Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment

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http://bmj.bmjjournals.com/cgi/content/full/328/7430/30

 

BMJ 2004;328:30-35 (3 January), doi:10.1136/bmj.328.7430.30

Clinical reviewScience, medicine, and the future

Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment

Jehangir N Din, research fellow1, David E Newby, reader1, Andrew D Flapan,

consultant cardiologist2

1 Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4SB, 2 Royal

Infirmary of Edinburgh, Edinburgh EH16 4SA

 

Correspondence to: J N Din jehangirdin

 

Omega 3 fatty acids from fish and fish oils can protect against coronary heart

disease. This article reviews the evidence regarding fish oils and coronary

disease and outlines the mechanisms through which fish oils might confer cardiac

benefits

 

 

Introduction

Omega 3 fatty acids from fish and fish oils can protect against coronary heart

disease. Both health professionals and the public are increasingly interested in

their role in the prevention and management of coronary heart disease. In this

era of multiple pharmacological treatments for cardiovascular disease many

believe that simple dietary interventions or nutritional supplements may be a

more natural and acceptable method of providing benefits.

Several areas of uncertainty remain. The optimal intake of omega 3 fatty acids

is not firmly established, nor is their mechanism of action fully understood.

Some studies have produced conflicting results, and concerns have been

increasing about environmental contamination of certain fish. This article

reviews the current evidence regarding fish oils and cardiovascular disease,

their possible mechanism of action, and potential future developments and

research strategies.

 

Sources and selection criteria

We searched PubMed for relevant articles by using the key words " fish, " " fish

oils, " " omega 3 fatty acids, " and " cardiovascular disease. " References

identified in the search are on bmj.com

 

Summary points

Coronary heart disease is still the most common cause of death in the United

Kingdom

Omega 3 fatty acids from fish and fish oils can protect against coronary heart

disease

There is evidence to support the use of fish or fish oil supplements after

myocardial infarction

The mechanisms by which fish oils confer their benefits are not fully understood

Unravelling these mechanisms may identify novel therapeutic targets and could

help guide the development of future treatments for coronary heart disease

Future trials may identify other patients who could benefit, such as those with

stable angina, risk factors for coronary heart disease, or left ventricular

dysfunction

 

 

 

 

Omega 3 polyunsaturated fatty acids

The association between omega 3 fatty acids and cardiovascular disease was

established following the observation that the Greenland Inuit had low mortality

from coronary heart disease despite a diet that is rich in fat. In the 1970s the

Danish investigators Bang and Dyerberg proposed that this could be because of

the high content of omega 3 fatty acid in the Inuit diet,1 which consisted

largely of fish, seal, and whale (fig 1).

 

 

Fig 1 Greenland Inuit gutting a seal in the early 1900s. Their diet consisted

largely of fish, whale, seal, and walrus, resulting in a high intake of omega 3

fatty acids. Copyright Arctic Institute, used with permission from Leif

Vanggaard, Arctic Institute

 

 

 

Omega 3 fatty acids, along with omega 6 fatty acids, are essential

polyunsaturated fatty acids (fig 2 and fig 3). The Western diet is abundant in

omega 6 fatty acids, mainly from vegetable oils rich in linoleic acid.2 However,

humans lack the necessary enzymes to convert omega 6 fatty acids to omega 3

fatty acids, and the latter must be obtained from separate dietary sources.

While linolenic acid (ALA) is available from certain plants, eicosapentanoic

acid (EPA) and docosahexanoic acid (DHA) are derived from fish and fish oils.

This review is limited to the two marine derived omega 3 fatty acids.

 

 

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Fig 2 Fatty acids are saturated, monounsaturated, or polyunsaturated. Two

types of polyunsaturated fatty acid exist—the omega 6 and the omega 3 fatty

acids. The omega 6 fatty acids are available mainly from vegetable oils. Three

types of omega 3 fatty acid exist: linolenic acid is available from certain

plants but eicosapentanoic acid and docosahexanoic acid must be obtained from

marine sources

 

 

 

 

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Fig 3 Structures of the two classes of polyunsaturated fatty acids. The omega

3 fatty acids have their first double bond at the third carbon molecule from the

methyl (CH3) end of the fatty acid, whereas the omega 6 fatty acids have their

first double bond at the sixth carbon molecule. The chemical names for each

fatty acid are also given: the number of carbon atoms is given first, followed

by the number of double bonds and the position of the first double bond. Omega 6

linoleic acid can be desaturated in certain plants to form omega 3 linolenic

acid. Whereas linoleic acid is mainly converted into arachidonic acid,

linolenic is elongated and desaturated into eicosapentanoic acid and then

docosahexanoic acid

 

 

 

 

 

Epidemiological and observational studies

Most studies have shown an inverse association between fish consumption and the

risk of coronary heart disease.3-5 Furthermore, both consumption of fish6 and

higher blood concentrations of omega 3 fatty acids7 are associated with a

reduced risk of sudden death. However, some studies8 w1 have not found a

relation between intake of fish and coronary heart disease. These

inconsistencies could be due to differences in methods, study populations, or

fish. Importantly, most studies showing no association were in populations with

an already moderate fish intake, potentially masking any relation. Overall, fish

consumption seems to be beneficial, and a systematic review of 11 prospective

cohort studies concluded that fish intake notably reduced mortality due to

coronary heart disease in populations at increased risk.9

 

Clinical intervention trials

Several trials have assessed the effects of fish and fish oil supplements on

coronary heart disease, mainly after myocardial infarction (table 1). The diet

and reinfarction trial (DART) randomised 2033 men with a recent myocardial

infarction to three dietary interventions.10 Patients who received advice on

fish had a relative reduction in total mortality of 29% during the two year

follow up (P < 0.05), mainly because of a reduction in deaths from coronary

heart disease. The open label Gruppo Italiano per lo Studio della Sopravvivenza

nell'Infarto Miocardico Prevenzione (GISSI-Prevenzione) trial randomised 11 324

patients after myocardial infarction to either a daily capsule of about 850 mg

omega 3 fatty acid, 300 mg vitamin E, both, or neither.11 After 3.5 years

participants randomised to fish oil capsules had a reduction in relative risk of

15% in the composite primary end point of total mortality, non-fatal myocardial

infarction, and stroke (P = 0.023). The relative risk of

cardiovascular death was also reduced, by 30% (P = 0.024), and of sudden death

by 45% (P = 0.01). These benefits were apparent within just four months of

randomisation.w2

 

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Table 1 Effect of marine derived omega 3 fatty acids on death from coronary

heart disease in secondary prevention of myocardial infarction

 

 

 

Two smaller secondary prevention trials have also assessed the effects of omega

3 fatty acids. In an Asian population patients with a suspected myocardial

infarction randomised to fish oil capsules experienced a significant reduction

in mortality from coronary heart disease after one year compared with placebo.12

However, a Norwegian study reported no benefit in patients after myocardial

infarction who were given fish oil capsules compared with placebo after 1.5

years.13 This may have been because of the high habitual fish consumption among

the general population in that area, with omega 3 supplementation conferring no

additional benefit.

A recent trial of 3114 men with angina unexpectedly found that individuals

advised to eat oily fish, and particularly those given fish oil capsules, had a

higher risk of cardiac death than people not given advice to eat fish (11.5% v

9%, P = 0.02).14 The investigators speculated that this may have arisen from

risk compensation or other changes in patients' behaviour. Several flaws in this

study weakened the validity of the results, and they should be viewed with

caution until more evidence becomes available.

 

Box 1: Possible mechanisms of action of omega 3 fatty acids

 

Antiarrhythmic

 

Antithrombotic

 

Antiatherosclerotic

 

Anti-inflammatory

 

Improves endothelial function

 

Lowers blood pressure

 

Lowers triglyceride concentrations

 

 

 

 

 

 

Mechanism of action

Although the weight of evidence outlined above supports a protective effect of

omega 3 fatty acids on coronary heart disease, the mechanisms through which they

confer these benefits remain unclear. Omega 3 fatty acids have several

potentially cardioprotective effects (box 1), although the relative contribution

of each of these is not fully understood.

Arrhythmias

The benefits of fish oils were originally thought to be due to their

antithrombotic effects, but recent evidence has indicated that the predominant

effect may be antiarrhythmic. In the GISSI-Prevenzione trial the decrease in

mortality was largely due to a reduction in sudden death,11 and, as in DART,10

no reduction in the rate of non-fatal myocardial infarction occurred. Fish oil

supplementation increases heart rate variability in patients after myocardial

infarction, which correlates with a lower risk of mortality and malignant

arrhythmia.15 In animal models fish oil protects against ventricular

fibrillation after surgical occlusion of a coronary artery.16 The addition of

eicosapentanoic acid or docosahexanoic acid can prevent or terminate

pharmacologically induced arrhythmias in cultured cardiomyocytes from newborn

rats.16 However, studies are necessary to show a direct antiarrhythmic effect in

humans and trials are currently under way in patients with implantable

defibrillators.

Thrombosis

Activation of platelets and their deposition at sites of unstable plaque rupture

promotes thrombus formation, and these critical events have become a common

therapeutic target in acute coronary syndromes. However, the effects of omega 3

fatty acids on platelet function and thrombosis are controversial. Large doses

reduce platelet aggregation, but smaller amounts have modest platelet inhibitory

effects.17 Omega 3 fatty acids have inconsistent effects on fibrinolysis and

little effect on blood coagulability.18 Therefore, although omega 3 fatty acids

have an antithrombotic effect, its relevance to the mortality reduction seen

with lower doses is unclear.

Atherosclerosis

Omega 3 fatty acids may also influence the atherosclerotic process. Fish oil fed

to experimental animals protects against progression of atherosclerotic

plaques.w3 w4 In humans with coronary heart disease omega 3 fatty acid

supplementation versus placebo for two years resulted in modest improvements in

atherosclerosis as assessed by angiography.w5 These effects may be due to a

reduction in lipids, inflammation, production of growth factor, or suppression

of smooth muscle cell proliferation.w6 An important recent study randomised

patients awaiting carotid endarterectomy to fish oil capsules, sunflower oil

capsules, or control until surgery and then assessed morphology of the plaque.19

Omega 3 fatty acids were readily incorporated into atherosclerotic plaques in

the fish oil group, and these plaques were more likely to have thick fibrous

caps and less inflammatory infiltrate. These features imply a plaque that is

less vulnerable to rupture and indicate that fish oils may be important

in establishing stability of the plaque.

Inflammation

Inflammation has a central role in the development and progression of coronary

artery disease. Omega 3 fatty acids have recognised anti-inflammatory actions

that may contribute to their beneficial cardiac effects. Omega 6 fatty acids can

be converted into arachidonic acid and then metabolised into the omega 6

eicosanoids (fig 4). 20 These cellular mediators enhance platelet aggregation

and are generally pro-inflammatory. Consumption of omega 3 fatty acids increases

eicosapentanoic acid in the cell membrane. This competes with arachidonic acid

for enzymatic conversion into its own metabolites, the omega 3 derived

eicosanoids. These are less active and can partly oppose or antagonise the

pro-inflammatory actions of the omega 6 eicosanoids.

 

 

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Fig 4 Synthesis of eicosanoids from omega 6 and omega 3 fatty acids.

Arachidonic acid and eicosapentanoic acid compete for the cyclo-oxygenase and

lipoxygenase enzymes for conversion into eicosanoids. Those derived from

arachidonic acid are pro-inflammatory and pro-aggregatory, whereas those derived

from omega 3 fatty acids are anti-inflammatory and inhibit platelet aggregation

 

 

 

Independent of the effects on the metabolism of eicosanoids fish oils suppress

pro-inflammatory cytokines and reduce expression of cell adhesion molecules.21

These are critical in recruiting circulating leucocytes to the vascular

endothelium, an important event in the pathogenesis of atherosclerosis and

inflammation. These effects may be mediated through actions on intracellular

signalling pathways, leading to reduced activation of transcription factors such

as NF-B.21 However, the precise effects of omega 3 fatty acids on these

fundamental cellular processes and their potential impact on coronary heart

disease are yet to be delineated completely.

Endothelial function

Abnormal endothelial function is found in individuals with cardiovascular risk

factors or established coronary heart disease. Omega 3 fatty acids have direct

effects on endothelial vasomotor function. Higher concentrations are associated

with improved dilation of the brachial artery in young adults with

cardiovascular risk factors, which implies a protective effect on endothelial

function.w7 In hyperlipidaemic men omega 3 fatty acid supplementation improved

systemic arterial compliancew8 and supplementation with docosahexanoic acid

increased vasodilator responses in the human forearm.w9

Blood pressure

Fish oils can produce modest reductions in blood pressure, possibly through

their effects on endothelial function discussed above. A recent meta-analysis of

36 randomised trials found a reduction in systolic blood pressure of 2.1 mm Hg

and in diastolic blood pressure of 1.6 mm Hg.22 However, most trials used

relatively high doses of fish oils (3.6 g/day), and the effects of lower intakes

of omega 3 fatty acids, such as those in the secondary prevention trials, remain

to be established.

 

Box 2: Recommendations for intake of omega 3 fatty acid

 

Patients without documented coronary heart disease: Eat a variety of

(preferably oily) fish at least twice weekly. Include oils and foods rich in

linolenic acid

 

Patients with documented coronary heart disease: Consume 1 g of

eicosapentanoic and docosahexanoic acid daily, preferably from oily fish.

Supplements could be considered in consultation with a doctor

 

Patients with hypertriglyceridaemia: Take 2-4 g of eicosapentanoic acid and

docosahexanoic acid daily, provided as capsules under a doctor's care

 

 

These are the recommendations of the American Heart Association.23

 

 

 

 

Box 3: Consumption and sources of marine derived omega 3 fatty acids

 

Current consumption of marine derived omega 3 fatty acids is low, at 0.1-0.2

g/day. An expert US panel of nutrition scientists has recommended an intake of

0.65 g/day whereas the British Nutrition Foundation's recommendation is 1.2

g/day.2 Secondary prevention trials after myocardial infarction indicate that

consumption of 0.5-1.8 g/day of eicosapentanoic and docosahexanoic acid from

fish or fish oil supplements may be beneficial. Intake of marine derived omega 3

fatty acids can be increased through diet or with fish oil supplements. Oily

fish such as mackerel, herring, tuna, salmon, sardines and trout are rich

sources of eicosapentanoic and docosahexanoic acid (table 2), and two to three

servings per week should provide approximately 1 g/day omega 3 fatty acids. Lean

fish such as cod or haddock have smaller amounts, and fried fish (for example,

from fast food establishments or frozen products) contains minimal amounts of

omega 3 fatty acids.

 

Concerns about the depletion of fish stocks will become more pressing if the

benefits of fish oils are confirmed beyond the population after myocardial

infarction, as this may result in an unsustainable increase in demand.

Alternative strategies to increase omega 3 intake include supplementing animal

feed with fish oil to augment the omega 3 content of eggs, meat, and milk.2

Available foods can also be enriched in eicosapentanoic and docosahexanoic acid,

although they may impart a fishy aroma or flavour. A different approach

independent of an adequate supply of fish oil would involve using modern

biotechnology to genetically modify certain plants species, thereby producing

plants and plant oils rich in eicosapentanoic and docosahexanoic acid.2

 

 

 

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Table 2 Content of omega 3 fatty acids of selected fish and seafood (adapted

from the guidelines of the American Heart Association23)

 

 

 

 

 

Triglyceride lowering

Omega 3 fatty acids reduce triglyceride concentrations in a dose dependent

manner, with intakes of about 4 g per day lowering serum triglycerides by

25-30%.w10 Their effect on cholesterol is small and of uncertain clinical

importance. Higher doses (3-5 g/day) can be used in the treatment of

hypertriglyceridaemia. Only a small reduction in triglycerides occurred at the

lower doses used in the GISSI-Prevenzione trial11 (about 1 g/day), and it

therefore seems unlikely that this effect alone could be responsible for the

cardiovascular benefits.

 

Clinical implications

Omega 3 fatty acids from fish or fish oil supplements should be considered in

the secondary prevention regimen of patients after myocardial infarction.

Patients should consume about 1 g/day of eicosapentanoic acid and docosahexanoic

acid, preferably by increasing their intake of oily fish to at least two

servings per week. Fish oil capsules may be considered for those unable to

tolerate fish or change their diet effectively. Approved pharmaceutical grade

capsules should be prescribed rather than encouraging over the counter

supplements.

 

Additional educational resources

Websites

www.nal.usda.gov/fnic/foodcomp/—USDA Nutrient Data Laboratory, a database with

online search function to find the omega 3 content of various foods

www.foodstandards.gov.uk/multimedia/pdfs/fsis40_2003.pdf—Food Standards Agency

UK, provides data on mercury content of various fish and advice on safe

consumption for pregnant women and women of childbearing potential.

Reviews

Hu FB, Willett WC. Optimal diets for the prevention of coronary heart disease.

JAMA 2002;288: 2569-78[Abstract/Free Full Text]

Calder PC, Grimble RF. Polyunsaturated fatty acids, inflammation and immunity.

Eur J Clin Nutr 2002;56(suppl 3): S14-9.[CrossRef][iSI][Medline]

Davis BC, Kris-Etherton PM. Achieving optimal essential fatty acid status in

vegetarians: current knowledge and practical implications. Am J Clin Nutr

2003;78(suppl 3): S640-6.[Abstract/Free Full Text]

American Journal of Clinical Nutrition 2000;71(suppl 1)—dedicated to fish oils

and omega 3 fatty acids. Twenty articles covering a range of subjects from

current intake and biological actions through to effects on a wide range of

medical conditions.

For patients

Omega 3 Information Service. A wealth of well balanced information about omega 3

fatty acids; including their effects on medical conditions apart from coronary

heart disease (www.omega-3info.com/)

British Nutrition Foundation. Charitable organisation promoting healthy eating

through impartial interpretation of nutritional knowledge and advice

(www.nutrition.org.uk/)

 

 

 

Recent guidelines from the American Heart Association (box 2) have gone further,

supporting the use of fish oil supplements for patients with " documented "

coronary heart disease.23 However, we believe that more evidence is required

before considering fish oil supplements for patients with coronary heart disease

outside the specific indication of myocardial infarction. Others have argued

that fish oil supplements should not be recommended routinely for patients after

myocardial infarction until more definitive evidence is available.w11

No trial has assessed the effects of fish oils on risk of coronary heart disease

in primary prevention, and therefore explicit recommendations for this group

cannot be made currently. Such a trial may prove impractical in terms of the

numbers required. However, on the basis of evidence from epidemiological and

observational studies the consumption of (preferably oily) fish at least twice

weekly should be encouraged as part of a balanced diet. Box 3 and table 2 show

current consumption and dietary sources of eicosapentanoic and docosahexanoic

acid.

Any recommendations regarding fish and fish oils should be balanced against

safety issues. Side effects such as fishy aftertaste are uncommon, and

gastrointestinal upset is infrequent at moderate intakes.23 Some reports show

that fish oil may worsen glycaemic control in diabetes, but two meta-analyses

found no adverse effect.w12 w13 Furthermore, a recent prospective cohort study

found that a higher consumption of omega 3 fatty acids was associated with a

lower incidence of coronary heart disease and mortality in diabetic women.w14

Concerns have been raised regarding adverse effects on low density lipoprotein

(LDL) cholesterol and oxidative stress, but increases in LDL cholesterol are

modest and studies into oxidative stress have been contradictory.w15 Overall

these effects are unlikely to be dominant given the apparent cardiac benefits of

omega 3 fatty acids. More specific concerns regarding dietary fish relate to

environmental contaminants, and a recent study showed that mercury in

fish may attenuate their cardioprotective effects.24 Contaminants accumulate in

larger, predatory fish, and consumption of a variety of fish should minimise any

possible adverse effects.23

 

Future directions

Despite advances in our understanding of the cardioprotective effects of fish

oils in the past three decades, many issues remain unresolved. A double blind,

placebo controlled trial of fish oil capsules in patients after myocardial

infarction is required, and further trials are needed in individuals with risk

factors for coronary heart disease or with heart failure. The specific effects

of eicosapentanoic acid versus docosahexanoic acid on risk of coronary heart

disease and the relative merits of oily fish compared with fish oil capsules

also require further investigation. In addition to trials with clinical end

points, research efforts should be focused on understanding the mechanisms by

which fish oils might confer cardiac benefits. This will allow us not only to

refine the clinical applications of fish oils but hopefully also to identify

other therapeutic targets and help guide the development of future treatments

for coronary heart disease.

 

 

 

 

Additional references (w1-w15) are on bmj.com

Contributors: JD researched and drafted the original manuscript. All authors

jointly contributed to the final paper. JD is the guarantor.

Funding: JD is funded by a project grant from the British Heart Foundation. DEN

is funded by the British Heart Foundation. ADF is employed by the National

Health Service.

Competing interests: None declared.

 

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(Accepted 6 November 2003)

 

 

 

 

 

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