Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites

Patients with well-controlled low-density lipoprotein cholesterol levels, but persistent high triglycerides, remain at increased risk for cardiovascular events as evidenced by multiple genetic and epidemiologic studies, as well as recent clinical outcome trials. While many trials of low-dose x3-polyunsaturated fatty acids (x3-PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown mixed results to reduce cardiovascular events, recent trials with high-dose x3-PUFAs have reignited interest in x3-PUFAs, particularly EPA, in cardiovascular disease (CVD). REDUCE-IT demonstrated that high-dose EPA (4 g/day icosapent-ethyl) reduced a composite of clinical events by 25% in statin-treated patients with established CVD or diabetes and other cardiovascular risk factors. Outcome trials in similar statin-treated patients using DHA-containing high-dose x3 formulations have not yet shown the benefits of EPA alone. However, there are data to show that high-dose x3-PUFAs in patients with acute myocardial infarction had reduced left ventricular remodelling, non-infarct myocardial fibrosis, and systemic inflammation. x3-polyunsaturated fatty acids, along with their metabolites, such as oxylipins and other lipid mediators, have complex effects on the cardiovascular system. Together they target free fatty acid receptors and peroxisome proliferator-activated receptors in various tissues to modulate inflammation and lipid metabolism. Here, we review these multifactorial mechanisms of x3-PUFAs in view of recent clinical findings. These findings indicate physico-chemical and biological diversity among x3-PUFAs that influence tissue distributions as well as disparate effects on membrane organization, rates of lipid oxidation, as well as various receptor-mediated signal transduction pathways and effects on gene expression.