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The Fats of Life
The Role of Omega-3 Fatty Acids in the Prevention of Coronary Heart Disease
Charles R. Harper, MD;
Terry A. Jacobson, MD
Arch Intern Med. 2001;161:2185-2192.
ABSTRACT
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Epidemiological and clinical trial evidence suggests that  -3
polyunsaturated fatty acids (PUFAs) might have a significant role in the prevention
of coronary heart disease. Dietary sources of -3 PUFA include fish
oils rich in eicosapentaenoic acid and docosahexaenoic acid along with plants
rich in  -linolenic acid. Randomized clinical trials with fish oils
(eicosapentaenoic acid and docosahexaenoic acid) and -linolenic acid
have demonstrated reductions in risk that compare favorably with those seen
in landmark secondary prevention trials with lipid-lowering drugs. Several
mechanisms explaining the cardioprotective effect of -3 PUFAs have
been suggested, including antiarrhythmic, hypolipidemic, and antithrombotic
roles. Although official US guidelines for the dietary intake of -3
PUFAs are not available, several international guidelines have been published.
Fish is an important source of -3 PUFAs in the US diet; however, vegetable
sources, including grains and oils, offer an alternative source for those
who are unable to regularly consume fish.
INTRODUCTION
The past 3 decades have been a period of rapid expansion in the scientific
knowledge of -3 polyunsaturated fatty acids (PUFAs). Beginning with
the study by Dyerberg et al1 involving Greenland
Eskimos in the late 1970s, the body of evidence supporting a role for -3
PUFAs in the prevention of coronary heart disease (CHD) has continued to grow.
Evidence from recent randomized trials2-5
in patients with CHD suggests that intake of -3 PUFAs from marine sources
(eicosapentaenoic acid [EPA]) and plant sources (-linolenic acid [ALA])
prevents cardiac death and nonfatal myocardial infarction (MI). This article
reviews the available epidemiological evidence concerning -3 PUFAs
and their inverse relationship with CHD. Review of their structure, nomenclature,
and possible cardioprotective effects are then explored. Evidence from recent
interventional clinical trials is reviewed, and clinical implications are
discussed.
EPIDEMIOLOGICAL EVIDENCE
In the 1970s, Dyerberg et al1 evaluated
the dietary habits of Greenland Eskimos, a population known to have a low
mortality rate from CHD. This was one of the first epidemiological studies
to explore the relationship between dietary -3 PUFA intake and the
rate of CHD. Results of dietary surveys indicated that the Eskimo diet was
not a low-fat diet and that approximately 39% of caloric (energy) intake was
from fat. Further analysis revealed the intake of saturated fat to be low
(9% of total calories), whereas the dietary intake of -3 polyunsaturated
fat (-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. The Danish diet had a comparable amount of
total fat (42% of total calories) but a much lower intake of -3 polyunsaturated
fat (<1% of total calories) and a much higher intake of saturated fat (22%
of total calories). A second similar study6
followed inhabitants of Greenland and Denmark for 25 years; a 10-fold increase
in MI was noted in the Danish Group.
In addition to cross-cultural epidemiological studies, results of various
prospective observational cohort studies have suggested a cardioprotective
effect of dietary -3 PUFAs. Early important cohort studies include
the Zutphen and Western Electric studies,7-8
which demonstrated an inverse relation between fish consumption and mortality
from CHD.
In a more recent prospective cohort study,9
the US Physicians Health Study, 20 551 US male physicians aged 40 to
84 years who were free of cardiovascular disease were evaluated. These men
were asked to complete food frequency questionnaires on fish consumption and
were then followed up for 11 years. Consuming at least 1 fish meal per week
reduced the risk of sudden cardiac death by 52% (P
= .03) compared with those consuming fish only monthly. All levels of fish
consumption up to 1 meal per week were associated with decreased risk of sudden
death. At levels of consumption greater than 1 fish meal per week the risk
reduction did not change, indicating a threshold effect.
The previously mentioned studies involved predominantly the -3
PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are
derived from marine sources. However, cohort studies have also examined plant-based
sources of -3 PUFA (ALA). In the usual care cohort (n = 6250 men) of
the Multiple Risk Factor Intervention Trial (MRFIT),10
multivariate regression analysis was used to determine the effect that dietary
PUFA intakes had on 10 -year mortality rates. Intake of PUFA was calculated
from 4 dietary recall interviews at baseline and 1-, 2-, and 3-year follow-up.
Significant inverse associations were demonstrated for the intake of the -3
PUFA ALA on mortality rates from CHD (P<.04),
total cardiovascular disease (P<.03), and all-cause
mortality (P<.02).
Participants in the Nurses Health Study11
consisted of 76 283 women aged 30 to 55 years who were free of cardiovascular
disease. Intake of ALA was derived 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 1.00 to 0.55 (P = .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 oil and vinegar salad dressing frequently were at lower
risk for fatal CHD. Salad dressings are typically made with unhydrogenated
soybean oil, which contains approximately 7% ALA.
Not all prospective cohort studies of the relationship between -3
PUFA consumption and cardiovascular mortality rates have reported inverse
associations. Three negative studies12-14
involved cohorts with higher baseline intakes of -3 PUFAs than the
earlier cohort studies. In addition, these studies had few participants who
consumed less than 1 fish meal per week. A threshold effect, in which fish
intake is cardioprotective in small amounts, could possibly explain these
discordant results. In addition, each population studied was already at low
risk for CHD.
Finally, a recent systematic review of 11 prospective cohort studies
by Marckmann and Gronbaek15 examined the relationship
between fish intake and CHD mortality rates. Four of these studies were judged
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 2 high-quality studies were performed
on populations at higher risk for CHD and found an inverse association between
fish consumption and CHD death. It was suggested that in these higher-risk
cohorts, consumption of 40 to 60 g of fish per day could reduce the risk of
CHD death by 40% to 60%. To date, there has been no systematic review that
examines -3 PUFA intake from both marine and plant sources.
STRUCTURE AND NOMENCLATURE
Fatty acids consist of a hydrocarbon chain with a hydrophobic methyl
group at one end and a hydrophilic carboxyl group at the other end (Figure 1).16
The methyl end of the molecule is also referred to as the omega end, and the
carboxyl group is located at the delta end. Biochemists describe fatty acids
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 and
the number and location of the double bonds determine the properties of the
different fatty acids. Fatty acids are also categorized by the number of double
bonds present in the fatty acid molecule. A fatty acid can be saturated (no
double bonds), monounsaturated (1 double bond), or polyunsaturated ( 2
double bonds).17
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Figure 1. Important fatty acids. The number
of carbon atoms is indicated first 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.16
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Polyunsaturated fatty acids can be divided into 2 subcategories: -3
and -6. The -3 PUFAs have their first double bond located at
the third carbon molecule (C-3), whereas the -6 PUFAs have their first
double bond located at C-6. The -6 and -3 PUFAs are considered
essential fatty acids because humans cannot synthesize them and they must
be obtained through the diet. The -3 PUFA ALA and the -6 PUFA
linoleic acid are the predominant essential fatty acids in humans.17 Linoleic acid can be elongated and desaturated to
arachidonic acid, whereas ALA is elongated and desaturated into EPA and then
into DHA (Figure 2). Eicosapentaenoic
acid and DHA are the major -3 PUFAs found in fish and are thought to
be responsible for the cardioprotective effect.18
It is thought that ALA conversion to EPA might depend on levels of the -6
PUFA linoleic acid because ALA and -6 PUFAs are competitive substrates
for the rate-limiting enzyme  6 desaturase (Figure 2).19 Leukotrienes, prostaglandins,
and thromboxanes are eicosanoids that are derived from the previously mentioned
essential fatty acids. Eicosanoids derived from arachidonic acid are generally
proinflammatory and proaggregatory agonists, whereas those derived from -3
PUFAs tend to inhibit platelet aggregation and be anti-inflammatory.20 Eicosapentaenoic acid and DHA are found predominantly
in certain fish, whereas ALA is found in flaxseed grain, canola oil, and certain
vegetables.
CARDIOVASCULAR EFFECTS OF -3 PUFAs
Although many researchers have suggested that -3 PUFAs might
be cardioprotective due to multiple mechanisms, their role as potential antiarrhythmics
has recently received serious attention. It is thought that -3 PUFAs
stabilize the electrical activity of cardiac myocytes by inhibiting sarcolemmal
ion channels, resulting in a prolonged relative refractory period.21 This antiarrhythmic effect was demonstrated by Leaf
and Kang22 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 were screened for susceptibility to ventricular
fibrillation when the cuff was inflated. Susceptible dogs (n = 13) were then
studied. Intravenous infusion of fish oil before the exercise ischemia test
prevented ventricular fibrillation in 10 of 13 dogs. In the control exercise
ischemia tests conducted 1 week before and 1 week after infusion of fish oil,
animals were given a soybean oil infusion instead and developed ventricular
fibrillation that required defibrillation. Using the same protocol, the dogs
were also given an intravenous infusion of the plant-derived -3 PUFA
ALA. Beneficial antiarrhythmic results similar to those in the fish oil group
were obtained with ALA.
The -3 PUFAs also have significant antithrombotic properties.
Eicosapentaenoic acid has been shown to inhibit the synthesis of thromboxane
A2, a prostaglandin that causes platelet aggregation and vasoconstriction.23 Ingestion of EPA results in reduced platelet adhesion
and reactivity, which manifests itself as increased bleeding time and decreased
adhesion of platelets to glass beads.24 Other
antithrombotic effects reported include reductions in fibrinogen and increases
in tissue plasminogen activator (Table 1).20
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Table 1. Effects of -3 PUFAs on Mediators of Atherosclerosis*
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Endothelial function is also favorably affected by -3 PUFAs because
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.25 It has been suggested that
this reduction in free radicals increases the bioavailability of nitrous oxide.
Studies26 using ultrasonic tracking of brachial
artery flow-mediated vasodilation have demonstrated improved large artery
endothelium-dependent dilation in patients treated with fish oil. Endothelial
function can also be improved by reducing the endothelial expression of vascular
cell adhesion molecules, thus resulting in a reduction in leukocyte binding
to the endothelium.27
Ingestion of EPA and DHA also has been shown in animal studies to inhibit
atherosclerotic plaque formation. Two important cells in the development of
an atherosclerotic plaque are smooth muscle cells and macrophages. Platelet-derived
growth factor is a key chemoattractant and mitogen for smooth muscle cells
and macrophages. Platelet-derived growth factor production and messenger RNA
synthesis are decreased by the ingestion of -3 PUFAs.28
The effect of -3 PUFAs on lipid metabolism is predominantly antiatherogenic.
Consuming fish oil (a rich source of EPA) has been shown to lower total cholesterol
and triglyceride concentrations by inhibiting very low-density lipoprotein
and triglyceride synthesis in the liver.29
Large doses of fish oil have been shown to have profound effects in reducing
triglyceride levels in hypertriglyceridemic patients. Apolipoprotein B production
is also reduced by fish oil consumption compared with vegetable oils not containing -3
PUFAs.29 Pretreatment with -3 PUFAs
also markedly reduces postprandial lipemia, which typically occurs after consumption
of a fatty meal, and postprandial lipoproteins are atherogenic. Postprandial
lipemia is also thrombogenic because it increases levels of activated factor
VII, a procoagulant. Ingesting olive oil results in the same degree of increase
in factor VII as ingesting butter, whereas consuming fish oil prevents this
postprandial increase.30
Unlike vegetable oils rich in -6 PUFAs, -3 PUFAs do not
lower high-density lipoprotein (HDL) cholesterol levels. In contrast, they
have been shown to result in a favorable change in HDL cholesterol metabolism.
It seems that -3 PUFAs cause an increase in the large cholesterol-rich
HDL2 subtype while decreasing the smaller triglycerol-enriched
HDL3 subtype31-32;
HDL2 is considered to be the most antiatherogenic HDL subtype.
Some concerns have been raised about potential atherogenic changes in
lipid metabolism caused by -3 PUFAs. Low-density lipoprotein cholesterol
levels have been shown to occasionally increase with -3 PUFA supplementation;
however, this effect does not occur consistently.31
Also, some concern has been raised about in vitro studies that demonstrate
that -3 PUFA supplementation might increase low-density lipoprotein
cholesterol susceptibility to oxidation. It has been demonstrated, however,
that this oxidation can be reduced by supplementation with the antioxidant
vitamin E.29
In summary, -3 PUFAs have mostly antiatherogenic properties.
Most of these antiatherogenic effects have been demonstrated with the marine-derived -3
PUFAs. Most studies with ALA have evaluated the efficiency with which it is
converted to the longer chain -3 PUFAs EPA and DHA. More studies are
needed to delineate the potential cardioprotective mechanisms of ALA.
ANGIOGRAPHIC TRIALS
Randomized, controlled trials with fish oils with angiographic end points
have had mixed results. In a Norwegian study,33
610 patients undergoing coronary artery bypass grafting were randomly assigned
either to a fish oil group (4 g/d) 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% confidence interval, 0.60-0.99; P = .034). It was also noted that there was an inverse relation between
relative changes in serum -3 PUFA levels and vein graft occlusions.33
In another more recent angiographic, randomized, controlled trial,34 223 patients with angiographically proven CHD were
randomized to receive fish oil capsules or to a control group receiving capsules
containing PUFAs resembling those in the average European diet. Results showed
that ingesting -3 PUFAs had a modest mitigating effect on the progression
of CHD.
Clinical trials in patients undergoing angioplasty generally have not
demonstrated a benefit from -3 PUFA supplementation. Although some
trials are exceptions, the larger high-quality trials have not shown a benefit.
A recent study35 with 500 patients undergoing
elective coronary angioplasty randomized participants to treatment with fish-derived -3
PUFA capsules (5 g/d) or a control group receiving corn oil capsules (5 g/d).
Treatment with -3 PUFA or corn oil was started 2 weeks before angioplasty
and was continued until evaluation by angiography at 6 months. Restenosis
occurred in 40.6% of the -3 PUFA group and 35.4% of the placebo group
(odds ratio, 1.25; 95% confidence interval, 0.87-1.80; P = .21). Treatment with -3 PUFAs does not seem to prevent the
high rate of restenosis experienced after angioplasty.35
CLINICAL TRIALS
Perhaps the most provocative studies concerning the role of dietary -3
PUFAs in CHD are the randomized, controlled, secondary prevention trials with
hard clinical end points (CHD death and nonfatal MI). Trials with clinical
end points have been completed recently with marine-based (EPA) and plant-based
(ALA) sources of -3 PUFA (Table 2).
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Table 2. Clinical Trials With -3 Polyunsaturated Fatty Acids*
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One of the first trials with clinical end points was the Diet and Reinfarction
Trial (DART),2 which involved 2033 Welsh men
who recovered from an MI. Participants were assigned to receive or not receive
advice on each of 3 dietary components: 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 participants were followed up for 2 years. The
advice on fat or fiber intake was not associated with any change in the mortality
rate. Participants in the fish advice group were instructed to eat mackerel
2 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 nonfish groups (P<.05). Consuming
fish 2 times per week resulted in an absolute risk reduction of 3.5%, with
a number needed to treat (NNT) to prevent 1 death of 28 during the 2-year
trial.
In the Lyon Diet Heart Study,3 the plant-derived -3
PUFA ALA was supplemented in a canola oil margarine, along with a Mediterranean
diet pattern. The rationale for this study was derived from a landmark dietary
study, The Seven-Country Study, in which a cohort from Crete had a lower mortality
rate from CHD compared with similar cohorts in other countries. Cretan participants
had 3-fold higher serum concentrations of ALA compared with a similar cohort
from the Netherlands.36 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
rates. The sources of ALA in the Cretan diet are thought to be leafy vegetables
such as purslane, in addition to nuts 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).36
After a first MI, 605 patients were randomly assigned to receive the
Mediterranean-style diet or to a control group receiving a diet similar to
the National Cholesterol Education Program Step I diet. At 27 months, there
was a 76% relative risk reduction in the major primary end points of cardiovascular
death and nonfatal MI. The NNT was 23.36 This
level of risk reduction occurred without significant changes in low-density
lipoprotein, HDL, or total cholesterol. The Lyon results compare favorably
with those of other secondary prevention trials with lipid-lowering drugs
such as the Scandinavian Simvastatin Survival Study37
(NNT = 12) and the Cholesterol and Recurrent Events (CARE) trial38
with pravastatin (NNT = 34). The risk reduction seen in the Lyon Diet Heart
Study was also maintained at 46-month follow-up of the Lyon patients. Although
these results are impressive, one limitation of 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 3-fold
higher dietary intake of ALA, the treatment group had significantly higher
oleic acid intake (olive oil), lower saturated fat intake, and decreased -6
PUFA (linoleic acid) intake. This makes it difficult to ascertain whether
the cardioprotective effects were from the ALA-supplemented margarine or from
other features of the Mediterranean diet. Although difficult to verify, the
study investigators suggest that most of the risk reduction was from the ALA
supplementation.3, 36
In another smaller secondary prevention trial, the Indian Experiment
of Infarct Survival,4 360 patients less than
1 day after MI were randomized to 1 of 3 arms: a group receiving fish oil
capsules (EPA, 1.08 g/d, and DHA, 0.72 g/d), a group receiving mustard seed
oil, 20 g/d (ALA, 2.9 g/d), and a control group (aluminum hydroxide, 100 mg/d).
After 1 year, total cardiac events (total cardiac deaths and nonfatal MI)
were significantly less in the fish oil and mustard oil groups compared with
the placebo group (24.5% and 28.0%, respectively, vs 34.7%; P<.01).4
Finally, in a recent secondary prevention trial, the GISSI-Prevenzione
Trial,5 11 324 post-MI patients in Italy
were followed up for 3 years. Participants were randomized to 1 of
4 groups: one receiving a fish oil supplement, 1 g/d, containing 850 mg of
EPA and DHA; a group receiving a vitamin E supplement (300 mg/d), a group
receiving both; and a control group receiving neither. Use of vitamin E did
not demonstrate any clinical benefit, whereas supplementation with EPA (850
mg/d) provided significant benefit. Supplementation with fish oil reduced
cardiovascular events (cardiovascular death, nonfatal MI, and nonfatal stroke)
by 20% (P = .008). That this degree of risk reduction
could occur in Italian heart attack survivors practicing a prototypical Mediterranean
diet suggests that greater benefits might be seen with -3 PUFAs in
a western-style diet typified by increased consumption of saturated fats and
low intake of -3 PUFAs.
CURRENT US CONSUMPTION AND RECOMMENDATIONS
In the United States, the average intake of -3 PUFAs is about
1.6 g/d (about 0.7% of a 9240-kJ [2200 kcal] diet). The principal sources
of -3 PUFA in the US diet are vegetable oils and fish.39
Vegetable oils (soybean and canola) are the primary source of ALA, and 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 -6 PUFAs
(linoleic acid) and trans fatty acids.40
Although no official recommendations for -3 PUFA intake have been made
in the United States, an expert panel of nutrition scientists recently suggested
some guidelines (Table 3).39 The British Nutrition Foundation as well as several
other international health organizations made similar recommendations.17 Based on these recommendations, ALA intake in the
United States would have to increase from 1.4 g/d to 2.2 g/d (a 57% increase)
and EPA and DHA intake would have to increase from 0.2 g/d to 0.65 g/d (a
400% increase) to comply with the previously mentioned recommendations.
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Table 3. Recommended Average -3 PUFA Intakes Compared With the
Average Intake in the United States*
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DIETARY SOURCES OF -3 PUFAs
One challenge facing physicians and other primary care providers is
recommending palatable sources of ALA, EPA, and DHA. Results of the Nationwide
Food Consumption Survey41 suggest that Americans
currently get the bulk of their -3 PUFA from 3 key food groups: (1)
meat, poultry, and fish; (2) vegetable oils and salad dressings; and (3) grain
products. Certain species of fatty cold water fish, such as halibut, mackerel,
herring, and salmon, are good sources of EPA and DHA (Table 4).42 Plant sources of -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 (Table 5).40 Purslane is a leafy green vegetable that is found
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.40 Purslane
is well known in the Mediterranean diet, but it is not typically consumed
in the US diet. In addition, various oils rich in ALA can be included in the
diet as replacements for other fats. Common oils known to be very high in
ALA include canola and soybean oil, and flaxseed oil has the highest known
concentration of ALA (58%) (Table 6). 42 These oils could be substituted for other current
sources of dietary fats, such as fats rich in saturated and trans-unsaturated fatty acids.
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Table 4. -3 Polyunsaturated Fatty Acid Content of Selected Fish*
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Table 5. Plant Sources of -Linolenic Acid
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Table 6. Fatty Acid Composition of Common Oils*
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Finally, a variety of marine -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.
A vegetarian source of DHA derived from algae is also now available. Cod liver
oil also has been touted as a good source of EPA and DHA; however, caution
should be used because this oil contains high levels of vitamins A and D.
CLINICAL IMPLICATIONS OF -3 PUFAs
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