Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid

Abstract

Patients with well-controlled LDL (low-density lipoprotein) levels still have residual cardiovascular risk associated with elevated triglycerides. Epidemiological studies have shown that elevated fasting triglyceride levels associate independently with incident cardiovascular events, and abundant recent human genetic data support the causality of TGRLs (triglyceride-rich lipoproteins) in atherothrombosis. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower blood triglyceride concentrations but likely exert additional atheroprotective properties at higher doses. Omega-3 fatty acids modulate T-cell differentiation and give rise to various prostaglandins and specialized proresolving lipid mediators that promote resolution of tissue injury and inflammation. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) with an EPA-only formulation lowered a composite of cardiovascular events by 25% in patients with established cardiovascular disease or diabetes mellitus and other cardiovascular risk factors. This clinical benefit likely arises from multiple molecular mechanisms discussed in this review. Indeed, human plaques readily incorporate EPA, which may render them less likely to trigger clinical events. EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and endothelial function as well as tissue distributions. Trials that have evaluated DHA-containing high-dose omega-3 fatty acids have thus far not shown the benefits of EPA alone demonstrated in REDUCE-IT. This review will consider the mechanistic evidence that helps to understand the potential mechanisms of benefit of EPA.

Keywords: eicosapentaenoic acid; fatty acids; inflammation; lipoproteins; triglycerides.

Figure 1.

Potential mechanisms of cardioprotection for omega-3 fatty acids. Omega-3 fatty acids may lessen risk of cardiovascular events through a number of mechanisms that contribute to their overall protective actions. Lowering of TGRL (triglyceride-rich lipoprotein) may account for some but certainly not all of the observed benefits (Figure 2). By boosting the production of anti-aggregatory and vasodilatory prostanoids, such as prostacyclin, omega-3 fatty acids may combat thrombosis as well as vasospasm. Omega-3 fatty acids can incorporate into plasma membranes and those of the mitochondria potentially stabilizing them to resist oxidation and confer protection against arrhythmias. Omega-3 fatty acids and certain prostanoids produced from them can exert anti-inflammatory actions. In addition, the omega-3 fatty acids can provide precursors for the synthesis of specialized proresolving mediators that can combat inflammation, perhaps causing less interference with his defenses than direct anti-inflammatory therapies. A combination of these various mechanisms may contribute to the cardiovascular protection associated with omega-3 fatty acid consumption. DHA indicates docosahexaenoic acid; and EPA, eicosapentaenoic acid.

Figure 2.

Atherogenic pathways for TGRLs (triglyceride-rich lipoproteins). TGRL (estimated by serum triglyceride measurements) can promote vascular dysfunction and atherosclerosis through a number of mechanisms. Saturated fatty acids, notably palmitate, can promote inflammation, in part, due to activation of the NLRP-3 (NLR family pyrin domain-containing 3) inflammasome, which produces activated forms of the proinflammatory cytokines IL (interleukin)-1β and IL-18. ApoC-III (Apolipoprotein CIII) can exert direct proinflammatory effects of cells involved in atherosclerosis, such as macrophages and endothelial cells. Human genetic studies strongly support the causality of ApoC-III in human atherothrombosis. TGRL particles deliver cholesterol effectively to macrophages and can promote foam cell formation. Omega-3 fatty acids may exert some of their apparent protective effect on atherothrombosis by blocking some of these proinflammatory and other deleterious effects of TGRL. EGR-1 indicates early growth response protein 1; LDL, low-density lipoprotein; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; PKC, protein kinase C; TLR, toll-like receptors; and VCAM-1, vascular cell adhesion molecule 1.

Figure 3.

Molecular membrane interactions of omega-3 fatty acids. Schematic illustration of the proposed location and contrasting effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on membrane structure. The insertion of EPA and DHA affect distinct regions of the membrane lipid bilayer due to differences in their hydrocarbon length and number of double bonds. The longer hydrocarbon length of DHA leads to more rapid isomerization and conformational changes that result in increased membrane fluidity and promotion of cholesterol domains. EPA has a more stable and extended structure that contributes to membrane stability as well as inhibition of lipid oxidation and cholesterol domain formation.

Figure 4.

Clinical advances in the management of residual cardiovascular risk. Beyond a plant-based diet and high-intensity statins, further potential strategies to reduce residual cardiovascular risk include those targeting LDL (low-density lipoprotein)-cholesterol, inflammation, thrombosis, triglycerides (TGs), and Lp(a). hsCRP indicates high-sensitivity C-reactive protein; and REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial.