Many clinical and epidemiological studies have shown that the polyunsaturated n-3 fatty acids EPA and DHA from fish and fish oils, provide cardiovascular protection, particularly in the setting of ...secondary prevention. n-3 Fatty acids beneficially influence a number of cardiometabolic risk factors including blood pressure, cardiac function, vascular reactivity and lipids, as well as having anti-platelet, anti-inflammatory and anti-oxidative actions. They do not appear to adversely interact with other medications such as statins and other lipid-lowering drugs or antihypertensive medications. n-3 Fatty acids have gained widespread usage by general practitioners and clinicians in a number of clinical settings such as pregnancy and infant development, secondary prevention in CHD patients, treatment of dyslipidaemias and haemodialysis patients. Small doses are achievable with consumption of two to three oily fish meals per week or via purified encapsulated preparations now readily available. n-3 Fatty acids, particularly when consumed as fish, should be considered an important component of a healthy diet. The present paper reviews the effects of n-3 fatty acids on cardiometabolic risk factors, concentrating particularly on the evidence from randomised controlled studies in human subjects.
Resolvins and protectins are families of local lipid mediators generated from the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during self-limited resolution of ...inflammation. We aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to measure these lipid mediators in human blood following n-3 fatty acid supplementation and to determine whether the blood collection method affects their measured concentration.
Blood samples from 20 healthy volunteers enrolled in an n-3 fatty acid supplementation trial were collected in EDTA, heparin, or citrate, or prepared as serum after volunteers had undergone 3 weeks of supplementation. Plasma or serum was purified by solid-phase chromatography and analyzed with LC-MS/MS.
The assay identified 18R/S-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid (18R/S-HEPE); 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17R/S-HDHA); 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (RvD1); 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E19Z-docosahexaenoicacid (17R-RvD1); 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid (RvD2); 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoicacid (10S,17S-DiHDHA); and 10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid (protectin D1, PD1). The limits of detection and quantification were 3 pg and 6 pg on-column, respectively. The pathway precursors 18R/S-HEPE and 17R/S-HDHA, but not the resolvins, were lower in serum compared with plasma. After n-3 fatty acid supplementation, mean (SD) EDTA plasma concentrations were: 18R/S-HEPE 386 (56) pg/mL, 17R/S-HDHA 365 (65) pg/mL, RvD2 26 (4) pg/mL, RvD1 31 (5) pg/mL, and 17R-RvD 161 (7) pg/mL. 10S,17S-DiHDHA and PD1 concentrations were below the limit of quantification.
This is the first study reporting 17R/S-HDHA, RvD1, and RvD2 concentrations measured in human blood following oral n-3 fatty acid supplementation. The concentrations of the antiinflammatory lipid mediators RvD1 and RvD2 were within the biological range known to have antiinflammatory and proresolving activities in isolated human leukocytes and in in vivo studies in mice.
Clinical and epidemiological studies provide support that the polyunsaturated omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid from fish and fish oils are cardioprotective, ...particularly in the setting of secondary prevention. Omega-3 fatty acids benefit multiple cardiometabolic risk factors including lipids, blood pressure, vascular reactivity and cardiac function, as well as having antithrombotic, anti-inflammatory and anti-oxidative actions. Omega-3 fatty acids do not associate with any adverse effects and do not adversely interact with prescriptive drugs such as lipid-lowering, antihypertensive or hypoglycaemic medications. Clinical studies suggest that doses up to 4 g daily when prescribed with anticoagulant or antiplatelet drugs do not associate with increased risk of major bleeding episodes. Omega-3 fatty acids have gained widespread usage by general practitioners and clinicians in clinical settings such as pregnancy and infant development, secondary prevention in coronary heart disease patients and treatment of dyslipidaemias. Health authorities currently recommend an intake of at least two oily fish meals per week for the general population which equates to approximately 500 mg per day of eicosapentaenoic acid and docosahexaenoic acid. In patients with coronary heart disease the guidelines recommend 1 g daily supplements and in hypertriglyceridaemic patients up to 4 g per day. These doses are now achievable with readily available purified encapsulated preparations of omega-3 fatty acids. However, a more practical recommendation for increasing omega-3 fatty acid intake in the general population is to incorporate fish as part of a healthy diet that includes increased consumption of fruits and vegetables, and moderation of salt intake.
A healthy dietary pattern can benefit multiple cardiovascular disease (CVD) risk factors. In conjunction with current standard-of-care pharmaceutical interventions it can provide an effective ...strategy for the prevention of CVD. Previous dietary recommendations have focused on targeting macronutrients. However, most of the recent international dietary guidelines now recommend a whole food, dietary pattern approach, whilst avoiding quantitative nutrient advice. The guidelines recommend: (1) increased intake of plant-based foods including complex, fibre-rich carbohydrates such as wholegrains, fruits and vegetables, but restricting the intake of refined starches; (2) substituting saturated fats with polyunsaturated and monounsaturated oils; (3) reducing salt intake; (4) increased fish consumption (or fish oils where applicable); (5) reducing sugar-sweetened drinks and added sugars; (6) avoiding butter and cream particularly in individuals at increased risk of CVD, but encouraging fermented products such as yoghurt; there is no specific advice on cheese and milk; (7) allowing consumption of lean meat in moderation but restricting processed meats; and (8) reducing cholesterol intake and foods rich in cholesterol (e.g., eggs and crustaceans) for those with diabetes and at increased CVD risk. The dietary guidelines should be adhered to in conjunction with low-to-moderate alcohol consumption, regular physical activity, avoiding tobacco and maintaining a healthy weight. This review summarises recently published research, international guidelines and position statements for minimizing CVD risk.
Background The National Heart Foundation of Australia (NHFA) 2008 review on omega-3 long-chain polyunsaturated fatty acids (LCPUFA) made recommendations with respect to supplementation for primary ...and secondary prevention of cardiovascular disease. Since then, new findings have been published regarding the relationship between omega-3 polyunsaturated fatty acids, including supplementation, and cardiovascular health. Methods A literature search was undertaken in PubMed and Medline, for literature published between January 1, 2007 and August 31, 2013. Results and Conclusions A total of eight research questions were developed and, using the National Health and Medical Research Council's evidence assessment framework, conclusions were made in relation to dietary intake of fish and omega-3 LCPUFA for cardiovascular health. In the evidence published since 2007, this summary of evidence concludes that dietary intake of fish was found to be mostly consistent with respect to protection from heart disease and stroke. Higher fish intake was associated with lower incident rates of heart failure in addition to lower sudden cardiac death, stroke and myocardial infarction. In relation to omega-3 LCPUFA supplementation, neither a beneficial nor adverse effect was demonstrated in primary or secondary prevention of coronary heart disease (CHD). Although the evidence continues to be positive for the role of omega-3 LCPUFA in the treatment of hypertriglyceridaemia and a modest positive benefit in heart failure. No further evidence was found to support the consumption of 2 g alpha-linolenic acid (ALA)/day over the current Australian guidelines for 1 g/day.
This narrative review discusses an important issue, the primary role of diet in reducing low-density lipoprotein cholesterol (LDLc) concentrations in polygenic hypercholesterolemia. Two effective ...drugs, statins, and ezetimibe, that lower LDLc > 20% are relatively inexpensive and potential competitors to strict dieting. Biochemical and genomic studies have shown that proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) and lipid metabolism. Clinical trials have demonstrated that inhibitory monoclonal antibodies of PCSK9 dose-dependently lower LDLc up to 60%, with evidence of both regression and stabilization of coronary atherosclerosis and a reduction in cardiovascular risk. Recent approaches using RNA interference to achieve PCSK9 inhibition are currently undergoing clinical evaluation. The latter presents an attractive option of twice-yearly injections. They are, however, currently expensive and unsuitable for moderate hypercholesterolemia, which is largely due to inappropriate patterns of eating. The best dietary approach, the substitution of saturated fatty acids by polyunsaturated fatty acids at 5% energy, yields > 10% lowering of LDLc. Foods such as nuts and brans, especially within a prudent, plant-based diet low in saturates complemented by supplements such as phytosterols, have the potential to reduce LDLc further. A combination of such foods has been shown to lower LDLc by 20%. A nutritional approach requires backing from industry to develop and market LDLc-lowering products before pharmacology replaces the diet option. Energetic support from health professionals is vital.
The review presents recent developments in the identification of specialized proresolving mediators (SPMs) of inflammation following supplementation with n-3 fatty acids in humans.
A number of ...reports have measured SPMs in human plasma after n-3 fatty acid supplementation. Although studies have shown some variability in plasma SPM levels, there is strong evidence that a number of resolvins are increased after n-3 fatty acids to concentrations that have been shown to have biological activity. SPM concentrations at the inflammatory site would be expected to be higher than that in blood. SPMs derived from docosapentaenoic acid require further investigation.
Resolution of inflammation is an active process with SPM playing a vital role in maintaining homeostasis. Studies in humans are providing evidence to suggest that this may be a relevant mechanism that can be stimulated by n-3 fatty acid supplementation. Further research is now required to determine SPM profiles in patients with different chronic conditions and to examine whether supplementation with n-3 fatty acids affects SPMs in relation to their clinical outcome.
Resolution of inflammation is an active process involving specialized proresolving mediators (SPM) formed from the n-3 fatty acids. This study examined the effect of n-3 fatty acid supplementation ...and aspirin on plasma SPMs in healthy humans. Healthy volunteers (n = 21) were supplemented with n-3 fatty acids (2.4g/day) for 7 days with random assignment to take aspirin (300 mg/day) or placebo from day 5 to day 7. Blood was collected at baseline (day 0), day 5, and day 7. Plasma 18R/S-HEPE, E-series resolvins, 17R/S-HDHA, D-series resolvins, 14R/S-HDHA, and MaR-1 were measured by LC/MS/MS. At baseline concentrations of E- and D- series resolvins and the upstream precursors 18R/S-HEPE, 17R/S-HDHA ranged from 0.1nM to 0.2nM. 14R/S-HDHA was 3-fold higher than the other SPMs at baseline but MaR-1 was below the limit of detection. Supplementation with n-3 fatty acids significantly increased RvE1, 18R/S-HEPE, 17R/S-HDHA, and 14R/S-HDHA but not other SPMs. The addition of aspirin after 5 days of n-3 fatty acids did not affect concentrations of any SPM. N-3 fatty acid supplementation for 5 days results in concentrations of SPMs that are biologically active in healthy humans. Aspirin administered after n-3 fatty acids did not offer any additional benefit in elevating the levels of SPMs.
Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid ...supplementation on the epigenetic regulation of genes in adult humans.
We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts.
These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function.
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