The cardioprotective benefits of marine-derived omega-3 fatty acids (n-3 FAs) were first identified by Danish researchers in the 1970s who observed a lower incidence of death from coronary artery disease in Greenland Eskimos compared with Danish persons living in Greenland. The reduced incident rate of coronary artery disease was thought to be caused by differences in the diets of these two populations. The traditional Eskimo diet was composed predominantly of foods such as seal, whale, and fish, which contained high levels of marine-derived n-3 FAs, whereas the Danish diet was high in saturated fat from high-fat meats and full-fat dairy products. This natural experiment demonstrated the cardiovascular (CV) benefit of eating fish, and research has since linked these health benefits from fish to marine-derived n-3 FAs. This discovery had a provocative effect on CV research because it showed that some fats can be healthy for your heart.
In recent years, marine-derived n-3 FAs have become the panacea for many chronic diseases, yet there is still confusion surrounding their purported health benefits. Because of the increased media attention, you, as a health professional, may be asked to give advice about different types of FAs, in particular, marine-derived n-3 FAs and how they should be incorporated in the diet for maximum CV benefit. In this article, we will discuss
- the different types of FAs and what constitutes a n-3 FA
- how to incorporate n-3 FAs into your diet
- biomarkers of marine-derived n-3 FA levels
- how marine-derived n-3 FAs prevent chronic diseases
- potential exercise and marine-derived n-3 FA interactions
TYPES OF FAs - WHERE DO MARINE-DERIVED N-3 FAs FIT IN?
Fatty acids are long chains of carbon and hydrogen atoms with a carboxylic acid group at one end. They are sources of energy and provide structural support in cell membranes. Fatty acids are classified by the number of double bonds or degree of saturation (by hydrogen): saturated, monounsaturated, polyunsaturated. Saturated FAs are devoid of double bonds and are solid at room temperature. In comparison, monounsaturated FAs have one double bond, and polyunsaturated FAs have multiple double bonds. Monounsaturated FAs and polyunsaturated FAs also are referred to as unsaturated FAs and are liquid at room temperature.
Polyunsaturated FAs are further classified on the basis of the position of their first double bond from the omega (n) end of the carbon chain, hence, the name omega-3 FAs. The n-3 FAs and n-6 FAs have their first double bonds 3 and 6 carbons from the omega end, respectively. The precursor FAs to these two families are α-linolenic acid ([ALA] 18:3) and linoleic acid ([LA] 18:6). These FAs also are known as essential FAs because they cannot be synthesized by humans and must be consumed in the diet. Both ALA and LA undergo a series of elongation and desaturation steps in the liver to produce FAs that contain more carbons and double bonds. However, in humans, the conversion of ALA to the longer chain FAs, eicosapentaenoic acid ([EPA] 20:5) and docosahexaenoic acid ([DHA] 22:6), is relatively small. For this reason, EPA and DHA should be obtained directly from the diet. Figure 1 illustrates this metabolic pathway and associated direct dietary sources of specific FAs. In this article, the term marine-derived n-3 FA refers only to EPA and DHA, whereas the term n-3 FA refers to all FAs in that family, including ALA.
HOW DO I GET OMEGA-3 FAs INTO MY DIET?
To avoid nutritional deficiency, the Accepted Macronutrient Distribution Range for n-3 FAs is set at 0.6% to 1.3% of total energy intake, of which 10% can come from the marine-derived n-3 FAs (EPA and DHA) (7). Recommendations for optimal intake of marine-derived n-3 FAs for the prevention of CV disease (CVD) have been made by the American Heart Association and health organizations worldwide. For prevention of CVD in healthy persons, adults should eat two servings per week of oily fish, which translates to 400 to 500 mg of EPA + DHA per day (see Recommended Resources). The recommended intake for individuals with coronary heart disease is 1 g/day of EPA + DHA and 2 to 4 g/day for individuals who need to lower triglycerides (>500 mg/dL).
Oily fish, such as salmon, tuna, and anchovies, are the most cost-effective sources of EPA and DHA. Plants (including nuts and seeds, e.g., walnuts and flax), vegetable oils, and margarines are good sources of short-chain n-3 FAs, such as ALA. However, for most Americans, fish and flax are not a normal part of the everyday diet. For this reason, a number of food manufacturers have begun to incorporate ALA, DHA, and EPA into many different foods. These n-3 FA-enriched foods are created by either adding n-3 FA powders or flax seed to the product or by putting n-3 FAs in the feed of animals. Eggs, juices, yogurts, and tortillas are just some of the food choices that are available with added n-3 FAs. However, these n-3-enriched products often contain ALA or provide considerably less marine-derived n-3 FAs than fish, which means that they are no substitute for this primary source (Table).
Although the U.S. Food and Drug Administration has yet to make an official recommendation for marine-derived n-3 FAs, it has deemed fish oil capsules as "generally recognized as safe." They have set an upper limit for intake of marine-derived n-3 FAs of 3 g/day, with no more than 2 g obtained directly from a supplement, unless taking prescription doses of marine-derived n-3 FAs (see Recommended Resources).
The fish oil in supplements comes either from small fish that are too bony to be consumed or from inedible tissues (i.e., nonfillet). Fish oil capsules range in their relative concentration of EPA and DHA (20%-85% of total FAs; 200-850 mg per 1,000-mg capsule). This means that taking a 1,000-mg capsule of fish oil will provide anywhere from 200 to 850 mg of EPA + DHA. In general, the less expensive capsules have lower EPA + DHA concentrations (200-650 mg), whereas more expensive, pharmaceutical-grade capsules are more concentrated (650-850 mg). It is important to read the label to ensure that the capsule is composed predominantly of EPA and DHA, and that the advertised active ingredients are not other FAs. A number of companies also are working to produce supplements that contain DHA and EPA from algae or bacteria, although these are yet to be marketed to the public.
There are a few known risks involved with taking marine-derived n-3 FA supplements. Gastrointestinal discomfort and a fishy taste can occur after taking multiple capsules, although this can be minimized by taking the capsules with food at night. In addition, taking pharmaceutical doses of marine-derived n-3 FAs may result in longer bleeding times, however, this claim has not been justified in clinical trials.
Environmental contaminants, such as methylmercury, dioxins, and polychlorinated biphenyls (PCB), are produced by both natural and human sources. Larger fish species, such as shark, swordfish, king mackerel, and tile fish (golden snapper), generally have higher concentrations because they consume smaller fish containing these contaminants, and therefore, the concentration accumulates during their longer life spans ((8), Figure 2). This has particular implications for pregnant women who are advised to avoid shark, tile fish, king mackerel, and swordfish because of their high mercury content (13). However, to promote the healthy development of their baby, they should consume up to 12 ounces per week (two average meals) of a variety of fish and shellfish lower in mercury, including salmon, trout, light tuna, shrimp, and scallops. Varying amounts of environmental toxins, such as PCB and dioxins, can be present in supplements, although these are usually present only in trace amounts. All supplements are free of mercury.
With the growing concern over the sustainability of the world's fisheries and the safety of eating fish with environmental contaminants, there is reason to weigh the benefits of eating fish. The decision to eat wild or farm-raised fish has many ecological and economical implications beyond the scope of this article. It is therefore important to emphasize that persons select fish that is high in marine-derived n-3 FAs and low in mercury and environmental toxins (Figure 2).
THE OMEGA-3 INDEX: A BIOMARKER OF MARINE-DERIVED N-3 FAs
Changes in dietary intake of EPA and DHA are reflected in the FA profile of several tissues, including red blood cells. Red blood cells are therefore a useful marker for assessing FA status, and there is good evidence that their FA composition reflects FA levels in other tissues, particularly cardiac tissue. This relationship has provided the basis for the development of the Omega-3 Index, which correlates red blood cell EPA + DHA level with risk for CV mortality (6). The Omega-3 Index suggests that the greatest protection against CV mortality is with EPA + DHA levels greater than 8% of total FAs. Knowing the Omega-3 Index can help health professionals better diagnose whether their clients need to increase their fish intake or if they require additional supplementation with fish oil.
CHRONIC DISEASE PREVENTION
The strongest evidence for the cardioprotective effectiveness of marine-derived n-3 FAs is in the prevention of sudden cardiac death. Sudden cardiac death, as opposed to myocardial infarction, can occur in individuals with or without a documented history of CVD. It is unexpected, usually caused by an arrhythmia of the heart, and death occurs within minutes of the onset of symptoms. In the United States, sudden cardiac death accounts for nearly 310,000 deaths each year and is therefore responsible for almost half of all coronary heart disease-related deaths (see Recommended Resources). Marine-derived n-3 FAs primarily lower the risk for sudden cardiac death by preventing arrhythmias.
One of the most conclusive trials to date, the GISSI Prevenzione Study, evaluated the effects of fish oil supplementation (850 mg EPA + DHA per day) in more than 11,000 myocardial infarction patients with a mean follow-up of 3.5 years (5). Compared with patients receiving placebo, the EPA + DHA-supplemented group had a 45% reduction in sudden cardiac death and a 20% reduction in all-cause mortality. In the U.S. Physicians' Health Study, modest fish consumption (once per week) was associated with a 52% lower risk of sudden cardiac death compared with men who ate fish less than once a month (1).
Metabolic syndrome refers to a clustering of CV risk factors that greatly increases the risk for developing Type II diabetes and CVD. According to the National Cholesterol Education Panel-Adult Treatment Panel III guidelines, individuals meet the criteria for metabolic syndrome if they present with three or more of the following risk factors:
- abdominal obesity: waist circumference greater than or equal to 102 cm (40 inches) in men and greater than or equal to 88 cm (35 inches) in women
- elevated blood glucose: greater than or equal to 110 mg/dL
- hypertension: greater than or equal to 130/85 mmHg
- elevated triglycerides: greater than or equal to 150 mg/dL
- low high-density lipoprotein cholesterol: less than or equal to 40 mg/dL in men and less than or equal to 50 mg/dL in women
Marine-derived n-3 FAs have direct affects on triglycerides and blood pressure and therefore may improve metabolic syndrome status. High-density lipoprotein cholesterol also may be improved by marine-derived n-3 FAs; however, the body of evidence is inconclusive. Metabolic syndrome also is associated with other emerging risk factors for CVD, such as endothelial dysfunction, thrombosis, and inflammation, and there is increasing evidence that these can be improved by increased consumption of marine-derived n-3 FAs (Figure 3).
Inflammatory bowel disease, lupus, and rheumatoid arthritis are often treated with marine-derived n-3 FAs. The evidence base for these inflammatory diseases is not as strong as that for CVD; however, there is a plausible biological rationale for how marine-derived n-3 FAs can mediate inflammation. Specifically, n-3 and n-6 FAs are precursors for eicosanoids, a group of physiologically active signaling molecules. These molecules have numerous biological effects, including platelet aggregation, blood vessel constriction, cell adhesion, and production of inflammatory mediators. Eicosanoids derived from the n-6 FA tend to be more inflammatory, aggregatory, and promote blood vessel constriction. Conversely, those from n-3 precursors are less inflammatory, less aggregatory, and may promote the resolution of an inflammatory event. Therefore, increased consumption of marine-derived n-3 FAs from fish or fish oil should produce less inflammation. This also may provide a mechanism for benefit in persons with CVD or metabolic syndrome, for which inflammation has been identified as a contributing factor in their development.
MECHANISMS OF ACTION
The biological mechanisms that explain the observed cardioprotective benefits of marine-derived n-3 FAs are still being explored. Several of these are summarized later, and their combined effects on CVD are displayed in Figure 3:
- Antiarrhythmic effects: marine-derived n-3 FAs are incorporated into the membranes of cardiac cells where they modify ion channel function, thereby altering the cardiac action potential and reducing vulnerability to ventricular arrhythmia (11).
- Triglyceride lowering: marine-derived n-3 FAs may increase the expression of genes that code for enzymes that promote lipolysis (degradation of triglycerides) and β-oxidation (metabolism of FAs). In addition, marine-derived n-3 FAs may directly inhibit triglyceride production in the liver.
- ○ 2 to 4 g/day can lower triglyceridess by 10% to 33% in persons with elevated levels at baseline (2).
- Decrease systolic and diastolic blood pressure: marine-derived n-3 FAs increase the production of vasodilatory eicosanoids, alter blood vessel reactivity, and improve autonomic function.
- ○ Lower doses (∼600 mg/day) can reduce blood pressure by 2 mmHg (2).
- Decrease platelet function/aggregation: EPA increases the production of a less potent platelet agonist, resulting in less blood clotting.
- ○ Lower doses (∼500 mg/day) can decrease platelet activation (4).
- Decrease inflammation: prevents metabolism of inflammatory mediators (interleukin-6 and tumor necrosis factor-α) and produces lipid mediators (resolvins) that resolve inflammation.
- Increase FA metabolism: marine-derived n-3 FAs act as ligands (molecules that bind to specific receptors) for several nuclear receptors that induce the transcription of genes encoding proteins for thermogenesis and fat metabolism.
- Improve vascular function: marine-derived n-3 FAs maintain vascular health by promoting nitric oxide production (a potent blood vessel dilator), inhibiting adhesion molecules and smooth muscle cell growth and proliferation, and increasing the production of vasodilatory eicosanoids.
POTENTIAL EXERCISE AND N-3 FA INTERACTIONS
Regular aerobic exercise and marine-derived n-3 FAs exert similar independent benefits on chronic disease risk factors (12). They improve heart rate variability; increase insulin sensitivity, blood flow, and artery diameter (via nitric oxide and eicosanoid production); favorably alter the lipid profile (reduce triglycerides and increase high-density lipoprotein cholesterol); and reduce fat mass, blood pressure, and resting heart rate. However, the potential for marine-derived n-3 FAs to influence exercise-associated performance or capacity is an emerging area of research. Several studies have demonstrated that supplementation with marine-derived n-3 FAs (1.9-3.2 g/day) for 5 to 12 weeks lowers heart rate during submaximal exercise in both trained and untrained individuals (3,9,10). This suggests that marine-derived n-3 FAs may improve cardiac efficiency and reduce myocardial oxygen demands during submaximal exercise. However, despite such improvements after supplementation, these studies failed to demonstrate an increase in overall performance or time to exhaustion.
Marine-derived n-3 FAs may, however, provide added CV protection in exercise-compromised individuals. O'Keefe et al. (10) reported that daily supplementation (810 mg DHA + EPA) improved 1-minute heart rate recovery after exercise. Heart rate recovery, which is reflective of autonomic or vagal tone, is thought to be representative of CV health. Animal models have shown that an extended postexercise heart rate recovery time predicts susceptibility to ventricular fibrillation.
The marine-derived n-3 FAs, EPA and DHA, are found in highest concentrations in cold-water oily fish, such as salmon, tuna, and anchovies. Eicosapentaenoic acid and DHA also can be metabolized, although in significantly smaller amounts, from the shorter chain n-3 FA, ALA, which is found in oils, seeds, and nuts. In recent years, concern for the sustainability of fisheries and the safety of eating fish with environmental contaminants has led many consumers to question the benefits of consuming fish. However, there is definitive evidence that marine-derived n-3 FAs are effective in the prevention and treatment of many chronic diseases, particularly CVD. These benefits are primarily caused by their effects on numerous CV risk factors, including antiarrhythmic effects, improved blood vessel and autonomic function, triglyceride and blood pressure lowering, and reduced platelet aggregation and inflammation. An emerging area of research is the potential for marine-derived n-3 FAs to influence exercise-associated performance or capacity. This body of research clearly demonstrates the importance of marine-derived n-3 FAs for optimal CV health, and fitness and health professionals should encourage individuals to increase their intake of marine-derived n-3 FAs, particularly from direct dietary sources such as oily fish and fish oil supplements.
CONDENSED VERSION AND BOTTOM LINE
Marine-derived omega-3 fatty acids (n-3 FAs) are recommended for the treatment and prevention of many chronic diseases, including cardiovascular disease and metabolic syndrome. Current clinical uses of marine-derived n-3 FAs include prevention of arrhythmias and triglyceride and blood pressure lowering; however, there are other health benefits associated with high intakes of these FAs. The best dietary sources of marine-derived n-3 FAs are cold-water oily fish, whereas shorter chain n-3 FAs, such as α-linolenic acid, are found in oils, nuts, and seeds. Increasing consumption of marine-derived n-3 FAs, especially from foods of marine origin (including fish and shellfish), will promote optimal CV health.
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