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The omega-3 fatty acids in the promotion of health and prevention of chronic diseases (1st part: The cardiovascular system)
Abstract
In the 1970s, several researchers were very much impressed by the low prevalence of ischemic heart disease among the inuit (eskimos) of Greenland despite following a diet rich in animal fat and protein, as well as in cholesterol. A detailed analysis of the diet showed that the inuit were eating greater quantities of fatty fish and marine animals which are specially rich in long chain polyunsaturated fatty acids of the omega-3 type. Since these initial observations, it has been shown that the omega-3 fatty acids are involved in a great number of processes that, practically, have an influence on all body systems, from the cardiovascular to the nervous system, from the renal function to that of the digestive system, from the immune system to inflammation, etc. In the first part of this review, an analysis of the effects of omega-3 fatty acids on several risk factors for the cardiovascular system is made. Special attention is devoted on the effects of these type of fatty acids on the plasma triglyceride levels, both in fasting and in post-prandial situations, and their more plausible mechanism of action; at the same time, their impact on the levels and characteristics of the low density lipoproteins is discussed. This is followed by a detailed description of the possible beneficial effects of omega-3 fatty acids on blood pressure. The protective role of omega-3 fatty acids on the prothrombotic and pro-inflamatory processes is reviewed evaluating the effects of these fatty acids on the balance between prothrombotic and anti-thrombotic eicosanoids. Omega-3 fatty acids, as components of cellular membranes, modulate the expression of several glycoproteins, located on the luminal surface of the endothelial cells, that determine the extent of adhesion and penetration of monocytes; at the same time, they influence the migration and proliferation of smooth muscle cells from the muscular layer to the subendothelial space. Both processes, fundamental in the development of the atherosclerotic plaque, are markedly attenuated by the omega-3 fatty acids. In the second part of this review, the influence of these fatty acids on processes related to obesity, the metabolic syndrome, diabetes, chronic inflammatory conditions, the development and function of the nervous system, the mental and affective status of the individual, etc., will be analyzed.
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Previous studies have shown that exogenous free n-3 polyunsaturated fatty acids (PUFA) can prevent tachyarrhythmias caused
by specific agents in isolated cardiac myocytes. However, the question as to whether incorporation of the n-3 PUFA into membrane
phospholipids has the same immediate protective effects remained to be answered. To answer this question, we increased the
content of n-3 PUFA in the phospholipids of cultured neonatal rat myocytes by growing them 2–3 d in a culture to which eicosapentaenoic
acid (EPA) or docosahexaenoic acid (DHA) in 15 μM concentration was added. Analysis of the fatty acid composition of membrane
phospholipids revealed a significantly higher level of EPA and DHA (from 0.2 to 7.6% and from 1.2 to 6.5%) in cells supplemented
with EPA or DHA, respectively. The responses of the myocytes grown in normal media or in media enriched with the PUFA to arrhythmogenic
agents were examined after free fatty acids were removed from the medium and the cells. The arrhythmogenic agents used were
the β-adrenergic agonist isoproterenol or an elevated extracellular concentration of calcium. The results showed that there
was no significant difference in the induction of tachyarrhythmias by isoproterenol or by elevated [Ca2+]o in cells grown in media enriched with PUFA, as compared with cells grown in normal media in the absence of the free PUFA.
Under the conditions of this study, only the unesterified PUFA were able to protect the cardiomyocytes against induced arrhythmias.
There was no antiarrhythmic effect due to an increased fraction of EPA or DHA in membrane phospholipids.
We have studied the effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (n-3 PUFA) daily for 6 wk on plasma lipids, haemostasis and monocyte chemotaxis in 10 patients with untreated hypertension. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides did not change, but the ratio of total to HDL-cholesterol was significantly reduced after the fish oil supplement. Platelet function was unaltered by intake of n-3. Plasma fibrinogen and fibronectin decreased after supplementation with n-3 PUFA, while the effects on fibrinolysis were equivocal. Monocyte chemotaxis was reduced by the supplement. These data lend support to a role for an increased intake of n-3 PUFA in the management of patients with hypertension.
Despite the clear-cut result of the Australian Therapeutic Trial in Mild Hypertension, which demonstrated prospectively the benefit of treatment of diastolic blood pressure in the range of 95 to 109 mm Hg, a retrospective analysis that classified subjects by the average diastolic pressure level attained during the trial purported to show an absence of treatment benefit at lower average diastolic pressures and a negative treatment effect at higher levels. However, the method of classification by average attained diastolic pressure introduced substantial selection bias, invalidating the retrospective analysis and rendering as spurious both the deleterious treatment effect and its lack of efficacy at lower diastolic levels.
(JAMA 1986;256:3134-3137)
1. Twelve healthy male subjects took a daily supplement of 20 ml of cod-liver oil for 6 weeks. This provided 1.8 g of eicosapentaenoic acid (20:5ω3) and 2.2 g of docosahexaenoic acid (22:6ω3). The effects of the supplement on blood lipids, haemostatic variables, bleeding time and plasma vitamin A and carotene were studied. In seven subjects platelet aggregation induced by adenosine 5′-pyrophosphate (ADP) was also studied.
2. The proportions of 20:5ω3 and 22: 6ω3 in platelet and erythrocyte phosphoglycerides were substantially increased by the supplement mainly at the expense of ω6 polyunsaturated fatty acids.
3. Mean plasma triglyceride concentrations were reduced and those of high-density-lipoprotein (HDL) cholesterol were increased by the supplement.
4. The mean bleeding time was significantly prolonged after 3 weeks of taking the supplement, but had returned to the presupplementation value 5 weeks after withdrawal of the supplement.
5. The maximum estimated response to platelet aggregation induced by ADP was increased by the supplement.
6. The mean levels of antithrombin III (immunological) and blood pressure were lower at the end of the period of supplementation and remained so 5 weeks after withdrawal of the supplement. No significant changes in other variables were noted.
In this study, we have investigated the effects of alimentary lipemia in 15 normotriglyceridemic individuals on high density lipoproteins2 (HDL2) with respect to structure, composition, and substrate efficacy for hepatic lipase in vitro. In the study subjects, HDL2 levels ranged widely from 4.7 to 151.7 mg/dl plasma. HDL2 were isolated in the postabsorptive (pa) state and in the postprandial (pp) state, i.e., 7 h after ingestion of a standard fatty meal. In going from the pa state to the pp state, HDL2 exhibited higher flotation rates and lower densities due to a decreased proportion of protein (38.7----36.2%) and a higher abundance in phospholipid (32.5----34.9%). There was a variable increase in triglyceride at the expense of cholesteryl esters; this increase was correlated positively with the magnitude of pp lipemia (r = 0.69, P less than 0.01) and inversely with HDL2 levels (r = -0.72, P less than 0.01). Hdl2 fractions were incubated with human hepatic lipase in vitro. Product lipoproteins formed from lipolysis of pa-HDL2 and triglyceride-poorer pp-HDL2 were reduced in phospholipid content (by 25 and 50%, respectively) but remained in the size and density range of native HDL2. By contrast, a major fraction of triglyceride-richer pp-HDL2 was converted to particles with density, size, and apoprotein composition of native HDL3. Changes consistent with these findings in vitro were observed in vivo also, where 15 h postprandially, individuals with high-level lipemia showed a decrease in HDL2 and rise in HDL3, while those with lower-level lipemia did not. This study indicates that the magnitude of postprandial lipemia determines the proportion of triglyceride in pp-HDL2, which in turn determines whether or not HDL2 are converted to HDL3 by hepatic lipase action.
Although malondialdehyde (MDA) is extensively metabolized to CO2, small amounts are nevertheless excreted in an acid-hydrolyzable form in rat urine. In this study, urinary MDA was evaluated as an indicator of lipid peroxidation in the diet and in the tissues. MDA was released from its bound form(s) in urine by acid treatment and determined as the TBA-MA derivative by HPLC. MDA excretion by the rat was found to be responsive to oral administration of the Na enol salt and to peroxidation of dietary lipids. Urinary MDA also increased in response to the increased lipid peroxidation in vivo produced by vitamin E deficiency and by administration of iron nitrilotriacetate. Chronic feeding of a diet containing cod liver oil led to increases in MDA excretion which were not completely eliminated by fasting or feeding a peroxide-free diet, indicating that there was increased lipid peroxidation in vivo. MDA excretion was not responsive to Se deficiency or CCl4 administration. DPPD, a biologically active antioxidant, but not BHA, a non-biologically active antioxidant, prevented the increase in MDA excretion in vitamin E deficient animals. The results indicate that MDA excretion can serve as an indicator of the extent of lipid peroxidation in the diet and, under conditions which preclude a dietary effect, as an index of lipid peroxidation in vivo.
A series off 3 BP measurements were carried out on 2 groups of people. People not accustomed to BP measurements showed a decrease in pressure between the 1st and 3rd cuff inflation, while people trained to having their BP measured showed no such change.
Measurement of the BP of 111 people on 2 successive occasions 8 days apart showed that the mean BP of the whole group decreased between visits. Approximately one third of the people showed a drop in pressure bringing them from borderline hypertension to normotension between the 2 visits.
People whose BP dropped substantially between the 1st and 2nd visits achieved higher anxiety scores on a questionnaire than did the remainder of the sample. This may partially explain their labile BP.
Single measurements tend to overestimate the BP and the frequency of hypertension. Training experimental subjects by repeated measurement of their BP may be useful in preventing spurious BP changes unrelated to experimental manoeuvres.
Dietary supplementation with marine oils attenuates the responses to noradrenaline and angiotensin II in human forearm resistance arteries. The mechanisms underlying these effects were the subject of the present study.
Twenty-two normal male adults were allocated to one of three groups. The first group (n = 11) received 10 g/day marine oil capsules (maxEPA) for 28 days. The second group (n = 7) received maxEPA plus 25 mg indomethacin three times a day on days 28 and 29. The third group (n = 4) received 10 g/day mixed-oil placebo capsules for 28 days, plus indomethacin on days 28 and 29 as in group 2. Forearm venous occlusion plethysmography was performed before and immediately after each treatment period.
Responses to acetylcholine, sodium nitroprusside or reactive hyperaemia (area under the time-response curve: pre-maxEPA 14,850 +/- 3502, post-maxEPA 17,118 +/- 4576 units) were unaffected by maxEPA. The suppressive effect of maxEPA on responses to noradrenaline and angiotensin II (from group 1) was no longer apparent in the group receiving indomethacin in addition to maxEPA. Indomethacin, in subjects on placebo capsules, had no effect on the responses to either agonist.
We conclude that the suppressive effects of maxEPA result from alterations to in vivo prostanoid profiles.