Omega-3 Fatty Acids and Cardiovascular Disease: Effects on Risk Factors, Molecular Pathways, and Clinical Events

Perspective:

The following are 10 points to remember about this state-of-the-art paper:

1. Fish are a major food source of long-chain n-3 polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) (20:5n-3) and docosahexaenoic acid (DHA) (22:6n-3). Alpha-linolenic acid (ALA) (18:3n-3) is an n-3 fatty acid found in plants, including some seeds, nuts, and nut oils. ALA cannot be synthesized in humans. Thus, tissue and circulating levels of EPA and DHA are predominantly determined by their direct dietary consumption.

2. Environmental concerns regarding fish consumption include potential contaminants such as mercury. However, the mercury content of most fish is low, with a few selected species containing higher levels. Availability of sustainable, environmentally sound commercial fishing must also be addressed to preserve this food source into the future.

3. N-3 PUFA has multiple physiological effects that may translate into reduced cardiovascular disease risk. Plasma triglycerides are lowered with n-3 PUFAs by decreased hepatic production of very low-density lipoprotein and enhanced clearance. Lower resting heart rate and blood pressure have also been observed with n-3 PUFA intake, which may occur through improved left ventricular diastolic filling or augmented vagal tone. In short-term trials, n-3 PUFA consumption increases biomarkers of nitric oxide production, mitigates peripheral vasoconstrictive responses to norepinephrine and angiotensin II, improves arterial wall compliance, and enhances vasodilatory responses. Such effects, separately or in sum, could account for lowering of systemic vascular resistance and blood pressure.

4. High doses of n-3 PUFA are considered to have antithrombotic effects; however, n-3 PUFA has not been shown to consistently affect platelet aggregation or levels of coagulation factors. No excess in clinical bleeding outcomes have been observed in randomized trials. Improved flow-mediated arterial dilation has been observed with n-3 PUFAs, along with lower circulating markers of endothelial dysfunction.

5. Some observational studies have noted a higher incidence of type 2 diabetes with n-3 PUFA or fish consumption. However, among controlled trials, no association has been noted between n-3 PUFAs and biomarkers of glucose-insulin homeostasis.

6. It remains unclear if n-3 PUFAs have anti-inflammatory effects. In several trials, n-3 PUFA supplementation reduced plasma and urine levels of arachidonic acid (AA)-derived eicosanoids such as leukotriene E4. Findings for other circulating biomarkers of inflammation, such as interleukin-1-beta and tumor necrosis factor-alpha, are mixed.

7. N-3 PUFA affects a myriad molecular pathways, including alteration of physical and chemical properties of cellular membranes, direct interaction with and modulation of membrane channels and proteins, regulation of gene expression via nuclear receptors and transcription factors, changes in eicosanoid profiles, and conversion of n-3 PUFA to bioactive metabolites.

8. In prospective observational studies and adequately powered randomized clinical trials, the benefits of n-3 PUFA seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on other cardiovascular outcomes are less well established, including conflicting evidence from observational studies and/or randomized trials for effects on nonfatal myocardial infarction, ischemic stroke, atrial fibrillation, recurrent ventricular arrhythmias, and heart failure.

9. Research gaps include the relative importance of different physiological and molecular mechanisms, precise dose responses of physiological and clinical effects, whether fish oil provides all the benefits of fish consumption, and clinical effects of plant-derived n-3 PUFA.

10. Overall, current data provide strong concordant evidence that n-3 PUFAs are bioactive compounds that reduce risk of cardiac death. National and international guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFAs or at least two servings/week of oily fish.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Diet

Keywords: Platelet Function Tests, Diabetes Mellitus, Type 2, Coronary Disease, Norepinephrine, Interleukin-1, Leukotriene E4, Biological Markers, Receptors, Cytoplasmic and Nuclear, Cardiovascular Diseases, Fatty Acids, Unsaturated, Homeostasis, Death, Sudden, Cardiac, Inflammation, Myocardial Infarction, Insulin, Stroke, Vascular Diseases, Transcription Factors, Tumor Necrosis Factor-alpha, Heart Rate, Blood Coagulation Factors, Eicosapentaenoic Acid, Nitric Oxide, Incidence, Fatty Acids, Omega-3, Platelet Aggregation, Docosahexaenoic Acids, Heart Failure, Vascular Resistance, Diet, Triglycerides, Diastole, Arachidonic Acid, Hemorrhage, Eicosanoids


< Back to Listings