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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 disease.
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 Fatty Acids?
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 acid molecule).
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
Epidemiological
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 Japanese population.1,14
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
Possible
Biochemical 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, and
- 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).
Intervention
Studies 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.
Lower
Triglycerides
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
Clinical
Trials 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).
Target
Intakes 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 intake.8
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
mortality.34
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 adults.36
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.
Future
Perspectives 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.
Treatment
For The Patient
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
References
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