Dr Frank Thies
Senior lecturer in human nutrition, University of Aberdeen, UK
Fat is one of the main components of human diets and represent around 30%–35% of total dietary energy intake in western countries. Fat’s main constituents are fatty acids, which are aliphatic chains of two to 30+ carbons ended by a carboxyl group.
Fatty acids chains that contain one or several double bonds are referred to as mono- or polyunsaturated fatty acids respectively. The position of the first double bond from the methyl terminal of the fatty acid chain determines the family of the fatty acid, such as n-9, n-6 or n-3 (or omega-9, -6 and -3) families.
Two fatty acids, linoleic (C18:2n-6) and α-linolenic (C18:3n-3) acids, are essential and have to be supplied by the diet, as animals – including humans – cannot synthesise them. However, mammals can convert these precursors to produce longer and more desaturated derivatives with 20 or 22 carbons, such as arachidonic (C20:6n-6), eicosapentaenoic (EPA, C20:5n-3) and docosahexaenoic (DHA, C22:6n-3) acids. These have very important biological functions. Our ability to synthesis of EPA and DHA from the precursor, α-linolenic acid, is limited. Therefore, there is little therapeutic benefit from increasing consumption of α-linolenic acid, at least at achievable levels of dietary intakes.
n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA ) EPA and DHA are found in abundance in oily fish and fish oils. Increased consumption has been associated with reduced risk of chronic inflammatory disease such as cardiovascular disease.1 The first observations suggesting a beneficial role of marine n-3 fatty acids against cardiovascular disease come from observational studies carried out in Inuit populations in the late ’60s.2 Subsequently, many epidemiological and case-control studies substantiated these findings. n-3 LCPUFA seem particularly effective for secondary prevention against mortality after myocardial infarction.
Benefits of oily fish
Two landmark randomised secondary intervention trials, involving increased consumption of n-3PUFA, supported the theory that n-3 LCPUFA could prevent atherosclerosis and thrombosis and associated disease. The DART study3 showed the consumption of two oily fish meals per week reduced total mortality and mortality related to coronary heart disease by 30%. Similarly, the GISSI Prevenzione study4 reported that 1g per day of n-3 LCPUFA supplementation significantly reduced cardiovascular mortality and the incidence of sudden death.
Another intervention trial supplementing patients with 1.7g daily of n-3 LCPUFA for two years found no effect on cardiovascular mortality but a reduction in the incidence of myocardial infarction.5 A prospective study of over 54,000 individuals indicated that men, but not women, eating 6g or more fatty fish per day could reduce their risk of acute coronary syndrome by 30%.6
How fish oils work in the body
Numerous physiological and cellular functions have been ascribed to n-3 PUFAs, which may, either individually or collectively, underlie some of their beneficial cardiovascular effects. Amongst those, their ability to affect atherosclerotic plaque compostion and stability has been described recently. n-3 LCPUFA given to patients with severe atherosclerosis (thickening of the arterial wall reducing gradually the blood flow to organs) are readily incorporated into carotid plaques, and their effects are associated with an increase in plaque stability possibly due to a reduction in inflammation.7 These findings have been confirmed by the OCEAN study, which results have been published recently.8
Interestingly, the effects on plaque stability seem to relate mostly to EPA, and not DHA. Furthermore, the results of the JELIS study9 indicated that supplementing 1.8g purified EPA alone to hypercholesterolemic patients reduced the risk of cardiac events even in subjects with a high background of n-3 fatty acid intake and treated with statins. Stabilisation of carotid plaque by n-3 LCPUFA could also be beneficial against the risk of stroke. However, this remains to be determined.
Efficacy in heart arrhythmias
Potential anti-arrhythmic properties of n-3 LCPUFA have been suggested, mainly based on cell culture and animal models, and the evidence has been reviewed recently.10 n-3 LCPUFA seem effective in reducing sudden cardiac death after myocardial infarction, perhaps by reducing ventricular arrhythmias. However, n-3 LCPUFA could predispose to an increased risk of ventricular arrhythmia in people with coronary heart disease but without previous myocardial infarction, suggesting that patient selection could be critical prior to starting n-3 LCPUFA therapy10.
A limited number of studies regarding the effects of n-3 LCPUFA on atrial arrhythmia indicate some possible benefits10 but further research is required to confirm these findings.
Efficacy in decreasing blood lipid concentrations
n-3 LCPUFA beneficial effects on risk markers for cardiovascular disease (CVD) are mainly limited to effectively reducing triglyceride plasma concentration. However, higher doses of n-3 LCPUFA (2-4g daily), not easily achievable by dietary means, are usually needed to observe the hypolipidemic effects, therefore requiring the use of supplements – concentrated fish oils or pharmaceutical preparations.
The trials carried out in atherosclerotic carotid arterial disease described above7,8 suggest that n-3PUFA could protect against CVD risk at least partly by reducing inflammation within atherosclerotic plaques.
Anti-inflammatory effect in arthritis
Anti-inflammatory properties of n-3 LCPUFA have been extensively studied, mainly in vitro and using animal models. These fatty acids are precursors of biologically active compounds including prostaglandins and other eicosanoids. These are much less potent in inducing inflammation compared to those produced by arachidonic acid. Furthermore, the recent discovery of another family of anti-inflammatory mediators11,12 synthesised from EPA and DHA, referred to as resolvins and neuroprotectins, strengthens the potential of n-3 LCPUFA being used as anti-inflammatory agents.
Many studies have looked at the effect of n-3 LCPUFA supplementation on various chronic or acute inflammatory disorders, such as rheumatoid arthritis, inflammatory bowel disease and asthma. Rheumatoid arthritis is characterised by joint inflammation leading to swelling, morning stiffness, pain, osteoporosis, functional impairment and muscle wasting.
Most placebo-controlled intervention studies carried out to date, using daily fish oil supplementation delivering from 2.1 to 7.1g per day EPA + DHA over 12 to 52 weeks, showed improvements in clinical outcomes such as number of tender or swollen joints, duration of morning stiffness, grip strength and patient’s global assessment by their GP. Furthermore, n-3 LCPUFA supplementation also decreased the need of using NSAIDs to control the pain and inflammation in some of the studies.13 Thus, marine n-3 LCPUFA could have some clinical benefits in rheumatoid arthritis.
Research in bowel disease and asthma
However, the evidence for their clinical efficacy for other inflammatory disorders such as bowel diseases (Crohn’s disease, ulcerative colitis) and asthma is weak. Fish oil supplementation showed beneficial effects in animal models of colitis. However, double-blind, randomised, placebo-controlled trials have produced conflicting results. Some showed some benefits on disease activity13 and anti-inflammatory drug requirements, while others found none. Furthermore, these fatty acids do not seem to affect relative risk of relapse in ulcerative colitis. Results from studies focusing on Crohn’s disease are scarce and showed also conflicting results.
Asthma is another inflammatory disorder that has been targeted for n-3 LCPUFA therapy. The results of several double-blind, randomised, placebo-controlled studies have been published, again with conflicting results. A report from the US Agency for Healthcare Research and Quality (AHRQ) in 2004 considered 26 studies carried out in asthmatic adults or children and could not reach any definitive conclusion with regards to the efficacy of supplementing asthmatic with n-3 LCPUFA.
Critically ill patients requiring parenteral nutrition could also benefit from including n-3 LCPUFA in lipid emulsions. Guidelines on parenteral nutrition in intensive care, published in 2009 by the European Society for Clinical Nutrition and Metabolism, indicate that the addition of EPA and DHA in lipid emulsions has demonstrable effect on inflammatory processes.
Most of the studies carried out so far involved patients who underwent gastrointestinal surgery. None of them showed deleterious effects of fish oil infusions. Furthermore, the report also indicates that using fish-oil-based lipid emulsions could decrease the length of hospitalisation for critically ill patients, with obvious benefits for health service resources. However, this needs to be confirmed by comprehensive, well-powered and adequately designed studies.
Conclusion
Clearly, increased fish consumption and/or supplementation with fish oil or pharmaceutical preparations could be beneficial for secondary prevention after myocardial infarction. In 2002, the joint American College of Cardiology and American Heart Association recommended an intake of at least two fish meals per week in patients with coronary heart disease, and supplementation for one year with 1g daily of n-3 LCPUFA for secondary prevention of myocardial infarction.
The efficacy of increasing n-3 LCPUFA intake for the primary prevention of coronary heart disease and other cardiovascular disorders remains to be determined. But for cardiovascular health, the International Society for the Study of Fatty Acids and Lipids (ISSFAL) in 2003 recommended a minimum intake of EPA and DHA combined of 500mg/d.
Despite relatively strong evidence for beneficial effects of marine n-3 LCPUFA supplementation in rheumatoid arthritis and critically ill patients, recommendations cannot yet be issued. Further studies are required not only to confirm the efficacy of n-3 LCPUFA supplementations, but also to determine optimal doses and duration.
References
- Tavani A et al. Circulation 2001;104:2269-72.
- Bang HO & Dyerberg J. Lipid metabolism and ischemic heart disease in Greenland Eskimos. In: Draper H, ed. Advances in Nutrition Research. New York: Plenum Press; 1980, 1-22.
- Burr ML et al. Lancet 1989;344:757-61.
- GISSI-Prevenzione Investigators. Lancet 1999;354:447-55.
- Svensson M et al, Clin J Am Soc Nephrol 2006;1:780-86.
- Bjerregaard LJ et al. Eur Heart J 2010;31:29-34.
- Thies F et al. Lancet 2003;361:477-85.
- Cawood A et al. Atherosclerosis 2010; doi:10.1016/j.atherosclerosis.2010.05.022.
- Yokoyama M et al. Lancet 2007;369:1090-8.
- Saravanan P et al. Lancet 2010;375:540-50.
- Serhan CN et al. Nat Rev Immunol 2008;8:349-61.
- Mukherjee PK et al. Proc Natl Acad Sci USA 2004;101:8491-96.
- Calder PC. Am J Clin Nutr 2006:83(suppl):1505S-19S
