New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease

Abstract

Purpose of ReviewTreatment of hypercholesterolemia with statins results in significant reductions in cardiovascular risk; however, individuals with well-controlled low-density lipoprotein cholesterol (LDL-C) levels, but persistent high triglycerides (TG), remain at increased risk. Genetic and epidemiologic studies have shown that elevated fasting TG levels are associated with incident cardiovascular events. At effective doses, omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower TG levels but may have additional atheroprotective properties compared to other TG-lowering therapies such as niacin and fibrates. The purpose of this review is to evaluate mechanisms related to the potential benefits of omega-3 fatty acids in atherothrombotic disease.Recent FindingsLarge randomized clinical trials are currently under way to test the cardiovascular benefits of omega-3 fatty acids at a pharmacologic dosage (4 g/day). A large randomized trial with a prescription EPA-only formulation was shown to reduce a composite of cardiovascular events by 25% in statin-treated patients with established cardiovascular disease or diabetes and other CV risk factors. EPA and DHA have distinct tissue distributions as well as disparate effects on membrane structure and lipid dynamics, rates of lipid oxidation, and signal transduction pathways. Compared to other TG-lowering therapies, EPA has been found to inhibit cholesterol crystal formation, inflammation, and oxidative modification of atherogenic lipoprotein particles. The anti-inflammatory and endothelial benefits of EPA are enhanced in combination with a statin.SummaryOmega-3 fatty acids like EPA only at a pharmacologic dose reduce fasting TG and interfere with mechanisms of atherosclerosis that results in reduced cardiovascular events. Additional mechanistic trials will provide further insights into their role in reducing cardiovascular risk in subjects with well-managed LDL-C but elevated TG levels.

Concentration-Dependent Effects of N-3 Long-Chain Fatty Acids on Na,K-ATPase Activity in Human Endothelial Cells

“…However, controversies exist on this topic [10]. Recently, EPA was shown to improve endothelial function [52]. This is crucial since endothelial cells are considered the gatekeeper of vascular health.…”

The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia

“…Recent findings concerning nutraceutical-mediated triglyceride-lowering have renewed the focus on lipids other than LDL-C. Evidence from RCTs, observational studies, and meta-analyses strongly suggest that consumption of oily fish and long-chain omega-3 polyunsaturated fatty acids (PUFAs) improves risk factors and biomarkers associated with cardiovascular disease [19,29,30], in a manner consistent with the understanding of the biological actions of PUFAs, in particular the triglyceridelowering effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [31]. Because these active components can be chemically identified and standardized and appear to be closely associated with improvements in risk factors, PUFAs are an attractive target for nutraceutical development, and unusually for the field of nutraceutical research, three large, rigorous clinical trials have been published.…”

Effects and Issues of Diet Fat on Cardiovascular Metabolism

“…REDUCE-IT had a mineral oil placebo, whereas STRENGTH had a corn oil placebo. An in vitro study has shown that EPA has direct antioxidant benefits in various apoBcontaining particles that are more pronounced than those of DHA and other TGlowering agents [185]. Although all these differences may explain partially the inconsistent results in the two studies, it appears most plausible that EPA may have different biological effects on CV events compared with those of DHA.…”

“…The daily dosage of n-3 supplements is usually 2 capsules containing the combination of 180 mg EPA and 120 mg DHA (=0.6 g/ day of n-3), and no more than 2 g/day as dietary n-3 supplements in the FDA recommendation of 2014 [183]. The rationale of 4 g EPA in REDUCE-IT was that the blood concentration at this dose (183 μg/ml) was similar to that in Japanese subjects in JELIS study who received 1.8 g of EPA (170 μg/ml) [156,185]. This occurred because Japanese people have much higher background intake of fish and thus have higher EPA and DHA blood concentrations than seen in Western populations.…”