Long-chain n-3 fatty acids enter advanced atherosclerotic plaques and are associated with decreased inflammation and decreased inflammatory gene expression.

Instability of atherosclerotic plaques is due to macrophage inflammatory activity and can result in rupture of the plaque (Plutzky, 1999). We previously showed that long-chain n-3 fatty acids enter advanced atherosclerotic plaques and alter their morphology to one indicative of greater stability (Thies et al. 2003). Whether these fatty acids decrease inflammatory activity within advanced plaques is not known. The objectives of the present study were to confirm that long-chain n-3 fatty acids enter advanced atherosclerotic plaques and to examine the effect on plaque inflammation and on the expression of selected inflammatory genes. Patients (n 121) awaiting carotid endarterectomy were randomly assigned to n-3 fatty acid ethyl esters (Omacor; Pronova Biocare AS, Lysaker, Norway) or olive oil as placebo (both 2 g/d) until surgery (7–109 d; median 21 d). Carotid-plaque phospholipid-fatty acid composition was determined by GC. Plaques were subject to histological examination, which identified the extent of inflammation and instability. Levels of mRNA encoding several matrix metalloproteinases (MMP), the inflammatory cytokine IL-6 and intercellular adhesion molecule (ICAM)-1 were determined by real-time RT–PCR using 36B4 as the housekeeping gene. The n-3 fatty acid EPA was significantly higher in plaque phospholipids from patients in the Omacor group (0.83 (SE 0.05) v. 0.43 (SE 0.05); P<0.0001). Plaque phospholipid-EPA content was significantly negatively correlated with plaque inflammation (P=0.011), plaque instability (P=0.021) and average plaque histology score, a composite end point that includes several histological features (P=0.043). Plaques from patients in the Omacor group expressed significantly lower levels of mRNA for MMP7, MMP9, MMP12, IL-6 and ICAM-1 (all P<0.05), but there was no difference in expression of mRNA for MMP3, MMP8 or MMP13. The present study confirms that long-chain n-3 fatty acids are incorporated into advanced atherosclerotic plaques over a short time period. Incorporation of EPA into advanced atherosclerotic plaques is associated with decreased expression of some of the MMP involved in inducing plaque instability and is associated with decreased plaque inflammation and instability. Incorporation of EPA into advanced atherosclerotic plaques is also associated with decreased expression of IL-6 and ICAM-1, indicating that these fatty acids exert anti-inflammatory actions within advanced plaques. These effects may result in increased plaque stability and so may play a role in decreasing cardiovascular events (see Calder, 2004)

Apolipoprotein E genotype and the cardiovascular disease risk phenotype: impact of sex and adiposity (the FINGEN study)

Here the impact of APOE genotype on CHD risk in UK adults is reported, along with an analysis of APOE genotype×BMI/age/sex interactions. APOE genotype had a significant impact on fasting total:LDL-cholesterol (TC:LDL-C) ratio, triglycerides, % HDL3, and the Framingham 10-year CVD risk score (P<0.05), with an overall trend towards lower and higher risk in E2- and E4-carriers, respectively, relative to the wild-type E3/E3 genotype. A greater impact of genotype on TC:HDL-C was observed in females, which explained 16% of the variability in this outcome versus 6% in males. APOE genotype was also associated with plasma C-reactive protein and adhesion molecule concentrations (P<0.05), with significant genotype×BMI interactions observed. Our observations indicate that the association between the APOE genotype and CHD risk is unlikely to be homogenous and highlights the risk of inaccurate estimations of genotype-phenotype associations in population subgroups without appropriate stratification for sex and adiposity

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN study

<b>Background</b>: The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well established and likely to contribute to cardioprotective benefits. <b>Objectives</b>: We aimed to determine the effect of moderate EPA and DHA intakes (<2 g EPA+DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed responses. <b>Design</b>: Three hundred twelve adults aged 20–70 y, who were prospectively recruited according to age, sex, and APOE genotype, completed a double-blind placebo-controlled crossover study. Participants consumed control oil, 0.7 g EPA+DHA/d (0.7FO), and 1.8 g EPA+DHA/d (1.8FO) capsules in random order, each for an 8-wk intervention period, separated by 12-wk washout periods. <b>Results</b>: In the group as a whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO, respectively (P < 0.001): significant sex x treatment (P = 0.038) and sex x genotype x treatment (P = 0.032) interactions were observed, and the greatest triacylglycerol-lowering responses (reductions of 15% and 23% after 0.7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol (P = 0.026) and higher LDL-cholesterol (P = 0.010), HDL-cholesterol (P < 0.001), and HDL2 (P < 0.001) concentrations were evident after fish-oil intervention. <b>Conclusions</b>: Supplements providing EPA+DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n–3 polyunsaturated fatty acids in males than in females