Introduction

The consumption of seed oils high in the omega-6 polyunsaturated fat (PUFA) linoleic acid (LA) contributes to low-grade inflammation, oxidative stress, endothelial dysfunction and atherosclerosis.1 Moreover, dietary LA significantly increases cyclooxygenase-2 (COX-2) expression in the aorta,2 converting arachidonic acid (AA) to proinflammatory eicosanoids. This may explain why increasing LA intake can actually lower AA levels due to an increased breakdown into harmful proinflammatory metabolites. Additionally, there is an AA-independent pathway of inflammation promoted by the intake of omega-6 seed oils such as increased production of oxidised linoleic acid metabolites (OXLAMs) and proinflammatory LA CYP-eicosanoids.3–5 OXLAMs formed from LA activate NF-kB and increase proinflammatory cytokines, endothelial adhesion molecules, as well as chemokines, all of which are paramount in the formation of atherosclerosis.5–8 LA also induces an inflammatory environment in endothelial cells that may increase the risk of coronary heart disease (CHD).8 OXLAMs are found at a 50-fold higher concentration in plasma than AA metabolites, suggesting that they are more consequential in CHD and other chronic diseases,2 3 9 and lowering dietary LA reduces OXLAMs in the body.3

By inhibiting COXs and lipoxygenases (LOXs), marine omega-3s can reduce inflammation caused by the metabolism of AA. Indeed, compared with high-oleic sunflower oil (3.5 g/day), fish oil (3.5 g/day) reduces acute phase reactants (haptoglobin precursor, haemopexin, alpha-1-antitrypsin precursor and serum amyloid P component). The authors concluded, ‘The alterations in serum proteins… imply that fish oil activates anti-inflammatory mechanisms believed to impede the early onset of CHD’.10 In human atherosclerotic lesions, as the atherosclerotic lesion becomes more advanced, the ratio between oxidised LA and unoxidised LA increases.11 Moreover, rats fed LA have a significant increase in tumour necrosis factor (TNF)-alpha (p<0.05) in plasma, and higher levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and NF-kB in aortas. The authors concluded that ‘…our results demonstrated that an excess of LA is more efficient to activate endothelial molecular process than an excess of saturated fatty acids’.2

Two phase III, double-blind studies randomised hypertriglyceridemic patients to marine omega-3s (icosapent ethyl trade name Vascepa 4 g/day, Vascepa 2 g/day or placebo).12 These included patients on statins with residual high TG ≥200 mg/dL<500 mg/dL (ANCHOR) or very high TG with or without statin (≥500 to <2000 mg/dL (MARINE). The authors concluded, ‘Compared with placebo, icosapent ethyl 4 g/day significantly decreased oxidized-low density lipoprotein (Ox-LDL) (13%, p<0.001, ANCHOR), Lp-PLA2 (14%, p<0.001, MARINE; 19%, p<0.001, ANCHOR), and high-sensitivity c-reactive protein (hsCRP) levels (36%, p<0.01, MARINE; 22%, p<0.001, ANCHOR)’.12 The benefits regarding a reduction in ox-LDL was not found with 2 g of Vascepa/day, suggesting that 4 g of Vascepa (3.4 g of eicosapentaenoic acid (EPA) as ethyl esters) may be ideal for reducing ox-LDL.12 Furthermore, DHA alone (at 3 g/day) has been found to reduce inflammation (interleukin (IL)-6, hsCRP and granulocyte monocyte-colony stimulating factor) in men with hypertriglyceridaemia after 3 months of use and to increase the anti-inflammatory matrix-metalloproteinase-2.13 Thus, it appears that both EPA and docosahexaenoic acid (DHA) have anti-inflammatory benefits. The recent announcement of results from the Reduction of Cardiovascular Events with EPA Intervention Trial (REDUCE-IT) study, which found a highly significant reduction in cardiovascular events using Vascepa 4 g per day, suggests how these anti-inflammatory benefits may cause reductions in clinical endpoints.

A systematic review of 26 randomised controlled trials (RCTs) concluded, ‘Dietary omega-3 fatty acids are associated with plasma biomarker levels, reflecting lower levels of inflammation and endothelial activation in cardiovascular disease and other chronic and acute diseases, including chronic renal disease, sepsis and acute pancreatitis’.14 DHA may be particularly effective for reducing cytokine-induced endothelial leucocyte adhesion molecules due to its ability to incorporate into cellular lipids.15 Moreover, DHA reduces COX-2 expression,16 which also reduces inflammatory eicosanoid production from AA.

Omega-3 PUFAs also reduces adhesion molecules (VCAM-1 and ICAM-1), chemokines (MCP-1), matrix metalloproteinases and inflammatory cytokines.17 Another meta-analysis of 18 RCTs found that supplementing with omega-3 PUFAs significantly reduces soluble intercellular adhesion molecule-1, suggesting that marine omega-3s inhibit atherosclerosis formation, whereas LA can activate vascular endothelial cells, which is a critical event in inducing atherosclerosis.18 19

In a cross-sectional study, the omega-3 index (omega-3 PUFA content of red blood cells) was inversely related to inflammation (C reactive protein (CRP) and IL-6) in patients with peripheral arterial disease (PAD).20 Those with a mean omega-3 index of 6.8% had the lowest log-CRP values (0.6 mg/L) compared with those with omega-3 indexes of 4.5% and 3.7% (1.4 mg/L for both). The authors suggested that fish oil in patients with PAD would likely improve inflammation, symptoms and possibly reduce the progression and severity of the disease. However, LA in red blood cells and in plasma does not correlate well with intake, whereas DHA, especially in red blood cells but also in plasma, had good correlation (EPA also had fairly good correlation with intake as well but only with red blood cell levels).21

The omega-3 index is an independent risk factor for CHD mortality22 and is inversely related with inflammation (CRP and IL-6) in patients with stable CAD.23 One study found that omega-3s (around 25 oz. of fatty fish weekly plus 15 mL (one tablespoonful) of sardine oil daily) in those over 60 years of age reduces inflammation (CRP and IL-6) and improves insulin sensitivity, which may partially be due to its ability to reduce free fatty acids release by catecholamines.24

Compared with 15 mL/day of safflower oil (rich in LA) consuming 15 mL of flaxseed oil (around 7 g of alpha linolenic acid (ALA)/day) for 3 months decreases CRP (38%), serum amyloid A (23.1%) and IL-6 (10.5%).25 Moreover, compared with margarine rich in LA, margarine rich in ALA (total ALA intake around 6–8 g/day) significantly reduced CRP after 1 and 2 years (−0.53 mg/L and −0.56 mg/L, respectively).26 Thirty grams of flaxseed flour (5 g of ALA/day) has been found to significantly reduce CRP, serum amyloid A, white cell count and fibronectin, suggesting that flaxseed may be beneficial for suppressing chronic low-grade inflammation in obesity.27