Beyond the Mediterranean Diet: The Role of Omega-3 Fatty Acids in the Prevention of Coronary Heart Disease

Charles R. Harper, MD, Terry A. Jacobson, MD

Prev Cardiol. 2003;6(3) 

Abstract and Introduction

Evidence from epidemiologic and clinical secondary prevention trials suggest that the omega-3 polyunsaturated fatty acids (n-3 PUFAs) may have a significant role in the prevention of coronary heart disease. Dietary sources of n-3 PUFAs include fish oils, rich in eicosapentaenoic acid and docosahexaenoic acid, along with plants rich in linolenic acid. Randomized secondary prevention clinical trials with fish oils (eicosapentaenoic acid, docosahexaenoic acid) and -linolenic acid have demonstrated reductions in risk that compare favorably to those seen in landmark secondary prevention trials with lipid-lowering drugs. Several mechanisms explaining the cardioprotective effect of the n-3 PUFA have been suggested including antiarrhythmic and antithrombotic roles. Although official US guidelines for the dietary intake of n-3 PUFA are not available, several international guidelines have been published. Fish is an important source of the n-3 PUFA in the US diet; however, vegetable sources including grains and oils offer an alternative source for those who are unable to regularly consume fish.

Scientific knowledge concerning the omega-3 polyunsaturated fatty acids (n-3 PUFAs) is rapidly expanding. Early work by Dyerberg et al.[1] with Greenlandic Inuits suggested the n-3 PUFAs may have a cardioprotective effect. Recent evidence from randomized trials in patients with coronary heart disease (CHD) suggests that n-3 fatty acids from marine (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and plant sources (linolenic acid [ALA]) prevents cardiac death and nonfatal myocardial infarction (MI). The authors begin with a brief review of fatty acid structure and nomenclature, followed by a summary of the available epidemiologic evidence. Recent evidence from clinical trials with angiographic and hard clinical end points is reviewed. Finally a review of possible mechanisms of action is followed by a discussion of the implications for clinicians.

Structure

Fatty acids consist of a hydrocarbon chain with a hydrophobic methyl group at one end and a hydrophilic carboxyl group at the other (Figure 1).[2] The methyl end of the molecule is also referred to as the omega end while the carboxyl group is located at the delta end. Fatty acids are described using the omega numbering system. In this system carbon atoms are numbered in order starting from the methyl end. The length of the carbon chain along with the location and number of the double bonds determines the properties of the different fatty acids. A fatty acid can be saturated (no double bonds), monounsaturated (one double bond), or polyunsaturated (two or more double bonds).[3]

Important fatty acids. The number of carbon atoms is indicated before, and the number of double bonds is indicated after, the colon. The position of the first double bond counted from the methyl end is listed after the comma.

PUFAs may be divided into two subcategories, the n-3 and the n-6 fatty acids. The n-3 PUFAs have their first double bond located at the third carbon molecule (C-3) while the n-6 PUFAs have their first double bond located at (C-6). The n-6 and n-3 PUFAs are considered "essential" fatty acids because humans cannot synthesize them and they must be included in the diet. The n-3 fatty acid, ALA, and the n-6 fatty acid, linoleic acid (LA), are the predominant essential fatty acids in humans.[3] LA can be elongated and desaturated to arachidonic acid while ALA is elongated and desaturated into EPA and then into DHA (Figure 2). EPA and DHA are the major n-3 fatty acids found in fish and are thought to be responsible for their cardioprotective effect.[4] It is thought that ALA conversion to EPA is dependent on levels of the n-6 fatty acid LA because ALA and the n-6 fatty acids are competitive substrates for the rate-limiting enzyme 6 desaturase (Figure 2).[5] Leukotrienes, prostaglandins, and thromboxanes are eicosanoids that are derived from the above mentioned essential fatty acids. Eicosanoids derived from arachidonic acid are generally proinflammatory and proaggregatory agonists, while those derived from the n-3 fatty acids tend to inhibit platelet aggregation and be anti-inflammatory or cause less inflammation.[6] EPA and DHA are found predominately in selected fish while ALA is found in flaxseed grain, canola (rapeseed) oil, certain nuts, and certain vegetables.

The pathways for the desaturation and elongation of omega-3 and omega-6 polyunsaturated fatty acid and eicosanoid production.

Epidemiologic Studies

In the 1970s Bang and Dyerberg[1] studied the dietary habits of Greenland Inuits, as this population was known to have a low mortality rate from CHD ( [7]). This was one of the earliest epidemiologic studies looking at the relationship of dietary n-3 fatty acid intake to the rate of CHD. Dietary surveys indicated that the Inuit diet was not a low-fat diet and that approximately 39% of caloric intake was from fat. Additional analysis revealed their consumption of saturated fat to be low (9% of total calories) while their dietary consumption of n-3 PUFA was high (4.2% of total calories). These findings contrasted sharply with the dietary habits of an ethnically similar population in Denmark with much higher rates of CHD.[8] The Danish diet had a comparable amount of total fat (42% of total calories) but a much lower intake of n-3 PUFA (<1% of total calories) and a much higher intake of saturated fat (22%).

  Table I. Platelet, Phospholipid Fatty Acid Content

In addition to cross-cultural epidemiologic studies, various prospective observational cohort studies have suggested a cardioprotective effect from dietary n-3 fatty acids. Early important cohort studies include the Zutphen and Western Electric studies,[9, 10] which demonstrated an inverse relation between fish consumption and mortality from CHD.

A more recent prospective cohort study, the US Physicians Health Study,[11] evaluated 20,551 US male physicians. The cohort consisted of physicians aged 40-84 without cardiovascular disease. Participants were asked to complete food frequency questionnaires on fish consumption and were then followed for 11 years. Consumption of at least one fish meal per week reduced the risk of sudden cardiac death by 52% (p=0.03), when compared with those consuming fish once a month. All levels of fish consumption up to one meal per week were associated with a decreased risk of sudden death. At levels of consumption greater than one fish meal per week the risk reduction did not change indicating a threshold effect.

Participants in the Physicians Health Study were also involved in a prospective, nested, case-control analysis of whole blood fatty acid composition.[12] The fatty acid composition of previously collected blood was analyzed from 94 men in whom sudden death was the first manifestation of CHD and matched with 184 controls based on age and smoking status. Blood levels of long-chain n-3 fatty acids were inversely related to risk of sudden death both before and after adjustment for potential confounders (p=0.007, for trend). As compared with men whose blood levels of long-chain n-3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the highest quartile (adjusted relative risk, 0.19; 95% confidence interval [CI], 0.05-0.71).

A large prospective cohort study with women has also been completed. Participants in the Nurses Health Study[13] included more than 84,000 female nurses aged 34-59 years without known CHD. Investigators examined the association between fish and long-chain n-3 fatty acid intake and incidence of CHD among women in the cohort during 16 years of follow-up. Compared with women who rarely ate fish (<1 time per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking status, and other cardiac risk factors, the multivariate relative risks of CHD were 0.79 (95% CI, 0.64-0.97) for fish consumption one to three times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for two to four times per week, and 0.66 (95% CI, 0.50-0.89) for five or more times per week (p=0.001, for the trend).

In addition to analyzing the intake of n-3 fatty acids from marine sources (EPA and DHA), The Nurses Health Study[14] examined plant-based sources of n-3 fatty acids (ALA). The intake of ALA was determined from a 116-item food frequency questionnaire. After adjustment for several possible confounding variables, a higher intake of ALA was associated with a lower relative risk of fatal CHD. The relative risks from lowest to highest quintiles ranged from 1.0-0.55 (p=0.01 for trend). The finding that consumption of foods known to be rich dietary sources of ALA was associated with reduced CHD risk further substantiated this inverse association between ALA and fatal CHD. Specifically, women who consumed salad dressings made from oil and vinegar frequently were found to be at lower risk for fatal CHD. Salad dressings are typically made from nonhydrogenated soybean oil which contains about 7% ALA.

In the usual care cohort (n=6250 men) of the Multiple Risk Factor Intervention Trial (MRFIT),[15] multivariate regression analysis was used to determine the effect dietary PUFA intakes had on 10.5-year mortality rates. PUFA intake was calculated from four dietary recall interviews at baseline and follow-up visits at 1, 2, and 3 years. Significant inverse associations were demonstrated for the intake of the n-3 PUFA, ALA, on mortality from CHD (p<0.04), total cardiovascular disease (p<0.03), and all-cause mortality (p<0.02).

Not all prospective cohort studies of the relationship between n-3 fatty acids consumption and cardiovascular mortality have reported inverse associations. Rodriguez et al.[16] evaluated participants of the Honolulu Heart program. This program was started in 1965 and involved 8006 Japanese American men aged 45-65 who lived in Hawaii. Fish intake was measured at baseline by a questionnaire. Fish intake was defined as low if less than two times per week and high if fish was eaten two or more times per week. No significant differences in CHD incidence or CHD mortality were observed between these two fish intake categories (p<0.05).

In another large prospective cohort study, The Health Professionals Follow-up Study,[17] 44,895 male health professionals 40-75 years of age who were free of known cardiovascular disease completed detailed and validated dietary questionnaires. After controlling for age and other coronary risk factors, no significant associations were observed between dietary intake of n-3 fatty acids or fish intake and the risk of coronary disease. For men in the top fifth quintile of intake of n-3 fatty acids, the multivariate risk of CHD was 1.12 (95% CI, 0.96-1.31) compared with men in the bottom fifth.

These studies with negative results involved cohorts with higher baseline intakes of n-3 PUFAs than the earlier cohort studies.[16,17] In addition, these studies had very few participants who consumed less than one fish meal per week and most participants were already at very low risk of CHD. A threshold effect, where fish intake is cardioprotective in very small amounts, could possibly explain these discordant results.

Finally, a recent systematic review of 11 prospective cohort studies by Marckmann and Gronbaek[18] examined the relationship between fish intake and CHD mortality. Four of these studies were assessed to be high quality in terms of study design. Two of the high-quality studies were performed on low-risk populations and demonstrated no cardioprotective effect from fish consumption. The other two high-quality studies were performed on populations at higher risk for CHD. In these higher-risk cohorts they found an inverse association between fish consumption and CHD death. It was suggested that in these higher-risk cohorts, 40-60 g of fish per day could reduce the risk of CHD death by 40%-60%.

Angiographic Trials

The results from randomized controlled trials with fish oils and angiographic end points have been mixed. In a Norwegian study,[19] 610 patients undergoing coronary artery bypass grafting were randomized either to a fish oil group (4 g/day) or to a control group. The primary end point was graft patency at 1 year, which was assessed by angiography. Vein graft occlusion rates were 27% in the fish oil group and 33% in the control group (odds ratio, 0.77; 95% CI, 0.60-0.99; p=0.034). It was also noted that there was an inverse relation between relative changes in serum n-3 PUFA levels and vein graft occlusion.

In another more recent angiographic randomized controlled trial,[20] 223 patients with angiographically proven CHD were randomized to fish oil capsules or a control group with capsules containing fatty acids resembling those in the average European diet. Results showed that n-3 PUFAs had a modest mitigating effect on CHD progression as measured angiographically.

Clinical trials in angioplasty patients have generally not demonstrated a benefit from n-3 PUFA supplementation. Although there have been some trials that are exceptions, the larger high-quality trials have not shown a benefit. A recent randomized trial[21] with 500 elective coronary angioplasty patients compared treatment with fish-derived n-3 PUFA capsules (5 g/day) with a control group receiving corn oil capsules (5 g/day). N-3 PUFA or corn oil was started 2 weeks before angioplasty and continued until evaluation by angiography at 6 months. Restenosis occurred in 40.6% of the n-3 PUFA group and 35.4% of the placebo group (odds ratio, 1.25; 95% CI, 0.87-1.80; p=0.21). On balance, the n-3 PUFAs do not appear to prevent the high rate of restenosis experienced after angioplasty.[21]

Randomized Controlled Secondary Prevention Trials

Large randomized controlled secondary prevention trials with hard clinical end points (CHD death and nonfatal MI) have also been conducted. Trials with clinical end points have been recently completed with both marine-(EPA) and plant-(ALA) based sources of n-3 PUFA ( ).

  Table II. Clinical Trials With n-3 Fatty Acids

One of the earliest trials with clinical end points was the Diet and Reinfarction Trial (DART).[22] This trial involved 2033 Welsh men who recovered from an MI. Participants were randomized to receive advice on one or several dietary changes: a reduction in fat intake, an increase in fish intake, and an increase in cereal fiber intake. Total mortality was the primary end point and the participants were followed for 2 years. The advice on fat or fiber intake was not associated with any change in mortality. The subjects in the fish advice group were instructed to eat mackerel two times per week or to take fish oil capsules if they could not tolerate the fish. Those advised to eat fish had a 29% reduction in 2-year all-cause mortality compared with the non-fish groups (p<0.05). Consuming fish up to two times per week resulted in an absolute risk reduction of 3.5% with the number needed to treat (NNT) to prevent one death equal to 28 over the 2-year length of the trial.

In another smaller secondary prevention trial, the Indian Experiment of Infarct Survival (EIS),[23] 360 patients who were less than 1-day post-MI were studied. These patients were randomized to one of three arms: a group receiving fish oil capsules (1.08 g/day of EPA and 0.72 g/day of DHA), a group receiving 20 g/day of mustard seed oil (2.9 g/day of ALA), and a control group (100 mg/day of aluminum hydroxide). After 1 year, total cardiac events (total cardiac deaths and nonfatal MIs) were significantly less in the fish oil and mustard oil groups compared with the placebo group (24.5% and 28% vs. 34.7%; p<0.01).[23]

In another secondary prevention trial, the Lyon Diet Heart Study,[24] the plant-derived n-3 PUFA ALA was supplemented in a canola oil margarine, along with a Mediterranean style dietary pattern. The rationale for this study was derived from the landmark dietary study, The Seven Country Study,[25] where a cohort from Crete was found to have a lower mortality rate from CHD compared with similar cohorts in other countries. Cretan subjects had three-fold higher serum concentrations of ALA compared with a similar cohort from the Netherlands.[26] With this background, the Lyon Diet Heart Study was conducted to evaluate the effect of a Cretan Mediterranean diet, high in fruits and vegetables, rich in monounsaturated fatty acids (olive oil), and high in ALA on CHD morbidity and mortality. The sources of ALA in the Cretan diet are thought to be leafy vegetables such as purslane in addition to walnuts and legumes. Because olive oil was not gastronomically acceptable to the study population in France, a customized margarine was used that had a fatty acid composition similar to olive oil in being rich in monounsaturated fat, yet supplemented with ALA. The composition of the margarine included 4.8% ALA and 48% monounsaturated fat (oleic acid).[26]

After an initial MI, 605 patients were randomly assigned to the Mediterranean style diet or control group receiving a diet similar to the National Cholesterol Education Program (NCEP) step I diet. Follow-up at 27 months revealed a 76% relative risk reduction in the major primary end points of cardiovascular death and nonfatal MI. The NNT to prevent a second MI or cardiac death was 23.[26] It should be noted that this level of risk reduction occurred without significant changes in low-density lipoprotein (LDL), high-density lipoprotein (HDL), or total cholesterol. The Lyon results compare favorably to other secondary prevention trials with lipid-lowering drugs such as the Scandinavian Simvastatin Survival Study (4S)27 (NNT=12) and the Cholesterol and Recurrent Events (CARE) trial[27] with pravastatin (NNT=34). The risk reduction seen in the Lyon Diet Heart Study was also maintained at the 46-month follow-up visit. Although these results are impressive, one limitation to the Lyon Study is that there were numerous other changes made in the diet of the treatment group so as to resemble a Mediterranean-style dietary pattern. In addition to a three-fold higher dietary intake of ALA, the treatment group was also noted to have significantly higher oleic acid intake (olive oil), a lower saturated fat intake, and a decreased n-6 (LA) intake. This makes it difficult to ascertain whether the cardioprotective effects were from the ALA supplemented margarine or other features of the Mediterranean diet. Although difficult to verify, the study investigators suggest that the majority of the risk reduction was from the ALA supplementation.[26]

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) Prevenzione trial,[29] a secondary prevention trial, enrolled 11,324 post-MI patients in Italy and followed them for 3.5 years. Participants were randomized to one of four groups: one receiving 1 g/day of a fish oil supplement containing 850 mg of EPA and DHA, a group receiving a vitamin E supplement (300 mg/day), a group receiving both, and a control group receiving neither. The primary combined end point was death, nonfatal MI, and stroke. Vitamin E did not demonstrate any clinical benefit, while supplementation with EPA and DHA (850 mg/day) provided significant benefit. Supplementation with fish oil reduced the primary end point 15% by four-way analysis. That this degree of risk reduction could occur in Italian MI survivors on a prototypical Mediterranean diet suggests that greater benefits may be seen with n-3 fatty acids in a Western-style diet typified by high consumption of saturated fats and low intake of n-3 fatty acids.

In a recent post hoc analysis of the time course of the benefit of n-3 fatty acids in the GISSI Prevenzione trial,[30] an early and highly significant reduction of sudden cardiac death was found. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk, 0.59; 95% CI, 0.36-0.97; p=0.037). The reduction in risk of sudden death was statistically significant at 4 months (relative risk, 0.47; 95% CI, 0.219-0.995; p=0.048). This early effect of low-dose n-3 fatty acids (1 g/day) on total mortality and sudden death supports the theory of an antiarrhythmic effect.

Finally, a meta-analysis[31] of 11 randomized controlled trials that compared dietary or supplemental intake of n-3 fatty acids with a control diet or placebo in patients with CHD was recently published.

The risk ratio of nonfatal MI in patients who were on n-3 fatty acid-enriched diets compared with control diets or placebo was 0.8 (95% CI, 0.5-1.2; p=0.16), and the risk ratio of fatal MI was 0.7 (95% CI, 0.6-0.8; p<0.001). Only five of the trials reported the incidence of sudden death. Sudden death was associated with a risk ratio of 0.7 (95% CI, 0.6-0.9; p<0.01). This analysis suggests that n-3 fatty acids, both plant-and fish-based, reduce sudden death in patients with CHD while having little effect on the incidence of nonfatal MI.

Mechanisms of Action

The provocative cardioprotective results of the above clinical trials have sharpened interest in determining the mechanism of action of the n-3 fatty acids cardioprotective effects. It has been suggested that the n-3 fatty acids may be cardioprotective due to multiple mechanisms, but their role as potential antiarrhythmics has recently received added attention. It is hypothesized that n-3 PUFAs stabilize the electrical activity of cardiac myocytes by inhibiting sarcolemmal ion channels resulting in a prolonged relative refractory period.[32] This antiarrhythmic effect was demonstrated by Leaf et al.[33] in work with dogs. Ligating the left main coronary artery while an inflatable cuff was placed around the left circumflex artery produced a surgically induced MI. The dogs were trained to run on a treadmill and screened for susceptibility to ventricular fibrillation when the cuff was inflated. Thirteen dogs were indentified that were susceptible to ventricular fibrillation. These dogs were entered into the study. Intravenous infusion of fish oil before the exercise ischemia test prevented ventricular fibrillation in 10 of 13 dogs. In the control exercise ischemia test conducted both 1 week before and 1 week after the infusion of fish oil, animals were given a soybean oil infusion instead and developed ventricular fibrillation requiring defibrillation. Using the same protocol above, the dogs were also given an intravenous infusion of the plant-derived n-3 fatty acid ALA. Beneficial antiarrhythmic results similar to the fish oil group were also obtained with ALA.

Endothelial function is also favorably affected by n-3 fatty acids, as the vasodilatory effect of nitrous oxide is enhanced by EPA. Treating humans with fish oil has been shown to decrease oxygen-derived free radical production in neutrophils.[34] It has been suggested that this reduction in free radicals increases the bioavailability of nitrous oxide. Studies using ultrasonic tracking of brachial artery flow-mediated vasodilatation have demonstrated improved large artery endothelium-dependent dilatation in patients treated with fish oil.[35] Endothelial function may also be improved by reducing the endothelial expression of vascular cell adhesion molecules thus resulting in a reduction in leukocyte binding to the endothelium.[36]

The n-3 fatty acids also have significant antithrombotic properties. EPA has been shown to inhibit the synthesis of thromboxane A2, a prostaglandin that causes platelet aggregation and vasoconstriction.[36] EPA results in reduced platelet adhesion and reactivity, which manifests itself by increased bleeding time and decreased adhesion of platelets to glass beads.[37] Other antithrombotic effects reported include reductions in fibrinogen and increases in tissue-type plasminogen activator ( ).

  Table III. Effects of n-3 PUFA on Mediators of Atherosclerosis

Ingestion of EPA and DHA has also been shown to inhibit atherosclerotic plaque formation in animal studies. Two important cells in the development of an atherosclerotic plaque are smooth muscle cells and macrophages. Platelet-derived growth factor (PDGF) is a key chemoattractant and mitogen for smooth muscle cells and macrophages. PDGF production and PDGF mRNA synthesis are decreased by ingestion of n-3 fatty acids.[38]

The influence of n-3 fatty acids on lipid metabolism is predominantly antiatherogenic. Fish oil (a rich source of EPA and DHA) has been shown to lower total cholesterol and triglyceride concentration by inhibiting very low-density lipoprotein and triglyceride synthesis in the liver.[39] Large doses of fish oil have been shown to have profound effects in reducing triglycerides in hypertriglyceridemic patients. Apolipoprotein B production is also reduced by fish oil consumption in comparison with vegetable oils not containing n-3 fatty acids.[39] Pretreatment with n-3 fatty acids also markedly reduces postprandial lipemia. Postprandial lipemia typically occurs after a fatty meal and the postpran-dial lipoproteins are atherogenic. Postprandial lipemia is also thrombogenic, as it increases levels of activated factor VII, a procoagulant. It is interesting to note that olive oil results in the same degree of increase in factor VII as butter while fish oil prevents this postprandial increase.[40]

Unlike vegetable oils rich in n-6 fatty acids, n-3 fatty acids do not lower HDL cholesterol levels. In contrast, they have been shown to result in a favorable change in HDL cholesterol metabolism. It appears that n-3 fatty acids cause an increase in the large cholesterol rich HDL2 subtype, while decreasing the smaller triglycerol-enriched HDL3 sub-type.[41, 42] HDL2 is considered to be the most antiatherogenic HDL subtype.

Some questions have been raised about potential atherogenic changes in lipid metabolism caused by the n-3 fatty acids. LDL cholesterol levels have been shown to occasionally increase with n-3 PUFA supplementation; however, this effect does not occur consistently and only occurs at higher doses.[39] Also, some concern has been raised about in vitro studies that demonstrate that n-3 PUFA supplementation may increase LDL cholesterol susceptibility to oxidation. However, it has been demonstrated that this oxidation can be reduced by supplementation with the antioxidant vitamin E.[39]

In summary, the n-3 PUFAs have predominantly antiatherogenic properties ( ). Most of these antiatherogenic effects have been demonstrated with the marine-derived n-3 PUFA. The majority of studies with ALA have evaluated the efficiency with which ALA is converted to the longer-chain n-3 fatty acids, EPA and DHA. More studies are needed to delineate the potential cardioprotective mechanisms of ALA.

  Table III. Effects of n-3 PUFA on Mediators of Atherosclerosis

Dietary Sources of N-3 Fatty Acids

One challenge facing clinicians is recommending palatable sources of ALA, EPA, and DHA. The nationwide Food Consumption Survey[43] suggests that Americans currently get the bulk of their n-3 PUFA from three key food groups: 1) meat, poultry, and fish; 2) vegetable oils and salad dressings; 3) grain products. Certain species of cold water fish such as halibut, mackerel, herring, and salmon are good sources of EPA and DHA ( ).[44] Plant sources of n-3 PUFA include some legumes, such as soy and pinto beans, along with nuts and seeds, especially walnuts and flaxseed. Other plant sources include vegetables such as leeks and purslane ( ).[45] Purslane is well known to the Mediterranean diet, but it is not typically consumed in the US diet. Purslane is a leafy green vegetable that grows in all 50 states and is unique because it is rich in ALA and is one of the few plants known to be a source of EPA.[45] Additionally, various oils rich in ALA can be included in the diet as replacements for other fats. A common oil known to be very high in ALA is canola oil, while flaxseed oil has the highest known concentrations of ALA (58%) ( ).[45] These oils could be substituted for other current sources of dietary fats, such as those fats rich in saturated and transunsaturated fatty acids.

  Table IV. N-3 Fatty Acid Content of Selected Fish

  Table V. Plant Sources of alpha-Linolenic Acid (ALA)

  Table VI. Fatty Acid Composition of Common Oils*

Finally, a variety of marine n-3 PUFA supplements are available to the consumer who cannot tolerate fish or increase their fish consumption. Supplements derived from marine oils contain various amounts of EPA and DHA ( ).[45] For those concerned about the possible mercury contamination of fish, a vegetarian source of DHA derived from algae is also now available. Cod liver oil has also been touted as a good source of EPA and DHA; however, caution should be used because this oil also contains high levels of vitamin and A and D.

  Table VII. Fish Oil Supplements

Current US Consumption and Recommendations

The average US intake of n-3 fatty acids is about 1.6 g/day (about 0.7% of a 2200 kcal diet). The principal sources of n-3 PUFA in the US diet are vegetable oils and fish.[43] Vegetable oils (soybean and canola) are the primary source of ALA, while fish is the leading source of EPA and DHA. Recommending an optimal dietary intake is complicated by the fact that the rate at which ALA is elongated to EPA is determined by the intake of other dietary fats, notably the n-6 PUFA (LA) and trans fatty acids.[43] Although no official recommendations for n-3 PUFA intake have been made in the United States, an expert panel of nutrition scientists recently has suggested some guidelines ( ).[43] The British Nutrition Foundation as well as several other international health organizations has made similar recommendations.[3] Based on these recommendations, ALA intake in the US would have to increase from currently 1.4 g/day to 2.2 g/day (a 57% increase) and EPA and DHA intake would need to be increased from 0.2 g/day to 0.65 g/day (a 400% increase) to comply with the above mentioned recommendations.

  Table VIII. Recommended Average PUFA Intakes Compared With Average Intake in the United States

Implications for Preventive Cardiologists

The available evidence from randomized clinical trials suggests that n-3 PUFAs should have a significant role in the secondary prevention of CHD ( ). Patients with CHD, in particular those at risk for sudden cardiac death (e.g., left ventricular dysfunction, ventricular dysrhythmia, or left ventricular hypertrophy), could initially be advised to increase fish consumption up to one or two servings of fish per week. However, if this was not gastronomically acceptable, one to two fish oil capsules per day (total EPA and DHA of 750-1000 mg) could be an alternative ( ). In general the complaints of an unpleasant fishy aftertaste are only experienced at higher doses of fish oils such as the doses used to treat severe hypertriglyceridemia. In addition to fish oil, plant-based n-3 PUFA (ALA) can be increased in the diet by using canola or flaxseed oil. Other sources of ALA include vegetables such as purslane and leeks, legumes such as pinto or soybeans, and nuts such as walnuts and butternuts. Consultation with a dietitian may be necessary to ensure that patients are not consuming an excess of calories in an attempt to increase n-3 PUFA levels.

  Table II. Clinical Trials With n-3 Fatty Acids

  Table VII. Fish Oil Supplements

In the primary prevention setting, additional evidence is needed before recommending extensive changes in the diet focusing on increasing n-3 PUFA levels. For now, it seems prudent to encourage patients to consume fish at least twice per week or consider ALA-enriched oils or margarine (flaxseed, canola) as substitutes for existing cooking oils and salad dressings. These changes are consistent with the current NCEP III total lifestyle change diet[46] and the latest revision of the American Heart Association dietary guidelines.[47] Primary prevention trials are needed before recommending large changes in the food supply or the consumption of n-3 supplements. However, if small changes in n-3 consumption can lead to the large CHD event reductions seen in secondary prevention, then the impact on public health could be significant.

Conclusions

Evidence from epidemiologic studies and human intervention trials supports a role for n-3 fatty acids in the prevention of CHD. The role of n-3 fatty acids in the secondary prevention of CHD is clearly supported by recent randomized clinical trials including the GISSI Prevenzione Study and the Lyon Diet Heart Study. While these trials have not definitively shown a reduction in nonfatal MI, they have clearly shown a reduction in sudden cardiac death, strongly suggesting an antiarrhythmic effect. The current US consumption of n-3 fatty acids is significantly below recommended levels and new American Heart Association recommendations suggest consuming at least two fish meals per week. Although additional trials are needed, the favorable safety profile and existing clinical trials suggest n-3 fatty acids should be considered a new important adjunct to existing cardiovascular prevention strategies.

References

  1. Dyerberg J, Bang HO, Stoffersen E. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet. 1978; 2(8081):117-119.

  2. Schmidt EB. N-3 fatty acids and the risk of coronary heart disease. Dan Med Bull. 1997;44(1):1-21.

  3. Roche HM. Unsaturated fatty acids. Proc Nutr Soc. 1999;58: 397-401.

  4. Alexander JW. Immunonutrition. The role of omega-fatty acids. Nutrition. 1998;14:627-633.

  5. Gerster H. Can adults adequately convert -linolenic acid (18: 3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)? Int J Vitam Nutr Res. 1998;68:159-173.

  6. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999;70(suppl):560S-569S.

  7. Weber PC. Clinical studies on the effects of n-3 fatty acids on cells and eicosanoids in the cardiovascular system. J Intern Med Suppl. 1989;225(731):61-68.

  8. Kroman N, Green A. Epidemiological studies in the Upernauik district, Greenland. Acta Med Scand. 1980;208:401-406.

  9. Kromhout D, Bosschieter EB, Coulander CEL. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312(19): 1205-1209.

  10. Davilgus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336:1046-1053.

  11. Albert CM, Hennekens CH, O'Donnell CO, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998;279(1):23-28.

  12. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002;346:1113-1118.

  13. Hu FB, Bronner L, Willet W, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002; 287:1815-1821.

  14. Hu FB, Stampfer MJ, Manson JE, et al. Dietary intake of alpha-linolenic acid and risk of fatal ischemic heart disease among women. Am J Clin Nutr. 1999;69:890-897.

  15. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Dietary PUFA and mortality. Proc Soc Exp Biol Med. 2000;2:177-182.

  16. Rodriguez BL, Sharp DS, Dan S, et al. Coronary heart disease/atherosclerosis/myocardial infarction: fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers: the Honolulu Heart Program. Circulation. 1996;94:952-956.

  17. Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary dis-ease among men. N Engl J Med. 1995;332:977-982.

  18. Marckmann P, Gronbaek M. Fish consumption and coronary heart disease mortality. A systematic review of prospective cohort studies. Eur J Clin Nutr. 1999;53:585-590.

  19. Eritsland J, Arnesen H, Gronseth K, et al. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J Cardiol. 1996;77(1):31-36.

  20. Von Schacky C, Angerer P, Kothny W, et al. The effect of dietary omega-3 fatty acids on coronary atherosclerosis - a randomized, double blind, placebo-controlled trial. Ann Intern Med. 1999; 130:554-562.

  21. Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90: 2248-2257.

  22. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2(8666):757-761.

  23. Singh RB, Niaz MA, Sarma JP, et al. Randomized, double blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian Experiment of Infarct Survial-4. Cardiovasc Drugs Ther. 1997; 11:485-491.

  24. De Lorgeril M, Salen P, Martin J-L, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction. Circulation. 1999;99: 779-785.

  25. Keys A. Seven Countries. A multivariate analysis of diet and coronary Heart Disease. Cambridge, MA: Harvard University Press; 1980.

  26. De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454-1459.

  27. The Scandinavian Simvastatin Survival Study (4S). Randomized trial of cholesterol lowering on 4444 patients with coronary heart disease. Lancet. 1994;344:1383-1389.

  28. Sacks FM, Pfeffer MA, Moye MA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.

  29. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione Trial. Lancet. 1999; 354:447-455.

  30. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction. Circulation. 2002;105:1897-1903.

  31. Bucher HC, Hengstler P, Schindler C, et al. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298-304.

  32. Leaf A, Kang JX. Omega-3 fatty acids and cardiovascular disease. World Rev Nutr Diet. 1998;83:24-37.

  33. Leaf A, Kang JX, Xiao Y, et al. N-3 fatty acids in the prevention of cardiac arrhythmias. Lipids. 1999;34:S187-S189.

  34. Goodnight SH Jr, Harris WS, Connor WE. The effects of dietary omega-3 fatty acids upon platelet composition and function in man: a prospective controlled study. Blood. 1981; 58:880-883.

  35. Goodfellow J, Bellamy MF, Ramsey MW, et al. Dietary supple-mentation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol. 2000;35(2):265-270.

  36. Vogel RA, Corretti MC, Plotnick GD, et al. The postprandial effect of components of the Mediterranean diet on endothelial function. J Am Coll Cardiol. 2000;36:1455-1460.

  37. De Caterina RD, Liao JK, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr. 2000;71(1 suppl): 213S-223S.

  38. Fox PL, Dicorleto PE. Fish oils inhibit endothelial cell production of platelet-derived growth factor-life protein. Science. 1988;241: 453-456.

  39. Nestel PJ. Fish oil and cardiovascular disease: lipids and arterial function. Am J Clin Nutr. 2000;71(1 suppl):228S-231S.

  40. Harris WS, Connor WE, Alam N, et al. The reduction of post-prandial triglyceridemia in humans by dietary n-3 fatty acids. J Lipid Res. 1988;29:1451-1460.

  41. Mori TA, Bao DQ, Burke V, et al. Dietary fish as a major component of a weight loss diet: effect on serum lipids, glucose and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr. 1999;70:817-825.

  42. Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71: 1085-1094.

  43. Kris-Etherton PM, Taylor DS, Yu-Poth S, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr. 2000;71(suppl):179S-188S.

  44. Simopoulos AP. The Return of Omega-3 Fatty Acids Into the Food Supply. Land-Based Animal Food Products and Their Health Effects. New York, NY: Karger; 1998.

  45. Simopoulos AP, Robinson J. Appendix. The Omega Diet. New ork, NY: Harper Collins Publishers; 1998.

  46. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol In Adults. (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

  47. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines, revision 2000; a statement for healthcare professionals from the nutrition committee of the AHA. Circulation. 2000;102(18): 2284-2299.