Relationship between Relationship betweenNutrition Nutrition and and CVD: CID: Epidemiological Findings Somogyi JC, Biró Biro Gy, Gy, Hitze! Hotzel D (eds): (eds): Nutrition and and Cardiovascular Cardiovascular Risks. Risks. Somogyi Bibl Nutr Dieta. Dieta. Basel, Basel, Karger, 1992, 1992, No 49, pp 10-17 No 49, Bib!
Dietary Lipids and Coronary Heart Disease Disease Epidemiological Evidence K. Huttunen Jussi Κ. National Public Public Health Institute, Helsinki, Helsinki, Finland National
Introduction Epidemiological, clinical Epidemiological, clinical and and experimental studies have provided strong and consistent evidence that nutritional nutritional factors factors have have an important role in the and important role On several etiology of coronary heart disease in man. Diet has a direct impact on atherosclerosis or mechanisms closely progression of atherosclerosis mechanisms closely linked linked either either to to progression or to precipitation of acute myocardial myocardial infarct infarct or sudden sudden cardiac cardiac death. death. These These precipitation mechanisms include changes in lipoprotein metabolism metabolism and and endothelial endothelial mechanisms include changes in lipoprotein pressure, disturbances disturbances in clotting and function, elevation elevation of blood pressure, function, in blood clotting cardiac platelet aggregability, aggregability, increase platelet increaseinin body body weight, weight, and and induction induction of cardiac Critical dietary dietary components components include include cholesterol, cholesterol, fatty acids and arrhythmias. Critical fiber, alcohol fiber, alcohol and and coffee, coffee, sodium, sodium, potassium potassium and and magnesium, magnesium, and and vitamins trace elements elements with antioxidant properties. and trace This overview overview examines association between between dietary lipids and This examines the the association dietary lipids disease with special emphasis on epidemiological studies. coronary heart disease
The association between the The association betweenintake intakeof of nutrients nutrients and/or and/or foods foods and and the of coronary heart disease has been difficult to demonstrate incidence incidence coronary heart disease has difficult to demonstrate in epidemiological studies difficulties are epidemiological studies within within populations. These difficulties are partially explained measuring human Some of the explained by by inherent inherent problems problems in in measuring human diets. diets. Some problems are illustrate the limitations of problems are briefly briefly outlined outlined here here in in order order to to illustrate dietary epidemiology. The information on dietary habits habits used used in virtually all studies published far covers covers only only a limited limited time time period, period, despite despite the fact fact that that coronary coronary so far
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Methodological Problems
Dietary Lipids and Coronary Heart Disease
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atherosclerosis most exposure over decatherosclerosis most probably probably results results from from cumulative exposure ades. Thus, Thus, in case-control case-control studies, usually available available for ades. studies, data data on diet are usually for a few years diagnosis of cases and for an an equivalent equivalent period period for for few years prior prior to to diagnosis of cases and for controls. In prospective studies information on diet diet has has often often been been collectcollectcontrols. ed only once and no information information was was gathered gathered on changes changes that may have occurred period. Secondly, the methods occurred during during the follow-up follow-up period. Secondly, the methods of dietary dietary many of of the the early early investigations investigations have been inadequate; inadequate; most intake in many most of these studies studies have have used used 24-hour 24-hour recall recall methods, methods, which poor these which provide provide aa poor assessment of all individuals individuals are exposed exposed to dieassessment of habitual habitual intake. intake. Thirdly, Thirdly, all factors and therefore therefore exposures exposures cannot be characterized characterized as present or tary factors as present absent; rather they are continuous variables, often with a limited range of absent; continuous variables, often with variation. Finally, Finally, the effects effects of many many nutrients are are strongly strongly correlated as variation. same food food items. Such Such a multicollinearity renders it they are present in the same difficult to distinguish between spurious associations associations in difficult to distinguish between causal causal and and spurious in the analysis of of epidemiological epidemiological studies. statistical analysis significant association between diet and Failure to observe a statistically significant risk of coronary coronary heart heart disease disease in in epidemiological epidemiological studies studies has has often often been been risk interpreted to mean the absence absence of such such an association. association. In view of the the interpreted to mean In view difficulties described difficulties described above, above, lack lack of of association association should should be be interpreted with caution. It may may result: result: (i) (i) from from insufficient insufficient variation diet; (ii) (ii) lack lack of caution. variation in diet; precision of the method method used used to to measure measure differences; differences; (iii) (iii) measurement measurement of precision after (or (or before) before) the the biologically biologically relevant relevant period period of ofexposure; exposure; (iv) (iv) neganegadiet after confounding, or or (v) (v) from low statistical power of the study. tive confounding,
The pioneering studies of Keys Keys and and his his international international collaborators in the Seven Countries Countries Study Study demonstrated demonstrated aa significant significant association association of dietary dietary Seven of cholesterol cholesterol and saturated fatty acids with mortality from coronary intake of disease at 5, 5, 10 10 and and 15 15 years years after baseline baseline examination in in 16 16 defined defined heart disease populations in seven seven countries countries [1]. [1]. In In another anotherecologic ecologic study study aasignificant significant relationship was was found found between between the percentage percentage of calories 12 relationship calories from from fat fat in 12 countries and and prevalence prevalence of of raised raised atherosclerotic atherosclerotic lesions lesions in in autopsy autopsy cases cases in countries same population population [2]. [2]. These These findings findings are further supported supported by by migrant migrant the same studies [3], [3], parallel trends of coronary heart disease incidence and consumpstudies of saturated saturated fat fat in in several several countries countries [4-6], [4-6], and and decreases decreases in deaths deaths tions of arteriosclerosis during when major reducreducascribed to arteriosclerosis during World World Wars Wars I and II when in total total and and animal animal fat fat consumptions consumptions occurred occurred in in Europe Europe [7]. [7]. tions in
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ofDietary Dietary Fat Quality and Quantity of
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relationship between fat intake and risk risk of of coronary coronary heart heart disease disease The relationship has been examined in relatively few few prospective cohort studies, and many of of were not primarily primarily designed designed as investigations of of diet and heart disease. them were Morris Morris et al. al. [8] [8] found found aastrong stronginverse inverse association association between between total total energy energy and risk risk of ofcoronary coronary heart heart disease. disease. A A similar similar although although weaker weaker inverse intake and was observed observed with and cereals, cereals, relationship was with consumption of dietary bread and whereas whereas no association association was was observed observed with with percentage percentage of of calories calories from from saturated fat fat or or with with cholesterol. cholesterol. saturated Significant positive associations were observed by Shekelle et al. [9] in Significant follow-up of 1,900 1,900 men men employed employed by by the the Western Western Electric Electric Company Company the follow-up of cardiovascular cardiovascular disease and and the the score score described described by by Keys Keys et al. between risk of dietary intakes intakes of of [[10] 10] for for predicting predicting serum serum cholesterol cholesterolon on the the basis basis of dietary and polyunsaturated polyunsaturated fat, fat, and andcholesterol. cholesterol. Surprisingly, Surprisingly, the intake saturated and of saturated saturated fatty fatty acids acids was was not not significantly significantly associated with risk. risk. Analysis of of follow-up data from the same study suggested that the risk associated 25-year follow-up high dietary dietary intake intake of of cholesterol cholesterol was was partly partly independent independent of of serum serum with high cholesterol [1 [11]. The Ireland-Boston Heart Study reported mortality experi1 ]. The Ireland-Boston Heart Study reported history interview interview 20 20 years years earlier ence of men who had completed a dietary history [[12]. 12]. Individuals Individuals who who subsequently subsequently died of coronary heart disease had a high intake of of saturated saturated fatty fatty acids acids and and cholesterol cholesterol and and aa low intake of ofpolyunsatuintake polyunsatufatty acids acids as as compared compared to to survivors. survivors. Fiber Fiberintake intakewas wassignificantly significantly rated fatty lower among those who died of coronary disease. Three prospective cohort studies (Puerto Rico, Rico, Framingham and Honolulu) included a 24-hour dietary recall in their baseline examinations in 1965 1965 Follow-up analyses analyses revealed between total [13-15]. Follow-up revealed an inverse association between energy intake disease in studies, but a energy intake and and risk risk of coronary coronary heart heart disease in all all three studies, significant positive significant positive association association between between saturated saturated fat and cholesterol intake coronary heart disease disease incidence only in Honolulu. and coronary
The effect effect of of fish fish consumption consumption on on coronary coronary heart disease disease mortality has investigated in several prospective studies. studies. A 50% 50% reduction been investigated reduction in corodisease mortality mortality was was observed observed during a 20-year 20-year follow-up follow-up in a nary heart disease Dutch study study in in men men consuming consuming more more than than 30 30ggof offish fish per perday day[ [16]. High 16]. High intakes fish were were associated associated with rates of coronary coronary heart heart disease disease intakes of fish with low low rates mortality also also in prospective prospective studies studies reported reported by by Shekelle Shekelle et et al. al. [[17] mortality 17] and Norell et al. [[18], 18],but butnot not in in aa third third study conducted among Norwegian men
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Fish Fish Consumption
Dietary Lipids Lipids and and Coronary Coronary Heart Heart Disease Dietary
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[[19]. 19].AAcausal causalassociation associationbetween betweenfish fishintake intakeand and protection protection against against heart disease is supported by a recent controlled trial which resulted 29% disease is supported by recent controlled trial which resulted in in a 29% reduction in coronary coronary heart heart disease disease mortality mortality among among subjects subjects who who were were reduction advised to increase their their fish fish intake [20].
Tissue and Plasma Fatty Acids
The fatty acid acid content content of of plasma plasma lipid lipid fractions, fractions, platelets, platelets, red red cell cell The fatty membranes, and subcutaneous subcutaneous fat membranes, fat has has been been used used as as a marker of fatty acid intake in several several case-control case-control studies and in aa few few prospective prospective studies [21]. [21]. Although the results are not entirely consistent, they do suggest that subjects with low low tissue tissue content content of linoleic linoleic acid acid and omega-3 omega-3 fatty fatty acids acids have have with increased risk coronary heart disease. Interpretation is, increased risk of coronary heart disease. Interpretation of these these data data is, however, difficult observations suggest suggest that smokers smokers consume consume however, difficult as as other observations of linoleic acid compared to nonsmokers nonsmokers [21]. [21]. substantially lower amounts of
classic diet-heart hypothesis hypothesis has largely largely focused effects of The classic focused on the effects cholesterol and saturated and polyunsaturated fatty acids on serum serum dietary cholesterol cholesterol concentration. Epidemiological Epidemiological studies and controlled trials total cholesterol however, that of of the two two main main cholesterol-containing cholesterol-containing lipoprohave shown, however, plasma, low-density low-density lipoprotein lipoprotein (LDL) (LDL) is is atherogenic, whereas whereas highteins in plasma, density lipoprotein lipoprotein (HDL) (HDL) is likely likely to to be be protective. protective. Effects Effects of of different different density categories of dietary fatty acids on the concentrations of serum lipoprotein categories dietary fatty acids of have recently recently been re-evaluated [22-25], and the results results may concentrations have discrepancies in the literature. help to explain some of the discrepancies Although there is overwhelming overwhelming evidence evidence that that saturated fatty acids as a class raise raise serum serum LDL LDL cholesterol cholesterol levels, series of of class levels, most most diets diets contain contain a series saturated fatty fatty acids acids of of different different chain chain lengths, lengths, and these may may not have have saturated and these effects on serum lipoprotein cholesterol cholesterol levels. levels. The two saturated identical effects that have have strongly strongly and consistently raised plasma cholesterol (and fatty acids that presumably LDL cholesterol) concentration are myristic (14:0) and palmitic (16:0) acids. Lauríc Lauric acid acid (12:0) (12:0) also also raises raises serum serum cholesterol, cholesterol, whereas whereas meme(16:0) dium-chain fatty acids (8:0 (8:0 and and 10:0) 10:0) do do not notaffect affect serum serumcholesterol. cholesterol. dium-chain fatty acids Furthermore, recent recent studies studies suggest suggest that stearic stearic acid acid (18:0) (18:0) lowers lowers LDL LDL Furthermore, level, perhaps as it is rapidly converted to to oleic oleic acid acid [24]. [24]. cholesterol level,
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Effects of of Specific Specific Fatty Acids
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Linoleic acid, polyunsaturated fatty acid acid of of the the Linoleic acid, the principal omega-6 polyunsaturated diet, diet, lowers lowers serum LDL cholesterol, cholesterol, and in high high quantities, quantities, also also the HDL HDL cholesterol level. the same same cholesterol level. The The omega-3 omega-3 polyunsaturated fatty acids have the HDL cholesterol cholesterol as omega-6 polyunsaturates, polyunsaturates, but they they effect on LDL and HDL effect also lower lower the plasma triglyceride concentration. In contrast, oleic oleic acid, the the also predominant monounsaturated monounsaturated fatty the diet, diet, lowers lowers serum serum LDL LDL predominant fatty acid of the HDLcholesterol cholesterol level level cholesterol concentration, but but does does not not influence influence the the HDL cholesterol [22, 23]. 23]. Trans Trans fatty fatty acids, acids, formed formed when when vegetable vegetable and marine oils oils are are [22, and marine HDL cholesterol hydrogenated, may may raise raise the the LDL LDL cholesterol cholesterol and and lower lower the HDL hydrogenated, [25]. levels [25]. risk of of coronary coronary heart heart The relationship relationship between between dietary dietary lipids lipids and and risk of dietary disease is further complicated by the fact fact that quality and quantity of also influence influence platelet aggregation, aggregation, blood fat also blood pressure, pressure, and cardiac arrhythpolyunsaturatedfatty fattyacids acidsmay maylower lower blood blood pressure pressure mias.High Highintake intakeofofpolyunsaturated rias. of [26] and and reduce reduce the the platelet platelet aggregability aggregability [27], [27], whereas whereas high high intakes intakes of [26] saturated fatty fatty acids acids have have had had an an opposite oppositeeffect. effect. Finally, Finally, there there is is evidence evidence saturated that ventricular ventricular arrhythmias arrhythmias can be prevented prevented by high high dietary dietary intakes intakes of experimental animals [28]. [28]. Thus, dietary fat linoleic acid both in man and in experimental probably influences influences the coronary heart heart disease disease through through several several probably the risk risk of coronary independent mechanisms. mechanisms.
ofLDL Experimental studies have suggested that oxidative modification of LDL cultured macrophages macrophages suggest suggest increases its atherogenicity [29]. Studies using cultured LDL must must first first undergo undergo modification modification in some way way to accelerate accelerate its that LDL in some cells to produce the cholesterol cholesterol accumulation seen in foam cells uptake into cells in atherosclerotic atherosclerotic plaques. plaques. Thus, Thus, two two key key factors factors may may be be required required for for the process, i.e. development of the atherosclerotic process, i.e. the presence of LDL and an oxidative process process to to transform transform the the lipoprotein lipoprotein into a potential stimulus for macrophage uptake. uptake. Several Several dietary dietary factors factors may, may, at at least least in in theory, theory, contribute contribute to to or prevent the oxidative modification of ofLDL. LDL. High intakes of selenium, selenium, vitamins vitamins C and E, E, and beta-carotene are likely to be protective, whereas very high high intakes of polyunsaturated fatty acids may be harmful. Indeed, epidemiological harmful. epidemiological studies coronary heart suggest negative correlation suggest aa negative correlation between between the the incidence incidence of coronary disease and levels of vitamin EE [30] [30] or levels of selenium [31] suggesting suggesting that that antioxidant may be relevant relevant to the the human human disease. disease. Interestingly, Interestingly, a antioxidant status status may
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Dietary Antioxidants Antioxidants
Dietary Lipids and Coronary Heart Disease
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Netherlands suggests suggests that high intakes of ofpolyunsaturecent study from the Netherlands polyunsaturated fatty acids acids are associated associated with high risk of coronary heart disease disease in insufficiently protected [32]. subjects insufficiently protected by by antioxidants antioxidants against peroxidation [32]. Final evidence for the antioxidant hypothesis can be obtained only from controlled studies. fact, preliminary preliminary data from from the the Physicians Physicians Health Health controlled studies. In In fact, suggest that Study suggest that beta-carotene reduces the risk of cardiovascular events in existing coronary coronary heart disease disease [33]. [33]. Several Several studies subjects with existing studies are currently on the the way way to to test test the the efficacy efficacy of beta-carotene beta-carotene and rently and vitamin vitamin E in of coronary heart disease. primary or secondary prevention of Concluding Remarks Concluding Remarks
An extensive body body of of data data supports supports the hypothesis hypothesis that dietary lipids are causal determinant of coronary coronary heart disease disease in man. man. The The mechanisms mechanisms a causal underlying this association are include effects effects on lipoprotein underlying this association are multiple and include pressure regulations, regulations, platelet platelet aggregability aggregability and possibly possibly metabolism, blood pressure The classic classic lipid hypothesis alone fails susceptibility to cardiac arrhythmias. The to explain the differing rates of of coronary coronary heart heart disease disease in in various various populations. populations. New concepts, concepts, particularly particularly the oxidative oxidative modification modification hypothesis, hypothesis, may may New some of of the conflicting conflicting observations. provide explanations for some
KeysA, A, Menotti Menotti A, A, Kanonen Karvonen MJ: MJ: The 15-year death death rate in in the the Seven Seven 1 Keys The diet and 15-year 1986; 124:903-915. Countries Study. Am JJ Epidemiol 1986;124:903-915. MA: Diet Dietand andatherosclerosis. atherosclerosis. Lab Lab Invest Invest 1968;18:6231968; 18:623ScrimshawNS, NS,Guzman GuzmanMA: 2 Scrimshaw 628. RobertsonTL, TL,Kato KatoH, H,Rhoads RhoadsGG, GG, Kagan Kagan A, A, Marmot Marmot M, M, Syre Syme SL, SL, Gordon T, 3 Robertson Belsky JL, S: Epidemiologic studies Worth RM, Belsky JL, Dock Dock DS, DS, Miyanishi Miyanishi M, M, Kawamoto S: of coronary coronary heart disease disease and living in Japan, Hawaii and and stroke stroke in Japanese men living death from from coronary coronary heart heart California: Incidence California: Incidence of of myocardial myocardial infarction infarction and and death disease. Am disease. Am JJ Cardiol 1977;39:239-243. The marked marked decline decline in coronary coronary heart heart disease disease mortality 4 Stamler J: J: The mortality rates rates in in the of findings and possible explanations. Cardiol1968-1982: Summary Summary of United States, 1968-1982: ogy 1985;72:11-22. 1985;72: 11-22. ogy Pyonila K, K, Salonen Salon en JT, Valkonen T: T: Trends in coronary heart disease mortality and 5 Pyorála Cardiology 1985;72:35-51. morbidity and related factors in Finland. Cardiology BeagleholeR: R:Trends Trendsinindietary dietaryfat fat and andcigarette cigarette smoking smoking and the decline JacksonR,R,Beaglehole 6 Jackson disease in New Zealand. Int J Epidemiol 1987;16:377-382. 1987;16:377-382. in coronary heart disease 7 Katz Katz LI, LN, Stamler JS : Experimental Atherosclerosis. Springfield, Springfield, Thomas, 7 Thomas, 1986, pp 24-32.
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8 Morris MorrisJN, IN,Marr MarrJW, JW,Clayton ClaytonDG: DG: Diet Diet and and heart: heart: A A postscript. postscript. Br Med J 1977;ií: 1977;ii: 1307-1314. 1307-1314. O, Lepper M, Stamler JS, PaulO, 9 Shekelle ShekelleRB, RB,Shryock ShryockAM, AM, Paul JS, Liu Liu S, S, Raynor Raynor WJ WJ Jr: Jr: Diet, Diet, serum serum cholesterol, cholesterol, and death death from from coronary coronary heart heartdisease disease— - the Western Western Electric Electric 1981 ;304:65-70. Study. N Engl J Med 1981;304:65-70. KeysA,A,Anderson AndersonJT, JT,Grande GrandeG: G:Serum Serumcholesterol cholesterol response response to to changes changes in 10 Keys in the diet. diet. Metabolism 1965;14:747-787. Metabolism 1II1 Shekelle Shekelle R, R, Stamler J: 1989; J: Dietary cholesterol and ischaemic heart disease. Lancet 1989; i:1177-1179. i:II77-1179. KushiLH, LH,Lew LewRA, RA,Stare StareFJ, FJ,Ellison EllisonCR, CR,El EILozy Lozy M, M, Bourke Bourke G, Daly L, 12 Kushi L, Graham I, Hickey N, 20-year mortality from Hickey N, Mulcahy Mulcahy R, R, Kevaney Kevaney J:J: Diet Diet and and 20-year from coronary heart disease: disease: The The Ireland-Boston Ireland-Boston diet-heart study. study. N Engl J Med 1985;312:811-818. 13 13 Garcia-Palmieri Garcia-Palmieri MR, MR, Sortie Sorlie PD, PD, Tillotson Tillotson J, Costas R, E, Rodriquez M: M: R, Cordero E, Relationship of dietary intake to subsequent coronary heart disease disease incidence: incidence: The Puerto Rico Heart Program. Am Am J Clin Nutr 1980;33:1818-1827. 1980;33: 1818-1827. DawberTR, TR,Nickerson NickersonRJ, RJ,Brand BrandFN, FN,Pool PoolJ:J:Eggs, Eggs, serum serum cholesterol, cholesterol, and coronary 14 Dawber heart disease. Am JJ Clin Clin Nutr 1982;36:617-625. 1982;36:617-625. disease. Am 15 McGee McGee DL, DL, Reed Reed DM, DM, Vano Yano K, K,Kagan Kagan A, A, Tillotson Tillotson J:J: Ten-year Ten-year incidence incidence of of 15 coronary heart disease in Honolulu Heart Program: Program: Relationship Relationship to coronary heart disease in the Honolulu to nutrient 1984;119:657-676. intake. Am J Epidemiol 1984;119:657-676. 16 Kromhout Kromhout D, D,Bosschieter Bosschieter EB, EB, de de Lezenne Lezenne Coulander Coulander C: C: The The inverse inverse relation relation 16 years mortality mortality from from coronary coronary heart heart disease. disease. between fish between fish consumption consumption and and 20 20 years N Engl J Med 1985;312:1205-1224. 1985;312: 1205-1224. 17 Shekelle ShekelleRB, RB, Missell Missell L, L, Paul PaulO, Shryock AM, AM, Stamler J: J: Fish Fish consumption consumption and 17 O, Shryock disease (letter). N Engl J Med 1985;313:820. mortality from coronary heart disease 18 Norell NorellSE, SE,Ahlbom AhlbornA, A,Feychting Feychting M, M, Pedersen Pedersen NL: NL: Fish consumption and mortality 18 disease. Br Br Med J 1986;293:426. 1986;293:426. from coronary heart disease. 19 Vollset VollsetSE, SE,Heuch Heuch1,I,Bjelke Bjelke E: E: Fish consumption and mortality mortality from from coronary heart 19 disease (letter). N Engl J Med 1985;313:820-882. ML,Fehily FehilyAM, AM,Gilbert GilbertJF, JF,Rogers Rogers S, S, Holliday Holliday RM, Sweenam RM, Elwood PC, Pc' BurrML, 20 Burr Deadman NM: NM: Effects Effects of of changes in fat, Deadman fat, fish, fish, and and fibre fibre intakes intakes on on death death and myocardial reinfarction: Diet and reinfarction trial trial (DART). (DART). Lancet Lancet 1989;ií:757-761. 1989;ii: 75 7-761. reinfarction: 21 Wood WoodDA, DA,Butler ButlerS,S,Riemersma RiemersmaRA, RA, Thomson Thomson M, M, Oliver Oliver MF, Fulton M, Birthwhis21 A, Elton R: R: Adipose disease in tie A, tle Adipose tissue tissue and platelet fatty acids and coronary heart disease Lancet Ι984;ii:117-121. 1984;ii: 117-121. Scottish men. Lancet 22 SM: Monounsaturated Monounsaturated fatty fatty acids acids and and cholesterol metabolism: Implications 22 Grundy Grundy SΜ: Nutr1989;1 1989; 119:529-533. for dietary recommendations. JJ Nutr 19:529-533. 23 Grundy GrundySM: SM:Comparison Comparisonofofmonounsaturated monounsaturated fatty fatty acids acids and and carbohydrates carbohydrates for for 23 N Engl J Med 1986;314:745-748. 1986;314:745-748. lowering plasma cholesterol. N A, Grundy Grundy SΜ: SM: Effect Effect of stearic 24 Bonanome BonanomeA, 24 stearic acid acid on plasma cholesterol and lipoprolevels. N N Engl J Med 1988;318:1244-1248. 1988;318: 1244-1248. tein levels. 25 Mensink MensinkRP, RP,Katan KatanMB: MB:Effect Effectofofdietary dietarytrans transfatty fattyacids acidson onhigh-density high-density and and lowlow25 lipoprotein cholesterol cholesterol levels levels in healthy healthy subjects. subjects. N N Engl J Med 1990:323: 1990:323: density lipoprotein 439-445. HuttunenJK: JK:Dietary Dietaryfat fatand andblood bloodpressure. pressure. AAreview. review. Eur Eur Heart Heart 26 Pietinen PietinenP,P,Huttunen 26 I 987;8(suppl B):9-17. J 1987;8(suppl Effectofofdietary dietarylipids lipidson onplatelet plateletfunctions functions and and thrombosis. thrombosis. Ann Ann Med 27 Hornstra Hornstra 27 G:G:Effect 1989;21:55-59. 1989;21:55-59.
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Huttunen
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Dr. Jussi Jussi K. K. Huttunen, National National Public Public Health Health Institute, Dr. Mannerheimintie 166, 166, SF-00300 SF-00300 Helsinki Helsinki (Finland) (Finland) Mannerheimintie
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28 Abraham 28 Abraham R, R, Riemersma Riemersma RA, RA, Wood Wood D, D, Elton Elton R, R, Oliver Oliver MF: MF: Adipose Adipose fatty fatty and serious ventricular ventricular arrhythmias arrhythmias in acute acute myocardial myocardial composition composition and and the the risk risk of serious infarction. Am Am JJ Cardiol Cardiol 1989;63:269-272. 1989;63:269-272. infarction. 29 SteinbergD, D,Witztum WitztumJL: JL:Lipoproteins Lipoproteinsand andatherogenesis. atherogenesis. Current Current concepts. concepts. J Am 29 Steinberg Assoc 1990;264:3047-3052. 1990;264:3047-3052. Med Assoc vitamin 30 Gey GeyKF, KF,Puska PuskaP,P,Jordan JordanP,P,Moser MoserUK: UK: Inverse Inverse correlation correlation between plasma vitamin E ischemic heart disease disease in in cross-cultural cross-cultural epidemiology. epidemiology. Am E and mortality from ischemic Am J lutr 1991 1991;53:326S-334S. Clin Nutr ;53:326S-334S. 31 Viriamo VirtamoJ,J,Huttunen HuttunenJK: JK:Minerals, Minerals,trace traceelements elementsand andcardiovascular cardiovascular disease. disease. An 31 overview. Ann Ann Clin Clin Res Res 1988;20: 1988;20:102-113. overview. 102-113. 32 32 Kok KokF, F, van van Poppel G, Meise Melse J, J, Verheut E, E, Schouter EG, Kruyssen Kruyssen DHCM, Hofman A: antioxidants and polyunsaturated fatty acids have aa combined combined association association A: Do Do antioxidants Atherosclerosis 1991 1991;31:85-90. with coronary atherosclerosis? atherosclerosis? Atherosclerosis ;31 :85-90. 33 33 Gaziano GazianoJM, JM, Manson Manson JE, JE, Ridker Ridker PM, PM, Buring Hennekens CH: CH: Beta carotene Ruring JE, JE, Hennekens therapy for chronic stable angina. Circulation 1990;(sυ 1990;(suppl 82): 111-20 I. ppl 82):111-201.
Dietary Lipids and Coronary Heart Disease Disease Epidemiological Evidence K. Huttunen Jussi Κ. National Public Public Health Institute, Helsinki, Helsinki, Finland National
Introduction Epidemiological, clinical Epidemiological, clinical and and experimental studies have provided strong and consistent evidence that nutritional nutritional factors factors have have an important role in the and important role On several etiology of coronary heart disease in man. Diet has a direct impact on atherosclerosis or mechanisms closely progression of atherosclerosis mechanisms closely linked linked either either to to progression or to precipitation of acute myocardial myocardial infarct infarct or sudden sudden cardiac cardiac death. death. These These precipitation mechanisms include changes in lipoprotein metabolism metabolism and and endothelial endothelial mechanisms include changes in lipoprotein pressure, disturbances disturbances in clotting and function, elevation elevation of blood pressure, function, in blood clotting cardiac platelet aggregability, aggregability, increase platelet increaseinin body body weight, weight, and and induction induction of cardiac Critical dietary dietary components components include include cholesterol, cholesterol, fatty acids and arrhythmias. Critical fiber, alcohol fiber, alcohol and and coffee, coffee, sodium, sodium, potassium potassium and and magnesium, magnesium, and and vitamins trace elements elements with antioxidant properties. and trace This overview overview examines association between between dietary lipids and This examines the the association dietary lipids disease with special emphasis on epidemiological studies. coronary heart disease
The association between the The association betweenintake intakeof of nutrients nutrients and/or and/or foods foods and and the of coronary heart disease has been difficult to demonstrate incidence incidence coronary heart disease has difficult to demonstrate in epidemiological studies difficulties are epidemiological studies within within populations. These difficulties are partially explained measuring human Some of the explained by by inherent inherent problems problems in in measuring human diets. diets. Some problems are illustrate the limitations of problems are briefly briefly outlined outlined here here in in order order to to illustrate dietary epidemiology. The information on dietary habits habits used used in virtually all studies published far covers covers only only a limited limited time time period, period, despite despite the fact fact that that coronary coronary so far
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Methodological Problems
Dietary Lipids and Coronary Heart Disease
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atherosclerosis most exposure over decatherosclerosis most probably probably results results from from cumulative exposure ades. Thus, Thus, in case-control case-control studies, usually available available for ades. studies, data data on diet are usually for a few years diagnosis of cases and for an an equivalent equivalent period period for for few years prior prior to to diagnosis of cases and for controls. In prospective studies information on diet diet has has often often been been collectcollectcontrols. ed only once and no information information was was gathered gathered on changes changes that may have occurred period. Secondly, the methods occurred during during the follow-up follow-up period. Secondly, the methods of dietary dietary many of of the the early early investigations investigations have been inadequate; inadequate; most intake in many most of these studies studies have have used used 24-hour 24-hour recall recall methods, methods, which poor these which provide provide aa poor assessment of all individuals individuals are exposed exposed to dieassessment of habitual habitual intake. intake. Thirdly, Thirdly, all factors and therefore therefore exposures exposures cannot be characterized characterized as present or tary factors as present absent; rather they are continuous variables, often with a limited range of absent; continuous variables, often with variation. Finally, Finally, the effects effects of many many nutrients are are strongly strongly correlated as variation. same food food items. Such Such a multicollinearity renders it they are present in the same difficult to distinguish between spurious associations associations in difficult to distinguish between causal causal and and spurious in the analysis of of epidemiological epidemiological studies. statistical analysis significant association between diet and Failure to observe a statistically significant risk of coronary coronary heart heart disease disease in in epidemiological epidemiological studies studies has has often often been been risk interpreted to mean the absence absence of such such an association. association. In view of the the interpreted to mean In view difficulties described difficulties described above, above, lack lack of of association association should should be be interpreted with caution. It may may result: result: (i) (i) from from insufficient insufficient variation diet; (ii) (ii) lack lack of caution. variation in diet; precision of the method method used used to to measure measure differences; differences; (iii) (iii) measurement measurement of precision after (or (or before) before) the the biologically biologically relevant relevant period period of ofexposure; exposure; (iv) (iv) neganegadiet after confounding, or or (v) (v) from low statistical power of the study. tive confounding,
The pioneering studies of Keys Keys and and his his international international collaborators in the Seven Countries Countries Study Study demonstrated demonstrated aa significant significant association association of dietary dietary Seven of cholesterol cholesterol and saturated fatty acids with mortality from coronary intake of disease at 5, 5, 10 10 and and 15 15 years years after baseline baseline examination in in 16 16 defined defined heart disease populations in seven seven countries countries [1]. [1]. In In another anotherecologic ecologic study study aasignificant significant relationship was was found found between between the percentage percentage of calories 12 relationship calories from from fat fat in 12 countries and and prevalence prevalence of of raised raised atherosclerotic atherosclerotic lesions lesions in in autopsy autopsy cases cases in countries same population population [2]. [2]. These These findings findings are further supported supported by by migrant migrant the same studies [3], [3], parallel trends of coronary heart disease incidence and consumpstudies of saturated saturated fat fat in in several several countries countries [4-6], [4-6], and and decreases decreases in deaths deaths tions of arteriosclerosis during when major reducreducascribed to arteriosclerosis during World World Wars Wars I and II when in total total and and animal animal fat fat consumptions consumptions occurred occurred in in Europe Europe [7]. [7]. tions in
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relationship between fat intake and risk risk of of coronary coronary heart heart disease disease The relationship has been examined in relatively few few prospective cohort studies, and many of of were not primarily primarily designed designed as investigations of of diet and heart disease. them were Morris Morris et al. al. [8] [8] found found aastrong stronginverse inverse association association between between total total energy energy and risk risk of ofcoronary coronary heart heart disease. disease. A A similar similar although although weaker weaker inverse intake and was observed observed with and cereals, cereals, relationship was with consumption of dietary bread and whereas whereas no association association was was observed observed with with percentage percentage of of calories calories from from saturated fat fat or or with with cholesterol. cholesterol. saturated Significant positive associations were observed by Shekelle et al. [9] in Significant follow-up of 1,900 1,900 men men employed employed by by the the Western Western Electric Electric Company Company the follow-up of cardiovascular cardiovascular disease and and the the score score described described by by Keys Keys et al. between risk of dietary intakes intakes of of [[10] 10] for for predicting predicting serum serum cholesterol cholesterolon on the the basis basis of dietary and polyunsaturated polyunsaturated fat, fat, and andcholesterol. cholesterol. Surprisingly, Surprisingly, the intake saturated and of saturated saturated fatty fatty acids acids was was not not significantly significantly associated with risk. risk. Analysis of of follow-up data from the same study suggested that the risk associated 25-year follow-up high dietary dietary intake intake of of cholesterol cholesterol was was partly partly independent independent of of serum serum with high cholesterol [1 [11]. The Ireland-Boston Heart Study reported mortality experi1 ]. The Ireland-Boston Heart Study reported history interview interview 20 20 years years earlier ence of men who had completed a dietary history [[12]. 12]. Individuals Individuals who who subsequently subsequently died of coronary heart disease had a high intake of of saturated saturated fatty fatty acids acids and and cholesterol cholesterol and and aa low intake of ofpolyunsatuintake polyunsatufatty acids acids as as compared compared to to survivors. survivors. Fiber Fiberintake intakewas wassignificantly significantly rated fatty lower among those who died of coronary disease. Three prospective cohort studies (Puerto Rico, Rico, Framingham and Honolulu) included a 24-hour dietary recall in their baseline examinations in 1965 1965 Follow-up analyses analyses revealed between total [13-15]. Follow-up revealed an inverse association between energy intake disease in studies, but a energy intake and and risk risk of coronary coronary heart heart disease in all all three studies, significant positive significant positive association association between between saturated saturated fat and cholesterol intake coronary heart disease disease incidence only in Honolulu. and coronary
The effect effect of of fish fish consumption consumption on on coronary coronary heart disease disease mortality has investigated in several prospective studies. studies. A 50% 50% reduction been investigated reduction in corodisease mortality mortality was was observed observed during a 20-year 20-year follow-up follow-up in a nary heart disease Dutch study study in in men men consuming consuming more more than than 30 30ggof offish fish per perday day[ [16]. High 16]. High intakes fish were were associated associated with rates of coronary coronary heart heart disease disease intakes of fish with low low rates mortality also also in prospective prospective studies studies reported reported by by Shekelle Shekelle et et al. al. [[17] mortality 17] and Norell et al. [[18], 18],but butnot not in in aa third third study conducted among Norwegian men
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[[19]. 19].AAcausal causalassociation associationbetween betweenfish fishintake intakeand and protection protection against against heart disease is supported by a recent controlled trial which resulted 29% disease is supported by recent controlled trial which resulted in in a 29% reduction in coronary coronary heart heart disease disease mortality mortality among among subjects subjects who who were were reduction advised to increase their their fish fish intake [20].
Tissue and Plasma Fatty Acids
The fatty acid acid content content of of plasma plasma lipid lipid fractions, fractions, platelets, platelets, red red cell cell The fatty membranes, and subcutaneous subcutaneous fat membranes, fat has has been been used used as as a marker of fatty acid intake in several several case-control case-control studies and in aa few few prospective prospective studies [21]. [21]. Although the results are not entirely consistent, they do suggest that subjects with low low tissue tissue content content of linoleic linoleic acid acid and omega-3 omega-3 fatty fatty acids acids have have with increased risk coronary heart disease. Interpretation is, increased risk of coronary heart disease. Interpretation of these these data data is, however, difficult observations suggest suggest that smokers smokers consume consume however, difficult as as other observations of linoleic acid compared to nonsmokers nonsmokers [21]. [21]. substantially lower amounts of
classic diet-heart hypothesis hypothesis has largely largely focused effects of The classic focused on the effects cholesterol and saturated and polyunsaturated fatty acids on serum serum dietary cholesterol cholesterol concentration. Epidemiological Epidemiological studies and controlled trials total cholesterol however, that of of the two two main main cholesterol-containing cholesterol-containing lipoprohave shown, however, plasma, low-density low-density lipoprotein lipoprotein (LDL) (LDL) is is atherogenic, whereas whereas highteins in plasma, density lipoprotein lipoprotein (HDL) (HDL) is likely likely to to be be protective. protective. Effects Effects of of different different density categories of dietary fatty acids on the concentrations of serum lipoprotein categories dietary fatty acids of have recently recently been re-evaluated [22-25], and the results results may concentrations have discrepancies in the literature. help to explain some of the discrepancies Although there is overwhelming overwhelming evidence evidence that that saturated fatty acids as a class raise raise serum serum LDL LDL cholesterol cholesterol levels, series of of class levels, most most diets diets contain contain a series saturated fatty fatty acids acids of of different different chain chain lengths, lengths, and these may may not have have saturated and these effects on serum lipoprotein cholesterol cholesterol levels. levels. The two saturated identical effects that have have strongly strongly and consistently raised plasma cholesterol (and fatty acids that presumably LDL cholesterol) concentration are myristic (14:0) and palmitic (16:0) acids. Lauríc Lauric acid acid (12:0) (12:0) also also raises raises serum serum cholesterol, cholesterol, whereas whereas meme(16:0) dium-chain fatty acids (8:0 (8:0 and and 10:0) 10:0) do do not notaffect affect serum serumcholesterol. cholesterol. dium-chain fatty acids Furthermore, recent recent studies studies suggest suggest that stearic stearic acid acid (18:0) (18:0) lowers lowers LDL LDL Furthermore, level, perhaps as it is rapidly converted to to oleic oleic acid acid [24]. [24]. cholesterol level,
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Linoleic acid, polyunsaturated fatty acid acid of of the the Linoleic acid, the principal omega-6 polyunsaturated diet, diet, lowers lowers serum LDL cholesterol, cholesterol, and in high high quantities, quantities, also also the HDL HDL cholesterol level. the same same cholesterol level. The The omega-3 omega-3 polyunsaturated fatty acids have the HDL cholesterol cholesterol as omega-6 polyunsaturates, polyunsaturates, but they they effect on LDL and HDL effect also lower lower the plasma triglyceride concentration. In contrast, oleic oleic acid, the the also predominant monounsaturated monounsaturated fatty the diet, diet, lowers lowers serum serum LDL LDL predominant fatty acid of the HDLcholesterol cholesterol level level cholesterol concentration, but but does does not not influence influence the the HDL cholesterol [22, 23]. 23]. Trans Trans fatty fatty acids, acids, formed formed when when vegetable vegetable and marine oils oils are are [22, and marine HDL cholesterol hydrogenated, may may raise raise the the LDL LDL cholesterol cholesterol and and lower lower the HDL hydrogenated, [25]. levels [25]. risk of of coronary coronary heart heart The relationship relationship between between dietary dietary lipids lipids and and risk of dietary disease is further complicated by the fact fact that quality and quantity of also influence influence platelet aggregation, aggregation, blood fat also blood pressure, pressure, and cardiac arrhythpolyunsaturatedfatty fattyacids acidsmay maylower lower blood blood pressure pressure mias.High Highintake intakeofofpolyunsaturated rias. of [26] and and reduce reduce the the platelet platelet aggregability aggregability [27], [27], whereas whereas high high intakes intakes of [26] saturated fatty fatty acids acids have have had had an an opposite oppositeeffect. effect. Finally, Finally, there there is is evidence evidence saturated that ventricular ventricular arrhythmias arrhythmias can be prevented prevented by high high dietary dietary intakes intakes of experimental animals [28]. [28]. Thus, dietary fat linoleic acid both in man and in experimental probably influences influences the coronary heart heart disease disease through through several several probably the risk risk of coronary independent mechanisms. mechanisms.
ofLDL Experimental studies have suggested that oxidative modification of LDL cultured macrophages macrophages suggest suggest increases its atherogenicity [29]. Studies using cultured LDL must must first first undergo undergo modification modification in some way way to accelerate accelerate its that LDL in some cells to produce the cholesterol cholesterol accumulation seen in foam cells uptake into cells in atherosclerotic atherosclerotic plaques. plaques. Thus, Thus, two two key key factors factors may may be be required required for for the process, i.e. development of the atherosclerotic process, i.e. the presence of LDL and an oxidative process process to to transform transform the the lipoprotein lipoprotein into a potential stimulus for macrophage uptake. uptake. Several Several dietary dietary factors factors may, may, at at least least in in theory, theory, contribute contribute to to or prevent the oxidative modification of ofLDL. LDL. High intakes of selenium, selenium, vitamins vitamins C and E, E, and beta-carotene are likely to be protective, whereas very high high intakes of polyunsaturated fatty acids may be harmful. Indeed, epidemiological harmful. epidemiological studies coronary heart suggest negative correlation suggest aa negative correlation between between the the incidence incidence of coronary disease and levels of vitamin EE [30] [30] or levels of selenium [31] suggesting suggesting that that antioxidant may be relevant relevant to the the human human disease. disease. Interestingly, Interestingly, a antioxidant status status may
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Dietary Antioxidants Antioxidants
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Netherlands suggests suggests that high intakes of ofpolyunsaturecent study from the Netherlands polyunsaturated fatty acids acids are associated associated with high risk of coronary heart disease disease in insufficiently protected [32]. subjects insufficiently protected by by antioxidants antioxidants against peroxidation [32]. Final evidence for the antioxidant hypothesis can be obtained only from controlled studies. fact, preliminary preliminary data from from the the Physicians Physicians Health Health controlled studies. In In fact, suggest that Study suggest that beta-carotene reduces the risk of cardiovascular events in existing coronary coronary heart disease disease [33]. [33]. Several Several studies subjects with existing studies are currently on the the way way to to test test the the efficacy efficacy of beta-carotene beta-carotene and rently and vitamin vitamin E in of coronary heart disease. primary or secondary prevention of Concluding Remarks Concluding Remarks
An extensive body body of of data data supports supports the hypothesis hypothesis that dietary lipids are causal determinant of coronary coronary heart disease disease in man. man. The The mechanisms mechanisms a causal underlying this association are include effects effects on lipoprotein underlying this association are multiple and include pressure regulations, regulations, platelet platelet aggregability aggregability and possibly possibly metabolism, blood pressure The classic classic lipid hypothesis alone fails susceptibility to cardiac arrhythmias. The to explain the differing rates of of coronary coronary heart heart disease disease in in various various populations. populations. New concepts, concepts, particularly particularly the oxidative oxidative modification modification hypothesis, hypothesis, may may New some of of the conflicting conflicting observations. provide explanations for some
KeysA, A, Menotti Menotti A, A, Kanonen Karvonen MJ: MJ: The 15-year death death rate in in the the Seven Seven 1 Keys The diet and 15-year 1986; 124:903-915. Countries Study. Am JJ Epidemiol 1986;124:903-915. MA: Diet Dietand andatherosclerosis. atherosclerosis. Lab Lab Invest Invest 1968;18:6231968; 18:623ScrimshawNS, NS,Guzman GuzmanMA: 2 Scrimshaw 628. RobertsonTL, TL,Kato KatoH, H,Rhoads RhoadsGG, GG, Kagan Kagan A, A, Marmot Marmot M, M, Syre Syme SL, SL, Gordon T, 3 Robertson Belsky JL, S: Epidemiologic studies Worth RM, Belsky JL, Dock Dock DS, DS, Miyanishi Miyanishi M, M, Kawamoto S: of coronary coronary heart disease disease and living in Japan, Hawaii and and stroke stroke in Japanese men living death from from coronary coronary heart heart California: Incidence California: Incidence of of myocardial myocardial infarction infarction and and death disease. Am disease. Am JJ Cardiol 1977;39:239-243. The marked marked decline decline in coronary coronary heart heart disease disease mortality 4 Stamler J: J: The mortality rates rates in in the of findings and possible explanations. Cardiol1968-1982: Summary Summary of United States, 1968-1982: ogy 1985;72:11-22. 1985;72: 11-22. ogy Pyonila K, K, Salonen Salon en JT, Valkonen T: T: Trends in coronary heart disease mortality and 5 Pyorála Cardiology 1985;72:35-51. morbidity and related factors in Finland. Cardiology BeagleholeR: R:Trends Trendsinindietary dietaryfat fat and andcigarette cigarette smoking smoking and the decline JacksonR,R,Beaglehole 6 Jackson disease in New Zealand. Int J Epidemiol 1987;16:377-382. 1987;16:377-382. in coronary heart disease 7 Katz Katz LI, LN, Stamler JS : Experimental Atherosclerosis. Springfield, Springfield, Thomas, 7 Thomas, 1986, pp 24-32.
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