By Dr. Holub
Professor, Department of
Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ont.
ON N1G 2W1
During the past few years, there has been
an increase in both scientific and public interest in the role of omega-3 fatty
acids found in fish and fish oils in the prevention and management of cardiovascular
The omega-3 fatty acids that are of particular
interest for cardiovascular care include EPA (eicosapentaenoic acid) and DHA (docosahexaenoic
acid), which are found predominantly in fish and fish oils.1,2,3 The basis of this
heightened interest in dietary intakes of EPA and DHA comes partly from epidemiological
and population studies4 indicating that increased consumption of fish as a source
of omega-3 fatty acids is often associated with decreased mortality (as well as
morbidity) from cardiovascular disease.
Controlled-intervention trials in humans have
indicated a favorable modifying effect of dietary fish oils on various risk factors
for cardiovascular disease independent of their lowering of blood cholesterol.1,2,3
Dietary supplementation with encapsulated
omega-3 fish oil concentrates has shown the potential to reduce both the progression
of cardiovascular disease and related mortality, including sudden cardiac death.5,6
What Are Omega-3
Omega-3 fatty acids are long-chain polyunsaturated
fatty acids (18-22 carbon atoms in chain length) with the first of many double bonds
beginning with the third carbon atom (when counting from the methyl end of the fatty
The fish-based and fish-oil-based omega-3
polyunsaturated fatty acids (also referred to as n-3 PUFA) consist of EPA (20 carbon
atoms, 5 double bonds) and DHA (22 carbon atoms, 6 double bonds).
Whereas plant foods and vegetable oils lack
EPA and DHA, some do contain varying amounts of the n-3 PUFA alpha-linolenic acid
(ALA), which has 18 carbon atoms and 3 double bonds. Many vegetable oils are greatly
enriched in omega-6 fatty acids (mainly as linoleic acid in corn, safflower, sunflower
and soybean oils), but canola oil (nonhydrogenated), ground flaxseed and walnuts
are rich sources of ALA.
The typical North American diet provides about
1-3 g of ALA per day but only 0.10-0.15 g
of EPA plus DHA per day.7,8 The very high intake of
n-6 PUFA, mostly as linoleic acid (LA) in our diet (12-15 g/day) from common vegetable oils (corn,
safflower, soybean) and other sources.
Although high intakes of LA can provide some
modest blood cholesterol lowering, experimental studies in animals have raised concerns
regarding the enhancing effect of these high intakes on certain cancers.10 This
association has not been established in human studies.11
Evidence For The Cardioprotective Effects Of EPA And DHA
It has long been recognized 12 that disease
patterns for the Greenland Inuit, when compared with those for the population of
Denmark, exhibit a significantly lower rate of death from acute myocardial infarction
despite only moderate differences in blood cholesterol levels.
The high-fat traditional Inuit diet provides
up to several grams of omega-3 fatty acid (EPA and DHA) daily in the form of marine
mammals (seal, whale), wildfowl (seabirds) and various fish.12,13
Furthermore, the higher fish intakes of the
Japanese population relative to that of North America have been associated with
considerably lower rates of acute myocardial infarctions, other ischemic heart disease
and atherosclerosis despite only moderately lower blood cholesterol levels in the
Various studies have also indicated that long-term
consumption of fish (up to 2-3 servings per week) appears to be associated with
lower primary and secondary heart attack rates and death from cardiovascular disease.4,15,16
Fatty acid analyses of serum and plasma phospholipid,
a biomarker for EPA and DHA intake and physiological status, have indicated that
omega-3 fatty acids in general and DHA levels in particular are inversely correlated
with coronary heart disease in men.17 Among the Inuit of Nunavik, progressive increases
in levels of EPA and DHA in plasma phospholipid have been found both to reflect
dietary intakes of these fatty acids and to be beneficially associated with key
risk factors for cardiovascular disease.18
And Physiological Mechanisms Of Action For EPA And DHA
Increasing the intake of EPA and DHA results
in a corresponding increase of these omega-3 fatty acids in tissue or cellular lipids
and circulatory lipids1,18 along with a simultaneous reduction in the omega-6 fatty
acids such as LA and arachidonic acid (AA).
The fatty acid shifts are particularly pronounced
in the cell membrane-bound phospholipid components. These changed profiles alter
the physicochemical properties of:
- Cell membranes and their functioning and
- Modify cell signaling,
- Gene expression and biosynthetic processes,
- Eicosanoid formations
The eicosanoids formed via oxygenase enzymes
acting on AA and EPA include prostaglandins, leukotrienes and thromboxanes.
The beneficial effects of omega-3 fatty acids
on cardiovascular disease are mediated by both eicosanoid-dependent and eicosanoid-independent
processes. For example, the reduced blood platelet reactivity (antithrombotic effect)
observed with increased EPA and DHA intakes involves the reduced formation of the
proaggregatory eicosanoid known as thromboxane A2 (TxA2).
And Risk Factor Modification Using EPA And DHA
Intervention studies using fish oil concentrates
that provide EPA and DHA at intakes of up to 2-4g/day over a few weeks1,2,3 have
shown that these fatty acids can favorably lower various risk factors for cardiovascular
disease (independent of any blood cholesterol-lowering effect). These effects include
an antithrombotic effect, lipid (triglyceride) lowering, reduced blood and plasma
viscosity, and improvements in endothelial dysfunction.1,2,3,19
Omega-3 fatty acids accumulate to a considerable
extent in various sites including circulating blood platelets, the heart and serum
phospholipid. The accumulation of EPA and DHA in platelets is associated with decreased
platelet adhesiveness and aggregation and an overall reduction in thrombogenicity.
Antiatherogenic effects of omega-3 fatty acids have also been shown in animal studies.
Human studies have revealed the potent ability
of EPA and DHA to significantly reduce circulating levels of blood triglyceride,20
which is of interest because only moderate elevations in triglyceride have been
associated with a progressively increased risk of ischemic heart disease.21
Within 2-3 weeks of EPA and DHA supplementation,
significantly reduced blood triglyceride levels with an approximate reduction of
6%-8% (or more) per gram of EPA and DHA consumed are routinely observed. In a placebo-controlled,
double-blind trial,22 a 26% lowering in fasting triglyceride levels in postmenopausal
women receiving 4 g omega-3 (EPA and DHA) daily over 28 days was recently demonstrated.
Supplementation with omega-3 (EPA and DHA),
as given in addition to statin therapy in patients with combined hyperlipidemia,23
was found to reduce levels of atherogenic lipoproteins while more effectively reducing
the hemostatic risk profile.
The antiarrhythmic potential of EPA and DHA
(upon accumulation in cardiac tissue) has been considered to be yet another important
mechanism24 by which consumption of these fatty acids can reduce mortality related
to cardiovascular disease (particularly sudden cardiac death). This last effect
is considered to be exhibited at even lower intakes of omega-3 (EPA and DHA combined)
of about 1 g/day.4
Because it appears that lower heart rate variability
may be used to predict an increased risk of coronary heart disease,25 mortality
and arrhythmic events, evidence that 4 g/day of EPA and DHA (about 1.5% of daily
energy intake) may increase heart rate variability in survivors of myocardial infarction
is of interest.26
Heart rate variability, a noninvasive marker
of autonomic nervous system function, is reduced with sympathetic predominance and
other factors (including reduced baroflex sensitivity) that may be favourably modified
by omega-3 fatty acids. Dietary supplementation with fish oil enriched with EPA
and DHA (up to 3-4 g omega-3/day) has also been reported to enhance systemic large-artery
endothelial function as measured in male subjects with hyperlipidemia by ultrasonic
vessel wall tracking.19
Consumption of EPA and DHA at levels approaching
2 g/day is similar to that seen in large sectors of the Japanese population and
well below the intakes of the Greenland Inuit.
Intakes of about 3-4 g of EPA and DHA per
day have resulted in a moderate increase in bleeding times that are generally lower
than those seen with ASA therapy. Particular attention should be given to hemostatic
factors in patients on high-dose EPA and DHA who are also receiving therapy that
affects blood coagulation and thrombogenic factors. On rare occasions, mild bouts
of diarrhea or other minor gastrointestinal disturbances are sometimes seen with
the use of encapsulated fish oil supplementation.
What about ALA?
For those who do not consume fish, the omega-3
fatty acid known as ALA can be a dietary source of some metabolically derived EPA
and DHA. Desaturation plus elongation reactions occur in the liver and elsewhere
in the body and provide for the conversion of dietary ALA to EPA and DHA.
The conversion of ALA to EPA and DHA occurs
to a low extent (about 10%-15% efficiency) in the adult human body.27 Nonetheless,
there is evidence28 that the benefits of the Mediterranean-type diet after myocardial
infarction may be partly caused by the higher intake of ALA (commonly found in nonhydrogenated
canola oil, ground flaxseed and other selected ALA-enriched foods).
A prospective cohort study (Nurses Health
Study) revealed an inverse relation between ALA intakes and the risk of fatal ischemic
heart disease among women.29 However, the Zutphen Elderly Study30 did not observe
a beneficial effect of dietary ALA on the 10-year risk of coronary artery disease.
The metabolic conversion
of ALA to the longer chain omega-3 fatty acids (EPA and DHA) is thought to mediate
any possible cardioprotective effects of dietary ALA. In contrast to the well-recognized
serum triglyceride-lowering effect of EPA and DHA, most human intervention studies
with ALA (e.g., using flaxseed oil) have not exhibited any lipid-lowering effects.
Whereas ALA (from flaxseed oil) at a relatively
high dose has been found to improve arterial compliance,31 considerably lower supplementation
levels of EPA and DHA improved arterial and endothelial functioning in subjects
with hypercholesterolemia19 and subjects with type 2 diabetes mellitus.32
With Fish Oil Supplements And "Hard" End Points
Recent studies have focused upon the potential
for fish oil supplements (enriched with EPA and DHA) to modify clinical end points
in patients with respect to coronary atherosclerosis and myocardial infarctions.
A European study of the effect of dietary
omega-3 fatty acids on coronary atherosclerosis (measured via coronary angiography)
in patients with cardiovascular disease using a randomized, double-blind, placebo-controlled
trial has been reported.33 This study revealed that patients with coronary artery
disease given omega-3 (EPA and DHA) therapy (at levels of about 1.5 g/day) over
2 years had moderately less progression and more regression of coronary artery disease
(discernible, modest mitigation of atherosclerosis) than did patients on placebo.
Fewer clinical cardiovascular events (fatal
and nonfatal myocardial infarctions, stroke) were noted in the omega-3 group. The
omega-3 supplementation was considered safe and well tolerated.
Very recently, the 1999 GISSI-Prevenzione
trial results have been reported from Italy.6 In this study, 11 324 patients who
had experienced a myocardial infarction were assigned to supplemental interventions
following the introduction of a Mediterranean-type diet (which included moderate
fish consumption), as well as aggressive treatment with various pharmaceutical agents
for cardiovascular care.
About half the patients received an encapsulated
omega-3 fish oil supplementation (providing 850-882 mg/day EPA plus DHA). Over the
subsequent interval (3.5 years), the individuals who received omega-3 supplements
were found to exhibit a significant reduction in overall cardiovascular deaths and
a reduction in sudden cardiac death of about 45%.
Vitamin E (-tocopherol) supplementation, which
was also studied in this trial, was without significant effect in this regard. These
findings support the concept that, independent of blood cholesterol lowering, EPA
and DHA intakes (including supplementation) can favorably influence mortality related
to cardiovascular disease (particularly sudden cardiac death) via various mechanisms
including antiarrhythmic effects (Table 2).
Of EPA And DHA For Cardiovascular Health
The mean current daily intake of EPA and DHA
combined in a typical North American diet (which includes about one fish serving
every 10 days) approaches 130 mg/day, which is about 0.15% of total dietary fat
Most dietary EPA and DHA is consumed in
the form of fish or seafood.
This dietary intake is markedly lower than
Japanese intakes and only a small fraction of the EPA and DHA consumed by the Greenland
and Nunavik Inuit. Fish consumed 2.5-3 times per week would provide a combined intake
of about 500 mg EPA and DHA per day.
This intake is about 4 times that of current
North American consumption rates. Epidemiological data from the Multiple Risk Factor
Intervention Trial in the United States have indicated that progressively higher
intakes of the fish-derived omega-3 fatty acids (up to about 665 mg/day) over 10.5
years were associated with a progressive reduction in mortality related to coronary
heart disease, as well as total mortality with no associated increase in total cancer-related
A recent review of the existing evidence indicated
that an increase in the consumption of fish may contribute to lower colorectal cancer
and breast cancer risks.35
In summary, there is evidence for the beneficial
effect of regular fish consumption (up to 2-3 times/week) both in healthy subjects
and in those at considerable risk for coronary artery disease or with established
coronary artery disease.
Fried or processed fish containing partially
hydrogenated fats ("trans" fatty acids) and salted or pickled fish, should
be avoided. A National Institutes of Health workshop held in 1999 resulted in the
recommendation of a combined average EPA and DHA intake of 650 mg/day for healthy
The newly released American Heart Association
guidelines37 included the following recommendations with respect to omega-3 fatty
acid supplements: "Consumption of 1 fatty fish meal per day (or alternatively,
a fish oil supplement) could result in an omega-3 fatty acid intake (ie, EPA and
DHA) of ~900mg/d, an amount shown to beneficially affect coronary heart disease
mortality rates in patients with coronary disease." Current mean intakes (adults)
of EPA and DHA (combined) are about 130 mg/d or 14%-20% of these target intakes
of 650 mg/d and 900 mg/d.
In Cardiovascular Care
Future nutrition labeling and health claims
should provide both listings for the omega-3 fatty acids of interest (ALA, EPA and
DHA) and evidence-based health claims for EPA and DHA related to lowering of blood
triglyceride levels, heart health and so on.
Omega-3-enriched supplements (nutraceuticals)
and functional foods (e.g., EPA- and DHA-enriched eggs and other food products)
with effective quantities of EPA and DHA in various forms will become increasingly
available as complementary options to fish.
Significant blood triglyceride lowering has
been recently reported38 in subjects fed 1000 kJ/day (240 kcal/day, that is about
10% of total daily energy intake) of a commercial liquid scrambled egg-type product
containing EPA and DHA. These and other such products will offer the possibility
of an overall increase in the daily consumption of EPA and DHA, which are currently
consumed only in moderate quantities in the form of fish and fish oil, thereby narrowing
the current nutritional gap.
Clinicians and other health professionals
will need to become fully educated about the evidence-based use of omega-3 fatty
acids from fish oils (dose, duration, expected benefits, monitoring and so on) in
the management of cardiovascular care. "Omega-3 therapeutics" will offer
alternative as well as complementary options and strategies for the informed practitioner.
Returning to the case, the physician learns
that the patient rarely eats fish. It would be reasonable to suggest to the patient
that he increase his intake of fish to 3 servings per week. He should also be advised
to consume fish that is broiled or baked, while avoiding breaded fish products or
fish sticks, fish and chips, and heavily salted or pickled fish.
Depending upon the patient"s preference, fish
oil supplements (taken with meals) or functional food sources (e.g., liquid egg
enriched in omega-3 PUFA) can serve as alternative dietary sources of the target
650-900 mg combined EPA and DHA average daily intake.
Canadian Medical Association Journal March 5, 2002 166:608-615