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Molecular and Cellular Biochemistry 263: 217–225, 2004. c 2004 Kluwer Academic Publishers. Printed in the Netherlands. Omega-3 fatty acids from fish oils and cardiovascular disease Darren J. Holub1 and Bruce J. Holub2 1 Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; 2 Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada Abstract Fish and fish oils contain the omega-3 fatty acids known as eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). Epidemiological studies have shown an inverse relation between the dietary consumption of fish containing EPA/DHA and mortality from coronary heart disease. These relationships have been substantiated from blood measures of omega-3 fatty acids including DHA as a physiological biomarker for omega-3 fatty acid status. Controlled intervention trials with fish oil supplements enriched in EPA/DHA have shown their potential to reduce mortality in post-myocardial infarction patients with a substantial reduction in the risk of sudden cardiac death. The cardioprotective effects of EPA/DHA are widespread, appear to act independently of blood cholesterol reduction, and are mediated by diverse mechanisms. Their overall effects include anti-arrhythmic, blood triglyceride-lowering, anti-thrombotic, anti-inflammatory, endothelial relaxation, plus others. Current dietary intakes of EPA/DHA in North America and elsewhere are well below those recommended by the American Heart Association for the management of patients with coronary heart disease. (Mol Cell Biochem 263: 217–225, 2004) Key words: anti-arrhythmic, coronary heart disease, eicosapentaenoic (EPA) plus docosahexaenoic acid (DHA), omega-3 fatty acids, secondary management, sudden cardiac death Introduction There has been a marked surge in both scientific support and clinical plus public interest in the role of omega-3 fatty acids (n-3 polyunsaturates) as found in fish/fish oils in the prevention and management of cardiovascular disease (CVD) and associated disorders [1–4]. Mounting epidemiological and interventional trials (both in healthy subjects and in patient groups) have indicated support for the marine-derived omega3 fatty acids to attenuate various risk factors for CVD plus myocardial infarctions and sudden cardiac death. Recent clinical trials and the promising results derived therefrom have contributed to the ongoing establishment of omega-3 therapeutics in both primary prevention and secondary management as part of complementary cardiovascular care/management. The omega-3 fatty acids (n-3 polyunsaturated fatty acids, n-3 PUFA) found in fish/fish oils include eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Structures, sources, and intakes of omega-3 fatty acids Omega-3 fatty acids are long-chain PUFA commonly having 18, 20, or 22 carbon atoms in chain length with the first of the 3–6 double bonds adjacent to the third carbon atom when counting from the methyl carbon end of the fatty acid molecule. The fish-based omega-3 PUFA consists mainly of EPA (20 carbon atoms, 5 double bonds – 20:5n-3) and DHA (22 carbon atoms, 6 double bonds – 22:6n-3). Much smaller amounts of docosapentaenoic acid (DPA, 22:5n-3) are found in fish and fish oils although they represent up to 5% of the fatty acids in certain marine mammal sources such as seal oils. The general structures for EPA and DHA are shown inFig. 1 and a few commonly available dietary sources of EPA and DHA are listed inTable 1. The vast majority of the dietary EPA/DHA (combined) in a typical North American diet Address for offprints: B.J. Holub, Animal Science and Nutrition Building, Room 342, Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1 (E-mail: [email protected]) 218 Fig. 1. Structures of omega-3 fatty acids (n-3 PUFA). is consumed in the form of fish/fish oils with much smaller contributions of DHA coming from miscellaneous sources including eggs, certain organ meats, etc. Plant foods and vegetable oils are devoid of EPA plus DHA, although certain types do contain varying amounts of the omega-3 fatty acid known as alpha-linolenic acid (LNA, 18:3n-3) which has 18 carbon atoms and 3 double bonds (see Fig. 1). Numerous vegetable oils (e.g., corn, sunflower, soybean, and safflower oils) are greatly enriched in the omega-6 fatty acid known as linoleic acid (LA, 18:2n-6). Significant sources of LNA include non-hydrogenated canola oil (approximately 10% by weight as LNA), ground flaxseed (approximately 20% by weight as LNA), and selected nuts (e.g., English walnuts contain approximately 8% by weight as LNA). The typical North American diet provides approximately 1–3 g of LNA per day but only 100–150 mg of EPA/DHA (combined) with a majority of the latter being represented by DHA (approximately 80 mg/day in adults) [5, 6]. The very high intake of omega-6 fatty acid (LA, 18:2n-6) in a typical North American diet (5–6% of daily energy or 12–15 g/day) from the common vegetable oils enriched in n-6 PUFA and other sources (including products from animals fed corn, soybean, etc.) yields an overall n-6:n-3 dietary ratio (total omega-6 fatty acids in our diet:total omega-3 fatty acids in our diet) of about 8:1 219 Table 1. Approximate omega-3 fatty acid contents (as EPA + DHA) of selected fish/seafood, functional foods, and fish oil supplementsa Product Concentration of EPA + DHA (sum) Servings per week needed to meet AHA guidelinesb (a) Fish/seafood (mg/100g) Mackerel 2500 3 Herring 1700 4 Salmon 1200 5 500 13 Trout Halibut 400 16 Tuna 400 16 Shrimp 300 21 Cod 300 21 900 7 **Standard (180/120) 300 21 ***Specialty (400/200) 600 11 (b) Functional food (mg/180 ml) *Liquid eggs (c) Fish oil supplements (mg/1 g capsule) EPA + DHA (sum) contents of the fish/seafood given will vary somewhat according to the species, source, and other factors. A fish/seafood serving is defined as 100 g. A serving of the liquid egg is 180 ml while one fish oil capsule (1 g) is considered a serving. b American Heart Association (AHA) dietary guidelines state that 900 mg/day of EPA + DHA combined is an amount shown to beneficially affect coronary heart disease mortality rates in patients with coronary disease. ∗ A ready-to-use scrambled egg mixture available in Canada. ∗∗ Contains 180 mg EPA plus 120 mg DHA. ∗∗∗ Contains 400 mg EPA plus 200 mg DHA. a The in North America. Certain government agencies (e.g., Health Canada) have recommended [7] that this ratio be lowered to as low as 4:1 so as to allow for a less than competitive influence of high LA intakes on LNA metabolism to its desaturation/elongation products (such as EPA plus DHA). The metabolic conversion of LNA to its longer-chain products via the various desaturation/elongation reactions is depicted inFig. 2. This figure also shows the conversion of LA to its corresponding omega-6 PUFA products including arachidonic acid (AA, 20:4n-6) which, like EPA plus DHA, accumulates in various tissues and cells in the body. In contrast to LA which is present at substantial concentrations in most cellular lipids (membrane phospholipids plus neutral lipids including triglyceride) throughout various cells and tissues, LNA usually does not accumulate to particularly high concentrations in cellular/tissue lipids even when consumed at substantial dietary levels. This is partly due to the extensive beta-oxidation of LNA in vivo. Figure 2 also indicates the potential for DHA to undergo peroxisomal-mediated retroconversion to EPA. Issues surrounding the cardioprotective potential of dietary LNA Evidence for the potential protective benefits of LNA come partly from studies on the LNA-rich Mediterranean diet in the secondary prevention of coronary heart disease [8]. In post-myocardial infarction, patients were randomly assigned to an experimental or control diet and followed over a 5-year period; cardiac deaths and non-fatal myocardial infarctions were significantly lower in the experimental (Mediterranean) as compared to the control diet. It was suggested that the higher intake of LNA in the Mediterranean diet, mainly in the form of margarine containing canola oils, may have been responsible for the beneficial effects. However, it needs to be pointed out that other dietary components may have contributed to the protective effects of the Mediterranean dietary pattern. The Nurses Health Study (a prospective cohort study) revealed an inverse relation between LNA intakes and the risk of fatal ischemic heart disease among women [9]. In contrast, the Zutphen Elderly Study [10] did not observe a beneficial effect of dietary LNA on the 10-year risk of coronary artery disease. In the National Heart, Lung, and Blood Institute Family Heart Study, a higher intake of LNA was inversely related to the prevalence odds ratio of coronary artery disease [11]. While some questions remain regarding the apparent inconsistency across such population studies, it has been suggested, although not unequivocally proven, that the Zutphen Elderly Study may have been compromised by accompanying dietary variables including trans fatty acid intakes across these subjects. In most human intervention trials, higher dietary intakes of LNA have usually not produced a significant increase in the circulating blood levels of the final 220 Fig. 2. Desaturation, elongation, and retroconversion of polyunsaturated fatty acids. desaturation/elongation product in the form of DHA. Moderate increases in the longer-chain fatty acids in the form of EPA and DPA have commonly been observed including a significant rise in the very low levels of LNA using high LNA intakes and low (e.g., 3:1) ratios of n-6:n-3 [12]. It remains to be established whether the moderate rise in these longerchain products (EPA and DPA) can account for any cardioprotective effects (anti-arrhythmic) of higher LNA intakes. In the case of the vegan-vegetarian subject who consumes no EPA/DHA, higher intakes of LNA and lower intakes of LA, providing a lowering in the n-6:n-3 ratio, may provide opportunities for somewhat better elevations in the levels of circulating EPA/DPA and perhaps also DHA (on the longer term). However, the very limited and varied conversion efficiency of dietary LNA to DHA as reported [13–15] in human adults (ranging from 0 to 9% on average) clearly indicates that the direct consumption of EPA and DHA is a much more potent means of enriching circulating lipids and target tissues/cells (including cardiac membrane phospholipid) in EPA/DHA. Because of the very limited conversion of LNA to DHA in infants, it has been concluded by Cunnane et al. [16] that preformed DHA in the diet should be consumed during the first 6 months of life to provide for its essential functioning in neurological and visual development. Epidemiological studies on the cardioprotective effects of EPA/DHA The high fat marine-based traditional diet of the Inuit (Greenland; Nunavik, Quebec) provides up to several thousand milligrams of omega-3 fatty acid in the form of EPA plus DHA (combined) daily as consumed in the form of marine mammals (seal, whale), various fishes, and wild fowl (sea birds). Disease patterns for the Greenland Inuit, as compared to those for the Danish population, have indicated a significantly lower rate of death from acute myocardial infarction [17] despite only moderate differences in blood cholesterol levels. The much higher intakes of the Japanese population (with EPA/DHA intakes approaching 1500 mg/day) relative to that of North America (approximately 130 mg/day) have been associated with considerably lower rates of acute 221 myocardial infarctions, other ischemic heart disease, and atherosclerosis despite only moderately lower blood cholesterol levels in the Japanese population [4]. Various studies have indicated that the long-term consumption of fish containing EPA/DHA (up to 2.5–3 servings per week) appears to be associated with lower primary and secondary heart attack rates from CVD [1]. The latter would provide a combined intake of 325–450 mg EPA plus DHA daily if one assumes that the current mean fish intake in North America of 110 gm/person/week [18] provides approximately 130–150 mg EPA/DHA daily [5, 6]. Recently, a 12-year follow-up study in men reported a 45% lower risk of ischemic stroke (multivariate analyses) with no change in hemorrhagic stroke with 2–4 servings/week of fish containing EPA/DHA [19]. Further, this inverse association was not materially modified by aspirin use. Interestingly, estimates of mean per capita consumption of fish in the US indicate one serving (110 g) per week of which 2/3 is marine-based and 1/3 is freshwater/estuarine fish [18]; these intakes are significantly lower than the aforementioned. The Multiple Risk Factor Intervention Trial in the US has indicated that progressively higher intakes of the fish-derived omega-3 fatty acids (up to 665 mg/day) over 10.5 years were associated with a progressive reduction in mortality related to coronary heart disease (CHD) and all-cause mortality with no associated increase in total cancer-related mortality [20]. Intervention trials with fish oil supplements containing EPA/DHA Numerous intervention and clinical trials with fish oil supplements containing EPA/DHA have been reported. Most have been relatively short-term intervention trials in healthy or at-risk subjects wherein various risk factors for CVD have been measured. Some promising longer-term trials in patients (both pre- and post-myocardial infarction) have been conducted with the monitoring of ‘hard’ end points including coronary angiography and fatal plus non-fatal myocardial infarctions. In a study reported by von Schacky et al. [21], this randomized, double-blind, placebo-controlled trial revealed that patients with coronary artery disease given omega-3 fatty acids (EPA/DHA) at therapeutic levels of approximately 1.5 g/day over 2 years exhibited moderately less progression and more regression of disease based on discernible, modest mitigation of atherosclerosis as compared to patients on placebo. In addition, fewer clinical cardiovascular events (fatal and non-fatal myocardial infarctions, stroke) were noted in the omega-3 supplementation group. In general, the supplementation regimen was considered safe and well tolerated. The 1999 GSSI-Prevenzione Trial from Italy employed 11,324 patients who had experienced a myocardial infarction [22]. All patients were assigned to supplemental interventions following introduction of a Mediterranean-type diet which included moderate fish consumption in addition to aggressive treatment with various pharmaceutical agents for cardioprotection. Approximately one-half the patients received an encapsulated omega-3 fish oil supplement providing 850–882 mg/day of EPA + DHA. Over the subsequent follow-up interval of 3.5 years, those patients receiving omega-3 supplementation exhibited a significant reduction in overall cardiovascular deaths and a reduction in sudden cardiac death of about 45%. Interestingly, Vitamin E (α-tocopherol) supplementation, which was also studied in this trial, was without significant effect in this regard. Other findings indicate that, independent of blood-cholesterol-lowering, EPA/DHA supplementation has the potential to favorably influence mortality related to CVD, particularly sudden cardiac death which may be related to the anti-arrhythmic effects of the n-3 PUFA [23]. Shorter-term intervention trials have generally supported the cardioprotective effects of EPA/DHA via a combination of effects including lipid (triglyceride)-lowering, antithrombotic effects, reduced blood and plasma viscosity, improvements in endothelial dysfunction, plus anti-arrhythmic effects and others as outlined inTable 2. Anti-atherogenic effects of omega-3 fatty acids have also been demonstrated in Table 2. Contributing mechanisms to the cardioprotective effects of omega-3 fatty acids (EPA/DHA) (1) Reduction in malignant ventricular arrhythmias (via enrichment of cardiac lipids in EPA/DHA) (2) Increase in heart rate variability (possibly via increased parasympathetic tone, altered cytokine levels, other factors) (3) Anti-thrombotic and other effects on the hemostatic system (reduced blood platelet reactivity associated with reduced cyclooxygenase-mediated conversion of AA to thromboxane A2 , moderately longer bleeding times, reduced plasma viscosity, others) (4) Lipid-lowering (reduction in fasting triglyceride and VLDL levels often accompanied via a moderate rise in HDL-cholesterol, attenuation of postprandial triglyceride response) (5) Improved endothelial relaxation (via enhancement of nitric oxide-dependent and independent vasodilation) (6) Inhibitory effect on atherosclerosis and inflammation (via inhibition of smooth muscle cell proliferation, altered eicosanoid synthesis, reduced expression of cell adhesion molecules) (7) Suppressed production of inflammatory cytokines (interleukins, tumor necrosis factor) and mitogens 222 animal studies. Most intervention trials using fish oil concentrates have provided EPA/DHA intakes (in combination) approaching 2–4 g/day over several weeks. The accumulation of omega-3 fatty acids (EPA/DHA) in various cells/tissues upon supplementation provides for altered membrane functionality (including transmembrane signaling processes via eicosanoid-dependent and independent mechanisms). The accumulation of EPA and DHA in circulating blood platelets provides for a partial replacement of AA (20:4n-6) in membrane phospholipids with a resulting reduction in the release of membrane phospholipid-bound AA via phospholipase activity upon platelet stimulation and reduced conversion of AA to the pro-aggregatory and vasoconstrictory thromboxane A2 due to the competitive inhibitory effects of EPA/DHA on cyclooxygenase activity [4]. The reduction in fasting triglyceride levels upon EPA/DHA supplementation approaches approximately 6–8% (or more) per gram within a 2–3-week period in many individuals [4, 24]. It is apparent that the future for combination-lipid lowering therapies will include the combination of a statin with appropriate dosages of EPA/DHA in supplemental form, particularly in patients with elevated LDL-cholesterol plus high triglyceride levels [25]. It is anticipated that the inclusion of omega-3 supplementation in patient management will provide additional cardioprotective benefits as outlined in Table 3. A number of trials employing omega-3 supplementation from fish oil for restenosis prevention after percutaneous transluminal coronary angioplasty (PCTA) have resulted in conflicting results [4]. A recent randomized, doubleblind, placebo-controlled study on EPA/DHA supplementation started before PCTA and 6 months thereafter showed that supplementation was associated with a small but significant decrease in the rates of post-coronary angioplasty restenosis before and after PTCA treatment compared with a placebo group [26]. Very recently, a randomized control trial of patients awaiting carotid endarterectomy has been reported by Thies et al. [27]. They reported that patients being treated with fish oil had fewer plaques with thin fibrous caps and signs of inflammation as well as more plaques with thick, fibrous caps and no signs of inflammation as compared to control patients or those given sunflower oil (rich in omega-6 fatty acids). The number of macrophages from patients receiving EPA/DHA supplementation was also lower than in the other two groups. The authors suggest that the stability of atherosclerotic plaques could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intakes. Blood levels of omega-3 fatty acids in risk factor assessment Increasing the concentration of dietary fish/fish oils containing the long-chain n-3 PUFA provides for the corresponding elevation in the levels of EPA and DHA in mammalian tissues and cells via their esterification into the 2-position of membrane phospholipids. Fatty acid analyses of serum (or plasma) phospholipid, a recognized biomarker for EPA and DHA intakes and overall physiological status, have exhibited an inverse correlation between n-3 PUFA and particularly DHA levels and the development of coronary heart disease in men [28]. An approximate 30% overall lower risk of coronary heart disease was estimated from higher DHA and total (summed) omega-3 levels in serum phospholipid (Table 3). Dewailly et al. [29] reported a progressively Table 3. Levels of omega-3 fatty acids in serum (or plasma) phospholipid and the risk of coronary heart disease or fatal ischemic heart diseasea Omega-3 fatty acid(s) Percentage of fatty acids in phospholipid (mean + 1 S.D.) Odds ratiob (i) Simon et al. [28] α-LNA ≥ 0.2 0.86 EPA ≥ 1.3 0.81 DPA ≥ 1.2 0.67 DHA ≥ 4.5 0.66 Omega-3* ≥ 7.2∗ 0.69* (ii) Lemaitre et al. [32] EPA + DHA ≥ 4.6 0.30 a Data from Simon et al. [28] on serum phospholipids and risk of coronary heart disease and Lemaitre et al. [32] on plasma phospholipids and fatal ischemic heart disease. b Odds ratio refers to the relative risk for coronary heart disease (Simon et al.) or fatal ischemic heart disease (Lemaitre et al.) when the omega-3 fatty acid levels in phospholipid rose to 1 S.D. above the group mean values (arbitrarily assigned an odds ratio of 1.00). For example, if the summed omega-3 levels reached at least 7.2% of total fatty acids, the disease risk was 31% lower relative to the group mean value (5.1% of fatty acids as the summed omega-3 levels). ∗ Based on weighted mean values + 1 S.D. (40% above weighted mean). 223 higher concentration of HDL-cholesterol and lower circulating triglycerides in a study population as the combined levels of EPA plus DHA in plasma phospholipids surpassed 6.4% of total fatty acids. A very strong inverse relation between the summed blood levels of the long-chain omega-3 PUFA and the risk of sudden cardiac death has been reported in men without prior evidence of cardiovascular disease [30]. Higher blood DHA levels were found to be associated with a higher heart rate variability [31] which may contribute to the lower risk of cardiac arrhythmia and sudden death with higher intakes of fish-derived fatty acids. Very recently, fatty acid compositional data on plasma phospholipids from the Cardiovascular Health Study [32], drawn 2 years before a cardiac event, exhibited a 70% lower odds ratio for fatal ischemic heart disease in those with higher blood levels of EPA plus DHA (Table 3). These and other studies have led to a recently published editorial [33] which raised the following question: ‘Should the laboratory assessment of blood n-3 fatty acid concentrations be included as part of a 21st century CHD risk panel?’ Psychiatric disorders in relation to coronary heart disease and omega-3 fatty acids Essential fatty acids are major constituents of synaptic membranes and are believed to play an integral role in neurological function including signal transduction. As a result, considerable research has examined the role of omega-3 fatty acids in a variety of psychiatric conditions including schizophrenia, bipolar disorder, major depressive disorder, post-partum depression, dementia, and borderline personality disorder. There is increasing evidence that symptomatic depression predisposes to CVD and that depression adversely affects cardiac events and outcomes (including post-myocardial infarction) in patients with ischemic heart disease [34–36]. A lower omega-3 fatty acid status has been observed in such patient groups and, as outlined earlier, in those at greater risk for CHD and fatal ischemic events. Omega-3 fatty acids in major depressive disorder have been investigated in epidemiological, case control, and preliminary intervention studies. An epidemiological study investigating fish consumption worldwide has demonstrated an increased prevalence of major depression in nations with less fish consumption per capita [37]. A Finnish study investigating fish consumption in the general population demonstrated an increased likelihood of depressive symptoms among infrequent compared with frequent fish consumers [38]. Several investigators have demonstrated a physiological depletion of omega-3 fatty acids in depressed patients as compared with control subjects [39– 42]. It is unclear whether this depletion represents primary etiological significance, or if it is secondary to the disorder or related to additional variables. This topic remains an active area of research and underlying hypotheses include altered dietary habits, abnormal metabolism, and the result of an inflammatory response. Two preliminary studies have investigated the efficacy of omega-3 supplementation in patients with major depressive disorder, with promising results. A preliminary double-blind, placebo-controlled trial investigated the addition of EPA to maintenance treatment in a small number of patients with major depressive disorder. A highly significant benefit was noted in the omega-3 treatment group [43]. An additional randomized controlled trial found augmentation with 1 g EPA daily to be beneficial, although doses of 2 and 4 g were found to be less effective [44]. Larger trials have been recommended to further investigate the potential role of omega-3 fatty acid supplementation in the treatment of major depressive disorder. Stoll et al. [45] used very high doses of omega-3 fatty acids from fish oil (9.6 g/day) as augmentation treatment in patients with bipolar disorder, with significant improvement noted in nearly all outcome measures. An interesting correlation between seafood consumption, the DHA content of mother’s milk, and the prevalence of postpartum depression was noted in a cross-national analysis by Hibbelin [46]. Rates of postpartum depression were found to be increased among populations with lower fish consumption and among populations with less DHA in maternal milk. Additional larger trials have been recommended to further investigate the potential role of omega-3 fatty acid supplementation in the treatment of major depressive disorder. It should be pointed out that some studies have not detected a link between omega-3 fatty acids and psychiatric disorders. For example, the Rotterdam Study found no relation between omega-3 fatty acid intakes and the risk of dementia or its subtypes [47]. The complex nature of these varied psychiatric disease states and multifactorial genetic and epigenetic mechanisms undoubtedly complicates the interpretation of some of the studies reported to date. Largescale, placebo-controlled, double-blind trials using varying doses of EPA/DHA are needed before these can be considered for entry into mainstream psychiatric management of specific patient groups. Recommendations and conclusions The suitability of fish oil supplements and EPA/DHAenriched concentrates for any eventual clinical application will need to ensure accurate content claims, oxidative stability, negligible levels of environmental contaminants (mercury, organochlorines, dioxins, etc.), the appropriate accompanying presence of physiological anti-oxidants, plus other factors. Different forms of EPA plus DHA (e.g., ethyl 224 esters vs. triglyceride) will be considered somewhat differently (pharmaceutical agents vs. ‘natural’ sources of omega3 fatty acids) in certain regulatory jurisdictions. Functional foods containing fish oils enriched in EPA/DHA or microencapsulated forms of these fatty acids will also face added regulatory barriers. Health and disease preventing/managing claims, including risk factor attenuation (e.g., blood triglyceride-lowering), will aid their entry into the health care system. It has been suggested that until further data from prospective, randomized clinical trials are available, the intake of the plant-based LNA should represent 1.5–3 g/day [48]. Current North American intakes are at the lower portion of this range. It remains to be seen if LNA itself can provide cardioprotective effects in subjects with substantial EPA/DHA intakes. A conservative and safer approach would presently appear to be an insurance of significant intakes of both LNA plus EPA/DHA. The 1999 workshop held on essential fatty acids at the NIH in Bethesda [49] recommended a combined EPA/DHA intake of 650 mg/day for healthy adults. Such intakes, if met from fish consumption as generally preferred, would require approximately 4–5 fish servings/week. Eating two servings per week (minimum recommended by the American Heart Association) [50] for those without CHD would provide approximately 300 mg EPA/DHA daily. For patients with documented CHD, the American Heart Association guidelines advise 900–1000 mg/day of EPA/DHA combined [50, 51]. They have indicated that for secondary prevention, this target would require one fatty fish meal per day or alternatively supplementation with EPA/DHA from fish oil sources. As indicated in Table 1, the 900 mg/day target for EPA/DHA could require 3–21 servings of fish/week depending upon the source/type chosen. Consequently, a high quality fish oil supplement/concentrate and functional foods enriched in EPA/DHA will become important vehicles for enhancing current low intakes of EPA/DHA. Higher doses of EPA/DHA (eg., up to 3 g/day) will also be of clinical interest for combined lipid-lowering (with statins) for diverse cardioprotective effects. Omega-3 (EPA/DHA) therapeutics along with future blood fatty acid monitoring are deserving of serious consideration in the overall management of those at risk for CVD or as part of a secondary prevention strategy for patients having CHD with or without a previous myocardial infarction. Acknowledgements The authors would like to express their appreciation to Dr. Diana Philbrick and Ms. Jessica Danelon for their assistance in the formulation of this manuscript. Prof. Holub’s research on omega-3 fatty acids for cardiovascular health is supported by a grant from the Heart and Stroke Foundation of Ontario. References 1. Schmidt EB, Skou HA, Christensen JH, Dyerberg J: n-3 Fatty acids from fish and coronary artery disease: Implications for public health. Public Health Nutr 31: 91–98, 2000 2. Angerer P, von Schacky C: N-3 polyunsaturated fatty acids and the cardiovascular system. Curr Opin Lipidol 11: 57–63, 2000 3. Connor WE: Importance on n-3 fatty acids in health and disease. 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