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ESSENTIAL - The 'essential' fatty acids were given their name when researchers found that they are essential to normal growth in young children and animals. The omega−3 fatty acid DHA, also known as docosahexaenoic acid, is found in high abundance in the human brain. It is produced by a desaturation process, but humans lack the desaturase enzyme, which acts to insert double bonds at the ω6 and ω3 position. Therefore, the ω6 and ω3 polyunsaturated fatty acids cannot be synthesized and are appropriately called essential fatty acids.
less meat from agriculture could mean a longer, healthier
life. Studies show that people who eat fatty fish are less
likely to suffer from cancer.
Omega−3 fatty acids, also called ω−3 fatty acids or n−3 fatty acids, are polyunsaturated fatty acids (PUFAs). The fatty acids have two ends, the carboxylic acid (-COOH) end, which is considered the beginning of the chain, thus "alpha", and the methyl (-CH3) end, which is considered the "tail" of the chain, thus "omega". One way in which a fatty acid is named is determined by the location of the first double bond, counted from the tail, that is, the omega (ω-) or the n- end. Thus, in omega-3 fatty acids the first double bond is between the third and fourth carbon atoms from the tail end. However, the standard (IUPAC) chemical nomenclature system starts from the carboxyl end.
The three types of omega−3 fatty acids involved in human physiology are α-linolenic acid (ALA), found in plant oils, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both commonly found in marine oils. Marine algae and phytoplankton are primary sources of omega−3 fatty acids. Common sources of plant oils containing ALA include walnut, edible seeds, clary sage seed oil, algal oil, flaxseed oil, Sacha Inchi oil, Echium oil, and hemp oil, while sources of animal omega−3 fatty acids EPA and DHA include fish, fish oils, eggs from chickens fed EPA and DHA, squid oils, and krill oil. Dietary supplementation with omega−3 fatty acids does not appear to affect the risk of death, cancer or heart disease. Furthermore, fish oil supplement studies have failed to support claims of preventing heart attacks or strokes or any vascular disease outcomes.
Omega−3 fatty acids are important for normal metabolism. Mammals are unable to synthesize omega−3 fatty acids, but can obtain the shorter-chain omega−3 fatty acid ALA (18 carbons and 3 double bonds) through diet and use it to form the more important long-chain omega−3 fatty acids, EPA (20 carbons and 5 double bonds) and then from EPA, the most crucial, DHA (22 carbons and 6 double bonds). The ability to make the longer-chain omega−3 fatty acids from ALA may be impaired in aging. In foods exposed to air, unsaturated fatty acids are vulnerable to oxidation and rancidity.
The evidence linking the consumption of marine omega−3 fats to a lower risk of cancer is poor. With the possible exception of breast cancer, there is insufficient evidence that supplementation with omega−3 fatty acids has an effect on different cancers. The effect of consumption on prostate cancer is not conclusive. There is a decreased risk with higher blood levels of DPA, but an increased risk of more aggressive prostate cancer was shown with higher blood levels of combined EPA and DHA. In people with advanced cancer and cachexia, omega−3 fatty acids supplements may be of benefit, improving appetite, weight, and quality of life.
Evidence in the population generally does not support a beneficial role for omega−3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death) or stroke. A 2018 meta-analysis found no support that daily intake of one gram of omega-3 fatty acid in individuals with a history of coronary heart disease prevents fatal coronary heart disease, nonfatal myocardial infarction or any other vascular event. However, omega−3 fatty acid supplementation greater than one gram daily for at least a year may be protective against cardiac death, sudden death, and myocardial infarction in people who have a history of cardiovascular disease. No protective effect against the development of stroke or all-cause mortality was seen in this population. Eating a diet high in fish that contain long chain omega−3 fatty acids does appear to decrease the risk of stroke. Fish oil supplementation has not been shown to benefit revascularization or abnormal heart rhythms and has no effect on heart failure hospital admission rates. Furthermore, fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.
Evidence suggests that omega−3 fatty acids modestly lower blood pressure (systolic and diastolic) in people with hypertension and in people with normal blood pressure. Some evidence suggests that people with certain circulatory problems, such as varicose veins, may benefit from the consumption of EPA and DHA, which may stimulate blood circulation and increase the breakdown of fibrin, a protein involved in blood clotting and scar formation. Omega−3 fatty acids reduce blood triglyceride levels but do not significantly change the level of LDL cholesterol or HDL cholesterol in the blood. The American Heart Association position (2011) is that borderline elevated triglycerides, defined as 150–199 mg/dL, can be lowered by 0.5-1.0 grams of EPA and DHA per day; high triglycerides 200–499 mg/dL benefit from 1-2 g/day; and >500 mg/dL be treated under a physician's supervision with 2-4 g/day using a prescription product.
ALA does not confer the cardiovascular health benefits of EPA and DHAs.
The effect of omega−3 polyunsaturated fatty acids on stroke is unclear, with a possible benefit in women.
There is some evidence that omega−3 fatty acids are related to mental health, including that they may tentatively be useful as an add-on for the treatment of depression associated with bipolar disorder. Significant benefits due to EPA supplementation were only seen, however, when treating depressive symptoms and not manic symptoms suggesting a link between omega−3 and depressive mood. There is also preliminary evidence that EPA supplementation is helpful in cases of depression. The link between omega−3 and depression has been attributed to the fact that many of the products of the omega−3 synthesis pathway play key roles in regulating inflammation (such as prostaglandin E3) which have been linked to depression. This link to inflammation regulation has been supported in both in vitro and in vivo studies as well as in meta-analysis studies. The exact mechanism in which omega−3 acts upon the inflammatory system is still controversial as it was commonly believed to have anti-inflammatory effects.
There is, however, significant difficulty in interpreting the literature due to participant recall and systematic differences in diets. There is also controversy as to the efficacy of omega−3, with many meta-analysis papers finding heterogeneity among results which can be explained mostly by publication bias. A significant correlation between shorter treatment trials was associated with increased omega−3 efficacy for treating depressed symptoms further implicating bias in publication.
A study in 2013, (Stafford, Jackson, Mayo-Wilson, Morrison, Kendall), stated the following in its conclusion: "Although evidence of benefits for any specific intervention is not conclusive, these findings suggest that it might be possible to delay or prevent transition to psychosis. Further research should be undertaken to establish conclusively the potential for benefit of psychological interventions in the treatment of people at high risk of psychosis."
Epidemiological studies are inconclusive about an effect of omega−3 fatty acids on the mechanisms of Alzheimer's disease. There is preliminary evidence of effect on mild cognitive problems, but none supporting an effect in healthy people or those with dementia.
BRAIN & VISUAL FUNCTION
Brain function and vision rely on dietary intake of DHA to support a broad range of cell membrane properties, particularly in grey matter, which is rich in membranes. A major structural component of the mammalian brain, DHA is the most abundant omega−3 fatty acid in the brain. It is under study as a candidate essential nutrient with roles in neurodevelopment, cognition, and neurodegenerative disorders.
Although omega−3 fatty acids have been known as essential to normal growth and health since the 1930s, awareness of their health benefits has dramatically increased since the 1980s.
On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA omega−3 fatty acids, stating, "supportive but not conclusive research shows that consumption of EPA and DHA [omega−3] fatty acids may reduce the risk of coronary heart disease". This updated and modified their health risk advice letter of 2001 (see below).
The Canadian Food Inspection Agency has recognized the importance of DHA omega−3 and permits the following claim for DHA: "DHA, an omega−3 fatty acid, supports the normal physical development of the brain, eyes and nerves primarily in children under two years of age."
Historically, whole food diets contained sufficient amounts of omega−3, but because omega−3 is readily oxidized, the trend to shelf-stable, processed foods has led to a deficiency in omega−3 in manufactured foods
In the United States, the Institute of Medicine publishes a system of Dietary Reference Intakes, which includes Recommended Dietary Allowances (RDAs) for individual nutrients, and Acceptable Macronutrient Distribution Ranges (AMDRs) for certain groups of nutrients, such as fats. When there is insufficient evidence to determine an RDA, the institute may publish an Adequate Intake (AI) instead, which has a similar meaning, but is less certain. The AI for α-linolenic acid is 1.6 grams/day for men and 1.1 grams/day for women, while the AMDR is 0.6% to 1.2% of total energy. Because the physiological potency of EPA and DHA is much greater than that of ALA, it is not possible to estimate one AMDR for all omega−3 fatty acids. Approximately 10 percent of the AMDR can be consumed as EPA and/or DHA. The Institute of Medicine has not established a RDA or AI for EPA, DHA or the combination, so there is no Daily Value (DVs are derived from RDAs), no labeling of foods or supplements as providing a DV percentage of these fatty acids per serving, and no labeling a food or supplement as an excellent source, or "High
in..." As for safety, there was insufficient evidence as of 2005 to set an upper tolerable limit for omega−3 fatty acids, although the FDA has advised that adults can safely consume up to a total of 3 grams per day of combined DHA and EPA, with no more than 2 g from dietary supplements.
The American Heart Association (AHA) has made recommendations for EPA and DHA due to their cardiovascular benefits: individuals with no history of coronary heart disease or myocardial infarction should consume oily fish two times per week; and "Treatment is reasonable" for those having been diagnosed with coronary heart disease. For the latter the AHA does not recommend a specific amount of EPA + DHA, although it notes that most trials were at or close to 1000 mg/day. The benefit appears to be on the order of a 9% decrease in relative
risk. The European Food Safety Authority (EFSA) approved a claim "EPA and DHA contributes to the normal function of the heart" for products that contain at least 250 mg EPA + DHA. The report did not address the issue of people with pre-existing heart disease. The World Health Organization recommends regular fish consumption (1-2 servings per week, equivalent to 200 to 500 mg/day EPA + DHA) as protective against coronary heart disease and ischaemic stroke.
The most widely available dietary source of EPA and DHA is oily fish, such as salmon, herring, mackerel, anchovies, menhaden, and sardines. Oils from these fish have a profile of around seven times as much omega−3 as omega−6. Other oily fish, such as tuna, also contain n-3 in somewhat lesser amounts. Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxins, which are known to accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health in the Journal of the American Medical Association (2006) reported that the benefits of fish intake generally far outweigh the potential risks. Although fish are a dietary source of omega−3 fatty acids, fish do not synthesize them; they obtain them from the algae (microalgae in particular) or plankton in their diets. In the case of farmed fish, omega-3 fatty acids is provided by fish oil; In 2009, 81% of the global fish oil production is used by aquaculture.
Marine and freshwater fish oil vary in content of arachidonic acid, EPA and DHA. They also differ in their effects on organ lipids.
Not all forms of fish oil may be equally digestible. Of four studies that compare bioavailability of the glyceryl ester form of fish oil vs. the ethyl ester form, two have concluded the natural glyceryl ester form is better, and the other two studies did not find a significant difference. No studies have shown the ethyl ester form to be superior, although it is cheaper to manufacture.
Krill oil is a source of omega−3 fatty acids. The effect of krill oil, at a lower dose of EPA + DHA (62.8%), was demonstrated to be similar to that of fish oil on blood lipid levels and markers of inflammation in healthy humans. While not an endangered species, krill are a mainstay of the diets of many ocean-based species including whales, causing environmental and scientific concerns about their sustainability.
Omega−3 fatty acids are formed in the chloroplasts of green leaves and algae. While seaweeds and algae are the source of omega−3 fatty acids present in fish, grass is the source of omega−3 fatty acids present in grass fed animals. When cattle are taken off omega−3 fatty acid rich grass and shipped to a feedlot to be fattened on omega−3 fatty acid deficient grain, they begin losing their store of this beneficial fat. Each day that an animal spends in the feedlot, the amount of omega−3 fatty acids in its meat is diminished.
The omega−6:omega−3 ratio of grass-fed beef is about 2:1, making it a more useful source of omega−3 than grain-fed beef, which usually has a ratio of 4:1.
In a 2009 joint study by the USDA and researchers at Clemson University in South Carolina, grass-fed beef was compared with grain-finished beef. The researchers found that grass-finished beef is higher in moisture content, 42.5% lower total lipid content, 54% lower in total fatty acids, 54% higher in beta-carotene, 288% higher in vitamin E (alpha-tocopherol), higher in the B-vitamins thiamin and riboflavin, higher in the minerals calcium, magnesium, and potassium, 193% higher in total omega−3s, 117% higher in CLA (cis-9, trans-11 octadecenoic acid, a cojugated linoleic acid, which is a potential cancer fighter), 90% higher in vaccenic acid (which can be transformed into CLA), lower in the saturated fats linked with heart disease, and has a healthier ratio of omega−6 to omega−3 fatty acids (1.65 vs 4.84). Protein and cholesterol content were equal.
In most countries, commercially available lamb is typically grass-fed, and thus higher in omega−3 than other grain-fed or grain-finished meat sources. In the United States,
lamb is often finished (i.e., fattened before slaughter) with grain, resulting in lower omega−3.
The omega−3 content of chicken meat may be enhanced by increasing the animals' dietary intake of grains high in omega−3, such as flax, chia, and canola.
Kangaroo meat is also a source of omega−3, with fillet and steak containing 74 mg per 100 g of raw meat.
HEART ASSOCIATION (AHA)
Since the first AHA Science Advisory “Fish Consumption, Fish Oil, Lipids, and Coronary Heart Disease,”1 important new findings, including evidence from randomized controlled trials (RCTs), have been reported about the beneficial effects of omega-3 (or n-3) fatty acids on cardiovascular disease (CVD) in patients with preexisting CVD as well as in healthy
individuals. New information about how omega-3 fatty acids affect cardiac function (including antiarrhythmic effects), hemodynamics (cardiac mechanics), and arterial endothelial function have helped clarify potential mechanisms of action. The present Statement will address distinctions between plant-derived (α-linolenic acid, C18:3n-3) and marine-derived (eicosapentaenoic acid, C20:5n-3 [EPA] and docosahexaenoic acid, C22:6n-3 [DHA]) omega-3 fatty acids. (Unless otherwise noted, the term omega-3 fatty acids will refer to the latter.) Evidence from epidemiological studies and RCTs will be reviewed, and recommendations reflecting the current state of knowledge will be made with regard to both fish consumption and omega-3 fatty acid (plant- and marine-derived) supplementation. This will be done in the context of recent guidance issued by the US Environmental Protection Agency and the Food and Drug Administration (FDA) about the presence of environmental contaminants in certain species of fish.
and OBSERVATIONAL STUDIES
Coronary Heart Disease
As reviewed by Stone,1 three prospective epidemiological studies within populations reported that men who ate at least some fish weekly had a lower coronary heart disease (CHD) mortality rate than that of men who ate none.3–6 More recent evidence that fish consumption favorably affects CHD mortality, especially nonsudden death from myocardial infarction (MI), has been reported in a 30-year follow-up of the Chicago Western Electric
Study. Men who consumed 35 g or more of fish daily compared with those who consumed none had a relative risk of death from CHD of 0.62 and a relative risk of nonsudden death from MI of 0.33. In an ecological study conducted by Zhang et
al, fish consumption was associated with a reduced risk from all-cause, ischemic heart disease and stroke mortality across 36 countries. In addition, in a study of Japanese living in Japan or Brazil, Mizushima et al9 reported a dose-response relationship between the frequency of weekly fish intake and reduced CVD risk factors (eg, obesity, hypertension, glycohemoglobin, ST-T segment change on the ECG). Until recently, little information was available about the effects of fish and omega-3 fatty acids and risk of CHD in women. A recent study conducted with women in the Nurses’ Health Study10 reported an inverse association between fish intake and omega-3 fatty acids and CHD death. Compared with women who rarely ate fish (less than once per month), the risk for CHD death was 21%, 29%, 31%, and 34% lower for fish consumption 1 to 3 times per month, once per week, 2 to 4 times per week, and >5 times per week, respectively (P for trend=0.001). Comparing the extreme quintiles of fish intake, the reduction in risk for CHD deaths seemed to be stronger for CHD death than for nonfatal MI (RR 0.55 versus 0.73).
Some studies have not reported a beneficial association of fish consumption and CHD mortality. In the Health Professionals’ Follow-up
Study, no significant association was observed between fish intake (and omega-3 fatty acids) and risk of any CHD (ie, fatal coronary disease including sudden death, nonfatal MI, coronary artery bypass grafting, or angioplasty). Likewise, the US Physicians’ Health Study did not show an association between fish consumption (or omega-3 fatty acid intake) and reduced risk of total MI, nonsudden cardiac death, or total cardiovascular
mortality. In contrast, however, fish consumption was related to a reduced risk of total mortality. The lack of an association between fish intake and CHD incidence and mortality also was reported from an analysis of the Seven Countries data and the EURAMIC (European Multicenter Case-Control Study on Antioxidants, Myocardial Infarction and Breast Cancer)
Study. In the Seven Countries Study, although an inverse association between fish consumption and 25-year mortality from CHD across several populations was
observed, when the confounding effects of saturated fatty acids, flavonoids, and smoking were considered, the association was not significant. In the EURAMIC Study, a large international case-control study, no evidence of a protective effect of adipose tissue DHA (a measure of long-term fish consumption) on the risk of developing MI was
Some investigators have speculated that the conflicting data from the epidemiological studies reflect differences in definitions of sudden death and the residual confounding of reference groups that had a less healthy lifestyle, 15 variability in the end points studied, experimental design or how fish intake was estimated, different study populations,16 and the possible confounding effect of an increase in hemorrhagic stroke. Albert et
al proposed that their lack of an association may have been due to the small fraction of their study population (3.1%) reporting little to no fish consumption. Only studies including sizable non–fish-eating populations have reported an inverse association between fish consumption and coronary mortality. In the EURAMIC Study, only survivors of MI were evaluated, and it is conceivable that individuals who did not survive ate less fish. Another explanation, based on a rigorous analysis of 11 prospective cohort studies, is that the protective effect of fish consumption relates to the CHD risk status of the population studied17; this analysis concluded that fish consumption reduced CHD mortality (RR=0.4 to 0.6) in high-risk but not low-risk populations. Another consideration relates to the type of fish consumed (ie, fatty versus lean fish). Oomen et
al reported a lower CHD mortality (RR=0.66) in populations that consumed fatty fish but not lean fish.
Finally, another explanation for the discordant results of epidemiological studies pertains to the hypothesized adverse effects of methylmercury, an environmental contaminant found in certain fish that may diminish the health benefits of omega-3 fatty
acids. Recent studies have produced conflicting results with regard to the effects of methylmercury on CHD
risk. Thus, the extent to which methylmercury in fish may mask the beneficial effects of omega-3 fatty acids requires further study.
Fish consumption has been shown to be related to reduced sudden cardiac death. In a population-based, nested, case-control study, a strong negative relationship was reported between fish intake and risk for sudden death (ie, 5.5 g of omega-3 fatty acids per month, equivalent to two fatty fish meals per week, was associated with a 50% reduced risk of primary cardiac
arrest). In the US Physicians’ Health Study, men who consumed fish at least once weekly had a relative risk of sudden death of 0.48 (P=0.04) versus men who consumed fish less than once per
month. A recent report from the Physicians’ Health Study reported an inverse relationship between blood levels of long-chain omega-3 fatty acids and risk of sudden death in men without a history of CVD. The relative risk of sudden death was significantly lower among men with levels in the third quartile (RR=0.28) and the fourth quartile (RR=0.19) compared with men whose blood levels were in the first quartile.
Further evidence for a protective effect of omega-3 fatty acids comes from two recent studies by Landmark et
al, who reported that chronic intake of fish or fish oil was associated with a reduction in infarct size as estimated by the frequency of Q-wave infarcts and by peak creatine kinase and lactate dehydrogenase activities after MI. In contrast to all the studies demonstrating a beneficial association, the Alpha- Tocopherol, Beta-Carotene Cancer Prevention Study found that estimated omega-3 fatty acid intake from fish was associated with a trend toward increased relative risk of coronary death after adjustment for trans, saturated, and cis-monounsaturated fatty
A growing body of evidence from recent epidemiological studies indicates that α-linolenic acid is associated with a lower risk of MI and fatal ischemic heart disease in women and in men. In the EURAMIC Study, Guallar et
al compared the highest quintile of adipose tissue α-linolenic acid to the lowest and found a relative risk for MI of 0.42 (P for trend=0.02). This became nonsignificant after adjusting for classic risk factors (primarily smoking). Using a food-frequency questionnaire from a 10-year follow-up of the Nurses’ Health Study, and after controlling for standard coronary risk factors, Hu et
al reported a dose-response relationship between α-linolenic acid intake and relative risk of fatal ischemic heart disease, which was reduced by 45% in the highest quintile (P for trend=0.01).
Similar findings were reported with the same methodology in the all-male Health Professionals’ Study, in which a 1% increase in α-linolenic acid intake was associated with a 0.41 relative risk for acute MI (P for
trend=0.01). Lowest-quintile intakes of α-linolenic acid in these latter two trials were 0.7 to 0.8 g/d, and highest quintile intakes, 1.4 to 1.5 g/d. In the National Heart, Lung, and Blood Institute Family Heart Study, a cross-sectional study with 4584 participants, α-linolenic acid was inversely related to coronary artery
disease. The prevalence odds ratio of coronary artery disease was reduced ≈40% for men in the top three quintiles of α-linolenic acid intake and ≈50% to 70% for women. In contrast, in the Zutphen Elderly Study, a prospective epidemiological study with 667 men, ages 64 to 84 years, there was no beneficial effect of α-linolenic acid intake on risk of 10-year coronary artery disease incidence.30 In the latter study, however, these negative results have been explained by the association between α-linolenic acid and trans-fatty acid
intake, as well as by limitations in the collection of the dietary
data. Despite this latter study, a growing epidemiological database demonstrates a protective effect of α-linolenic acid on coronary disease. Nonetheless, intervention studies are needed to establish a causal relationship between α-linolenic acid intake and coronary disease.
Compared with the literature describing the effects of omega-3 fatty acids on CHD, relatively little information about the association of omega-3 fatty acids and cerebral infarctions (stroke) is available. Several epidemiological studies have examined the relationship between fish intake and stroke incidence. In the Zutphen Study, the unadjusted hazard ratio of men who consumed an average of 20 g/d of fish was 0.49 (P<0.05) compared with those who consumed less.32 Likewise, in the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study, white females who consumed fish more than once per week had an age-adjusted stroke incidence that was only half that of women who reported not consuming
fish. A similar protective effect was seen in both black women and men but not in white men. A trend (P=0.06) toward reduced risk for stroke with increasing reported fish consumption was also reported in the Nurses’ Health Study.34 In contrast, both the Chicago Western Electric Study35 and the Physicians’ Health Study36 failed to find any relationship between reported fish intake and reduced stroke risk.
According to the serum fatty acid profiles of subjects in the Multiple Risk Factor Intervention Trial, α-linolenic acid was negatively associated with stroke
incidence. In both the Lyon Diet Heart Study (testing a Mediterranean-style diet enriched with α-linolenic acid) and the GISSI-Prevention
Study (testing the effects of 850 mg of supplemental omega-3 fatty acids), there was no significant effect on the incidence of stroke.
The evidence to date is primarily for total stroke risk, and associations could differ if the data were analyzed for type-specific stroke incidence. For example, evidence exists for an inverse relationship between small intakes of fish (1 portion per week) and ischemic
stroke and for a possible increased risk for hemorrhagic stroke with “Eskimo” intakes of omega-3 fatty
acids. Thus, as Zhang et al have noted, linking fish consumption with total stroke risk is likely to underestimate the strength of the real associations between fish consumption and type-specific stroke risk.
Randomized Controlled Trials
At the time of the first Advisory, the only RCT of omega-3 fatty acids in secondary prevention of CHD was the Diet And Reinfarction Trial (DART), which reported a 29% reduction in all-cause mortality over a 2-year period in male MI survivors advised to increase their intake of oily fish (200 to 400 g of fatty fish per week, which provided an additional 500 to 800 mg/d of omega-3 fatty
acids). The greatest benefit was seen in fatal MIs, and this observation led to the hypothesis that omega-3 fatty acids might protect the myocardium against the adverse sequela of acute ischemic stress. A post hoc analysis of patients receiving fish oil capsules (900 mg/d of EPA+DHA) in DART suggested that the protective effect was attributable to omega-3 fatty
The first of three recent RCTs designed to detect the effects of supplemental EPA and DHA on clinical events was reported by Singh et
al. Patients admitted to the hospital with suspected acute MIs were randomized to either fish oil capsules (containing 1.8 g/d of EPA+DHA), mustard oil (20 g/d providing 2.9 g α-linolenic acid), or placebo. After one year, total cardiac events were 25% and 28% in the fish oil and mustard oil groups, respectively, versus 35% in the placebo group (P<0.01). As in the DART, nonfatal MIs were significantly lower in the fish oil and mustard oil groups.
The largest prospective RCT to test the efficacy of omega-3 fatty acids for secondary prevention of CHD is the GISSI-Prevention
Study. In this study, 11,324 patients with preexisting CHD (who were receiving conventional cardiac pharmacotherapy) were randomized to either 300 mg of vitamin E, 850 mg of omega-3 fatty acid ethyl esters (as EPA and DHA), both, or neither. After 3.5 years of follow-up, the group given the omega-3 fatty acids alone experienced a 15% reduction in the primary end point of death, nonfatal MI, and nonfatal stroke (P<0.02). There was a 20% reduction in all-cause mortality (P=0.01) and a 45% reduction in sudden death (P<0.001) compared with the control group; vitamin E provided no additional benefit. Triglycerides decreased by 4% and LDL cholesterol levels increased by 2.5% after six months in the omega-3 fatty acid treatment groups compared with controls. This trial, although very large and carried out in a relatively “usual-care” setting, was not placebo controlled, and dropout rates were high (>25%). A follow-up study44 assessed the time-course of the benefit of omega-3 fatty acids on mortality in subjects in the GISSI Study and found that survival curves diverged early after randomization. Total mortality was significantly lowered after 3 months of treatment (RR=0.59), and by 4 months, risk of sudden death was reduced (RR=0.47).
In contrast to the growing body of evidence supporting a protective effect of omega-3 fatty acids in secondary prevention, a recent study reported no effect of 3.5 g/d of DHA+EPA versus corn oil on cardiac events in post-MI patients (n=300) after 1.5 years of
intervention. The authors speculated that the lack of an omega-3 fatty acid effect may have been due to the high habitual fish intake in western
Norway, which could have afforded maximal protection beyond which no additional effects would be expected. Thus, further research is needed to confirm and further define the role of omega-3 fatty acid supplements for secondary prevention of coronary disease.
The first study to explore the effects of omega-3 fatty acids on angiographic progression rates provided 59 patients either 6 g/d of omega-3 fatty acids or olive oil for 2 years.46 No benefit was observed. More recently, a larger trial using lower and more practical intakes of omega-3 fatty acids has been
reported. Patients presenting for coronary angiography (n=223) were randomized to either placebo or omega-3 fatty acids (3 g/d for 3 months followed by 1.5 g/d for 21 months). The latter group exhibited significantly (P=0.04) less progression, more regression, and a trend toward fewer clinical events (7 versus 2, P=0.1). Finally, Eritsland et al48 reported that in 610 patients undergoing coronary artery bypass grafting, the provision of 3.4 g of omega-3 fatty acid ethyl esters lowered vein graft occlusion rates from 33% (control) to 27% (P=0.03).
Several randomized trials of fish oil were conducted over the past 10 years to test the hypothesis that omega-3 fatty acids could prevent restenosis after percutaneous transluminal coronary angioplasty. Although a meta-analysis of seven early trials concluded that supplementation was
beneficial, more recent trials (with large study populations given 5 to 7 g/d of omega-3 fatty acids) have not supported this
conclusion. Most investigators have concluded that further trials are not warranted.
The question of the efficacy of α-linolenic acid in CHD prevention has been examined in four trials. The Indian Experiment of Infarct
Survival discussed above reported a significant decrease in total cardiac events in the group assigned to mustard seed oil. The Lyon Heart Trial was a secondary prevention trial designed to test whether a Mediterranean-type diet (including increased amounts of α-linolenic acid) would reduce reoccurrence rates of cardiac events compared with a prudent Western
diet. Marked reductions were seen in cardiac death and nonfatal MI, major secondary end points, and minor events. The difference in intakes of α-linolenic acid between groups was 0.5 versus 1.5 g/d. It is impossible, however, to ascribe the benefit unambiguously to α-linolenic acid because many other dietary variables were present: Saturated fat and cholesterol decreased and monounsaturated fat increased, as did the consumption of fruits and vegetables.
Although the Indian Experiment of Infarct
Survival and the Lyon Heart Trial provide clinical trial evidence in support of a beneficial effect of α-linolenic acid, the Norwegian Vegetable Oil
Experiment and the Mediterranean Alpha-Linolenic Enriched Groningen Dietary Intervention (MARGARIN)
Study do not. The Norwegian Vegetable Oil Experiment was a double-blind RCT in which >13 000 men ages 50 to 59 with no history of MI were randomized to consume 5.5 g/d of α-linolenic acid (from 10 mL of linseed oil) or 10 mL of sunflower seed oil for one year. There were 27 cases of new CHD or sudden death in each group, and 40 versus 43 deaths from any cause in the control versus the linseed oil groups. In the MARGARIN Study, free-living subjects (n=124 men and 158 women) with multiple CVD risk factors were provided with margarines high in either α-linolenic acid or linoleic acid and followed up for 2
years. According to effects on CVD risk factors, the 10-year estimated ischemic heart disease risk decreased similarly in both groups (2.1% and 2.5%, respectively). Of note, however, was a trend toward fewer CVD events in the α-linolenic acid group (1.8% versus 5.7%, P=0.20). It is important that additional studies be conducted to clarify the role of α-linolenic acid in reducing CHD risk.
In aggregate, available RCTs show a beneficial effect of dietary and supplemental omega-3 fatty acids, including both EPA+DHA and α-linolenic acid, on CHD. This has been summarized in a recent meta-analysis of 11 RCTs with 7951 patients in the intervention
groups. In this meta-analysis, the risk ratio of nonfatal MI was 0.8, for fatal MI it was 0.7, and for sudden
death (in 5 trials) it was 0.7.
- Nice fish. A large Alaskan pollock caught by the prolific
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fatty acids such as Omega 3.
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