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Kromhout,D., Bosschieter,E.B., & Coulander, C.,D.L.

The inverse relation between fish consumption and 20 year mortality from coronary heart disease.

The authors present the results from a 20 years study of fish consumption and coronary heart deaths from the Dutch town of Zutphen. The followed the fate of 852 men age 40-59 using the cross check dietary history method to obtain details of food intake. Medical examination was also carried out. After 20 years of follow up the results were examined. Average fish consumption was 20g/day in 1960, of which 2/3rds was lean fish(cod/plaice).19% did not eat fish at all, and the highest 20% of fish eaters had only half the CHD risk of the men who did not eat fish at all. The authors concluded that as little as one or two fish dishes per week may have value in preventing coronary heart disease.

New Engl.J.Med.,1985;312(19):1205-9.

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Kromann, N.,& Green, A.

Epidemiological studies in the Upernarvik district, Greenland. Incidence of some chronic diseases 1950-1974.

The two researchers studied the medical records of the Upernavik district of Northwest Greenland, covering the period 1950-74. The population was approximately 1,800 and using hospital diagnoses, the authors examined the incidence rates of a number of common ailments, and compared the rates with what would have been expected from a population of comparable size in Denmark. They found that cancer cases were slightly less than would be expected in Denmark, (46 v 53), psoriasis was 2 compared with an expected 40 cases, and heart attack incidence was 3 compared with an expected 40. The Eskimos also had a relative absence of peptic ulcer, asthma, diabetes and multiple sclerosis. On the distaff side, the Eskimos had more apoplexy (heamorrhagic stroke) 25 v 15- and more epilepsy , 16 cases compared with an expected 8 in Denmark.

Acta Med Scand,1980;208 p401-6.


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Leaf, A., & Kang, J.X.

Prevention of cardiac sudden death by N-3 fatty acids: A review of the evidence.

The essential n-6 and n-3 polyunsaturated fatty acids can prevent ischaemia-induced ventricular fibrillation in rats, dogs and marmosets. In isolated neonatal rat cardiac myocytes, these have been shown to prevent tachyarrhythmias elevated calcium concentrations, toxic ouabain, a beta-adrenergic agent (isoproterenol), lysophosphatidylcholine and acylcarnitine. The antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning of the free polyunsaturated fatty acids into the phospholipid cell membranes of the cardiac myocytes, which modulates membrane ion channels. Two clinical trials suggest they could prevent sudden cardiac death in humans.

Journal of Internal Medicine, 1996,240;1:5-12.

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McLennan, P.L., Bridle, T.M., Abeywardena, M.Y. & Charnock, J.S.

Comparative Efficacy of N-3 and N-6 Polyunsaturated Fatty Acids in Modulating Ventricular Fibrillation Threshold in Marmoset Monkeys.

Programmed electrical stimulation in anesthetized marmoset monkeys was used to examine relative antiarrhythmic efficacies of dietary n-3 and n-6 polyunsaturated fatty acids (PUFAs) from fish and plant oils. Diets contained 31% of energy (en%) as fat, comprising 15 en% saturated fat and 7 en% PUFAs, obtained by blending sheep fat with sunflower seed (SF/SSO) or fish oil (SF/FO) and a base diet. After 16-wk feeding, ventricular fibrillation (VF) was inducible in 6 of 10 animals on each diet under control conditions. The VF threshold (VFT) was significantly elevated in the SF/FO group (33.3 +/- 3.1 mA; n = 6) compared with the SF/SSO group (14.3 +/-4.9 mA; n = 6). VFT, reduced during acute myocardial ischemia with 10 of 10 animals inducible per diet, remained significantly higher with SF/FO feeding. The SF/FO diet contained 3.8 en% as n-3 PUFAs, which was incorporated as 31% of myocardial membrane fatty acids. Dietary n-3 PUFA reduced vulnerability of normal or ischemic myocardium to arrhythmias in a nonhuman primate.

American Journal of Clinical Nutrition, 1993,58,5,666-669.

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Malle, E., Sattler, W., Prenner, E., Leis, H.J., Hermetter, A., Gries, A.& Kostner, G.M.

Effects of Dietary Fish Oil Supplementation on Platelet Aggregability and Platelet Membrane Fluidity in Normolipemic Subjects with and Without High Plasma Lp(a) Concentrations.

The purpose of this study was to compare the relative effect of n - 3 fatty acids on plasma lipids and platelet function in normolipemic subjects (n = 8) with plasma Lp(a) levels > 30 mg/dl and normolipemic subjects (n = 7) without detectable plasma Lp(a) concentrations. Six weeks of dietary supplementation (3.8 g EPA and 2.9 g DHA/d) significantly reduced (P < 0.005) plasma TGs in both groups whereas no changes of plasma TC, LDL-C, HDL-C, and Lp(a), respectively, were found. Collagen- or thrombin-stimulated platelet aggregation and collagen- or thrombin-induced TXB2 generation from platelets decreased by approx. 45%in Lp(a)-negative and Lp(a)-positive platelet donors after a 6 week dietary intake. Four more weeks without n - 3 supplementation restored the pretreatment values of TGs, platelet aggregability and TXB2 release. The biophysical properties of platelets from normolipemics with and without high plasma Lp(a) concentrations revealed a similar structural order of platelets at 37-degrees-C using DPH, TMA-DPH, or 6-AS as fluorescent probes. Also similar temperature-dependent changes in platelet fluidity from 37-degrees-C to 17-degrees-C were observed in platelet preparations from Lp(a)-positive and Lp(a)-negative subjects. However, no subtle changes in the structural order of platelets due to nutrient intakes were found in all subjects (n = 15, 19-28 yrs) using fluorescence polarization technique. The present data suggest a similar in vitro platelet behaviour from normolipemic subjects with and without high plasma levels of Lp(a) (which is considered a risk for premature atherosclerosis) in contrast to platelet aggregability and platelet fluidity in certain hyperlipidemic stages.

Atherosclerosis,June 1991,88,2-3,193-201.

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Morris, M.C., Sacks, F, & Rosner,B.

Does Fish Oil Lower Blood Pressure? A meta-analysis of controlled trials.

Background - In a meta-analysis of 31 placebo-controlled trials on 1356 subjects, we examined the effect of w-3 fatty acids in fish oil on blood pressure by grouping studies that were similar in fish oil dose, length of treatment, health of subjects, or study design. Conclusions -There is a dose-response effect of fish oil on blood pressure of -0.66 -0.35 mm Hg/g w-3 fatty acids. The hypotensive effect may be strongest in hypertensive subjects and those with clinical atherosclerotic disease of hypercholesterolemia.

Circulation, 1993,8;523-533.

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Mortensen,J.Z.,Schmidt,E.B., Nielsen,A.H, & Dyerberg,J.

The effect of n-6 & n-3 polyunsaturated fatty acids on haemostasis, blood lipids & blood pressure.

20 healthy male volunteers took 10g of either MaxEPA or a corn-olive oil mixture daily for 4 wks in a double-blind crossover design. No dietary changes were permitted. MaxEPA significantly increased bleeding time. Platelet count, mean volume, platelet aggregation were not significantly affected although the threshold value for collagen increased by 26% in the MaxEPA group. Platelet lipid C20:5 & C22:6 increased significantly in the MaxEPA period. C20:4 n-6 fell significantly. MaxEPA significantly reduced serum triglycerides, plasma total lipids, systolic blood pressure and VLDL concentration. Plasma antithrombin III (AT-III) rose significantly.

The authors concluded that an omega-3 supplement to the Western diet exerts an effect that is generally considered to be beneficial in terms of he risks of developing cardiovascular diseases. They considered omega-3 to be superior to omega-6 in this regard.

Thromb Haemost,1983 50 p543-546

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Sanders, T.A.B. & Hinds, A.

The Influence of a Fish Oil High in Docosahexaenoic Acid on Plasma Lipoprotein and Vitamin E Concentrations and Haemostatic Function in Healthy Male Volunteers.

Nine healthy male subjects consumed a daily fish oil supplement providing 2.1 g docosahexaenoic acid (22:6 n-3; DHA) and 0.8 g eicosapentaenoic acid (20:5 n-3; EPA) for 6 weeks. The proportion of EPA and DHA in plasma, erythrocytes, leucocytes and platelet phospholipids was increased by the supplement. Plasma concentration of triacylglycerol and very-low-density-lipoprotein-cholesterol were lowered and those of high-density-lipoprotein (HDL)- and HDL2-cholesterol and apoprotein B were increased. Platelet aggregation and thromboxane B2 production induced by collagen were partially inhibited. Both systolic and diastolic blood pressure fell during treatment and rose following withdrawal of the supplement. Statistically significant reductions in erythrocyte counts, packed cell volume and haemoglobin and increases in total leucocyte and monocyte counts occurred with the supplement. Plasma alpha-tocopherol concentrations fell below the normal range during the period of supplementation. It is suggested that future studies consider components other than EPA in fish oil. Further studies are needed to investigate the extent to which fish oil increases the requirement for antioxidant nutrients.

British Journal of Nutrition,July 1992,68,1,163-173.

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Sanders,T.A.B., Vickers, M., & Haines,A.P.

Effect on blood lipids & heamostasis of a supplement of cod liver oil, rich in eicosapentaenoic and docosahexaenoic acids, in healthy young men.

12 healthy volunteers took 20ml cod liver oil ( providing 1.8g EPA and 2.2g DHA) daily for 6 weeks. Their platelet & erythrocyte phospholipids increased in EPA & DHA, at expense of w-6 acids. Fasting plasma triglyceride fell from 0.89 to 0.69 mmol/l, and HDL cholesterol rose from 1.35 to 1.48 mmol/l. Estimated maximum response of platelet aggregation on stimulation with ADP was also increased, the significance of which is unknown.Bleeding time increased from 4.5 to 6.3 mins. Antithrombin III levels fell, as did systolic (124 to 111 mmHg) & diastolic (81 to 69mmHg) blood pressure.

Clinical Science.,1981;61:317-324,416

Saynor, R., & Gillott, T.

Changes in Blood Lipids and Fibrinogen with a Note on Safety in a Long Term Study on the Effects of n-3 Fatty Acids in Subjects Receiving Fish Oil Supplements and Followed for 7 Years.

The present study was designed to assess the effectiveness of the n-3 fatty acids in modifying serum total, low density lipoprotein and high density lipoprotein (HDL) cholesterol, as well as serum triglycerides, over a seven-year period. Changes in plasma fibrinogen were recorded and long term safety assessed. A total of 365 subjects with ischemic heart disease (IHD), hyperlipidemia or a strong family history of IHD had their diet supplemented with MaxEPA (Seven Seas Ltd., Hull, England) fish oil containing 18-19% eicosapentaenoic acid. Venous blood samples were taken at regular intervals for lipid and fibrinogen assays and routine clinical chemistry and hematological profiling. Current medication was recorded and no further dietary modification was attempted. Triglyceride and fibrinogen were significantly reduced, whereas a significant reduction in total cholesterol occurred only in the subjects with a pre-oil level > 6.5 mmol/L. HDL cholesterol significantly increased over the study period. Clinical chemistry and hematological profiles were not adversely affected, and platelet count did not change significantly. The type of lipid changes observed were those usually considered antiatherogenic. Reducing fibrinogen may result in beneficial changes in the pathological processes leading to thrombotic occlusion. The consumption of MaxEPA by our patients over a seven-year period did not indicate any adverse effects.

Lipids 1992,27;7:533-538.

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Saynor, R. , & Verel, D.

Effect of a marine oil high in eicosapentaenoic acid on blood lipids and coagulation.

5 normal subjects took 20 ml MaxEPA as an addition to their normal diet for 5 wks. Mean serum total cholesterol (4.7 to 4.9 mmol/l) levels did not change significantly but HDL cholesterol did (1.3 to 1.52 mmol/l). Mean serum triglyceride concentrations fell significantly (1.16 to 0.75 mmol/l). Blood coagulation parameters (platelet count, prothrombin ratio, partial thromboplastin time, thrombin time, fibrinogen level, ADP-induced platelet aggregation & antithrombin III levels) were not significantly affected by the supplement.

I.R.C.S. Med Sci,1980, 8: p378-379.

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Schmidt, E.B., Lervang, H.H., Varming, K., Madsen, P., & Dyerberg, J.

Long-Term Supplementation with n-3 Fatty Acids .1. Effect on Blood Lipids, Haemostasis and Blood Pressure.

The effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (PUFA) daily for 9 months on blood pressure, plasma lipids and lipoproteins, platelet function, coagulation and fibrinolysis was studied in 24 healthy volunteers. Each variable was determined before, after 6 weeks and 9 months of supplementation with n-3 PUFA, and 3 months after the supplementation period had ended. Systolic and diastolic blood pressure declined after intake of n-3 PUFAs. Plasma triglycerides were reduced, and there was a trend towards an increase in HDL-cholesterol after 9 months of supplementation, while total cholesterol, LDL-cholesterol and apolipoproteins A1 and B were unaltered. The bleeding time was increased, and plasma levels of von Willebrand factor decreased after 9 months supplementation with n-3 PUFA. Fibrinogen levels increased, while fibrinolysis was reduced after 9 months supplementation with n-3 PUFA. Overall, no clear benefit on lipid pattern and haemostasis was achieved with respect to development of coronary heart disease.

Scandinavian Journal of Clinical & Laboratory Investigation,May 1992,52,3,221-228.

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Sellmayer, A., Witzgall, H., Lorenz, R.L. & Weber, P.C.

Effects of dietary fish oil on ventricular premature complexes.

A randomized, placebo-controlled study of 16 weeks' supplementation with fish oil or sunflower seed oil (placebo) in 68 patients explored the effect on ventricular extrasystoles, The proportion of patients with a relevant reduction in ventricular premature complexes by > 70% was 44% after fish oil versus 15% in the placebo group (p < 0.01).

American Journal of Cardiology, 1995,76;12:974.

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Siebert, B.D., Mclennan, P.L., Woodhouse, J.A. & Charnock, J.S.

Cardiac Arrhythmia in Rats in Response to Dietary n-3 Fatty Acids from Red Meat, Fish Oil and Canola Oil.

In the first of two experiments, the incidence and duration of cardiac arrhythmia was significantly less in rats fed fish oil containing eicosapentaenoic acid (EPA) than in rats fed sheep fat. The phospholipid of red meat contains EPA to some extent and its concentration can be raised by feeding fish oil to beef cattle, but the amount present in diets containing red meat or red meat from animals fed fish oil was apparently insufficient to reduce arrhythmia in rats. The rate of mortality was significantly less also in fish oil fed rats. In a second experiment, arrhythmia was significantly reduced again with fish oil but in this case in the presence of red meat. A similar result was obtained with canola oil fed with meat. Both the canola oil and fish oil diets significantly reduced the rate of mortality. The amount of red meat present in the diet had no significant effect.

Nutrition Research, 1993,13,12,1407-1418.

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Singh, R.B.,Niaz, M.A.,Sharma, J.P.,Kumar, R., Rastogi, V.& Moshiri, .

Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: The Indian experiment of infarct survival .

In a randomized, placebo-controlled trial, the effects of treatment with fish oil (eicosapentaenoic acid, 1.08 g/day) and mustard oil (alpha-linolenic acid, 2.9 g/day) were compared for 1 year in the management of 122 patients (fish oil, group A), 120 patients (mustard oil, group B), and 118 patients (placebo, group C) with suspected acute myocardial infarction (AMI). Treatments were administered about (mean) 18 hours after the symptoms of AMI in all three groups. The extent of cardiac disease, rise in cardiac enzymes, and lipid peroxides were comparable among the groups at entry into the study. After 1 year total cardiac events were significantly less in the fish oil and mustard oil groups compared with the placebo group (24.5% and 28% vs. 34.7%,p < 0.01). Nonfatal infarctions were also significantly less in the fish oil and mustard oil groups compared with the placebo group (13.0% and 15.0% vs. 25.4%,p < 0.05). Total cardiac deaths showed no significant reduction in the mustard oil group; however, the fish oil group had significantly less cardiac deaths compared with the placebo group (11.4% vs. 22.0%, p < 0.05). Apart from the decrease in the cardiac event rate, the fish oil and mustard oil groups also showed a significant reduction in total cardiac arrhythmias, left ventricular enlargement, and angina pectoris compared with the placebo group. Reductions in blood Lipoproteins in the two intervention groups were modest and do not appear to be the cause of the benefit in the two groups. Diene conjugates showed a significant reduction in the fish oil and mustard oil groups, indicating that a part of the benefit may be caused by the reduction in oxidative stress. The findings of this study suggest that fish oil and mustard oil, possibly due to the presence of n-3 fatty acids, may provide rapid protective effects in patients with AMI. However, a large study is necessary to confirm this suggestion

Cardiovascular Drugs and Therapy, 1997,11,3,485-491.

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Siscovick, D.S., Raghunathan,T.E., King,I., Weinmann,S., Wickland,K.G., et al

Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.

Objective.-To assess whether the dietary intake of long-chain n-3 polyunsaturated fatty acids from seafood, assessed both directly and indirectly through a biomarker, is associated with a reduced risk of primary cardiac arrest.

Design.-Population-based case-control study. Setting.-Seattle and suburban King County, Washington, Participants.-A total of 334 case patients with primary cardiac arrest, aged 25 to 74 years, attended by paramedics during 1988 to 1994 and 493 population-based control cases and controls, matched for age and sex, randomly identified from the community. All cases and controls were free of prior clinical heart disease, major comorbidity, and use of fish oil supplements. Measures of Exposure.-Spouses of case patients and control subjects were interviewed to quantify dietary n-3 polyunsaturated fatty acid intake from seafood during the prior month and other clinical characteristics. Blood specimens from 82 cases (collected in the field) and 108 controls were analyzed to determine red blood cell membrane fatty acid composition, a biomarker of dietary n-3 polyunsaturated fatty acid intake.

Results.-Compared with no dietary intake of eicosapentaenoic acid (C-20:5n-3) and docosahexaenoic acid (C-22:6n-3), an intake of 5.5 g of n-3 fatty acids per month (the mean of the third quartile and the equivalent of one fatty fish meal per week) was associated with a 50% reduction in the risk of primary cardiac arrest (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4 to 0.8), after adjustment for potential confounding factors. Compared with a red blood cell membrane n-3 polyunsaturated fatty acid level of 3.3% of total fatty acids (the mean of the lowest quartile), a red blood cell n-3 polyunsaturated fatty acid level of 5.0% of total fatty acids (the mean of the third quartile) was associated with a 70% reduction in the risk of primary cardiac arrest (OR, 0.3; 95% CI, 0.2 to 0.6).

Conclusion.-Dietary intake of n-3 polyunsaturated fatty acids from seafood is associated with a reduced risk of primary cardiac arrest.

JAMA 1995,274;17:1363-1367.

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Toth, K., Ernst, E., Habon, T., Horvath, I./, Juricskay, I., & Mozsik, G.

Hemorheological and hemodynamical effects of fish oil (AMEU) in patients with ischemic heart disease and hyperlipoproteinemia.

Omega-3-fatty acids (n-3-FA) have various positive hemorheological effects in different clinical conditions. Ten male patients (mean age: 50 years) with ischemic heart disease and hyperlipoproteinemia were studied. They were treated by 10 capsules of Ameu (Omega Pharma, Berlin, Germany; 0.5 g salmon oil with 33% of n-3-FA) daily for two months. Besides routine laboratory parameters, hemorheological measurements (whole blood, plasma and serum viscosity) and exercise stress test with noninvasive hemodynamic control at baseline and after two months of treatment were carried out. Significant decrease (p < 0.01) of triglycerides (58%) was found. Cholesterol and plasma viscosity showed only a moderate decrease. Whole blood viscosity, exercise capacity and the measured hemodynamic parameters improved significantly (p < 0.05 or better). Our results show that this preparation can be useful in clinical practice because it has a beneficial effect on plasma lipids and on hemorheological and hemodynamic parameters.

Clinical Hemorheology, 1995,15;6:867-875.

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Tremoli, E, Maderna, P., Marangoni, F., Colli, S., Eligini, S., Catalano, I., et al.

Prolonged inhibition of platelet aggregation after n-3 fatty acid ethyl ester ingestion by healthy volunteers.

This study addressed two questions: 1) whether a relatively low dose of n-3 fatty acid ethyl esters (n-3 FAs) administered to healthy volunteers for a prolonged period of time would exert beneficial effects on plasma lipids, platelet function, and thromboxane biosynthesis; and 2) whether a short-term loading treatment (6 wk) with 6 g n-3 FAs/d followed by 12 wk with 3 g/d results in more pronounced effects. After 6 wk treatment a reduction of plasma triglyceride concentration and an accumulation of EPA and DHA in plasma were observed. A longer period of treatment with n-3 FAs was necessary to affect platelet aggregation and thromboxane A, biosynthesis. At 12 and 18 wk, platelet aggregation, thromboxane A, formation, and the excretion of thromboxane metabolites in urine were reduced, particularly in subjects who received 6 g n-3 FAs/d during the initial 6 wk. After treatment ended, triglyceride and thromboxane A biosynthesis returned to baseline values within 4 weeks, whereas platelet aggregation remained impaired for greater than or equal to 14 weeks. The long-lasting impairment in platelet aggregation was accompanied by the retention of n-3 FAs in platelet phospholipids.

American Journal of Clinical Nutrition,March 1995,61,3,607-613.

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Valagussa, F., Franzosi, M.G., Geraci, E.,  et al. 

Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. 

Background :There is conflicting evidence on the benefits of foods rich in vitamin E (alpha- tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. 

Methods: From October, 1993, to September, 1995, 11324 patients surviving recent (less than or equal to 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (Ig daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). 

Findings: Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative risk decrease 10% [95% CI 1-18] by two- way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]).

 Interpretation :Dietary supplementation with n-3 PUFA led to a clinically important and statistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.


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Woodcock, B.E. Smith,E., Lambert,.W.H., Jones, W.M., Galloway,J.H., Greaves,M., and Preston,F.E.

Beneficial effect of fish oil on blood viscosity in peripheral vascular disease.

A double blind randomised investigation was conducted on the effect on blood viscosity of dietary supplementation with an oil rich in eicosapentaenoic acid, (using a corn/olive oil blend as a placebo) in patients with peripheral arterial disease. A statistically significant reduction in whole blood viscosity was observed at seven weeks in those patients receiving the eicosapentaenoic acid rich oil. No changes in plasma viscosity, haemoglobin concentration, packed cell volume, or platelet count were seen. The authors concluded that the rheological changes resulting from a diet rich in eicosapentaenoic acid may contribute to the suggested protective effects of such a diet against arterial disease, and that such changes are of potential therapeutic importance in established arterial disease.

Brit Med Journal,1984;288:592-594.

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