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

R Preston Mason, R Preston Mason

Abstract

Purpose of review: Treatment 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 findings: Large 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. Omega-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.

Keywords: Atherosclerosis; Cholesterol; Eicosapentaenoic; Lipoproteins; Omega-3 fatty acids; Triglycerides.

Conflict of interest statement

Conflict of Interest

R. Preston Mason has received grant/research support from Amarin Pharma Inc., Pfizer Inc., Amgen Inc., ARCA Biopharma, and Novartis AG. Dr. Mason is also a paid speaker and consultant for Amarin Pharma Inc., Pfizer Inc., and Novartis AG.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Figures

Fig. 1
Fig. 1
Hypothesized effects of EPA and DHA on endothelial and neuronal cell membrane structural organization, respectively, based on model membrane experiments. DHA is proposed to undergo rapid conformational changes in the neuronal cell plasma membrane where it may promote the formation of cholesterol-rich lipid domains and fluidity—a structural feature shown to be essential to neuronal function. EPA, by contrast, is proposed to intercalate into the membrane phospholipid hydrocarbon core region where it inhibits free radical propagation while preserving a more homogenous cholesterol distribution [••, , , , , •, •]. Note: This figure contains graphic elements that were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License

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