmol/l and triglycerides from 1.68+/-0.70 to 1.39+/- 0.54 mmol/l. HDL cholesterol increased from 0.94+/-0.27 to 1. 03+/-0.26 mmol/l demonstrating significant treatment effects (P=0.007, 0.02 and 0.0003, respectively) as well as compliance with treatment.

There were no significant differences in ex vivo N-formyl- methionyl-leucyl-phenylalanine-stimulated neutrophil superoxide anion generation or myeloperoxidase release at recruitment, pre -operatively and at end-CPB.
Apoptosis at end-CPB was equally reduced in both groups from 23+/-9% to 13+/-4% in the fish oil group (P<0.001) and 35+/-14% to 15+/-3% in the placebo group (P=0.001). At end-CPB overall troponin I levels averaged 0.91+/-0.60 ng/ml which clearly exceeded diagnostic levels (0.15 ng/ml).

At 24h troponin I fell significantly in the fish oil group to 46+/-23% of end-CPB levels (P=0.0002) whereas it peaked in the placebo group to 107+/-72% (P=0.098 vs. end-CPB); this difference was significant: P=0.013.

At 48 h the placebo-treated patients had higher troponins but not significantly so (P=0.059). Area-under-the-curve analysis did not conclusively support this (P=0.068).

We conclude that fish oil did not significantly decrease post-CPB neutrophil activation (as detected ex vivo) but may moderate post-operative myocardial damage.

Yates A, Bradley JP, Maroon J, et al. Evaluation of lipid profiles, inflammatory markers and the use of Omega-3 EFA in Professional Football Players. Initiation: 2006

Introduction: The risk of cardiovascular disease becomes significant in males at age 30. Because many professional football players carry a large amount of weight and are required to exert extreme bursts of maximal physical effort, they make up a unique class of individuals that may have a higher risk for adverse cardiac events such as heart attacks and death.

Family heart history, obesity and other diet and lifestyle factor also play a major role. Cardiac risk assessment is critical to ensure the health of these premier athletes.

The Pittsburgh Steelers have undertaken a rigorous health screening program using both conventional physical exams and now state of the art blood test to assess these risks.

This same physical contact often results in painful joints which are often treated with NSAIDs. The recent withdrawal of Vioxx and the concern of serious side effects make long term use of the COX-2 family of NSAIDs a significant risk factor.

For this evaluation we plan to evaluate the use of Omega-3 EFAs for both their cardiovascular protective effect, by reducing vascular inflammation and plaque stabilization and their ability to relieve joint tissue inflammation and the associated pain.

Materials and Methods: The study will recruit a total of 40 players of which 20 will be given 2,800 mg of omega-3 EFA (EPA/DHA) at the start of the pre-season for the duration of the season. The other 20 players will be the control group. Both groups will be asked to complete questionnaires, diary logs, NSAIDs usage and pain assessments. Routine pre-, mid- and post season cardiac risk assessment blood work and history and physical exams data will also be collected and results used for this analysis.

With this pilot analysis of 40 NFL players we hope to assess any potential beneficial affects of omega-3 EFA on both reducing cardiac risk by improved blood inflammation and lipid markers and by quantifying any reduction in NSAIDs use and improved pain scores in the treatment group.

Weber P, Raederstorff D. Triglyceride-lowering effect of omega-3 LC-polyunsaturated fatty acids. Nutr Metab Cardiovasc Dis 2000 Feb;10(1):28-37.

Abstract: There is increasing evidence that serum triglycerides are a significant and independent risk factor for CVD. The aim of this report is to review recent literature pertinent to the triglyceride-lowering effect of omega-3 long chain polyunsaturated fatty acids (LC-PUFA). Animal data are not considered because they are difficult to extrapolate to the human situation. A large body of evidence derived from epidemiological studies and clinical trials has consistently demonstrated that this effect is dose-dependent and can be achieved by diet.

The smallest amount of omega-3 LC-PUFA needed to significantly lower serum triglycerides appears to be approximately 1 g/day as provided by a fish diet. Use of fish oil administering as little as 0.21 g EPA and 0.12 g DHA per day significantly lowered serum triglycerides in hyperlipidemics. In normolipidemics, a daily intake of 0.17 g EPA and 0.11 g DHA, given as a fish oil supplement, induced a non-significant reduction of 22%.

These findings must be considered as preliminary and warrant further research. Intake of omega-3 LC-PUFA is frequently reported to modestly increase LDL cholesterol. However, in normo- or slightly hyperlipidemic individuals who received omega-3 LC-PUFA for 4 months or longer, changes of LDL cholesterol were not significantly different from a placebo group. Both EPA and DHA lower serum triglycerides, but they may have a differential effect on lipoproteins. Intake of omega-3 LC-PUFA in the amount mentioned above is safe.