White fish (cod, coley, plaice,haddock) con- tain about 1% fat .... naturally occurring toxins derived from the marine ... there is evidence that VLDLs are toxic to the.
Br Heart J 1987;57:214-9
Editorial Fish and coronary artery disease T A B SANDERS From the Department of Food and Nutritional Sciences, King's College London, University of London
Does fish consumption protect against coronary heart disease? If so what are the mechanisms for such protection and how much fish (and of what types) would need to be consumed? Atherosclerosis is apparently rare among Eskimos on a tradititional diet of seal, caribou, and fish but not among those on a western diet.' Necropsy data showed that atherosclerosis was less severe in Canadian Eskimos2 than in white Canadians. From an analysis of hospital records Kromann and Green concluded that acute myocardial infarction was extremely rare amongst Eskimos from the West Coast of Greenland who still eat large amounts of seafood.3 The reliability of the mortality statistics for Eskimos may be questioned owing to a high mortality rate from accidents (for example through falling into holes in the ice) and a low necropsy rate. Cardiovascular mortality rates in Japanese fishermen, however, are reported to be lower than in Japanese farmers.4 Fish based diets provide more protein, less saturated fat, and a different type of polyunsaturated fat than the average western diet. Sinclair subsisted for three months on food derived entirely from marine animals, notably seal.5 This resulted in considerable changes in haemostatic variables and serum lipids, especially in the fatty acid composition of the cholesterol esters and phospholipids. The most pronounced change was the replacement of polyunsaturated fatty acids of the w6 series, notably linoleic and its derivative, arachidonic acid, by those of the o3 series, notably eicosapentaenoic acid (20:5 co3) and docosahexaenoic acid (22:6 c)3). The latter are the major polyunsaturates in marine animals whereas linoleic acid (18: o6) and a linolenic acid (18:3 w3) are the major ones in plant
food.6 Eicosapentaenoic acid and docosahexaenoic acid can influence the metabolism of lipoproteins and eicosanoids (prostaglandins, thromboxanes, prostacyclins, and leukotrienes) in a way that might afford protection from coronary artery disease.
Dietary values Before discussing the various studies that have investigated the effects of fish or fish oil consumption, it is necessary to relate these studies to the amounts of eicosapentaenoic acid and docosahexaenoic acid provided by these foodstuffs. The fat content of fish varies seasonally, geographically, and by species67 and is dependent on the marine food chain. White fish (cod, coley, plaice, haddock) contain about 1% fat by weight and oily fish (trout, salmon, mackerel, herring, pilchard, and sardine) contain 5-25% fat, depending upon when they are caught. In oily fish between 10% and 15% of the dietary energy is saturated fat compared with 1-2% in white fish. On an isocaloric basis oily fish provide about two to three times as much eicosapentaenoic acid and docosahexaenoic acid as white fish; 100g of oily fish provides about 200 kcal (837 kJ), 1 g of eicosapentaenoic acid and 0.5-2 g of docosahexaenoic acid depending upon species; 100 g of white fish provides 96 kcal (402 kJ), 0-2 g eicosapentaenoic acid, and 0-3 g docosahexaenoic acid. A fish oil concentrate called MaxEPA (Seven Seas Health Care) has been used in some studies; 10 g provides 1-8g eicosapentaenoic acid, 1-2g docosahexaenoic acid, and 60 mg cholesterol.
Requests for reprints to Dr T A B Sanders, Department of Food and Nutritional Sciences, King's College London, University of London, Campden Hill Road, London W8 7AH.
214
Influence of the Eskimo diet proteins
on
plasma lipo-
Greenland Eskimos have moderately low concentrations of low density lipoprotein (LDL) choles-
Fish and coronary artery disease terol, very low concentrations of low density lipoprotein (VLDL) triglycerides, and high concentrations of high density lipoprotein (HDL) cholesterol compared with Eskimos living on a western diet.8 The consumption of an Eskimo diet,5 mackerel9 (200 g/day) but not salmon,10 or fish oil supplements (20 g/day)" 12 slightly increased HDL cholesterol concentrations. Similar intakes considerably reduced triglyceride concentrations in both normal91l and hypertriglyceridaemic subjects 35 by reducing the synthesis of both triglyceride15 16 and apoprotein B(apoB)"6 in VLDL. In vitro studies have shown that eicosapentaenoic acid and docosahexaenoic acid are reversible inhibitors of hepatic triglyceride synthesis.17 Total plasma cholesterol concentrations are reduced by fish consumption but most of the reduction occurs in the VLDL fraction. Very high intakes of fish oil (90-120 g/day) do lower the concentration of both LDL cholesterol and LDL apoB by decreasing the rate of LDL synthesis."8 Such high intakes also prevent the rise in plasma cholesterol obtained with dietary cholesterol.19 At lower intakes (15 g/day), however, there is a tendency for LDL cholesterol and LDL apoB concentration20 to rise, particularly in patients with type V hyperlipoproteinaemia.'4 A likely explanation is that a moderate intake of fish oil decreases hepatic triglyceride synthesis so that smaller than normal VLDL particles are secreted. These small particles are known2 lto be more readily converted to LDL than the larger -triglyceride rich ones. Thus on the one hand the reduction in VLDL synthesis by fish diets probably reduces the risk of atherosclerosis, whereas on the other the increase in LDL may be deleterious.
215 Cyclo-oxygenase metabolites of arachidonic acid (20:4cw6), which have opposing effects in different locations, are believed to regulate platelet behaviour at the site of injury: thromboxane A2 produced by platelets causes platelet aggregation and vasoconstriction; prostacycline PGI2 produced by the vascular endothelium counteracts the effects of thromboxane A2. Coronary atherosclerosis decreases the capacity of the endothelium to produce prostacyclin so that the balance between thromboxane and prostacyclin is altered in a direction that increases the risk of coronary thrombosis.25 This view is supported by the observation that aspirin, which inhibits cyclo-oxygenase, halves the risk of myocardial infarction in patients with unstable angina. 266 Arachidonic acid is also converted to other important metabolites by platelets and neutrophils via the lipoxygenase pathway, which is not inhibited by aspirin. These metabolites, particularly leukotriene B4, are strongly chemotactic for leucocytes and may be responsible for the massive leucocyte migration into the myocardium that occurs in the vicinity of an experimental coronary occlusion. The ability of eicosapentaenoic acid to partially inhibit both cyclo-oxygenase and lipoxygenase pathways may explain why the infarct volume in dogs in which myocardial infarction was experimentally induced was lower in those treated with fish oil than in controls.24 Dietary eicosapentaenoic acid and docosahexaenoic acid displace arachidonic acid from membrane phospholipids. 1l 27 They also decrease the conversion of linoleic acid to arachidonic acid.28 This incorporation of eicosapentaenoic acid into the erythrocyte membrane is accompanied by a reduction in whole blood viscosity and an increase in erythrocyte deformability29-phenomena which are and Antithrombotic anti-inflammatory unrelated to eicosanoid production. In subjects given large amounts of fish or fish oil (usually in effects excess of 15 g/day), however, the capacity to produce Evidence is emerging that suggests that protection thromboxane A230-32 and leukotriene B433 is also against atherosclerosis may be afforded by a mech- reduced, but the urinary excretion of prostacyclin anism that overrides the influence of plasma lipo- PGI2 metabolites is not decreased32 34 except in proteins. For example, intimal hyperplasia of vein patients with atherosclerosis.32 Dietary eicosapentgrafts in hypercholesterolaemic dogs was inhibited aenoic acid and docosahexaenoic acid decrease the by feeding fish oil.22 A recent study showed that the formation of eicosanoids derived from arachidonic development of coronary atherosclerosis in hyper- acid, probably by displacing arachidonic acid from lipidaemic pigs could be prevented by supple- precursor pools and by acting as competitive menting their diet with cod-liver oil.23 It was argued inhibitions of cyclo-oxgenase35 and lipoxygenase.36 Eskimos are liable to profuse nosebleeds and have that protection was afforded by changes in eicosanoid metabolism. It has also been argued that extended template bleeding times; low platelet dietary eicosapentaenoic acid and docosahexaenoic counts are also common.8 Reductions in platelet acid', decrease the risk of arterial thrombosis and counts are occasionally seen with very high intakes mitigate damage to the myocardium by reducing of marine oil5 or fish oil.27 However, the regular local inflammation and by maintaining collateral consumption of oily fish (200 g/day) or fish oil supplements (20 g/day) prolongs template bleeding time circulation.24
216
Sanders (> 200 g/day) or smaller amounts of fish oil (about lOg MaxEPA/day) to affect plasma lipid concentrations and eicosanoid production. Generally, larger amounts of fish oil are needed to alter eicosanoid production than to lower plasma triglycerides. Consumption of a linolenic acid, which is found in vegetable oils,6 48 49 does not have the same effects as dietary eicosapentaenoic acid and docosahexaenoic acid.50 A high intake of eicosapentaenoic acid and docosahexaenoic acid seems a plausible explanation for the low incidence of coronary artery disease among the Eskimos. Their extreme dietary practices are interesting because they shed light on the mechanisms leading to coronary artery disease; but it does not follow that such diets should be advocated for the general population. Fish oil supplements have yet to be shown of value in the treatment of hypercholesterolaemia but they can be used to treat hypertriglyceridaemia. Multivariate analysis of several epidemiological studies suggests that plasma triglyceride concentrations is not an independent risk factor for coronary artery disease. None the less, there are several triglyceride bearing lipoprotein particleschylomicrons, VLDL, and intermediate density lipoproteins (IDL)- and elevated plasma triglycerides may represent an increase in any one of these particles. A raised concentration of plasma triglyceride caused by raised chylomicron concentration is Fish is a good source of selenium but is a poor source not associated with an increased risk of atheroof vitamin E. Myocardial fibrosis occurred in sclerosis, whereas raised concentrations of plasma in on fish and infants fed oily domesticated animals associated with raised VLDL and IDL triglyceride fed rancid cod-liver oil.45 This was caused by lipid concentrations even when LDL concentrations peroxides. Precautions, therefore, need to be taken are low. Severalare, recent angiographic studies showed to guard against the formation of lipid peroxides, that high concentrations of plasma triglyceride particularly in fish oil supplements, and to ensure an associated with raised VLDL and IDL were adequate intake of vitamin E. Mackerel, herring, predictive of coronary atherosclerosis. In addition, and salmon gadoleic (20:1 to 1)_ and cetoleic there is evidence that VLDLs are toxic to the (22:1 co1 1) acids caused a transient myocardial lip- vascular endothelium.51 Hypertriglyceridaemia is idosis when fed to experimental animals in large often by reduced concentrations of amounts.46 There is no evidence that eating these HDL accompanied and a tendency to hypercholesterol fish causes lipidosis in man, however. The salt con- coagulability. Since amelioration of hypertriglyctent of many preserved fish (pickled herrings, kip- eridaemia can both raise HDL cholesterol and pers) is high,6 and this may have an undesirable reduce the level of certain clotting factors it is a effect on blood pressure. Pickled fish also contains potentially beneficial endeavour. This line of reahigh concentrations of tyramine and histamine and soning must, however, be tempered by the knowlso should be avoided by patients treated with mono- edge that moderate doses of fish oil not only reduce amine oxidase inhibitors. Excessive intakes of hista- VLDL triglycerides but may also increase LDL mine in spoilt oily fish are believed to be the cause of concentrations at the same time. The overall assessscomboid toxicity.47 Fish are very susceptible to ment of risk will depend upon the size of the industrial pollution and are occasionally affected by respective changes. Large quantities of fish oil seem naturally occurring toxins derived from the marine free from this disadvantage but have the drawback of food chain. being too unpalatable for long term consumption. There are reasons from believing that fish oil Conclusion might be of benefit to patients with thrombogenic It is necessary to eat large amounts of oily fish disorders, but the necessary clinical trials have yet to
after about three weeks of treatment without affecting the platelet count11 12 37 or the activity of clotting factors.- Although there are similarities between the effects of consumption of oily fish and those obtained with aspirin, the reductions of thromboxane A2 production and platelet aggregation are modest compared with those brought about by small doses of aspirin. Furthermore, because aspirin potentiates the prolongation of bleeding time brought about by fish feeding37 it seems likely that a different mechanism is responsible especially as the urinary excretion of total prostaglandin metabolites is not significantly lower in Eskimos than in Danes.38 Eicosanoids can be formed from eicosapentaenoic acid but they tend to be less active than those derived from arachidonic acid. For example, thromboxane A339 40 and leukotriene B533 are less active but prostacyclin PGI3 is as active.39 40 Thromboxane B33241 PGI3323442 and leukotriene B 543 have been detected after consumption of massive amounts of fish (400-800g mackerel/day) or large amounts of fish oil (20-50 g/day). These observations support the hypothesis44 that eicosapentaenoic acid modulates the production of active eicosanoids. Potential hazards of high fish consumption
Fish and coronary artery disease be carried out. Fish oil does prolong bleeding time and the precise mechanism for this effect remains uncertain. It may well involve altered vascular reactivity rather than altered platelet behaviour, especially as a recent study showed that fish oil supplementation lowered blood pressure.52 It should be borne in mind that fish oil may well potentiate the action of some drugs such as aspirin and P blockers. Formerly, fish was an important part of the British diet. It had the advantage of being available throughout the year. For religious reasons, it was eaten on Fridays and other fish days and almost daily during Lent. Lord Trenchard in his review of consumption patterns concluded that the decrease in fish consumption is one of the major changes in the British diet this century.53 Cod-liver oil supplements were also widely used up until the 1950s. Fish contains several nutrients and foreign compounds that are scarce in other foods. For example, relatively small quantities of fish in the diet can contribute greatly to the total intake of retinol, vitamin D, taurine, and selenium. Consequently, fish might be providing some other yet to be identified protective factor. Selenium is a possible candidate, especially as selenium supplements prolong template bleeding time54 and low serum selenium concentrations are associated with increased risk of coronary heart disease.55 Kromhout et al recently claimed that eating fish once or twice weekly might reduce the risk of coronary heart disease. 56 In this prospective study a reduction in risk was found with an average daily intake of 30 g fish (two thirds white fish, one third oily), an amount that would provide far less eicosapentaenoic acid and docosahexaenoic acid than the minimum shown to influence either plasma lipid concentrations or eicosanoid production. This effect was independent of other known risk factors such as smoking, blood pressure, and plasma cholesterol concentration. The protective influence of fish consumption has been confirmed in one study in the United States57 but not in studies in Hawai58 or Norway59 where fish was consumed more frequently. In most cases the habitual diet of the subjects was assessed by a single 24 hour dietary recall. The assumption that one single dietary measurement is representative of an individual's diet over the next twenty years is dubious especially as food consumption patterns are continually changing. The association between modest fish consumption and protection from coronary heart disease requires further confirmation and must be assessed in the light of total mortality statistics. It is also necessary to consider which foods were replaced by fish. Despite these uncertainties it makes good sense to
217 encourage people to eat more fish, but not fried or salted, in place of foods with a high content of saturated fat (such as cheese, meat products, and fatty meats). Such a change would also be in accord with the current dietary guidelines for the prevention of coronary heart disease.60 References 1 Sinclair HM. The diet of Canadian Indians and Eskimos. Proc Nutr Soc 1953;12:69-82. 2 Schaeffer 0. Medical observations on Canadian Eskimos. Can Med Assoc J 1959;81:386-93. 3 Kromann N, Green A. Epidemiological studies in the Upernavik District, Greenland. Acta Med Scand 1980;208:401-6. 4 Hirai A, Hamazaki T, Terano T, et al. Eicosapentaenoic acid and platelet function in Japanese. Lancet 1980;ii: 1 132-3. 5 Sinclair HM. Advantages and disadvantages of an Eskimo diet. In: Fumagalli R, Kritchevsky D, Peoletti R, eds. Drugs affecting lipid metabolism. Amsterdam: Elsevier/North Holland Biomedical Press, 1980:363-70. 6 Paul AA, Southgate DAT. McCane and Widdowson's The composition offoods. 4th ed (MRC Special Report No. 297.) London: HMSO, 1978. 7 Ackman RG. Fatty acid composition of fish oils. In: Barlow SM, Stansby ME, eds. Nutritional evaluation of long chain fatty acids infish oils. London: Academic Press, 1982:25-88. 8 Bang HO, Dyerberg J. Lipid metabolism in Greenland Eskimos. In: Draper HH, ed. Advances in nutrition research. New York: Plenum Press, 1980;3:1-40. 9 Von Lossonczy TO, Ruiter A, Bronsgeest-Schoute HG, et al. The effect of a fish diet on serum lipids in healthy human subjects. Am J Clin Nutr 1978;31:1340-6. 10 Harris WS, Connor WE, McMurry MP. The comparative reductions of the plasma lipids and lipoproteins by dietary polyunsaturated fats: salmon vs vegetable oil. Metabolism 1983;32:179-84. 11 Sanders TAB, Vickers M, Haines AP. Effect on blood lipids and haemostasis of a supplement of cod-liver oil, rich in eicosapentaenic and docosahexaenoic acids, in healthy young men. Clin Sci 1981;61:317-24. 12 Saynor R, Verel D, Gillot T. The long term effect of dietary supplementation with fish lipid concentrate on serum lipids, bleeding time, platelets and angina. Atherosclerosis 1984;50:3-10. 13 Simons LA, Hickie JB, Balasubramaniam S. On the effects of dietary n-3 fatty acid (MaxEPA) on plasma lipids and lipoprotein in patients with hyperlipidaemia. Atherosclerosis 1985;54:75-88. 14 Phillipson BE, Rothrock DW, Connor WE, Harris WS, Illingworth DR. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N Engl J Med
1985;19:1210-6.
15 Sanders TAB, Sullivan DR, Reeve J, Thompson GR.
218 Triglyceride-lowering effect of marine polyunsaturates in patients with hypertriglyceridemia. Arteriosclerosis 1985;5:459-65. 16 Nestel PJ, Connor WR, Reardon MF, etal. Suppression by diets rich in fish oil of very low density lipoprotein production in man. J Clin Invest 1984;74:82-9. 17 Wong S, Reardon M, Nestel P. Reduced triglyceride formation from long-chain polyenoic fatty acids in rat hepatocytes. Metabolism 1985;34:900-5. 18 Illingworth DR, Harris WS, Connor WE. Inhibition of low density lipoprotein synthesis by dietary omega-3 fatty acids in humans. Arteriosclerosis 1984;4:270-5. 19 Nestel PJ. Fish oil attenuate the cholesterol induced rise in lipoprotein cholesterol. Am J Clin Nutr 1986;43:752-7. 20 Sullivan DR, Sanders TAB, Trayner IM, Thompson GR. Paradoxical elevation of LDL apoprotein B levels in hypertriglyceridaemic patients and normal subjects ingesting fish oil. Astherosclerosis 1986; 61:129-34. 21 Packard CJ, Munro A, Lorimer AR, Gotto AM, Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoprotein of normal and hypertriglyceridemic subjects. J Clin Invest 1984;75:2178-92. 22 Landymore RW, Kinley CE, Cooper JH, etal. Codliver oil in the prevention of intimal hyperplasia in autologous vein grafts used for arterial bypass. J Thorac Cardiovasc Surg 1985;89:351-7. 23 Weiner BH, Ockene IS, Levine PH, etal. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine mode. N Engl J Med 1986;315:841-6. 24 Culp BR, Lands WEM, Lucches BR, Pitt R, Romson J. The effect of dietary supplementation of fish oil on experimental myocardial infarction. Prostaglandins 1980;20:1021-31. 25 Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood vessel walls. N Engl J Med 1979;300: 1142-7. 26 Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter-trial. N Engl J Med 1985;313: 1369-75. 27 Goodnight SH, Harris WS, Connor WE. The effects of dietary cw3 fatty acids on platelet composition and function in man: a prospective controlled study. Blood 1981;58:880-5. 28 Brenner RR, Peluffo RO. Inhibitory effect of docosa-4, 7, 10, 13, 16, 19-hexaenoic acid upon the oxidative desaturation of linoleic into f-linolenic acid and of a-linolenic acid into octadeca-6, 9, 12, 15,-tetraenoic acid. Biochim Biophys Acta 1967;137:184-6. 29 Terano T, Hirai A, Hamazaki T, etal. Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis 1983;46:321-31. 30 Siess W, Scherer B, Bohlig B, et al. Platelet membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet 1980;i:441-4.
Sanders 31 Lorenz R, Spengler U, Fischer S, et al. Platelet function, thromboxane formation and blood pressure control during supplementation of the western diet with cod-liver oil. Circulation 1983;67:504-1 1. 32 Knapp HR, Reilly AG, Allesandrini P, Fitzgerald GA. In vivo indexes of platelet and vascular function during fish oil administration in patients with atherosclerosis. N Engl J Med 1986;314:937-42. 33 Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 1985;312:1217-24. 34 Von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine co3 fatty acids upon plasma and cellular lipids platelet function and eicosanoid formation in humans. J Clin Invest 1985;76:1629-31. 35 Lands WEM, LeTellier PR, Rome LH, Vanderhoek JY. Inhibition of prostaglandin biosynthesis. Adv Biosci 1972;9:15-28. 36 Corey EJ, Shih C, Cashman JR. Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc Natl Acad Sci USA 1983;80:3581-4. 37 Thorngren M, Gustafson A. Effects of 11 week increase in dietary eicosapentaenoic acid on bleeding time, lipids and platelet aggregation. Lancet 1983; ii:1 190-3. 38 Zuccato E, Hornstra G, Dyerberg J. Long term marine diet in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites. Prostaglandins 1985;30:465-77. 39 Needleman P, Raz A, Minkes MS, Ferrendelli JA, Sprecher HA. Triene prostaglandins prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Natl Acad Sci USA 1979;76:944-8. 40 Gryglewski RJ, Salmon JA, Ubatuba FB, Weatherby BC, Moncada S, Vane JR. Effects of all cis-5, 8, 11, 14, 17-eicosapentaenoic acid and PGI3 on platelet
aggregation. Prostaglandins 1979;18:453-78. 41 Fischer S, Weber PC. Thromboxane A3(TxA3) is formed in human platelets after dietary eicosapentaenoic acid (C20:5co3). Biochem Biophys Res Commun 1983;1 16:1091-9. 42 Fischer S, Weber PC. Prostaglandin I3 is formed in man after dietary eicosapentaenoic acid. Nature
1984;307:165-8. 43 Prescott SM, Zimmerman GA, Morrison AR. The effect of a diet rich in fish oil on human neutrophils: identification of leukotriene B5 as a metabolite. Pros-
taglandins 1984;30:209-27. 44 Dyerberg J, Bang HO, Stofferson E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978;i: 117-9. 45 McCollum EV. A history of nutrition. Cambridge Massachusetts: Riverside Press, 1957. 46 FAO/WHO. Dietary fats and oils in human nutrition a joint FAO/WHO report. Rome: FAO, 1977. 47 Committee on Food Protection, Food and Nutrition Board, National Research Council. Naturally occurring toxicants in foods. Washington: National Academy of Sciences, 1973.
219
Fish and coronary artery disease 48 Weiner MA. Cholesterol in foods rich in omega-3 fatty acids. N Engl J Med 1986;315:833. 49 Simopoulos AP, Salem N. Purslance: a terrestial source of omega-3 fatty acids. N Engl J Med 1986;315:833. 50 Sanders TAB, Roshania F. The influence of different types of co3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci 1983;64:91-9. 51 Gianturco SH, Eskin SG, Navarro LT, Lahart CJ, Smith LC, Gotto AM. Abnormal effects of hypertriacylglycerolemic very low-density lipoproteins on 3-hydroxy-3-methylglutaryl-coA reductase activity and viability of cultured bovine aortic endothelial cells. Biochim Biophys Acta 1980;618:143-52. 52 Norris PG, Jones CJH, Weston MJ. Effect of dietary supplementation with fish oil on systolic blood pressure in mild essential hypertension. Br Med J 1986;ii: 104-5. 53 Lord Trenchard. The inter-relationship of marketing and nutrition. In: Yudkin J, ed. Diet of man: needs and wants. London: Applied Science Publishers, 1978:225-42. 54 Schiavon R, Freeman GE, Guidi GC, Perona G, Zatti M, Kakkar VV. Selenium enhances prostacyclin
55
56
57 58 59
60
production by cultured endothelial cells: possible explanation for increased bleeding time in volunteers taking selenium as a dietary supplement. Thromb Res 1984;34:389-96. Sallonen JT, Alflhan G, Huttunen JK, Pikkarainea J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched pair longitudinal study. Lancet 1982;ii: 175-9. Kromhout D, Bosschieter EB, Coulander CL. The inverse relation between fish consumption and 20-year mortality from coronary disease. N Engl J Med 1985;312:1205-9. Shekelle RB, Missell L, Oglesby P, et al. Fish consumption and mortality from cardiovascular disease. N Engl J Med 1985;313:820. Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from cardiovascular disease. N EnglJ Med 1985;313:820-1. Curb JD, Reed DM. Fish consumption and mortality from cardiovascular disease. N Engi J Med 1985;313:821-2. DHSS. Diet and cardiovascular disease. Report on health and social subjects No 28. London: HMSO, 1984.
