The Use of Omega-3 Fatty Acids for Cardiovascular Disease
By Susan T. Marcolina, MD, FACP. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no financial relationship to this field of study.
The volatility of the investment markets on Wall Street should make us consider our own investment in overall health, especially our cardiovascular health. For women in the United States, the leading cause of death continues to be coronary heart disease (CHD) and the mortality in women has shown no decline for the past 20 years as it has in men.1 In fact, most women who die suddenly of CHD had no previous symptoms but did have a high prevalence of CHD risk factors (see Table 1).2 Another complication is the finding by Khot et al that 20% of all coronary events occur in individuals without any of the established risk factors identified in the Framingham risk score.3 Such statistics require primary care physicians to reallocate and diversify strategies to decrease risk by ensuring that current established guidelines from the American Heart Association4-6 (see Table 2) are implemented and individualized for all female (and male) patients as well as by identifying and treating those women (and men) at risk who may not fit the traditional profiles.
Cardiovascular Disease Risk Prediction for Women
Over the past 10 years, prospective epidemiologic studies such as the Women's Health Study (WHS) have identified chronic inflammatory states, evidenced by elevations in plasma high sensitivity C-reactive protein (hs-CRP) levels, as independent risk factors for cardiovascular disease (CVD) along with the typical risk factors identified in Table 1. The WHS followed more than 15,000 initially healthy women older than age 45 over 10 years for the occurrence of CV events. Of all of the laboratory data compiled over this time, levels of non-HDL cholesterol and total/HDL-C were most predictive of CV events and hs-CRP levels added prognostic information to all lipid fractions. Based on these data, the Reynolds Risk Point Score (RRPS) was created to estimate the risk of myocardial infarction (MI) in women. This score predicted risk of MI as well as the Framingham risk score did for women at high and low risk. However, for women identified as intermediate risk, it proved to be a better tool due to the incorporation of two additional risk factors: 1) having a parent with a myocardial infarction prior to age 60, and 2) having a hs-CRP level greater than 2 mg/L.7
For these intermediate-risk patients, the new scoring re-classified 50% of the women from the intermediate group into either the high- or the low-risk group so they could be appropriately identified for early intervention to decrease the chronic inflammatory state or reassured regarding their low risk for CVD. Subsequently, these new classifications accurately predicted the clinical outcomes of these women over the ensuing 10 years.8 Ridker et al, in the recent JUPITER trial, affirmed the value of hs-CRP in the global CV risk assessment of both middle-aged men and postmenopausal women, especially those who would otherwise be categorized as low-to-intermediate risk based on acceptable levels of lipid fraction determinations and, therefore, not offered inflammation-lowering treatment, which were statins in this study.6
Association of CAD with Chronic Inflammatory Diseases
Certain patient groups such as those with psoriasis, rheumatoid arthritis, and periodontal disease are known to have an increased risk for CVD due to chronic inflammatory states. Addressing the underlying inflammatory state through the use of medications such as methotrexate (psoriasis, RA), intake of dietary omega-3 fatty acids and dietary antioxidants (RA), and subgingival and supragingival removal of dental plaque (as well as scaling, root planning, and local antibiotic administration for periodontal disease) may diminish inflammation and mitigate CV risk as suggested by observational studies.9-13 Such interventions, particularly the dietary incorporation of omega-3 fatty acids, are low-cost strategies relatively easily implemented into a patient's daily routine.
Functional Foods for CV Health
Since everyone has to eat to live, new dietary approaches to reduce CV risk by incorporating cholesterol- and inflammation-lowering functional foods into daily eating plan makes sense. As a matter of fact, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the American Heart Association (AHA) recommend the use of a variety of foods high in components that reduce cholesterol (see Table 3).14,15 Jenkins et al found such a portfolio diet to be as effective as lovastatin in decreasing the LDL-cholesterol to the goal levels of 130 mg/dL in a group of hyperlipidemic, healthy middle-aged outpatients (41% women).16 The omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish and fish oils and alpha linolenic acid (ALA) found in plant sources, are a fifth group of functional foods to be added to Table 3 for their favorable effects on lipid and trigylceride profiles. They are, however, much more versatile for improving both general and cardiovascular health due to their antithrombotic, antiarrythmic, anti-inflammatory, and vasodilating properties.
The omega-3 and omega-6 fatty acids are considered essential fatty acids because the human body cannot manufacture them and they must be obtained through the diet. Therefore, they are an excellent (and essential) way to diversify the portfolio of dietary strategies to decrease CV risk.17
Pharmacologic Actions of Omega-3 Fatty Acids
EPA and DHA are precursors to a group of eicosanoids (prostaglandins, leukotrienes, and thromboxanes), which have anti-inflammatory, antithrombotic, and vasodilatory effects (leukotriene B5, thromboxane A3, and prostaglandin E3). Although EPA and DHA can be endogenously produced from dietary ALA, the conversion process is limited and inefficient since ALA and omega-6 fatty acids are competitive substrates for the rate-limiting enzyme delta 6 desaturase, which controls the metabolic conversion of the omega-6 and omega-3 PUFAs into their respective eicosanoids. The greater dietary concentration of omega-6 fatty acids, particularly arachidonic acid, favors its formation into a group of eicosanoids that has proinflammatory, prothrombotic, and vasoconstricting effects such as tumor necrosis factor alpha (TNF alpha), thromboxane A2, prostaglandin E2, and leukotriene B4 (LTB4). The EPA in fish oil and fish competitively inhibits arachidonic metabolism, resulting in the synthesis of less thrombogenic and less inflammatory eicosanoids.18 Generally, the eicosanoids derived from omega-3 fatty acids have biological potencies for the induction of cellular inflammatory responses that are 1/10 to 1/100 of those derived from the omega-6 fatty acids.19
Factors Affecting hs-CRP Levels
Although smoking, obesity, and aging can elevate hs-CRP levels, clinical studies that control for these factors continue to show a significant association with CVD. Since intercurrent illness can cause transient increases in hs-CRP, a single measurement may not represent the true basal level and two determinations are currently recommended.20
Clinical Studies of Omega-3 Fatty Acids and CVD
Dyerberg et al initially described the epidemiologic connection between high dietary fat intake and low incidence of CHD in Greenland Eskimos (Inuit). This study sparked both scientific and public interest in the role of various types of fatty acids in the prevention and treatment of chronic diseases, particularly CHD.21 Subsequently, both epidemiological22 and randomized controlled studies of omega-3 fatty acid dietary supplementation have shown decreased CHD morbidity and mortality, particularly the secondary prevention trials.
Secondary Prevention Trials. In the GISSI Prevenzione Study, more than 11,000 post MI patients in the Italian public health system were randomized to receive either omega-3 PUFA (1 g/d) alone, vitamin E (300 mg/d alpha tocopherol), omega-3 PUFA + vitamin E, or placebo for 3.5 years. The group receiving the omega-3 fatty acids alone had a 20% reduction in CV death as well as nonfatal MI and stroke. Importantly, the risk of sudden cardiac death also decreased 45% in this group compared to vitamin E alone and placebo.23 The DART trial compared three dietary interventions (increased dietary polyunsaturated/saturated fats vs increased fatty fish intake vs increased dietary cereal fiber) in 2,033 post infarction men for two years. The omega-3 PUFA consumption in the form of fatty fish was the only intervention to significantly reduce mortality by 29%. Interestingly, the CV benefits were seen with consumption of only two fish meals per week or as little as 1 g/d of omega-3 PUFA (EPA + DHA) supplements (GISSI Trial).24
Primary Prevention Trials. Micallef et al, in a three-week, randomized, placebo-controlled, double-blind parallel study of 60 hyperlipidemic, community-dwelling, healthy patients (35-70 years of age), demonstrated that subjects assigned to a combined marine fish oil capsules (1.4 g/d) and plant sterol supplement (2 g/d) had a significant decrease in the inflammatory markers hs-CRP (39%), TNF alpha (10%), interleukin-6 (10.7%), and LTB4 (15.3%) compared to baseline and to the placebo group on sunola oil (sunflower oil, i.e., monounsaturated high oleic acid oil) after only three weeks of treatment. This represented a 22.6% reduction in overall CV risk with the plant sterols acting synergistically to produce a greater anti-inflammatory effect when used in combination with the omega-3 fatty acid supplementation. Interestingly, use of the plant sterols alone had no anti-inflammatory effect in this study.25
Characteristics of Fish Oil Supplements and Dosage
Lovaza®, a standardized omega-3 fatty acid ethyl esters product, is available via prescription as a liquid filled gel capsule. Each gel capsule is 1 g and contained at least 900 mg of the ethyl esters of omega-3 fatty acids, predominately a combination of EPA (approximately 465 mg) and DHA (approximately 375 mg).26 Dosage of over-the-counter fish oil supplements should be based upon the amount of EPA and DHA in the product. Commonly, supplements contain 0.18 g of EPA and 0.12 g of DHA; they should be sourced from wild not farm-raised fish. Supplements should also be chosen from a reliable brand that has the Consumer Lab (CL) seal of approval, which designates that CL has evaluated and verified the product's EPA and DHA content, tested it for purity (i.e., contains no methylmercury, polychlorinated biphenyls, or dioxin) and for freshness (i.e., oxidation of the fish oil generates free radicals and renders it unsuitable for ingestion).27
Storage and Cooking Considerations
Omega-3 fatty acid supplements are subject to denaturation by light and heat. Check cooking temperatures for all oils to be certain that the smoke point is not exceeded during the cooking or baking process. They should be maintained in dark containers and in cool, dry places for maximum shelf-life. Some products like flax oil should be refrigerated and completely used within a few weeks of opening.27
Adverse Effects of Omega-3 Fatty Acids
Persons allergic or hypersensitive to fish should avoid products containing fish oil or omega-3 fatty acid products derived from fish. Gastrointestinal symptoms are common with the use of fish oil supplements. The most common symptoms are nausea, increased eructation, reflux, indigestion, and a fishy aftertaste. Such side effects can be minimized if the fish oils are taken with a meal and initial dosages are low and gradually increased.
Omega-3 PUFAs have antiplatelet properties and can cause prolongation of bleeding times, particularly in high doses (> 3 g/d) and in persons taking concomitant anticoagulants or antiplatelet medications such as warfarin, aspirin, clopidogrel, etc.28 Although some concern was raised regarding in vitro studies that demonstrated an increased susceptibility to oxidation of LDL-cholesterol by omega-3 PUFA supplementation, the effect can be reduced by supplementation with vitamin E.29
Dosage of Omega-3 Fatty PUFAs for CAD
Recommendations from the symposium Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with omega-3 Fatty Acids are for a daily intake of 250-500 mg DHA and EPA from either dietary or supplement sources for the primary prevention of CHD death and after a coronary event to reduce risk of CHD death. Lovaza is currently FDA-approved for treatment of very high triglycerides and the dosage for this indication is four 1 g gel capsules taken once or twice daily with a meal.30
The AHA recommendations for persons with known CHD are to eat one fatty fish meal at least twice a week or take 1 g/d of omega-3 PUFAs (EPA + DHA). There are no specific recommendations for those at increased risk for CHD without known disease.31 Clinical trials have used a range of doses from 1-3 g of EPA + DHA daily and the duration has been from three weeks to 3.5 years.
Dietary Sources of Omega-3 Fatty Acids
Fish is an important source of omega-3 fatty acids in the U.S. diet, especially salmon, mackerel, and sardines; however, vegetable sources including flaxseeds and flaxseed oil, soybean and canola oils, walnuts, leeks, and enriched eggs offer alternatives for those unable to consume fish.18
The use of dietary manipulations as therapy to diminish both primary and secondary CV risk is a cost-effective, well-tolerated, and multifaceted approach to a complex problem amenable to customization by the physician-patient team. Omega-3 fatty acid supplementation has broad implications for reducing the risk of CVD as well as modifying the course of other inflammatory disorders such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
A dietary portfolio consisting of 10-25 g of soluble fiber from a variety of sources combined with 20-30 g of soy protein, one-half ounce serving of nuts, 2 g of plant sterol/stanol spread rounded out with 250-500 mg supplemental DHA + EPA per day or two fatty fish meals weekly is a diversified, cost-effective, and interesting way to balance risk and maximize overall health returns.
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