Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment
http://www.100md.com
《英国医生杂志》
1 Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4SB, 2 Royal Infirmary of Edinburgh, Edinburgh EH16 4SA
Correspondence to: J N Din jehangirdin@hotmail.com
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
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
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
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.
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
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
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.
References
Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975;28: 958-66.
Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000;71(suppl): S179-88.
Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312: 1205-9.
Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336: 1046-53.
Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287: 1815-21.
Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, Willett WC, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279: 23-8.
Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002;346: 1113-8.
Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med 1995;332: 977-82.
Marckmann P, Gronbaek M. Fish consumption and coronary heart disease mortality. A systematic review of prospective cohort studies. Eur J Clin Nutr 1999;53: 585-90.
Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2: 757-61.
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lancet 1999;354: 447-55.
Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4. Cardiovasc Drugs Ther 1997;11: 485-91.
Nilsen DW, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr 2001;74: 50-6.
Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57: 193-200.
Christensen JH, Gustenhoff P, Korup E, Aaroe J, Toft E, Moller J, et al. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial. BMJ 1996;312: 677-8.
Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003;107: 2646-52.
Mori TA, Beilin LJ, Burke V, Morris J, Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997;17: 279-86.
Kristensen SD, Iversen AM, Schmidt EB. n-3 polyunsaturated fatty acids and coronary thrombosis. Lipids 2001;36(suppl): S79-82.
Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003;361: 477-85.
Heller A, Koch T, Schmeck J, van Ackern K. Lipid mediators in inflammatory disorders. Drugs 1998;55: 487-96
De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000;71(suppl): S213-223.
Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens 2002;20: 1493-9.
Kris-Etherton PM, Harris WS, Appel LJ for the Nutrition Committee. AHA scientific statement. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106: 2747-57.
Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A, Gomez-Aracena J, et al. Mercury, fish oils, and the risk of myocardial infarction.. Heavy Metals and Myocardial Infarction Study Group. N Engl J Med 2002;347: 1747-54.(Jehangir N Din, research )
Correspondence to: J N Din jehangirdin@hotmail.com
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
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
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
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.
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
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
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.
References
Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975;28: 958-66.
Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000;71(suppl): S179-88.
Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312: 1205-9.
Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336: 1046-53.
Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287: 1815-21.
Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, Willett WC, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279: 23-8.
Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002;346: 1113-8.
Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med 1995;332: 977-82.
Marckmann P, Gronbaek M. Fish consumption and coronary heart disease mortality. A systematic review of prospective cohort studies. Eur J Clin Nutr 1999;53: 585-90.
Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2: 757-61.
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lancet 1999;354: 447-55.
Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4. Cardiovasc Drugs Ther 1997;11: 485-91.
Nilsen DW, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr 2001;74: 50-6.
Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57: 193-200.
Christensen JH, Gustenhoff P, Korup E, Aaroe J, Toft E, Moller J, et al. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial. BMJ 1996;312: 677-8.
Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 2003;107: 2646-52.
Mori TA, Beilin LJ, Burke V, Morris J, Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997;17: 279-86.
Kristensen SD, Iversen AM, Schmidt EB. n-3 polyunsaturated fatty acids and coronary thrombosis. Lipids 2001;36(suppl): S79-82.
Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003;361: 477-85.
Heller A, Koch T, Schmeck J, van Ackern K. Lipid mediators in inflammatory disorders. Drugs 1998;55: 487-96
De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000;71(suppl): S213-223.
Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens 2002;20: 1493-9.
Kris-Etherton PM, Harris WS, Appel LJ for the Nutrition Committee. AHA scientific statement. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106: 2747-57.
Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A, Gomez-Aracena J, et al. Mercury, fish oils, and the risk of myocardial infarction.. Heavy Metals and Myocardial Infarction Study Group. N Engl J Med 2002;347: 1747-54.(Jehangir N Din, research )