The mechanism of action of omega-3 fatty acids in secondary prevention post-myocardial infarction

ABSTRACT

Background: Omega-3 fatty acids from fish and fish oils can protect against coronary heart disease (CHD), which is still the most common cause of death in the Western economies. Evidence from epidemiological and case cohort studies indicate that consumption of fatty fish and omega-3 fatty acids reduces the risk of cardiovascular mortality.

Objective: This article briefly reviews the evidence regarding omega-3 fatty acids and CHD and outlines the mechanisms through which omega-3 fatty acids might confer cardiac benefits over and above the standard secondary prevention strategies.

Conclusion: The conclusion reached is that omega-3 fatty acids play a significant role in secondary prevention post-myocardial infarction. The mechanisms through which two of these omega-3 fatty acids, eicosapentaenoic acid and docosahexanoic acid, exert their action appear to be distinct and adjuvant to the available standard secondary prevention therapies. The role to be played by the administration of a newly licensed 90% concentrate EPA + DHA formulation (1?g/day capsule: Omacor) is explored.     

The role of omega-3 fatty acids in mood disorders

Research has established that docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid (PUFA), plays a fundamental role in brain structure and function. Epidemiological and cross-sectional studies have also identified a role for long-chain omega-3 PUFA, which includes DHA, eicosapentaenoic acid, and docosapentaenoic acid, in the etiology of depression. In the past ten years, there have been 12 intervention studies conducted using various preparations of longchain omega-3 PUFA in unipolar and bipolar depression. The majority of these studies administered long-chain omega-3 PUFA as an adjunct therapy. The studies have been conducted over 4 to 16 weeks of intervention and have often included small cohorts. In four out of the seven studies conducted in depressed individuals and in two out of the five studies in bipolar patients, individuals have reported a positive outcome following supplementation with ethyl-eicosapentaenoic acid or fish oil containing long-chain omega-3 PUFA. In the three trials that researched the influence of DHA-rich preparations, no significant effects were reported. The mechanisms that have been invoked to account for the benefits of long-chain omega-3 PUFA in depression include reductions in prostaglandins derived from arachidonic acid, which lead to decreased brain-derived neurotrophic factor levels and/or alterations in blood flow to the brain.     

Pleiotropic effects of omega-3 fatty acids

Omega-3 fatty acids except for their effect on triglycerides levels have cardioprotective properties as well as antiarrhythmic properties.The pleiotropic effects of omega-3 fatty acids, also, include lowering of blood pressure and the favorable effect on endothelial function and high-density cholesterol levels. Furthermore, studies have showed their favorable action in subjects with dementia, Alzheimer's disease and learning disorders. In this paper, a review of the recent patents on omega-3 fatty acids will be presented.     

ω-3脂肪酸对心血管疾病的防治作用研究进展

大量研究表明,ω-3脂肪酸可降低血浆三酰甘油水平,并具有抗炎、抗心律失常、抗栓等心血管保护作用。临床研究提示,补充ω-3脂肪酸可改善心血管疾病预后,其与他汀合用有助于降低非HDL-C水平,且安全性良好。近年来ω-3脂肪酸联合他汀能否进一步降低心血管病的残余风险引起人们高度关注。本文主要对ω-3脂肪酸对心血管疾病的防治作用和研究进展进行综述。     

Role of omega-6 and omega-3 fatty acids in fetal programming

Maternal nutrition plays a critical role in fetal development and can influence adult onset of disease. Linoleic acid (LA) and alpha-linolenic acid (ALA) are major omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA), respectively, that are essential in our diet. LA and ALA are critical for the development of the fetal neurological and immune systems. However, in recent years, the consumption of n-6 PUFA has increased gradually worldwide, and elevated n-6 PUFA consumption may be harmful to human health. Consumption of diets with high levels of n-6 PUFA before or during pregnancy may have detrimental effects on fetal development and may influence overall health of offspring in adulthood. This review discusses the role of n-6 PUFA in fetal programming, the importance of a balance between n-6 and n-3 PUFAs in the maternal diet, and the need of further animal models and human studies that critically evaluate both n-6 and n-3 PUFA contents in diets.     

Do omega-3 fatty acids help in depression?

There is an increasing number of studies assessing whether omega-3 fatty acids play a role in behavioural and mood disorders, particularly depression. Findings of this research have been highlighted in the media, and in recent reports by the Mental Health Foundation and the food charity Sustain. As a result of such raising of awareness, patients might ask their GPs and mental health professionals about taking omega-3 fatty acids as a treatment for depression. Here we assess whether omega-3 fatty acids have a role in the management of such individuals.     

A multi-country health economic evaluation of highly concentrated N-3 polyunsaturated fatty acids in secondary prevention after myocardial infarction

BACKGROUND: Patients who survive an acute myocardial infarction (MI) are at an increased risk of subsequent major cardiovascular events and (often sudden) cardiac death. The use of highly concentrated and purified omega-3 polyunsaturated fatty acids (n-3 PUFAs), in addition to standard secondary prevention after MI, results in a significant reduction in the risk of sudden death versus no n-3 PUFAs. This study assessed the cost effectiveness of adding n-3 PUFAs to the current secondary prevention treatment versus standard prevention alone after acute MI in five countries: Australia, Belgium, Canada, Germany and Poland. METHODS: Based on the clinical outcomes of GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico - Prevenzione) [MI, stroke, revascularisation rate and mortality], a decision model was built in DataProtrade mark. The implications of adding n-3 PUFAs to standard treatment in patients aged 59 years with a recent history of MI were analysed from the healthcare payer's perspective. The time horizon was 3.5 years (identical to GISSI-Prevenzione) but the effects on life expectancy through avoidance of cardiac events were calculated lifelong. Event costs were based on literature data. Life expectancy data for survivors of cardiac disease were taken from the Saskatchewan database and then adjusted by country. Results are expressed as extra cost (Euro) per life-year gained (LYG). Annual discounting of 5% was applied to health effects and costs. RESULTS: Treatment with highly concentrated n-3 PUFAs yielded between 0.261 (Poland) and 0.284 (Australia) LYG, at an additional cost of 787 Euros(Canada) to 1,439 Euros(Belgium). The ICER varied between 2,788 Euros(Canada) and 5,097 Euros(Belgium) per LYG. Sensitivity analyses on effectiveness, cost of complications and discounting proved the robustness of the results. A second-order Monte Carlo simulation based on the 95% confidence intervals obtained from GISSI-P suggests that highly concentrated n-3 PUFAs are cost effective in 93% of simulations in Poland and in >98% of simulations in the other countries, assuming the country-specific societal willingness-to-pay threshold. Total costs were considerably increased by including healthcare costs incurred during the remaining life-years, but this had no impact on the ICER-based treatment recommendation. CONCLUSIONS: Adding highly concentrated n-3 PUFAs to standard treatment in the secondary prevention of MI appears to be cost effective versus standard treatment alone in the five countries studied.     

Biological mechanisms and cardiovascular effects of omega-3 fatty acids

The mechanisms and cardiovascular effects of omega-3 fatty acids are reviewed. Omega-3 polyunsaturated fatty acids are the major ingredient found in commercially available fish oil products. The incidence of many diseases, including coronary heart disease, diabetes mellitus, and psoriasis, is lower in Eskimos, who ingest diets rich in omega-3 fatty acids, compared with European controls. Potential mechanisms by which these fatty acids cause their many physiologic effects include competing with omega-6 fatty acids for prostaglandin and leukotriene pathways and enhancing cell membrane fluidity by virtue of the high degree of unsaturation. Numerous studies have documented longer bleeding times and decreased platelet aggregation in subjects ingesting omega-3 fatty acids. Omega-3 fatty acids may reduce serum cholesterol concentrations by decreasing the synthesis of very low density lipoprotein and, therefore, low-density lipoprotein. Blood viscosity is significantly and uniformly lower in subjects receiving omega-3 fatty acids compared with controls. Potential risks of supplementation with fish oils include hypervitaminosis A and D, vitamin E deficiency, increased bleeding times, decreased platelets, and ingestion of contaminated fish. Supplementation with moderate amounts of omega-3 fatty acids appears to be relatively safe. Possible adverse effects include nausea, diarrhea, and a "fishy" taste. Properly controlled, long-term clinical trials are needed to determine whether supplementation with omega-3 fatty acids would be therapeutically beneficial in various patient populations and disease states.     

Depression and serum adiponectin and adipose omega-3 and omega-6 fatty acids in adolescents

The purpose of the present study was to investigate for a possible relationship between depression and serum adiponectin and adipose tissue omega-3 and omega-6 PUFA. The sample consisted of 90 healthy adolescent volunteers from the island of Crete. There were 54 girls and 36 boys, aged 13 to 18. The mean age was 15.2 years. Subjects were examined by the Preventive Medicine and Nutrition Clinic of the University of Crete. Depression was assessed through the use of the Beck Depression Inventory (BDI) and the Center for Epidemiologic Studies Depression Scale (CES-D). Fatty acids were determined by gas chromatography in adipose tissue. CES-D correlated with dihomo-gamma linolenic acid (DGLA). Multiple linear regression analyses showed that BDI was negatively associated with eicosapentaenoic acid (EPA), while CES-D was positively associated with DGLA in adipose tissue. Serum adiponectin was not significantly associated with depression. The negative relationship between adipose EPA and depression in adolescents, is in line with findings of previous studies involving adult and elderly subjects, demonstrating negative relations between depression and adipose omega-3 PUFA. This is the first literature report of a relationship between depression and an individual omega-3 fatty acid in adolescents. The inverse relationship between adipose EPA and depression indicates that a low long-term dietary intake of EPA is associated with an increased risk for depression in adolescents.     

Clinical potential of omega-3 fatty acids in the treatment of schizophrenia

The phospholipids in the neuronal membranes of the brain are rich in highly unsaturated essential fatty acids (EFAs). It has been hypothesised that abnormalities of phospholipid metabolism are present in patients with schizophrenia and that the EFAs omega-3 polyunsaturated fatty acids, and eicosapentaenoic acid (EPA) in particular, may have a role in treating this illness. Considerable preclinical and clinical evidence provides support for this proposal. An epidemiological study reported a better outcome for patients with schizophrenia in countries where the diet is rich in unsaturated fatty acids. Evidence of abnormalities of EFAs has been found in erythrocyte membranes and cultured skin fibroblasts of patients with schizophrenia, and abnormal retinal function and niacin skin flush tests (markers of omega-3 polyunsaturated fatty acid depletion) have also been reported. Case reports and an open-label clinical trial reported efficacy for EPA in schizophrenia. Four randomised, controlled trials of EPA versus placebo as supplemental medication have now been reported. Two of these trials showed significant benefit with EPA on the positive and negative symptom scale total scores, whereas the other two did not show any effects on this primary efficacy measure. One study also reported a beneficial effect on dyskinesia. In the only published trial in which EPA was used as monotherapy versus placebo in schizophrenia, some evidence was found to suggest antipsychotic activity. Taken together, there is considerable evidence to suggest abnormalities of EFAs in cell membranes of patients with schizophrenia, and there is preliminary evidence that EPA is an effective adjunct to antipsychotics.     

Effects of omega-3, omega-6 and omega-9 fatty acids on vascular smooth muscle tone.

The comparative effects of omega-3, omega-6 and omega-9 fatty acids on vascular smooth muscle tone were investigated. Docosahexaenoic acid (1-255 microM) and eicosapentaenoic acid (31-255 microM) inhibited phenylephrine-induced contractions, (8-63%) and (20-65%), respectively, which were not altered by indomethacin, NDGA, or by removal of the endothelium. Linoleic acid (18:2n6) and arachidonic acid (20:4n6) also induced significant relaxation. Therefore, fatty acid-induced relaxation of the rat aorta is specific to polyunsaturated fatty acids, 20:5n3, 22:6n3, 18:2n6 and 20:4n6.