There is considerable evidence from clinical, experimental and epidemiological studies that polyunsaturated n-3 fatty acids, particularly EPA (20 : 5) and DHA (22 : 6) the two main n-3 fatty acids from fish and fish oils, are protective against atherosclerotic heart disease and sudden coronary death( Reference Schmidt, Arnesen and de Caterina 1 – Reference Mozaffarian and Wu 4 ). n-3 Fatty acids have multiple effects benefiting a number of cardiometabolic risk factors including blood pressure( Reference Appel, Miller and Seidler 5 – Reference Morris, Sacks and Rosner 8 ) and cardiac function( Reference Mozaffarian and Wu 4 , Reference Mori, Burke, Beilin, Lip and Hall 7 ), arterial compliance( Reference McVeigh, Brennan and Cohn 9 , Reference Nestel, Shige and Pomeroy 10 ), vascular reactivity( Reference Chin 11 , Reference Mori, Watts and Burke 12 ), lipid metabolism( Reference Harris 13 , Reference Harris 14 ), reduced leucocyte-derived cytokine formation( Reference Calder 15 ), anti-platelet( Reference Knapp 16 ), anti-inflammatory( Reference Mori and Beilin 17 , Reference Calder 18 ) and pro-resolving( Reference Serhan and Petasis 19 ) effects, and antioxidative actions( Reference Mas, Woodman and Burke 20 ). There is also evidence from studies in human subjects that EPA and DHA have differential effects on blood pressure, heart rate, lipids and vascular reactivity( Reference Mori and Woodman 21 ). The aim of the present paper is to review the evidence for beneficial effects of n-3 fatty acids on cardiometabolic risk factors, concentrating particularly on randomised controlled studies in human subjects.
Population studies
A number of population studies have demonstrated an inverse association between n-3 fatty acid consumption and CVD (Table 1). In meta-analyses, Wang et al. ( Reference Wang, Harris and Chung 22 ) showed that increased consumption of n-3 fatty acids from fish or fish oil supplements reduces rates of all-cause mortality, cardiac and sudden death, and Bucher et al. ( Reference Bucher, Hengstler and Schindler 23 ), He et al. ( Reference He, Song and Daviglus 24 ) and Whelton et al. ( Reference Whelton, He and Whelton 25 ) showed an inverse association between n-3 fatty acids and CHD. An inverse relationship has also been shown between n-3 fatty acids and heart failure( Reference Levitan, Wolk and Mittleman 26 ), particularly with consumption of tuna or other broiled or baked fish, but not fried fish( Reference Mozaffarian, Bryson and Lemaitre 27 ). Several meta-analyses have shown an inverse association between increased intake of n-3 fatty acids and risk of stroke, particularly ischaemic stroke( Reference He, Song and Daviglus 28 , Reference Xun, Qin and Song 29 ).
Studies examining the effect of n-3 fatty acids as fish or fish oils on CHD, stroke and total mortality
MI, myocardial infarction.
Randomised controlled trials
Several randomised controlled trials have shown the beneficial effects of n-3 fatty acids, especially in secondary prevention of CHD (Table 1). The Diet and Reinfarction Trial study showed that n-3 fatty acids given either as oily fish or fish oil capsules, reduced all-cause mortality by 29 % in 2033 men with recent myocardial infarction( Reference Burr, Gilbert and Holliday 30 ). The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI) study randomised 11 323 post-myocardial infarction patients to one daily capsule containing 850 mg n-3 fatty acids v. usual care( Reference Valagussa, Franzosi and Geraci 31 ). After 1 year, patients taking n-3 fatty acids had a 21, 30 and 45 % reduction in total and cardiovascular mortality, and sudden cardiac death, respectively. In a follow-up study in approximately 7000 patients with class II to IV heart failure (GISSI-HF), the same investigators showed that the same dose of n-3 fatty acids had a significant effect in reducing total mortality by 9 % and total mortality or hospitalisation for cardiovascular diseases by 8 %( Reference Tavazzi, Maggioni and Marchioli 32 ). The Japan EPA Lipid Intervention Study trial, randomised 18 645 patients with hypercholesterolaemia to statin alone or statin plus 1800 mg/d highly purified EPA( Reference Yokoyama, Origasa and Matsuzaki 33 ). At the end of the 5-year study, there was a 19 % reduction in major cardiovascular events in those patients randomised to EPA.
Studies demonstrating the benefits of n-3 fatty acids on cardiovascular outcomes need to be considered against several randomised controlled large-scale interventions where n-3 fatty acids at a dose of 1 g daily have not provided benefit. In the ORIGIN trial( Reference Bosch, Gerstein and Dagenais 34 ) in 12 536 patients with or at high risk for diabetes, n-3 fatty acids did not reduce the rate of cardiovascular events. Similarly, the OPERA study, comprising 1516 patients undergoing cardiac surgery, showed that n-3 fatty acids did not reduce the risk of post-operative atrial fibrillation relative to placebo( Reference Mozaffarian, Marchioli and Macchia 35 ). A trial examining 12 513 patients with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction, found that n-3 fatty acids did not reduce cardiovascular mortality and morbidity( Reference Roncaglioni, Tombesi and Avanzini 36 ). There are a number of possibilities that may account for differences between these latter studies and others showing the benefit of n-3 fatty acids. Perhaps n-3 fatty acids provide greater benefit to patients with recent myocardial infarction or heart failure due to their antiarrhythmic effects, or possibly studies have had limited power to detect a reduction in sudden deaths from cardiac causes or arrhythmic events. Other factors include the presence of confounding comorbidities, the effects of concomitant medications and the likelihood that patients are receiving optimal clinical care, studies using doses of n-3 fatty acids that are lower than the 800–900 mg/d previously shown to have an effect, and dietary background particularly in relation to n-3 fatty acid intake.
Effects on blood pressure, endothelial function and cardiac function
Meta-analyses
Randomised controlled intervention trials providing fish meals or fish oils unequivocally demonstrate that n-3 fatty acids lower blood pressure. Although some studies have reported no effect on blood pressure this is probably due to study design, relatively small sample sizes leading to a lack of statistical power and/or an insufficiently high dose of n-3 fatty acids. Three meta-analyses have examined the effect of n-3 fatty acids on blood pressure. Morris et al. ( Reference Morris, Sacks and Rosner 8 ) analysed thirty-one placebo controlled trials involving 1536 subjects and showed an overall reduction of –3·0/−1·5 mmHg with an average dose of 4·8 g/d. The hypotensive effect was strongest in treated and untreated hypertensives (−3·4/−2·0 mmHg) although healthy subjects showed no significant change (−0·4/−0·7 mmHg). Significant dose–response effects were observed with doses of greater than 6 g/d n-3 fatty acids. It was predicted that each 1 g/d increase in n-3 fatty acids decreased blood pressure −0·66/−0·35 mmHg. The dose–response effect was also greater for DHA than for EPA. Appel et al. ( Reference Appel, Miller and Seidler 5 ) estimated that blood pressure fell −5·5/−3·5 mmHg in untreated hypertensives (from six trials) and −1·0/−0·5 mmHg in normotensives (from eleven trials) with an average intake of >3 g/d n-3 fatty acids. The authors did not show a dose–response effect. Geleijnse et al. ( Reference Geleijnse, Giltay and Grobbee 6 ) examined thirty-six trials in which 50 % of the participants were hypertensive (systolic blood pressure>140 mmHg and/or diastolic blood pressure>90 mmHg), the mean trial duration was 11·7 years and the median dose of the n-3 fatty acids was 3·7 g/d. Overall, n-3 fatty acids reduced blood pressure by −2·1/−1·6 mmHg, with the greatest effects in older (>45 years; −3·5/−2·4) and hypertensive (≥140/90 mmHg; −4·0/−2·5) individuals.
A meta-analysis by Dickinson et al. ( Reference Dickinson, Mason and Nicolson 37 ) examined the efficacy of dietary nutrients and lifestyle in patients with raised blood pressure in 105 trials randomising 6805 participants with a mean baseline blood pressure of 147/92 mmHg and a mean age of 50 years. They showed that 0·1–1·7 g/d n-3 fatty acids reduced blood pressure by −2·3/−2·2 mmHg. These effects were modest in comparison with the estimated benefits of improved diet, salt restriction, aerobic exercise and alcohol restriction. Dokholyan et al. ( Reference Dokholyan, Albert and Appel 38 ) showed that low doses of n-3 fatty acids were ineffective in reducing blood pressure in patients with high–normal diastolic blood pressure or stage 1 hypertension, and concluded that relatively high doses of n-3 fatty acids (>3 g/d) are required for blood pressure reduction.
Clinical trials
The blood pressure-lowering effects of n-3 fatty acids were potentiated by concomitant sodium restriction in healthy elderly volunteers( Reference Cobiac, Nestel and Wing 39 ) and by β-adrenergic receptor blockade in mild-to-moderate hypertensives( Reference Singer, Melzer and Goschel 40 ). Lungershausen et al. ( Reference Lungershausen, Abbey and Nestel 41 ) also showed that n-3 fatty acids potentiated the antihypertensive effects of β-blockers or diuretics in treated hypertensives.
Bao et al. ( Reference Bao, Mori and Burke 42 ) reported that n-3 fatty acids were additive to the blood pressure-lowering effects of weight reduction. Sixty-three overweight treated hypertensives were randomised to an energy-restricted weight loss programme, a daily fish meal providing approximately 3·65 g/d n-3 fatty acids, the two regimens combined or a control diet, for 4 months. Weight fell on average 5·6 kg in the two weight-loss groups. Relative to the control group, daytime blood pressures fell −6·0/−3·0 mmHg in the fish group, −5·5/−2·2 in the weight loss group and −13·0/−9·3 with the combined regimens. Awake heart rate was reduced by 1·8, 4·3 and 6·1 bpm in the weight loss, fish and combined weight loss+fish groups, respectively, relative to controls, suggesting an autonomic/cardiac component to the blood pressure reduction.
Independent effects of EPA and DHA
Blood pressure and heart rate are differentially affected by EPA and DHA. Mori et al. ( Reference Mori, Bao and Burke 43 ) showed in overweight, mildly hypercholesterolaemic patients, that 4 g/d highly purified DHA, but not EPA, supplemented for 6 weeks, significantly reduced 24 h (−5·8/−3·3 mmHg) and awake (−3·5/−2·0 mmHg) blood pressure, relative to olive oil. DHA, but not EPA, also significantly reduced 24 h, awake and asleep heart rate by −3·5, −3·7 and −2·8 bpm, respectively( Reference Mori, Bao and Burke 43 ). Of note, EPA resulted in a small, but non-significant rise in heart rate. These differential effects of EPA and DHA on heart rate responses in human subjects were supported by Grimsgaard et al. ( Reference Grimsgaard, Bonaa and Hansen 44 ). The blood pressure changes with DHA( Reference Mori, Bao and Burke 43 ) were accompanied by significant improvements in endothelial and smooth muscle function as well as reduced vasoconstrictor responses, in the forearm microcirculation( Reference Mori, Watts and Burke 12 ). DHA, but not EPA, improved vasodilator responses to endogenous and exogenous nitric oxide donors and attenuated vasoconstrictor response to noradrenaline in the forearm microcirculation. The mechanisms were predominantly endothelium-independent, based on the fact that co-infusion of acetylcholine with NG-monomethyl-L-arginine and infusion of nitroprusside, both of which are endothelium-independent, resulted in enhanced vasodilatory responses. However, the data do not preclude an endothelial component in the dilatory responses associated with DHA. These findings contrast with those reported by Woodman et al. ( Reference Woodman, Mori and Burke 45 ) who showed that using the same study design neither EPA nor DHA decreased blood pressure in treated hypertensive type 2 diabetic patients. The lack of effect in the latter trial could be related to concomitant use of pharmacological agents, the presence of glycaemia and increased blood pressure variability in diabetic patients.
Possible mechanisms
The antihypertensive effects of n-3 fatty acids are likely to be multifactorial involving improvements in endothelial function and arterial compliance, along with a cardiac effect mediated by a decrease in heart rate( Reference Mori, Burke, Beilin, Lip and Hall 7 ). Possible mechanisms include suppression of vasoconstrictor prostanoids, enhanced production and/or release of nitric oxide, reduced plasma noradrenaline, changes in calcium flux, increased membrane fluidity, antioxidative actions of n-3 fatty acids or an increase in HDL cholesterol( Reference Mori, Burke, Beilin, Lip and Hall 7 ).
n-3 Fatty acids reduce heart rate( Reference Mori, Burke, Beilin, Lip and Hall 7 , Reference Bao, Mori and Burke 42 , Reference Mori, Bao and Burke 43 , Reference Mozaffarian, Geelen and Brouwer 46 ) suggesting a significant cardiac component associated with the antihypertensive effects possibly mediated by effects on cardiac myocytes, autonomic nerve function or β-adrenoreceptor activity. In a meta-analysis of thirty studies Mozaffarian et al. ( Reference Mozaffarian, Geelen and Brouwer 46 ) showed that n-3 fatty acids reduce heart rate overall by −1·6 bpm, with a greater reduction in trials with baseline heart rate greater than 69 bpm (−2·5 bpm) and those of longer than 12 weeks duration (−2·5 bpm).
It is well recognised that blood pressure is strongly affected by arterial compliance, which in turn is influenced by endothelial function. McVeigh et al. ( Reference McVeigh, Brennan and Cohn 9 ) showed that in individuals with type 2 diabetes compliance in the large arteries and more peripheral vasculature improved significantly after 6 weeks of fish oil compared with olive oil. EPA and DHA supplementation also improved arterial compliance by 35 and 27 %, respectively, in patients with dyslipidaemia( Reference Nestel, Shige and Pomeroy 10 ). Pase et al. ( Reference Pase, Grima and Sarris 47 ) showed in a meta-analysis that included ten randomised controlled trials, four using pulse wave velocity and six using arterial compliance measured as capacitance compliance or systemic arterial compliance, that n-3 fatty acids significantly improved both pulse wave velocity and arterial compliance.
Human studies strongly suggest that n-3 fatty acids increase heart rate variability in patients at high risk of sudden cardiac death and in healthy individuals( Reference Christensen 48 , Reference Christensen and Schmidt 49 ). A meta-analysis that included fifteen randomised controlled trials showed that short-term n-3 fatty acid supplementation favourably affects the frequency domain of heart rate variability as indicated by enhancement of vagal tone, which may be an important mechanism underlying the antiarrhythmic effect of n-3 fatty acids( Reference Xin, Wei and Li 50 ).
Mechanisms through which the n-3 fatty acids affect heart rate probably relate to their incorporation into myocardial cells and altering electrophysiological function in a manner that reduces the vulnerability to ventricular fibrillation( Reference Leaf, Kang and Xiao 51 ). The anti-arrhythmic effects of n-3 fatty acids are due to their ability to inhibit the fast, voltage-dependent sodium current and the L-type calcium currents, and also to modulate potassium channels( Reference Leaf, Kang and Xiao 51 ).
Effects on plasma lipids and lipoproteins
n-3 Fatty acids reduce plasma TAG by approximately 20–30 %, but have very little effect on total cholesterol, HDL cholesterol and LDL cholesterol( Reference Harris 13 , Reference Harris 14 ). In overweight, treated hypertensive patients( Reference Mori, Bao and Burke 52 ) and in dyslipidaemic men( Reference Mori, Burke and Puddey 53 ), n-3 fatty acids increased HDL cholesterol due primarily to an increase in HDL2-cholesterol subfraction. A reduction in hepatic very-low density lipoprotein cholesterol synthesis probably contributes to the fall in plasma TAG. Mechanisms for this effect include a reduction in fatty acid availability for TAG synthesis as a result of decreased de novo lipogenesis, increased fatty acid β-oxidation, a reduction in the delivery of NEFA to the liver, altered enzymatic activity for TAG assembly in the liver and increased hepatic synthesis of phospholipids instead of TAG( Reference Harris 13 , Reference Harris 14 , Reference Harris and Bulchandani 54 ). Using proton magnetic resonance spectroscopy, Cussons et al. ( Reference Cussons, Watts and Mori 55 ) showed that n-3 fatty acids significantly reduced liver fat by 18 % in women with hepatic steatosis.
Mozaffarian et al. ( Reference Mozaffarian and Wu 4 ) have shown that TAG lowering is linearly dose-dependent across a wide range of n-3 fatty acid consumption. Overall plasma TAG are reduced by 0·33 mm for a 1 g/d increase in EPA plus DHA. In trials supplementing highly purified EPA or DHA, Mori et al. ( Reference Woodman, Mori and Burke 45 , Reference Mori, Burke and Puddey 53 ) showed the TAG-lowering actions of n-3 fatty acids were attributable to both EPA and DHA.
A small, albeit significant increase in LDL cholesterol observed in some studies supplementing n-3 fatty acids, is accompanied by an increase in LDL particle size. Mori et al. ( Reference Mori, Burke and Puddey 53 , Reference Woodman, Mori and Burke 56 ) showed that DHA and not EPA supplementation increased LDL particle size, suggesting that the lipid-regulating effects of DHA are at least as important as those of EPA. Reduced LDL particle size is an important cardiovascular risk factor( Reference Hulthe, Bokemark and Wikstrand 57 ) and correlates with sub-clinical atherosclerosis as measured by intima-media thickening( Reference Lahdenpera, Syvanne and Kahri 58 ).
Chan et al. ( Reference Chan, Watts and Mori 59 ) also demonstrated in dyslipidaemic, viscerally obese men with insulin resistance, that n-3 fatty acid supplementation combined with statin therapy provided the optimal change in lipid profile, as reflected by decreased plasma TAG and increased HDL cholesterol.
Effects on glycaemic control, insulin sensitivity and secretion
Reports of disparate results on glycaemia, particularly from early studies examining the effects of n-3 fatty acids on glycaemic control in type 2 diabetic patients, are probably related to the dose of n-3 fatty acids provided, concomitant oral diabetic medication, presence of obesity and/or insulin resistance, presence of other comorbidities such as hypertension, not controlling subjects’ diets during intervention and duration of intervention( Reference Friedberg, Janssen and Heine 60 ). However, three independent meta-analyses of twenty-six, eighteen and twenty-three randomised controlled studies, have shown no overall effect of the n-3 fatty acids in a dose range of 0·9 to 18 g/d on fasting glucose or glycated Hb in patients with type 2 diabetes( Reference Friedberg, Janssen and Heine 60 – Reference Montori, Farmer and Wollan 62 ).
Two placebo-controlled trials have examined the independent effects of purified EPA or DHA supplementation on plasma glucose and insulin in type 2 diabetic patients( Reference Woodman, Mori and Burke 45 ) and in mild dyslipidaemic men( Reference Mori, Burke and Puddey 53 ). These studies showed the differential effects of EPA and DHA on plasma glucose and insulin levels depending on the background condition. Mori et al. ( Reference Mori, Burke and Puddey 53 ) reported a borderline increase in fasting glucose with 4 g daily EPA but no change with DHA. Fasting serum insulin significantly increased relative to placebo after DHA but not after EPA( Reference Mori, Burke and Puddey 53 ). Woodman et al. ( Reference Woodman, Mori and Burke 45 ) reported that in type 2 diabetic patients fasting glucose increased following 4 g daily EPA or DHA, but insulin and C-peptide were not altered by either fatty acid( Reference Woodman, Mori and Burke 45 ). Self-monitored blood glucose measured four times daily on 4 d of each week throughout the 6-week intervention, rose following EPA and DHA in the first 3 weeks, but had returned to baseline values by week 6( Reference Woodman, Mori and Burke 45 ). Overall, HbA1c, insulin secretion and insulin sensitivity were unaffected by EPA or DHA( Reference Woodman, Mori and Burke 45 ).
Effects on platelet function and thrombosis
A number of trials have studied the effect of n-3 fatty acids on platelet function, and measures of coagulation and fibrinolysis, in healthy human subjects and in patients at increased risk of CVD( Reference Knapp 16 , Reference Mori, Beilin and Burke 63 ). n-3 Fatty acids, particularly at large doses, reduced ex vivo platelet aggregation, an effect mediated, in part, via alterations in thromboxane formation( Reference Mori, Beilin and Burke 63 ). In contrast, n-3 Fatty acids have shown inconsistent and minor effects on measures of fibrinolysis and coagulability( Reference Kristensen, Iversen and Schmidt 64 ). To date, there is little evidence that an increased intake of n-3 fatty acids will increase the risk of major bleeding in patients receiving anticoagulants or platelet inhibitors.
Effects on inflammation
The anti-inflammatory and immunomodulatory effects of n-3 fatty acids are most probably related to their attenuating actions on inflammatory eicosanoids including altered leucotriene formation, cytokines, oxidative stress, endothelial and cell–cell activation and immune cell function( Reference Mori and Beilin 17 , Reference Calder 18 ). n-3 Fatty acids were shown to reduce ex vivo production of proinflammatory cytokines including TNFα, IL-1 and IL-6 following lipopolysaccharide-stimulation of monocytes/lymphocytes( Reference Calder 15 , Reference Mori and Beilin 17 , Reference Calder 18 ). In-vitro studies also showed that DHA but not EPA decreased the expression of pro-inflammatory cytokines, cell-adhesion molecules and monocyte adhesion to endothelial cells( Reference De Caterina, Liao and Libby 65 ). n-3 Fatty acids attenuated the expression of adhesion molecules on the surface of cultured human endothelial cells, monocytes and lymphocytes( Reference De Caterina, Liao and Libby 65 ). Of note, DHA was more potent than EPA in inhibiting the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin, after stimulation. The EPA and DHA-induced reduction in adhesion molecule expression was accompanied by decreased binding of human lymphocytes and monocytes to cytokine-stimulated endothelial cells( Reference De Caterina, Liao and Libby 65 ).
The anti-inflammatory effects of n-3 fatty acids are in part mediated by a novel family of local lipid mediators generated during self-limited resolution of inflammation. Serhan et al. ( Reference Serhan and Petasis 19 ) described the E-series resolvins derived from EPA, and D-series resolvins, protectins, neuroprotectins and maresins derived from DHA( Reference Bannenberg, Arita and Serhan 66 – Reference Serhan, Brain and Buckley 69 ). These mediators acting via G-coupled protein receptors( Reference Serhan and Chiang 70 ) have potent anti-inflammatory and pro-resolving actions( Reference Ji, Xu and Strichartz 71 , Reference Serhan, Chiang and Van Dyke 72 ) and increase with time during the inflammatory process( Reference Serhan and Petasis 19 , Reference Tabas 73 ). Two series of resolvins and protectins have been identified: those derived via lipoxygenase metabolism of EPA and DHA, and a second series derived from aspirin-triggered cyclooxygenase-2 or cytochrome P450 metabolism of EPA and DHA. Mas et al. ( Reference Mas, Croft and Zahra 74 ) have shown that the resolvin and protectin pathway precursors 18R/S-HEPE and 17R/S-HDHA, as well as the resolvins 17S-RvD2, 17S-RvD1 and 17R-RvD1, were present in human plasma following n-3 fatty acid supplementation, at concentrations that are known to have potent anti-inflammatory effects.
The anti-inflammatory effects of n-3 fatty acids may play an important role in preventing plaque development and also in plaque stabilisation. Thies et al. ( Reference Thies, Garry and Yaqoob 75 ) supplemented n-3 fatty acids to patients with symptomatic carotid atherosclerotic disease undergoing carotid endarterectomy. n-3 Fatty acids were readily incorporated into the atherosclerotic plaque and this associated with reduced macrophage infiltration into the plaque and a thickened fibrous cap, suggestive of increased plaque stability. These findings represent an important mechanism by which n-3 fatty acids could reduce ischaemic cardiovascular events.
Effects on oxidative stress
Despite any benefits of n-3 fatty acids, there remains concern that these fatty acids may increase lipid peroxidation and oxidative stress. In contrast, n-3 fatty acids given as fish meals( Reference Mori, Dunstan and Burke 76 ) or purified EPA or DHA to patients with type 2 diabetes( Reference Mori, Woodman and Burke 77 ), and purified EPA or DHA supplemented to overweight, mildly dyslipidaemic men( Reference Mori, Puddey and Burke 78 ) decreased urinary F2-isoprostane excretion. F2-isoprostanes are lipid peroxidation products derived from the non-enzymatic free radical oxidation of arachidonic acid in membrane lipids and are considered the most reliable biomarkers of in vivo lipid peroxidative damage( Reference Milne, Yin and Hardy 79 ). Barden et al. ( Reference Barden, Mori and Dunstan 80 ) also showed that cord plasma and urinary F2-isoprostanes were reduced in infants whose mother received a daily n-3 fatty acid supplement during pregnancy. Mas et al. ( Reference Mas, Woodman and Burke 20 ) showed that plasma F2-isoprostanes were reduced by EPA and DHA in type 2 diabetic and overweight, dyslipidaemic men. Furthermore, the fall in plasma F2-isoprostanes was not altered in analyses that corrected for changes in plasma arachidonic acid, EPA or DHA( Reference Mas, Woodman and Burke 20 ). The mechanisms by which n-3 fatty acids reduce oxidative stress remain unresolved, but probably relate to decreased leucocyte activation and the immunomodulatory actions of these fatty acids. This hypothesis is supported by data from Mori et al. ( Reference Mori, Woodman and Burke 77 ) who showed that changes in urinary F2-isoprostanes were significantly positively associated with changes in TNFα.
Conclusions
Present data support the concept that n-3 fatty acids beneficially influence a number of cardiometabolic risk factors. Most, albeit not all, clinical trials demonstrate that n-3 fatty acids are protective particularly in the setting of secondary prevention. There are no clinically significant adverse effects of n-3 fatty acids at doses up to at least 4 g/d. n-3 Fatty acids also do not appear to have adverse interactions with medications such as statins and other lipid-lowering drugs or antihypertensive medications. Small doses of 1 g/d are achievable with consumption of two to three oily fish meals per week; otherwise numerous purified encapsulated preparations are now readily available. n-3 Fatty acids consumed as fish should be considered an important component of a healthy diet and as a potential therapeutic modality in patients with coronary artery disease and those at heightened risk of CVD( Reference Lloyd-Jones, Hong and Labarthe 81 ).
Acknowledgements
Aspects of the research work described from the author's laboratory presented in this review were supported by various grants from the National Health & Medical Research Council of Australia; the National Heart Foundation of Australia; the Fish Oil Test Materials Programme of the National Institutes of Health/Department of Commerce, USA; and the Medical Research Foundation of Royal Perth Hospital, Perth, Western Australia.
Financial support
The author is supported in part by a Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (1042255). The NHMRC had no role in the design, analysis or writing of this article.
Conflicts of interest
None.
Authorship
The author is solely responsible for the research and writing of this review.
