Fish oil fatty acids as cardiovascular drugs

Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text: n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; alpha-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.     

Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders

Epidemiological and experimental studies have indicated that consumption of more n-3 long-chain polyunsaturated fatty acids may reduce the risk for a variety of diseases, including cardiovascular, neurological and immunological disorders, diabetes and cancer. This article focuses on the role of marine n-3 long-chain polyunsaturated fatty acids in brain functions, including the development of the central nervous system and neurological disorders. An overview of the major animal studies and clinical trials is provided here, focusing on fatty acid supplementation during pregnancy and infancy, and prevention and management of Alzheimer's disease, schizophrenia, depression and attention deficit hyperactive disorder. Although an optimal balance in n-3/n-6 long-chain polyunsaturated fatty acid ratio is important for proper neurodevelopment and cognitive functions, results from randomized controlled trials are controversial and do not confirm any useful effect of supplementation on development of preterm and term infants. The relationship between fatty acid status and mental disorders is confirmed by reduced levels of n-3 long-chain polyunsaturated fatty acids in erythrocyte membranes of patients with central nervous system disorders. Nevertheless, there are very little data supporting the use of fish oil in those patients. The only way to verify whether n-3 long-chain polyunsaturated fatty acids are a potential therapeutic option in the management and prevention of mental disorders is to conduct a large definitive randomized controlled trials similar to those required for the licensing of any new pharmacological treatment.     

Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature

The elderly population is at an increased risk for major bleeding, possibly due to increased sensitivity to anticoagulation, multiple comorbidities, and polypharmacy. Elderly patients receiving antiplatelet and anticoagulant therapy have an additional risk for bleeding. Omega-3 fatty acids, also known as fish oil, have been used for hyperlipidemia, coronary heart disease, hypertension, and other conditions. Some studies have demonstrated that consumption of fish oil concentrate, n-3 polyunsaturated fatty acid (n-3 PUFA), results in cardiovascular benefits that include reductions in mortality, sudden death, nonfatal myocardial infarction, and thrombotic stoke, as well as improvement in graft patency. The mechanism of action of n-3 PUFA is not completely understood, but a dual antiplatelet and anticoagulant effect has been proposed. Few data exist on whether or not fish oil can be used safely with other antiplatelet or anticoagulant drugs. We report the case of a patient who after a minor fall developed a subdural hematoma requiring craniotomy that likely was precipitated by concomitant use of high-dose omega-3 fatty acids 6 g/day with both aspirin and warfarin. These findings are important because of the wide availability of omega-3 fatty acids and the propensity for use of complementary and alternative medicine in patients with cardiovascular disease who are already taking antiplatelet and/or anticoagulant agents. Judicious use of these combinations is advised, and pharmacists can play an important role in educating patients and other health care providers about the bleeding risks associated with combination therapy.     

Fish oils and vascular disease prevention: an update

Considerable epidemiological data confirmed the existence of favorable associations between fish consumption and mortality from cardiovascular disease. Accumulating evidence suggests that n-3 polyunsaturated fatty acids supplementation is an effective additive treatment for the primary and secondary prevention of cardiovascular disease. Another indication for the use of n-3 PUFA is the treatment of hypertriglyceridemia as monotherapy or in combination with other lipid lowering agents (e.g. statins or fibrates). However, high doses of n-3 PUFA are required for this effect (e.g. 3-4 g/day). Fish oils may be acting via several mechanisms that include antiarrhythmic, antithrombotic and anti-inflammatory effects as well as plaque stabilization. Despite the current evidence supporting a beneficial effect of fish oils on vascular disease, more definitive studies than the ones already performed are required. Some ongoing trials may provide further insight into the indications for fish oil supplementation. This review considers the mechanisms accounting for the cardioprotective properties of n-3 polyunsaturated fatty acids. We also discuss the epidemiological and interventional studies evaluating the relationship between n-3 polyunsaturated fatty acids consumption and cardiovascular disease.     

Section Review—Cardiovascular & Renal: n-3 Fatty Acids as Adjuvants to Conventional Therapy in Patients with Coronary Artery Disease

Whether dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) (also called omega-3 fatty acids or fish oils) may be beneficial in patients with coronary artery disease (CAD) is at the present time a matter of debate. In this review, we consider some basic concepts of n-3 PUFA, discuss epidemiological data, animal experiments and the effects of n-3 PUFA on cardiovascular risk factors. The studies on clinical outcome in patients with CAD and safety aspects are reviewed in order to provide a basis for further understanding of the potential value of dietary supplementation with n-3 PUFA. Some recommendations for daily clinical practice and suggestions for future research are also given.     

Long-chain n-3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease

Evidence from observational studies, prospective cohort studies and randomized clinical intervention studies indicate that moderate doses of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) significantly decrease risk of fatal coronary heart disease (CHD). Higher doses and longer duration of intervention may also protect from non-fatal CHD events. The exact mechanisms through which LC n-3 PUFA has an effect on CHD are not well established but may include a decrease in fasting and postprandial triacylglycerol levels, a decrease in arrhythmias, modulation of platelet aggregation and decreased synthesis of pro-inflammatory agents. The mechanistic relation between LC n-3 PUFA and inflammation has attracted great interest, and in vitro studies have revealed that these fatty acids decrease endothelial activation, affect eicosanoid metabolism (including epoxygenation pathways) and induce inflammatory resolution. However, the effects of LC n-3 PUFA on established biomarkers of inflammation and endothelial activation in vivo are not strong. Consequently we need new and more sensitive and systemic biomarkers to reveal the effects of LC n-3 PUFA on localized inflammatory processes.     

Unsaturated fatty acids and pain

Fatty acids, which are the essential nutrients for humans, are an important source of energy and an essential component of cell membranes. They also function as signal transduction molecules in a range of biological phenomena. Recently, an increasing number of physiologic and pharmacologic reports on fatty acids have improved our understanding of the association of fatty acids with certain diseases. It has also become apparent that functional properties of fatty acids are modulated by factors such as the amount of individual fatty acid intake and their distribution among organs. Recently, the functional relationship between polyunsaturated fatty acids and pain has been the focus of many studies. Both basic and clinical studies have shown that a dietary intake of n-3 series polyunsaturated fatty acids results in a reduction in the pain associated with rheumatoid arthritis, dysmenorrhea, inflammatory bowl disease, and neuropathy. In addition, levels of n-6 series polyunsaturated fatty acids are high in patients with chronic pain. These results indicate that polyunsaturated fatty acids play a vital role in pain regulation. In this review, we summarize a number of basic and clinical studies on polyunsaturated fatty acids and their association with pain.     

Differential anti-cancer effects of purified EPA and DHA and possible mechanisms involved

As the concepts of pharmaconutrition are receiving increasing attention, it seems essential to clearly assess the effects of specific dietary compounds in specific groups of patients or clinical conditions. We are herein interested in better defining the differential anti-neoplastic effects of the two major n-3 long chain polyunsaturated fatty acids present in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The efficiency of these fatty acids represents a subject of intense interest and debate, and whereas plenty of preclinical studies have strongly demonstrated their preventive and therapeutic effect in different kinds of cancers, the results of the epidemiologic studies are still controversial, and only a few trials have been performed. It has been reported that EPA and DHA may act either through the same or different mechanisms, thus suggesting that a differential efficacy could exist. At present, however, this point has not been clarified, although its better comprehension would allow a more proper and effective use of these fatty acids in the human interventional studies. In an attempt to elucidate this aspect we have herein analyzed the data obtained in the studies which have directly compared the antitumor effects of separate treatments with EPA or DHA. Most of the in vitro data indicate DHA as the more powerful antineoplastic agent. However, an equivalent efficiency of EPA and DHA is suggested by the few in vivo studies. Possible reasons for this discrepancy are discussed and pathways of cell growth that could be differentially influenced by EPA and DHA are described.     

n-3多不饱和脂肪酸类药物在心血管疾病中的临床应用进展

许多临床试验表明n-3多不饱和脂肪酸(n-3 PUFAs)对于冠心病、血脂异常和心力衰竭等人群均具有保护作用,而且已有建议推荐心肌梗死后患者和高甘油三酯血症人群口服此类提纯药物。但在应用过程中,仍有一些值得临床关注的问题,如药物安全性、药物成分和用量等。笔者认为,随着对n-3 PUFAs药物的深入研究,其将有更广阔的应用前景。     

The emerging role of docosahexaenoic acid in neuroinflammation

Epidemiological studies have linked fish consumption to lower rates of neurological diseases. Fish contains high levels of omega-3 polyunsaturated fatty acids (n-3 PUFA), and several lines of evidence suggest that the n-3 PUFA docosahexaenoic acid (DHA; 22:6n-3) acts in the brain via anti-apoptotic and neurotrophic pathways. In addition, DHA may act through anti-neuroinflammatory pathways, as DHA possesses anti-inflammatory properties in the periphery. Evidence from animal models has indicated that DHA and its derivatives (resolvin D1 and protectin D1) attenuate colitis, peritonitis and ischemic stroke. n-3 PUFA deprivation in rats decreases brain levels of DHA and increases markers of the brain arachidonic acid (20:4n-6) cascade, a proinflammatory pathway. Thus, chronic low intake of n-3 PUFA may predispose the brain to weak anti-inflammatory, as well as strong proinflammatory signals. Neurological disorders, including Alzheimer's disease, Parkinson's disease and major depression, display a neuroinflammatory component. n-3 PUFA supplementation, as well as drugs targeting brain PUFA metabolism, are promising candidates in the prevention and treatment of neurological disorders.     

Health benefits of docosahexaenoic acid (DHA)

Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers.     

Differential effects of eicosapentaenoic and docosahexaenoic acids upon oxidant-stimulated release and uptake of arachidonic acid in human lymphoma U937 cells.

The use of n-3 polyunsaturated fatty acids, as found in fish-oil derived dietary supplements, as anti-inflammatory agents is supported by a variety of biochemical and physiological data. Recent studies investigating the therapeutic potential of long chain (>C20) n-3 fatty acids in mental illness have lead to the conclusion, however, that not all n-3 fatty acid types are equally efficacious. In particular eicosapentaeoic acid (EPA) appears to possess antidepressant and antipsychotic activity, while docosahexaenoic acid (DHA) does not, an effect suggested to be due to a differential ability to antagonize arachidonic acid (AA)-dependent cell signalling. In this study, we examine the effect of EPA and DHA supplementation upon uptake and release of arachidonic acid stimulated by tert-butyl hydroperoxide/Fe2+ in U937 cells. Oxidant-stimulated 3H-AA release from cells was enhanced by pre-treatment with EPA, DHA and AA, but not stearic or oleic acids for 18 days, with the order of effect magnitude being EPA > DHA = AA. Supplementation of cells for 1 day gave qualitatively similar results, although the effect magnitude was smaller. To determine whether enhanced release was due to decreased reuptake of AA, cells were cultured in the presence of 10 microM fatty acids. Pre-treatment of cells with EPA, and to a lesser extent AA, but not DHA, inhibited uptake of 3H-AA measured subsequent to the removal of unesterified fatty acids. This study suggests that, in U937 cells, EPA can alter the rate of uptake and release of AA from phospholipids in an exposure time-dependent manner, whereas DHA has no or little effect. Our results predict that EPA will have a more pronounced effect upon AA-dependent processes compared to DHA, and suggests that the relative amounts of EPA and DHA in fish oil supplements may modify their biochemical, and potentially, behavioural effects.     

The relationship between tissue RBC n-3 fatty acids and pulse wave velocity

Consumption of n-3 fatty acids is well-known to prevent deaths from coronary heart disease. However, not many studies have investigated the effects of n-3 fatty acids on arteriosclerosis in free living subjects. The pulse wave velocity between the brachia and ankles (baPWV) of 161 healthy male subjects was measured and the fatty acid composition of the total phospholipid fraction of their red blood cells (RBC) analyzed. There was a significant inverse correlation between the eicosapentaenoic acid concentrations in the RBC phospholipid fraction and baPWV of the subjects after adjustment for age, pulse rate and diastolic pressure, or further for body mass index, smoking status, diabetes and the ratio of low-density cholesterol to high-density cholesterol. Although baPWV values may not directly indicate arteriosclerosis, the present study suggests that long-term n-3 fatty acid intake is beneficial for the vascular system.     

Tissue-specific distribution of fatty acids,polychlorinated biphenyls and polybrominated diphenyl ethers in fish from Taihu Lake,China, and the benefit-risk assessment of their co-ingestion

The fish tissues from four species collected from Taihu Lake, China, were analyzed including dorsal, ventral, and tail muscles, heart, liver, and kidney. The highest and lowest concentrations of fatty acids were respectively observed in livers and muscles. There were significant intraspecies and interspecies differences in the compositions of most fatty acids among muscle, heart, liver, and kidney. All the tissues were generally beneficial for consumption considering fatty acids. People mainly consume the muscle. Hence, the benefits from two polyunsaturated fatty acids, i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and risks from PCBs and PBDEs via fish consumption were evaluated by calculating the benefit-risk quotient (BFQ) for the intake of fish muscle containing EPA + DHA vs. PCBs or PBDEs. The BFQ values considering carcinogenic and noncarcinogenic effects for PCBs were ∼3000 and 10 times higher than those of PBDEs via fish consumption to achieve the recommended EPA + DHA intake of 250 mg d⁻¹, respectively. The results also suggested that the risk consuming the dorsal muscle was generally lower than the ventral and tail muscles.     

Fatty acids and atherosclerotic risk

Most research concerning the effects of dietary fatty acids on atherosclerotic risk has focused on their effects on lipid and lipoprotein metabolism. However, it is known that fatty acids also influence a number of other relevant mechanisms involved in atherosclerosis such as lipid peroxidation, inflammation and haemostasis. The most favourable distribution of cholesterol over the various lipoproteins is achieved when saturated and trans fatty acids are replaced by a mixture of cis-unsaturated fatty acids. Furthermore, fatty acids from fish oil lower triacylglycerol concentrations. Effects on other atherosclerotic risk markers are less evident. Monounsaturated fatty acids maybe preferable above other fatty acids with respect to low-density lipoprotein oxidation as measured by indirect in vitro assays. The relevance of these assays for the in vivo situation is, however, limited. With respect to inflammation, mainly the effects of n-3 polyunsaturated fatty acids from fish oil have been studied, but results were inconsistent. Also results from studies evaluating the effects of fatty acids on haemostatic risk markers were inconsistent, which may be partly related to the use of different analytical methods. The most consistent finding however is the potential beneficial effect of moderate intakes of fish oil on platelet aggregation. Furthermore, reducing total fat intake rather than changing the fatty acid composition of the diet may beneficially affect the coagulation system. In conclusion, while beneficial effects on atherosclerotic risk are mainly ascribed to cis-unsaturated fatty acids, it remains debateable whether trans and saturated fatty acids in the diet have to be replaced by cis-unsaturated fatty acids or by carbohydrates. To answer this question adequately more validated methods are needed that reflect in vivo lipid peroxidation, inflammation and haemostasis.     

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.     

n-3多不饱和脂肪酸在慢性肾脏疾病中的应用

数十年来的动物研究支持鱼油中的主要成分n-3多不饱和脂肪酸(n-3PUFA)在肾脏疾病治疗中的有效性,在一些人类肾小球疾病如IgA肾病中n-3PUFA也被证实有益,但临床试验结果并不一致。n-3PUFA应用能否成为肾脏疾病的一种新的治疗手段,仍需进一步的大规模临床研究。