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REVIEW ARTICLE

Coronary heart disease: seven dietary factors

The dietary factors believed to be linked with the incidence of coronary heart disease are reviewed in the light of evidence with regard to their functional role, either in protection or in promotion. Detailed analysis of the evidence shows that the relations are more complex than the current lipid hypothesis suggests. It is proposed that, in particular, the polyunsaturated/saturated ratio as a measure of the propensity of the diet to influence the incidence of coronary heart disease should be replaced by indices of atherogenicity and thrombogenicity.

Coronary heart disease (CHD) is in most instances due to obstruction of coronary vessels by atherosclerosis or thrombosis, singly or in combination. This paper is concerned with the dietary factors that promote or protect against the development of CHD subsequent to the onset of atherosclerosis. The primary cause(s) or initiator of atherosclerosis is unknown, although one hypothesis now receiving attention is that the primary event is free radical damage to cholesterol in circulating low density

lipoproteins. It is possible to recognise seven dietary factors that are implicated in these processes. Two are promoters of the development of CHD--cholesterol-raising (and by inference atherogenic) saturated fatty acids (SFA), and thrombogenic SFA. Five are protective-polyunsaturated fatty acids (PUFA) of the n-6 (linoleic) acid series, PUFA of the n-3 (linolenic) acid series, monounsaturated fatty acids (MUFA), dietary fibre, and antioxidants. While it is customary to consider these factors independently, in most cases the response to these dietary factors will be an integrated one. We do not know whether the effects of the different factors are additive or integrated in a more subtle way, but intuitively one would expect the latter.

Furthermore,

in all

epidemiological

data energy intake

appears as a confounding variable that is difficult to isolate from fat intake. CHD as manifested in myocardial infarction

represents an integration of two, probably distinct, effects of

dietary factors. An index of atherogenicity (IA) and an index of thrombogenicity (IT) are proposed which take into account the effects of the first five of the above factors and allow comparison of different foods and diets. In the light of the above, the results of clinical trials and the soundness of dietary advice can be reconsidered.

Promoting factors In 1956 Sinclair suggested that a deficiency in dietary essential fatty acids (EFA), which is often associated with a high intake of SFA, might be related to the incidence of CHD.1 He later repeatedly emphasised that the processes of atherosclerosis and coronary thrombosis are different: the first does not necessarily lead to the second.2 We have tried to bear this in mind in our paper.

Hypercholesterolaemic fatty acids There is a wealth of epidemiological and experimental evidence indicating that a diet high in SFA is associated with high levels of serum cholesterol which in turn are related to high incidences of CHD, although there are some striking anomalies in the evidence, some of which will be considered later. The raised levels of cholesterol, especially of low density lipoprotein cholesterol (LDL), appear to be important in atheroma, and oxidised LDL is taken up by macrophages and deposited in the plaque; inhibition of LDL oxidation slows the progression of atherosclerotic lesions.3 A first question, however, is: are all SFA equally likely to cause hypercholesterolaemia? The new results that ADDRESSES: 2 Eyot Gardens, London W6 9TN, UK (Prof T. L. V. Ulbricht, DSc); AFRC Institute of Food Research, Norwich Laboratory, Colney Lane, Norwich NR4 7UA, UK (Prof D A. T. Southgate, DSc) Correspondence to Professor Ulbricht.

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emerged since the 1984 report of the Committee on Medical Aspects of Food Policy (COMA) have been discussed elsewherebut the essential points are: firstly, earlier work showing that diets high in C 18:0 (stearic acid) do not raise serum cholesterol (eg, refs 5-7) have been confirmed ;8 secondly, short-chain SFA (C 10 and below) likewise do not raise blood cholesterol, so the putative atherogenic SFA are C 12:0 (lauric), C 14:0 (myristic), and C 16:0 (palmitic), a fact already recognised by Keys in 1965.’ Hegsted6 thought that myristic acid was the most atherogenic, with about four times the cholesterol-raising potential of palmitic acid. The ratio of PUFA to SFA-the P/S ratio-often used as an indicator or measure of whether a diet is atherogenic or promotes CHD, is obviously inappropriate, since only three of the SFA are in fact hypercholesterolaemic. We shall return to this point later because it has important implications for the assessment of diets and dietary guidance. have

Thrombogenic fatty acids The difficulty in drawing firm conclusions about these is that many of the studies have been done in rats and other laboratory animals, or with highly artificial clotting systems, so, as pointed out by one of the investigators, the relevance to clotting in human arteries must be in doubt.9 However, in-vitro studies with human blood and platelets do seem to point in the same direction. Many studies have shown that long-chain SFA accelerate thrombus formation whereas PUFA and MUFA do not,10-13 and that it is the longer-chain SFA (that is, C 14:0, C 16:0 and C 18:0) which are thrombogenic;10 in rats in which platelet aggregation was induced by thrombin, the best correlation (r 0 99) was with the sum of those three SFA." Butter-enriched (but not lard-enriched) diets reduce the production of arterial prostacylin, a prostaglandin that is a strong antagonist of platelet aggregation.14 Eicosatrienoic acid is the C 20:3 metabolic product of the n-9 (oleic) acid series which accumulates in atherosclerotic patients and in animals that are deficient in EFA or have been fed with SFA. Addition of this acid simultaneously with the aggregating agents greatly potentiates platelet aggregation,11,15 and it is the only fatty acid in platelet phospholipids whose concentration is related to the clotting activity of platelets and their response to thrombin-induced =

aggregation. Sinclair’s original hypothesis has often been simplified as follows:

Sinclair rejected this; the processes of atherosclerosis and of coronary thrombosis are different. The SFA which are thrombogenic are not quite the same as those which are atherogenic. Although Hornstra16 regarded the P/S ratio as an important determinant of thrombogenicity, we do not believe it to be a satisfactory measure, especially since different unsaturated fatty acids protect to different degrees against atheroma and against thrombosis (see

below). Protective factors PUFA of the n-6 series The n-6

fatty acids, whose parent member, linoleic acid, is commonly found in vegetable seeds oils, have long been

known to reduce serum cholesterol and it has therefore been widely recommended that SFA in the diet should be partly replaced by n-6 PUFA; such dietary changes have been a feature of clinical trials. However, diets high in these

depress high-density lipoprotein (HDL), which is protective against CHD, as well as lowering LDL.17-19 Crouse2o has pointed out that high LDL concentrations are PUFA

risk factor in women, whereas low concentrations of HDL are, therefore diets that reduce both types of lipoprotein will not benefit women. CHD has declined in the USA and other countries as dairy products in the diet (especially butter with its very low content of linoleic acid) have been replaced increasingly by fats high in linoleic acid. Moreover, low levels of adipose tissue linoleic acid (a reflection of long-term intake) are related to CHD incidence and mortality.21 Thus one may conclude that a modest increase in the intake of n-6 fatty acids is likely to be beneficial in protecting against atheroma. (Risks of diets high in PUFA will be considered later.) What about thrombosis? In considering the evidence, one has to bear in mind that there are three series of prostanoids (fig 1) derived from three different PUFA-namely, from dihomogammalinolenic acid (DHLA), from arachidonic acid (AA), and from eicosapentaenoic acid (EPA). DHLA and AA are metabolites of linoleic acid, formed quite slowly. In a normally functioning healthy body it is clear that vasodilatation has to prevail over vasoconstriction, and that adhesion to the arterial wall and platelet aggregation are to be prevented. PGE,, which is formed from DHLA, has antiaggregating activity, and the fact that unstimulated platelets contain more PGEt than PGE222 indicates that the prostanoids of the first series are predominant. In this situation of normal functioning, the prostanoids seem to be formed from a metabolic pool derived from EFA in the diet, whereas during injury they derive from a different pool, the membrane phospholipids from which they are released by phospholipase.23 The principal fatty acid released in response to injury is AA, from which both the thromboxane TXA2, which strongly aggregates platelets, and also prostacyclin, PGIz, the potent antagonist of platelet aggregation, are formed.24 Since PG 12 is synthesised only by arterial endothelium and PGEt from the small amount of its precursor available, the large amount of phosphoglyceride AA released by phospholipase as a result of injury is mainly converted to TXA2 and PGE2 (which does not act on arterioles or platelets), leading to clotting. Many studies indicate that long-chain unsaturated fatty acids slow down intra-arterial occlusion and platelet aggregation.10-13 Dienoic and trienoic PUFA are more antithrombotic than MUFA, and the ability of fatty acids to inhibit platelet aggregation is inversely correlated with their melting-points (hence SFA < MUFA < PUFA in not a

KEY TO ABBREVIATIONS

AA = arachidonic acid CH D =coronary heart disease

DHLA = dihomogammalinolenic acid EFA = essential fatty acids EPA= eicosapentaenoic acid HDL= high-density lipoprotein cholesterol IA = Index of atherogenicity IT= index of thrombogenicity LD L = low density lipoprotein cholesterol M U FA = monou nsatu rated fatty acids PG prostaglandins PUFA polyunsaturated fatty acids SFA = saturated fatty acids =

=

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Fig 1-Prostanoids formed from different fatty acids.

inhibitory activity). This inhibitory effect of cis-PUFA

on

platelet activation is therefore related to an increase in the fluidity of platelet membranes. It has been suggested that diets which have a relatively high content of SFA or a high ratio of n-6 to n-3 PUFA facilitate the production of TXA, and inhibit production of PGI2, thereby increasing the risk of thrombosis zs Trans-PUFA, in contrast to cis-PUFA, are said to increase (rather than inhibit) the aggregation of platelets by thrombin.26 PUFA of the n-3 series

Alpha-linolenic acid, C18:3, is the principal PUFA that occurs in the green tissue of plants. In animals (x-linolenic acid is converted to a series of longer-chain PUFA of which the most important are EPA, C20:5, already mentioned as the precursor of the series three prostanoids, and docosahexaenoic acid (DHA), C22:6 (fig 1). These fatty acids therefore occur in meat, though in ruminants the amounts are diminished by hydrogenation in the rumen and will also depend on the relative proportions of forage and other feedstuffs in their diets. Alpha-linolenic acid occurs in phytoplankton, and EPA and DHA therefore are found in fish; the only concentrated edible sources of these PUFA are oily fish and the oils derived from them. There has lately been a great upsurge of interest in these PUFA.27,28 Early reports indicated that diets containing fish oil lowered LDL and total serum cholesterol but not HDL; it now appears that total cholesterol is reduced only if initial levels are high, by depression of LDL; HDL is increased and triglycerides decline.29 In fact depression of LDL concentrations is due to a reduction in very-low-density lipoprotein (VLDL) and this in turn may be due to a reduction in the rate of synthesis of apolipoprotein B (apo B). Apo B (a principal component of LDL) may be the main influence on atherogenesis, whereas high levels of apo(a), a genetic trait, increase the likelihood of thrombosis on the resulting atheromatous plaque.10 Thus, the n-3 PUFA are antiatherogenic but act differently from the n-6 acids. PUFA also differ in their antithrombogenic activity, which is most pronounced in the n-3 series, especially EPA and DHA. These two acids are particularly effective in inhibiting platelet aggregation31 and act by inhibiting the conversion of arachidonic acid to the prostanoid thromboxane (TXA2) by platelets.32 A diet high in n-3 PUFA will also facilitate the production of the prostanoid PGI3, a potent inhibitor of platelet aggregation, whereas the corresponding thromboxane TXA3is a very weak platelet aggregator-hence the prediction27 that a high fish diet will lead to antithrombotic changes in prostanoids. Similarly, it has been concluded that the clotting activity of platelets and their aggregation to a thrombus is closely related to the intake of long-chain SFA and that the principal effect of increasing the intake of n-6 PUFA is antiatherogenic (reduction of serum lipids), whereas that of n-3 PUFA is

of platelet activity).13 These different effects of the different PUFA emerge clearly from

antithrombogenic (reduction the

study in which Danes (high incidence of CHD) were compared with Greenland Eskimos (very low incidence). The linoleic acid content of the food of the Eskimos was half that of the Danes, and the linoleic acid content of the platelets of the Eskimos less than half that of the Danes.33 However, the Eskimos consumed nearly five times as much n-3 PUFA and nearly twice as much monounsaturated fatty acid (MUFA) as the Danes. These facts have a considerable bearing on the interpretation of clinical trial results (see

below). Fish oils also lead to a reduction in fibrinogen,29 which is the association between plasma

noteworthy in view of fibrinogen and CHD. 34 MUFA

A 1957 paper reporting that olive oil lowers serum cholesterol35 was followed by a hiatus of almost 30 years in which MUFA and their influence on CHD were neglected. We now know that diets high in MUFA are as effective as those rich in PUFA in lowering serum cholesterol but, in contrast to the effect of n-6 PUFA, MUFA do not lower HDL.18,19,36,37 In the later analysis and discussion of the Seven Countries Study, Keys et al noted that there was a negative correlation between MUFA consumption (and also the MUFA/SFA ratio) and death rate, and that the all-cause and CHD death rates were lowest in cohorts with olive oil as the main fat.38 The cohorts who dwelt in rural areas fell into two groups-five in the Mediterranean, where olive oil provided 15-30 % of dietary energy, and four others (Finland, Yugoslavia) with a very different diet, consuming milk, drinking beer and spirits in place of wine, and eating less fruit and vegetables. The standardised death rate from CHD was more than twice as great in the second group, and the non-CHD death rate was also higher. There were no data on fish consumption. In rabbits fed with a high-oleic sunflower oil, the LDL became enriched in oleic acid and highly resistant to oxidation. The results suggest that diets sufficiently rich in oleic acid, in addition to their LDLlowering effect, may slow the progression of atherosclerosis by generating LDL which is resistant to oxidation, reduces consumption of antioxidants, and thus makes antioxidants more effective.3 The antithrombogenic activity of MUFA has been studied much less than that of PUFA. In some systems MUFA inhibit platelet aggregation, though less so than PUFA. 12,24 Oleic acid is the only MUFA that has been investigated so far. A comparison of diets containing 10% dietary energy from oleic acid, trans isomers of oleic, or SFA, showed that the trans isomers raised LDL and lowered HDL, whereas SFA raised LDL but did not lower HDL. The LDL/HDL ratio was highest in the diet containing trans oleic.39

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TABLE I-INDICES OF ATHEROGENICITY AND INDICES OF THROMBOGENICITY FOR SOME FOODS AND DIETS

All data from ref 46 unless otherwise stated b Data from Prof M. Crawford. c. Ref 33. d Ref 47. e. Later data show a small reduction (Dr D H Buss, unpublished) f. Because the equation includesthe ratio (n-6)/n-3),theva!uesof!T(untiketA)wi!! be affected by the units chosen The values shown are those obtained by using the data in the form given by ref 46, ie, g per 100 g.

elements (selenium, copper, manganese, and zinc). The second is by means of antioxidants, especially vitamins C and E, and carotenoids, which quench the reactive oxygen species, singlet oxygen. The beneficial effect may be linked to protection of LDL cholesterol against oxidation. The role of oxidants and antioxidants in cardiovascular disease has lately been reviewed by Duthie et al.’ Clinical trials suggest that vitamin E reduces platelet aggregability, and the strong association between low serum selenium and platelet aggregability indicates that antioxidants may be important in the regulation of platelet function.45 In the light of the experimental studies, it may be possible to resolve some of the anomalies in the epidemiological data on CHD incidence. Thus, the Mediterranean populations who have a low incidence of CHD have a high intake of fruit and vegetables (as well as of olive oil, garlic, wine, and probably fibre). The further north one goes in Europe, the lower, in general, the consumption of fruit and vegetables (the sources of the antioxidants as well as important sources of trace minerals) and the higher the incidence of CHD. The same pattern is evident in the UK, with the highest incidence of CHD in Northern Ireland and Scotland, and a higher incidence also in the lower socioeconomic classes, who consume less fruit and vegetables. These differences correlate poorly or not at all with serum cholesterol concentrations.

a.

Dietary fibre The finding that men consuming large amounts of bread and other cereal products had a low CHD rate40 has never been satisfactorily explained. The study had well-defined data based on the seven-day weighed intake technique. The effect appeared to be of the whole grain cereal fibre, with a faecal bulking rather than a cholesterol lowering effect. Oat gum reduces the uptake of cholesterol in the rat,41 and oat bran lowers LDL in hypercholesterolaemic men.42 The evidence from human studies is, however, conflicting-partly because alteration of the fibre content of the diet invariably produces other changes in dietary composition which confound the statistical interpretation. Detailed study of the published work on the effects of oats suggests that the effects are more evident where the subjects have an initially raised cholesterol.43 The dietary fibre hypothesis related to the protective effects of diets rich in foods containing plant cell walls,43 and we must not forget that these diets have other attributes that are consequential on the types of foods that provide dietary fibre. In assessing the validity of the dietary fibre hypothesis in relation to protection from CHD, we must distinguish between the effects of diets rich in dietary fibre because of different dietary constituents (eg, more vegetables) and diets containing dietary fibre as an added ingredient. Antioxidants

Living organisms have two principal means of protecting themselves from the potentially injurious effects of free radicals-eg, lipid peroxidation and the formation of lipid peroxides. One is via enzymes such as glutathione peroxidase and catalase which contain specific trace

Characterising diets in relation to CHD These arguments show that characterisation of diets in of their total fat content, their saturated fat content, their P/S ratio, the proportion of energy from fat, or their PUFA n-3 or n-6 content alone can lead to misleadingly naive statements about diets and to simplistic dietary advice. "The ratio of P to S fails to recognise the multiple and different effects of n-6 and n-3 PUFAs", as Kinsella 25 has written. Ideally some multidimensional integration of all the dietary, environmental, and possibly individual personal risk factors will be developed. Meanwhile it is possible to suggest more rational indices on the basis of the information we already have. We proceeded on an iterative basis, making successive modifications to the P/S ratio to take account of the available evidence, and then seeing whether the resulting values were in accord with it. terms

Index of atherognicity As

pointed out earlier, the P/S ratio is not a suitable atherogenicity or thrombogenicity of a diet or of foods. To arrive at an Index of Atherogenicity (IA) we began by inverting the P/S ratio, so that the IA would be highest for the most atherogenic dietary components. The lower-chain-length SFA and stearic acid should be omitted from "S", for reasons previously stated, and "P" should be was

measure of the

widened becomes:

to

include the MUFA. The ratio therefore

where S’ = C 12:0, S" = C 14:0 and S’" = C 16:0, P =sumof n-6 and n-3 PUFA; M = oleic acid (C 18:1); and M’ = sum of other MUFA. a-f are empirical constants; b has been set at 4, for reasons already given, and a, c, d, e, and f have been provisonally set at unity, since we have no firm evidence to assign other values. The results are shown in table 1. Why have we been so conservative and not modified the ratio more radically? In fact, the figures that have emerged make reasonable sense, especially compared with those from

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the simple S/P ratio (table n), which excludes MUFA and assumes that all SFA are equivalent. If S/P were a correct measure of atherogenicity, then fish would be more antiatherogenic than olive oil and sunflower oil very much more antiatherogenic than olive oil, neither of which is the

TABLE II-EFFECTS OF MODIFYING THE CALCULATION OF SATURATED TO POLYUNSATURATED RATIOS I

I

-

case.

We did explore some other mathematical manipulations. The most promising and therefore the one explored in most detail was S - P and 2S - P (with various modifications of both S and P) in place of S/P. However, because of the wide variation in the fatty acid composition of foods we concluded that a ratio worked better, as well as making a comparison with the simple S/P ratio more meaningful. In table I the value of IA for the British diet is near unity and one can readily see that increasing the consumption of dairy products would make the diet more atherogenic; eating more palm oil or lamb would have little effect; eating more of other meats or hard margarine would reduce it; eating more PUFA margarine or fish would reduce it more, and sunflower and olive oil would reduce the atherogenicity of our diet most of all. The most obvious possible errors in the proposed index are:

1. If there is confirmation of the work showing that in man stearic acid acts like oleic acid in reducing LDL,8 then stearic acid should appear in the denominator. 2. The PUFA have been weighted equally, but this can hardly be correct. Although n-6 PUFA are more antiatherogenic than the n-3 PUFA, there is also a difference between the parent members of the two series, linoleic acid and linolenic acid, and their longer chain homologues, such as AA, EPA, and DHA, which occur in meat or fish. The parent compounds are poorly converted in man whereas their homologues are much more efficiently utilised. It is probable, therefore, that the values in table I exaggerate the beneficial effects of unsaturated vegetable oils and margarines compared with meat and fish. 3. No allowance has been made for the effects of trans fatty acids because of conflicting evidence.

Index of thrombogenicity To arrive at this index we again began with S/P, restricted "S" to C 14, 16, and 18 for reasons previously given, and widened "P" to include MUFA. The simple S/P ratio, which assumes that all SFA and all PUFA are equivalent to each other, would suggest (see table 11) that sunflower oil, followed by PUFA margarine, would be the most antithrombogenic foods-significantly more so than fish, which is definitely not so. (We therefore do not agree with the view that the P/S ratio is a major determinant of arterial thrombosis tendency,16 at least in man.) The modified ratio shown in the second column of table II is also unsatisfactory. Palm oil appears to be almost as antithrombogenic as fish, ox liver the most thrombogenic meat, and vegetable oils and PUFA margarine more antithrombogenic than fish. This showed us that it was necessary to weight the n-3 PUFA in this formula. The Index of Thrombogenicity (IT) we propose is:

because MUFA and n-6 PUFA are less antiatherogenic than n-3 PUFA; q has been assigned the value 3. The proposed ratio is tentative and will certainly require modification in the light of further evidence, especially in the assessment of the values of the constants. The denominator has been so devised as to give fish the lowest IT values. A point that no one seems to have commented on is that fish contain high amounts of other MUFA in addition to oleic acid. Raw mackerel, for example, contains (g per 100 g fish) 3-69 n-3, 0 38 n-6, 2-70 oleic acid, and 3-58 of other MUFA.’ No other foods contain anything like such amounts of other MUFA relative to other fatty acids. Perhaps these MUFA have an important role, but at present we do not know. Again, we have not allowed for the possible effects of trans fatty acids. We see from table I that the Eskimo diet differs from the Danish and British diets even more when measured by IT than when measured by IA. Examining the IT values in relation to that for the British diet, we see that dairy products are the most thrombogenic component of the diet, followed by palm oil and then most meats. Fish are the most antithrombogenic, followed by olive and sunflower oil. Other mathematical manipulations were explored, but none yielded figures that looked as meaningful as the IT values in table 1. A weakness of all these figures is that they are based on out-of date analytical data. Some foods have changed in composition (beef, and especially pork, have become leaner) and at the time the main data were compiled46 long-chain PUFA could not be clearly separated from each other. Table I includes one set of duplicate figures, for roast lean topside. The old and recent data give similar values for IA, but for IT the recent analysis gives a much lower figure (079 versus 106), indicating that lean meat is an important source of long-chain PUFA.

Intervention where Siv = sum of C 14:0, C 16:0, and C 18:0; n-6 = n-6 PUFA ; n-3 n-3 PUFA. M and M’ are as before, and m, n, o, p, and q are empirical (unknown) constants. m has been set at unity; n, o, and p have been assigned the value 0-5 =

Clinical trials The results of clinical trials of cholesterol-lowering drugs, and of trials in which a control diet has been compared with

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with n-6 PUFA content and very high P/S ratio, have been disappointing to those who believe that merely lowering serum cholesterol should decrease CHD incidence. It follows from our analysis that such regimens will only slow down or arrest the further development of atheroma. Ornish et all saw regression of coronary arterial lesions on a very low fat diet (6-8% of dietary energy). The experimental diets (eg, ref 49) used in clinical trials have also been less thrombogenic, but the change made was entirely by the partial replacement of SFA by n-6 PUFA. In the only trial that showed a clear reduction in deaths from CHD the effective diet contained oily fish or fish oils"—evidence that the n-3 PUFA are indeed effective in reducing thrombosis. Several investigations have shown that people who regularly consume fish have CHD rates less than those who do not (eg, ref 51). The fall in mortality from CHD in wartime Norway52 and the increase after the war closely paralleled the decline and subsequent rise in the consumption of fat from butter, milk, cheese, and eggs (ie, SFA) while the consumption of fish (n-3 PUFA), cereals (dietary fibre), potatoes, and vegetables (antioxidants) rose during the war and later again fell.

one

Risks from

high

PUFA diets

PUFA are very liable to peroxidation and we therefore have the paradox that diets high in PUFA may actually be dangerous in initiating CHD or cancer. As regards the latter, the fear that cholesterol-lowering diets increase the risk of cancer do not seem to be justified ; a meta-analysis of six primary prevention trials did not indicate a correlation between reduction of serum cholesterol and cancer.53 We should note, however, that despite the extraordinary diversity of diets that exist in the world, there are no populations consuming high quantities of n-6 PUFA such as have been used in some clinical trials, and we therefore have no knowledge of the long-term consequences of these diets. Reviewing the disappointing results of clinical trials, Renaud concluded that high P/S values (over 1-0) would probably increase platelet reactivity to ADP. We know from the Eskimos that a diet very high in n-3 PUFA leads to a tendency to bleed easily and to a higher incidence of strokes, but this would certainly not be expected from the moderate amounts of oily fish consumed in the Diet and Reinfarction Trial. 50 Wahle and co-workers26,44 have pointed out that the availability of EFA to the body may be affected not only by high dietary levels of SFA but also by lack of adequate antioxidant protection in situ, leading to their peroxidative catabolism and the production of cytotoxic derivatives. A deleterious effect of processing is the removal of the natural antioxidant tocopherols from the unsaturated vegetable oils, and we do not know whether their synthetic replacements (eg, butylated hydroxytoluene) are as effective in protecting EFA from lipid peroxidation in vivo.

Dietary advice Eat less fat As already noted by Keys, the correlation of total fat consumption (as a percentage of dietary energy) with serum cholesterol concentrations and CHD incidence is very weak. In the past 25 years during which CHD incidence has fallen steadily in the US (by 50% in all), the total intake of dietary fat has hardly changed.55 In all these international studies it is important to recognise that many estimates are based on movement of food supplies into consumption-ie, food

Fig 2-intake

of red carcass total meat in and deaths from coronary heart disease.

European countries

. Meats from beef, lamb and goat; Ototal meat consumption. Male deaths age standardised mortality rates per 100 000. Source, ref 64

disappearance data. These are therefore overestimates of actual food ingestion, sometimes by as much as 25%. Fat intake is amongst the most difficult of all major components to estimate, because of the use of fat as a cooking medium and because of the wide variations in the lean/fat ratio in meats at carcass, primal joint, retail cut, and individual ingestion level. There is a low incidence of CHD in Mediterranean countries where fat consumption is high ’16 as well as amongst the Eskimos. There is no evidence of a relation between total fat consumption and CHD incidence, and advice to eat less fat is almost certainly counterproductive since it is very difficult to follow. 57 One could argue that, as far as CHD is concerned, advice to eat less fat should be restricted to individuals in whom it is meaningful (eg, to those who are hyperlipidaemic or obese). Eat less meat or eat less red meat

Dairy products provide 42-5% of the SFA and 8-1% of diet, and meat and meat products

the PUFA in the British

provide25-4% of the SFAand 17-4% of the PUF A. 58 If one is seeking to reduce consumption of SFA, it is natural to look first at these items. Simons59 used OECD statistics to relate the consumption of different foodstuffs to mortality from ischaemic heart disease in nineteen countries. Consumption of dairy fat (excluding cheese) was closely related to IHD mortality (r=0’78). Dairy products are both atherogenic and thrombogenic. Meat is an important source of PUFA, mainly in the form of the readily utilised longer-chain homologues mentioned earlier. Hence one finds sizeable differences between the values of IA and IT for dairy products and meats. Is there any relation betwe meat-eating and CHD incidence? During the years of dc .ning CHD incidence in the USA there has been little change in meat consumption, though butter consumption fell to one-half between 195759 and 1984, and the direct use of beef fat and its indirect use in shortenings and in margarine increased. 55 Fig 2 shows a plot of the consumption of meat and of red meat in EC countries against CHD incidence. No relation is discernible. The UK had the second lowest meat consumption and the second highest CHD incidence; Greece, with the highest red meat consumption, had one of the lowest rates of CHD.

991

More than 30 years ago Mahnros and Wigand35 noted that the lower level of serum cholesterol obtained on a diet containing corn oil was unaffected by the addition of 100 g of lean meat per day. More recently, a comparison has been made between isocaloric diets all containing 35% dietary energy from fat, with 60% of the fat being coconut oil (high in SFA), safflower oil (high in n-6 PUFA), or beef fat (MUFA > SFA > PUFA). The plasma total cholesterol and LDL concentrations in subjects taking the beef fat diet were intermediate between the levels on coconut oil (on which they were higher) and safflower oil (on which they were lower).60 Diets including 180 g of lean meat per day which had less energy from fat and a much higher P/S ratio were effective in lowering plasma total cholesterol, and LDL in particular .61 What dietary advice

can

be given?

A modest increase in the consumption of both n-6 and n-3 PUFA so that the P/S ratio reaches a value of 0-5-0-7 (the value in Mediterranean countries) and an increase in the consumption of MUFA, coupled with a corresponding decrease in the consumption of SFA, can be recommended. Such a change is most readily achieved by replacing butter and hard margarine by a PUFA margarine, replacing full fat milk by semi-skimmed or skimmed milk, eating more fish (especially oily fish) and lean meat, and eating more fibre-rich foods, fresh fruit, and vegetables (which also provide antioxidants). Those who can afford it can use more olive oil. (Why is there no high-oleic soft margarine on the British market? High-oleic varieties of safflower and sunflower oil do exist.) We do not yet know the best n-6/n-3 ratio; in the Japanese diet the ratio is 4/ 1. Thorogood et a15’ recently noted that health conscious individuals select a fat-modified rather than a low-fat diet, with a reduction in saturated fatty acids compensated by an increase in unsaturated fats. "It appears that individuals can choose a diet whose total fat and total carbohydrate are similar to that of the general population but where a greater percentage of that fat is PUFA and there is a higher intake of fibre. This diet may prove to be more acceptable than a low fat, high carbohydrate diet and will increase compliance with dietary advice".

Conclusions and suggestions for research We have focused on seven dietary factors in this paper but claiming that these will turn out to be the only ones that are important. Some readers would doubtless wish dietary cholesterol to be included although the evidence for its importance seems weak. 58 Sinclair, who so often turned out to be right, believed to the end that trans FA acted like SFA. It is strange, to say the least, that we do not possess accurate analytical figures on the FA content of our foods; in particular, we do not really know the contents of the long-chain n-6 and n-3 PUFAs or of the trans isomers of the different unsaturated fatty acids. An "anomalous" result that provides food for thought is the Scottish study.b2 This found no correlation between total cholesterol concentrations and standardised mortality ratios (SMR) in two suburbs of Dundee. In Eastwood (middle class) and Monklands (working class) the cholesterol levels were the same, but the SMR were 51 and 136, respectively. (There were more smokers in the Monklands population, but with regard to smoking and CHD there are anomalies also. Japanese men smoke more cigarettes than any other population group, yet have a very low incidence of CHD and are not

the

highest male life expectancy in the world. cigarette consumption is also very high.) The

In Greece latest data

from the WHO-MONICA survey showed no correlation between ischaemic heart disease (IHD) and serum cholesterol in populations with concentrations in the average range of 57-6-2 mmol/l. The best correlation was with vitamin E; and lipid-standardised vitamins E and A, serum cholesterol, and diastolic blood pressure explained 87% of the IHD incidence.63 These results suggest that antioxidants in the diet may be much more important than we thought. Are the differences between Eastwood and Monklands due to a lifetime’s difference in fruit and

vegetable consumption? Of the seven dietary factors discussed, the evidence for an effect on CHD is weakest for fibre, though this element too is probably antiatherogenic. (There is no evidence that it is antithrombogenic, hence it would not influence the outcome of a clinical trial, as indeed was found to be the case. 50) Regarding the others, it is important to bear in mind that some, by their very nature, are slow acting and take decades to have an effect. Were it possible to make a diet less atherogenic without making it less thrombogenic, then eventually CHD incidence would fall. Hence, in considering the unsatisfactory results of the clinical trials that have aimed at cutting CHD incidence by reducing serum cholesterol, we should remember that they were conducted with middle-aged men and that dietary advice of the kind suggested above would, if followed from childhood, be expected to lead to a substantial reduction in CHD incidence. To have an impact on those already middle-aged, only the n-3 PUFA seem sufficiently antithrombogenic. We suggest that any future clinical trials should be aimed not at reducing total fat intake (unless it is over 40% of dietary energy) but at reducing SFA and increasing MUFA and both series of PUFA. The IA and IT of the two diets should be determined, so that the data can be used to test and improve the indices.

Future directions and the formulations of dietary advice One clear conclusion that emerges from this analysis is that the incidence of CHD cannot be related to any single attribute of the diet. The incidence of any chronic disease is an integration of dietary, environmental, and populationspecific risk factors. CHD has some special features, primarily because it involves two types of pathological effects-atheroma, which is in all probability related to long-term effects of diet (and probably other factors); and thrombogenesis, which seems to be related to short-term dietary factors and to be influenced very strongly by hormonal responses to external events affecting the lifestyle of the individuals within the population. The incidence is thus determined in a multidimensional way in which one of the dimensions is time. Future research, unless it recognises these factors, will continue to produce conflicting evidence from epidemiological studies. The from translation of conclusions such multidimensional analysis (should it ever become possible) into advice for the consumer on reducing chronic disease risk will always require simplification. Such simplification, however, must be compatible with the evidence that exists and must be presented in a way that the consumer can understand. Research is therefore also needed on how the advice should be presented. This paper is dedicated

to

the memory of Hugh Sinclair.

992

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