Review

High blood cholesterol levels are one of the major control- lable risk factors for cardiovascular disease. Reducing dietary fat intake or increasing dietary fiber intake can decrease

blood cholesterol levels and, hence, susceptibility to cardio-

vascular disease. Reducing dietary cholesterol intake will also influence blood cholesterol levels, but not as effectively as

reducing fat intake. However, dietary modification alone is not sufficient for all people. Nor are optimum dietary choles- terol levels a simple matter of 'the lower the better'; extremely low blood cholesterol levels also appear to be harmful.

Whether and how best to lower blood cholesterol levels re-

mains a subject of intense discussion.

Cardiovascular disease has been characterized as a "life style' disease, meaning a disease of multiple etiology. There is no unequivocal test for an impending bean at- tack (see Glossary) but there are a number of indicators of increased risk. These indicators are designated as risk factors and offer a statistical diagnosis by indicating the odds of a heart attack. The major risk factors, at the time of writing, are male gender, obesity, cigarette smok- ing, hypertension and hypercholesternlemia. The role of hypertriglyceridemia has fluctuated between risk factor and non-risk factor status and opinion is again begin- ning to lean towards it being a risk factor. All of the major risk factors together account for only half to two thirds of risk. Hopkins and Williams ~ identified 246 risk factors for cardiovascular disease. Family history of cardiovascular disease and gender are beyond medical control. The other risks are amenable to medical or behavioral alteration.

In approaching hypercholesternlemia we must bear in mind that it is only one of an array of risk factors but it has achieved singular public regard and is treated as if it, and it alone, was the culprit. Cholesterol in the plasma is transported as a component of a protein-lipid continuum whose fractions are identified by their hydrated densities and their protein (apolipoprotein) components. The principal lipoproteins of concern are the low-density lipoproteins (LDL), which carry most of the blood's cholesterol and are popularly characterized as the 'bad cholesterol', and the high-density lipopro- reins (HDL), which are 50% protein and are thought to be the "good cholesterol'. Since the lipoproteins are characterized primarily by their hydrated densities it stands to reason that they may vary in size and compo- sition. Indeed, molecular size affects the ease with which LDL may enter the arterial wall'-. When LDL subclass patterns of plasma from 109 people with cardiovascular disease and 121 people free of cardiovascular disease were analyzed, subjects exhibiting small, dense LDL particles were a( a threefold increased risk of being

David Kritchevsky is at The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268, USA.

The rationale behind the use of diet and dietary

ingredients to lower blood cholesterol levels

David Kritchevsky

among those who had suffered from a heart attack. The increase in risk was independent of age, gender or rela- tive body weight. The apolipoproteins offer the oppor- tunity for genetic characterization of risk status. Apo- lipoprotein B is the sole apoprotein associated with LDL and presents yet another basis for diagnosis and risk assessment. Apolipoprotein E phenotype now offers a new insight into susceptibility and potential response to treatmenP.

Cholesterol is a component of every cell and a pre- cursor of vital substances like corticosteroids, bile acids and sex hormones. Generally cholesterol comprises ~0.2% of body weight with most of it being found in muscle, brain and spinal cord. Cholesterol is syn- thesized by most tissues and normally we synthesize and degrade more than we ingest. In as~ssing the influ- ences of diet on blood cholesterol levels we must recog- nize their potential lability. Cholesterol levels fluctuate seasonally in most individuals, generally being high in

i Glossary

I Atherogenic: Tending to cause a disorder of the walls of arteries characteristic of atherosclerosis.

Atherosclerosis: Coexisting atheroma and arteriosclerosis. Atheroma are raised 'plaques' of fibrous tissue and other material (including calcium desposits in advanced cases) Ihat form in ', the arterial wall. These may rupture; the released contents may then block or partially block the artery, as well as causing the formation of bloc~l clots. In the coronary artery, which supplies blood to the heart, such blockage can lead to a heart atlaS. ,~eriosclerosis is commonly referred to as 'hardening of the artl~es', i

Cardiovascular disease: Disease of the vessels supplying blood to the heart.

Cohort: A group of individuals having experienced an event in common during the same time period (e.g. suffered a heart attack), which is often the object of long-term investigation,

i usually up to the death of the last surviving member. E ', Heart altack: Sudden disorder of the heart, usually causing r damage to its contractile, muscular layer (the myocardiumL This [ damage results from a sudden loss of blood tlow to the area. often ! du~ to the blockage of local blood vessels by a blood clot.

Trends in Food Science & Technology July t 994 IVoL 51 ,~1~,~4. El~.er S~,,,n,e Ud 0q:4 -224.'~4S., ,~ 21

January and low in June. Blood cholesterol levels rise in response to stress but the cause of other observed fluctu- ations is unknown. The subject has been reviewed at length 4.s, and the phenomenon is real even if the etiology i~ unclear. There are also vagaries of methodology but they wiil not be touched upon in this discussion. Thus, we must understatid that single analyses are not a suf- ficient basis for risk assessment. It is true that a single reading above 300 mg/dl (7.76 rrml) is cause for alarm but in the borderline risk area caution is advised. A study of 177 men over a 5-year period revealed that most of them showed serum cholesterol fluctuations of 20-30% (Ref. 6). Interestingly there were 16 heart attacks in that group and all occurred in men whose cholesterol levels had fluctuated by 50% or more.

Much of the experimental literature on atheroselerosis is based on experiments in which susceptible animals (rabbits, chickens, pigeons, pigs and some monkey species) were fed cholesterol. Thus it appeared logical to focus initial attention in humans on cholesterol feed- ing. Dietary cholesterol has little or t~o effect on blood cholesterol levels in dogs and rats unless they are ren- dered hypothyroid either surgically or chemically.

Dietary cholesterol and serum cholesterol The literature abounds with studies in which choles-

terol feeding (usually in the form of eggs) does or does not raise blood cholesterol levels. There is a tendency for different reviewers to choose exmnples from the literature that fit their own scientific bias. In 1950 Gertler e t a l . 7 studied two cohorts of 40 men; one group with cardiovascular disease and one free from it. Each cohort of 40 was broken down into four groups of ten men each. The subgroups represented the men who had the highest or lowest cholesterol levels or the men who ate the most or least cholesterol. In every case the sub- group with cardiovascular disease exhibited signifi- cantly higher blood cholesterol levels than the controls but there was no relation to their cholesterol intake. For instance, among the controls the men who ingested 7 .0+0.3 g of cholesterol per week had an average blood cholesterol level of 213 mg/dl (5.51 raM), whereas those who ate only 1.44-0.1 g per week had a blood choles- terol level of 222 mg/dl (5.74 mM). Similarly, no re- lation between dietary cholesterol intake and blood chol- esterol levels has been reported from the Framingham Project, an ongoing prospective study of factors influ- encing cardiovascular disease, which is being carried out in the city of Framingham, MA, USA. In the early days of the Framingham study, which began more than 40 years ago, 431 men and 442 women were divided into groups based on blood cholesterol levels below 180 mg/dl (4.65 mM), above 300 mg/dl (7.76 mM), or in between. There was no relation between groups and any dietary component s. In the same study Dawber e t a l . 9

later reported no correlation between dietary cholesterol intake and blood cholesterol level. Other studies con- ducted on free-living subjects also find little relation between cholesterol intake and serum or plasma choles- terol levels.

In contrast, Connor and Connor I° cite 26 metabolic ex- periments involving 196 human subjects (7.5 subjects/ study) in which dietary cholesterol levels profoundly influenced both total plasma cholesterol and LDL chol- esterol levels. MeNamara u carried out a meta-analysis of 68 studies involving 1490 subjects (21.9 subjects/ study) and concluded that the average effect of dietary cholesterol on blood cholesterol level was an increase of 2.3 + 0.2 mg cholesterol per deciliter of blood (0.06 mM) per 100 mg of dietary cholesterol. Polemics generated by different interpretations of the same data are charac- teristic.

Quintao and Sperotto j2 reviewed the effects of dietary cholesterol in regulating human body cholesterol. The blood cholesterol levels of the subjects under review were in the range 115-717 mg/dl (2.97-18.54 mM). They concluded the following:

• In the absence of dietary cholesterol, cholesterol syn- thesis is similar in individuals with normo- and hyper- cholesterolemia.

• The major mechanism by which dietary cholesterol affects cholesterol metabolism is by the interruption of cholesterol synthesis.

• An increase in bile acid output plays a secondary but significant role, whereas fecal neutral steroids have negligible influence. (Bile acids are the principal products of cholesterol metabolism. Increased bile acid excretion often reflects increased cholesterol turnover and lower serum cholesterol.)

• The magnitude of the compensatory mechanism is similar in individuals with normo- and hypercholes- terolemia.

• A very high level of cholesterol absorption leads to accumulation.

• Variability in individual responses in cholesterol metabolism may be attributed to cholesterol intake.

What is the principal rationale for lowering choles- terol levels? As stated above, elevated plasma choles- terol levels are one of the major risk factors for cardio- vascular disease. The lipid hypothesis states that there is a relationship between dietary cholesterol levels and risk and if we lower dietary, cholesterol levels we can re- duce risk. There are a number of clinical trials in which the lowering of blood cholesterol levels by diet or drugs reduced the number of new cases of cardiovascular disease or showed angiographic evidence of plaque re- gression ~. However, as we shall see later, the picture is not quite so rosy since the total number of deaths in the test groups is usually the same as that in the controls. However, let us first examine dietary approaches to low- ering blood cholesterol levels.

Influence of dietary fat The first line of attack is dietary fat, which is a

major dietary determinant of plasma cholesterol levels. Studies with rabbits have shown that saturated fat is

220 Trends in Food Science & Technology Ju.ly 1994 [Vol. 51

more atberogenic than unsaturated fat regardless of the cholesterol content of the diet t4"~5. The term saturated fat refers to a fat containing a preponderance of saturated fatty acids and unsaturated fat refers to a fat rich in unsaturated fatty acids. There is no reference point beyond which a given fat can be judged as saturated or unsaturated. As we learn more about fat composition we discover that individual fatty acids may exert specific effects. Hegsted e t a l . t6 and Keys e t a l } 7 formulated equations for predicting changes in blood cholesterol levels as a function of the saturated and unsaturated fatty acids present in the diet. In both cases stearic acid was regarded as neutral and indeed stearic acid-rich fats such as cocoa butter are much less atherogenic than might be deduced from their level of saturation. Derr e t a l? 8 have introduced another equation for determining changes in blood cholesterol levels that provides coefficients for a number of individual fatty acids. In a re-evaluation of a number of studies, Hegsted e t al . ~9 concluded that saturated and polyunsaturated fatty acids dictate plasma cholesterol levels and that oleie acid is essentially neutral although others have suggested that it has cholesterol- lowering properties. Hayes and Khosla 2° studied the effects of blended naturally occurring fats on cholesterol metabolism in hamsters and monkeys and concluded that linoleie acid is hypocholesterolemic until it reaches 5 -6% of dietary calories then has no further effect; tuyristic acid is hypercholesterolemic at any level of intake; and paltuitic acid raises blood cholesterol levels when ingested with a high-cholesterol diet (>400 mg/d) or in subjects whose cholesterol level exceeds 225 mg/ml (5.82 M). The triacylglycerol structure of a fat may also be important. Peanut oil, a relatively unsaturated fat, is unexpectedly atherogeni¢ for rabbits, rats and monkeys but randomization (antointeresterifleation) reduces its atherogenicityZL Randomization does not alter fatty acid composition but does change triacylglycerol structure. Even in rabbits fed high levels of cholesterol, random- ized lard is 10% less atherogenic than lard in its native state 2z. Randomized butter has been reported to reduce cholesterol levels in men 2~.

The relative effects of dietary cholesterol levels and fat saturation were clearly shown in a study by MeNamara e t al . z4, who fed human volunteers diets high (~800 rag/d) or low (-240 rag/d) in saturated or unsatu- rated fat. Differences in serum cholesterol levels were only 2-3% between subjects ingesting high and lr, w amounts of cholesterol as saturated fat. The same was true for high and low amounts of cholesterol as unsatu- rated fat. However, changing from unsaturated to satu- rated fat raised serum cholesterol levels by 10-12% regardless of the amount of cholesterol in the diet. They also observed that -67% of their subjects compensated for high dietary cholesterol intake by reducing endogen- ous cholesterol synthesis.

One means of decreasing cholesterol intake has been the substitution of margarine for butter. Margarine is usually produced by hydrogenation of plant or marine oils. This process leads to double-bond shifts and isom- erizations so that margarine may contain double bonds

(both cis and t rans ) anywhere between C-4 and C-16 (Ref. 25). The concern about fats containing t rans

unsaturated double bonds ( t rans fatty acids: TFA) is not new. Studies performed on rabbits showed TFA to be more cholesterolemie but not more atherogenic than conventional f-*s 26. Houtsmuller 27 concluded that TFA should be regarded as quasi-saturated fats. Some -'~ but not all 29 studies with TFA find large (>10%) increases in human blood cholesterol levels. Effects on levels of lipoprotein(a) similarly show 3° or do not show ~1 increases. The effect on lipoprotein(a) may reflect the action of a specific t rans unsaturated fatty acid.

Influence of protein The earliest purely nutritional studies of experimental

atherosclernsi,; were predicated on the idea that protein of animal origil~ was atherogenic 3-'. Meeker and Kesten ~ found that casein was more atberugenic for rabbits than soy protein, an observation that has been confirmed by many other workers. Beef protein or casein is more choles- terolemic and atherogenic for rabbits than is textured vegetable protein (TVP). but a I : 1 mixture of TVP and beef protein is no more atheroganic and only slightly more cholesterolemic than TVP alone ~. The results argue for a mixed diet. Hodges e t a l ) 5 showed that switching human subjects from mixed protein to plant protein diets was more hypocholesterolemic than any changes in carbohydrate or fat. Sirlori e t al . 3~ have shown that soy protein significantly lowers blood chol- esterol levels in hypercholesterolemic subjects, but Holmes e t aL 37 have not had similar success.

Influence of fiber The fiber hypothesis suggests that populations ingest-

ing diets high in fiber are relatively free of "Western' diseases such as cardiovascular disease. A high-fiber diet is one rich in food of plant origin that also contains other substances such as antioxidant vitamins, plant pro- teins or plant sterols, which may also be hypolipidemic and anti-atherogenic. Truswell and Beynen 3s summar- ized data from 11 studies in which the hypocholesterol- emic properties of legumes (beans, peas, lentils) were tested. Serum cholesterol levels were reduced in 10 of the studies and in 7 of these studies the reduction was statistically significant. The average dietary level of leg- umes was - 190 _+ 41 g/d and the average duration of feed- ing was 31 + 10 d: the average reduction in cholesterol level was 7 .8_ + 1.6%. Wheat bran has virtually no ef- fect on serum cholesterol levels. Fiber may be extracted from food and fed in a concentrated, purified form that does not resemble its native state, and in this state may be regarded as a pharmaceutical agent. The soluble fibers from pectin, gnat" gum and psyllium when fed in purified form all show hypocholesterolemic properties. A comparison of blood cholesterol levels in Seventh Day Adventists who were vegans, lacto-ovo vegetarians or omnivores showed that the vegans had significantly lower levels than the other two groups. One major dif- ference in their diets was that the vegans ingested 70-80% more pectin than did the other two groups 3~. In

Trends in Food Science & TechnoloGy July 1994 [Vol. 51 22

this case the pectin was in its natural state. Humble e t a l . 4° assessed the association between cardiovascular disease among 1801 hypereholesterolemie, middle-aged men who were part of the control group of a large heart attack prevention trial and found a modest inverse correlation between fiber intake and cardiovascular disease.

There is a point, then, to lowering cholesterol levels since the prediction of the lipid hypothesis that lowering cholesterol may reduce the risk of cardiovascular dis- ease has been borne out in a number of clinical studies usiu~ either diet or drugs. We have also seen that a diet in which calories from saturated fat have been reduced or one rich in fiber or richer in plant protein may be an effective hypocholesterolemic regimen. Does this then close the book on the entire issue? Definitely not!

About a decade ago many investigators were con- vinced that we had solved the cholesterol part of the car- diovascular disease puzzle even though there were trials in which total mortality in the test and control groups did not differ. That many of the deaths in the test group may be attributable to cancer has been a long-standing concern4L Eventually, closer examination of the overall effects in many diet and drug trials began to intrude on the general feeling of complacency.

The Multiple Risk Factor Intervention Trial (MRFIT) carried out in the USA involved screening 361 662 men to provide two test groups. One group of 6428 men were given advice on coping with diet, smoking, hyper- tension and other risk factors and another of 6438 men received "usual care'. After 7 years there were 38 heart attacks in the test group and 35 in the control; total deaths in the two groups numbered 265 and 260, respect- ively 4-'. Three years later deaths due to cardiovascular disease in the test group numbered 266 against 290 in the control group (p=0.16) and total deaths were 496 al~d 537 (p--0.10), respectively 43. If serum cholesterol levels are plotted against deaths due to card~,ovascular disease in the MRFIT trial one can obtain a smooth exponentially increasing parabolic curve starting at 140 mg/dl (3.62 raM) with a marked change in slope at 240 mg/dl (6.20 raM). If serum cholesterol levels are plotted against all causes of mortality the result is a J-shaped curve with the low point at 170-180mg/dl (4.39-4.65 mM) (Ref. 44). Cowan e t a l . 4"s examined mor- tality in 2753 men and 2476 women who had partici- pated in the Lipid Research Clinics Program Mortality Follow-up Study and found that men, but not women, who were in the lowest quartile of serum cholesterol levels (below 187 mg/dl or 4.84 mM) were at increased risk of colon cancer.

A Finnish trial similar to the MRFIT study involved 612 patients receiving instruction and/or treatment and 610 controls. Long-term mortality (reported in 1991) showed that the group receiving intervention had 34 deaths due to heart attack compared with 14 in the control group (p<0.004) and 13 violent deaths compared with 1 in the control group (p<0.002). There were 67 deaths in the test group compared with 46 in the control group. There were more deaths from cancer in the

control group. During tile term of the trial (1974-1980) the total number of deaths was 10 in the test group and 5 in the control group ~6. Frantz e t a l . 47 described a diet study conducted on 9057 institutionalized subjects in Minnesota, USA. One group was fed a diet with a polyunsaturated : saturated fatty acid ratio (P/S ratio) of 0.28 and which provided 446 mg of cholesterol daily. The other group was fed a diet conlaining a higher level of unsaturated fat (P/S= 1.60) and providing only 166mg of cholesterol daily. Serum cholesterol levels rose by 2% in the first group and fell by 14% in the sec- ond. In the second group there were 269 deaths of which 141 (52.4%) were due to cardiovascular disease; in the first group there were 248 deaths of which 144 (58. 1%) were due to cardiovascular disease.

Muldoon e t a L a8 analyzed data from 6 primary pre- vention trials of cholesterol reduction. These trials in- cluded a total of 24 847 males (mean age 47.5 years) and their mean duration was 4.8 years. Mortality from cardiovascular disease was reduced in men in the treat- ment groups (p=0.06) but total mortality was unaf- fected. The groups receiving the hypocholesterolemic treatment showed a significant increase in deaths from accidents, suicide or violence (p=0.004). Mortality from cancer was increased significantly in the 2 diet trials (p=O.O04) and increased non-significantly (p=0.11) in the 4 drug trials. Holme 49 carried out a meta-analysis on 22 cholesterol-lowering trials - diet and drug, primary and secondary, single or multifactorial. The average starting cholesterol level was 267 + 6 mg/dl (6.90 + 0.16 raM). The trials contained as many as 24615 or as few as 47 men. Among the 62 336 men receiving treatment the total mortality was 4149 (6.66%) and among the 63 346 controls the total mortality was 4237 (6.69%). There were fewer heart attacks in the low-cholesterol group (5.64 versus 6.41%). The percentages of total deaths are similar for the test and control groups if we only con- sider trials numbering more than 1000 men (8 trials, total deaths 6.29 versus 6.26%) or more than 2500 men (5 trials, total deaths 5.74 versus 5.'/7%). Holme argues that the cholesterol reductions were modest and at the level of cholesterol reduction observed a much larger trial would be needed to show a definite effect. Ravnskov 5° examined data from 22 controlled choles- terol-lowering trials and concluded that lowering serum cholesterol concentrations did not reduce mortality and probably would not prevent cardiovascular disease. He asserts that those trials that did not support the lipid hypothesis were not cited widely alter about 1970.

A recent review of a large number of trials found that men whose cholesterol levels were below 160mg/dl (4.14mM) had 20% more deaths from cancer, 40% more non-cardiovascular, non-cancer deaths, 35% more deaths from injury and 50% more due to digestive problems ~t. The report did not cite the paper of Cowan e t a l . 4"~, which showed that levels of cholesterol below 187mg/dl (4.84mM) might expose men to risk of cancer. It also prompted all editorial suggesting that we rethink policies relating to the treatment of hypercholesterolemia ~-'. Otl~ers, including Barratt and

222 Trends in Food Science & Technology July 1994 IVol, 5J

Irwig ~3, have begun to question the wisdom of across- only negative consequence of low or reduced serum the-board cholesterol reduction as a primary prevention cholesterol levels. These observations are at odds with strategy, the publications cited earlier. Since all of the analyse..;

Conclusions The question is whom to treat and whet1. Davey Smith

e t a l . 5~ analyzed the results of 35 cholesterol-lowering trials and concluded that: persons at high risk benefit from drug treatment: those at medium risk derive neither benefit nor harm; and for persons at low risk, treatment may be harmful. The aggressive treatment of subjects clearly at risk such as those with severe hypereholesternlemia, especially in persons with a fam- ily history of coronary disease has been commented on -~-~,~6. The major treatment for others should be a pru- dent diet coupled with greater attention to other risk fac- tors including weight reduction and cessation of tobacco use. The dangers of obesity 57 and the benefits of main- taining desirable weight should also be emphasized. Caution in treating men older than 65 years is advised ~. Grover e t a l . s8 estimated the benefits of cholesterol low- ering among high- and low-risk individuals. The years of life gained were shown to be a function ,rf pretreatment blood cholesterol levels, mode of treatment (diet or drugs), gender and age at which treatment was initiated. Dietary treatment was assumed to lower blood chol- esterol levels by 5% and drugs to lower levels to 201 mg/dl (5.2 raM). For a 35-year-old, 10w-risk male with a pretreatment blood cholesterol level of 302 mg/dl (7.8 raM) diet therapy would save 0.32 years of life and drugs would save 1.64 years: for a 65-year-old man the extension of life would be 0.14 and 0.78 years, respect- ively. In women the years saved would be fewer. In a high-risk male with the same high cholesterol level, diet would save 0.60 years of life and medication 3.16 years. In a high-risk, 65-year-old male the savings of life by dietary modification would be 0.09 years and by medication 1.40 years. If the calculations are repeated for a male subject with a pretreatment cholesterol of 220 mg/dl (5.7 mM) the number of years of life gained by medication for a 35-year-old is 0.23 and for a 65-year-old is 0.05 years. Clearly, age, risk status and mode of treatment must be carefully thought out, In a paper reviewing data obtained from 21 414 men who attended the medical center of the British United Provident Association in London between 1975-1982, Law e t al. 59 concluded that there is a very strong associ- ation between serum cholesterol levels and cardiovascu- lar disease. A second paper 60 reviewing data from lO cohort studies, 3 international studies and 28 random- ized, controlled trials asserts that an easily achievable 10% reduction in serum cholesterol levels may lower risk of cardiovascular disease by 50% at age 40 and by 20% at age 70. The authors state that the lO cohort trials included 494 804 subjects but in their first table they included 361 662 subjects as being in the MRFIT trial. That is actually the number of persons screened; the trial itself contained a total of 12 866 men, half of whom were controls. A further review of these studies 6~ finds that increased mortality from hemorrhagic stroke is the

are derived from the same body of data the discrep- ancies suggest a need for further analysis of the analyses. McCormick and Skrabanek 6-', after analysis of the re- suits from several intervention trials, conclude that they "provide no data to justify the time, energy and money being dew,ted tf~ This crusade'.

The accumulated data show that elevated blood chol- esterol levels (and we need a very precise definition of elevated) are a risk factor for cardiovascular disease, not a disease in themselves, and under proper conditions they should be treated aggressively. However, the poss- ible dangers of low blood cholesterol levels must be ad- dressed. Obviously if very low blood cholesterol levels per se were a danger half the human population would be dead. but something happens in the course of the trials that increases mortality for reasons oiler than car- diovascular disease in the low-cholesterol groups. The question of low serum cholesterol levels and cancer risk has been reviewed recently ~'~. Cancer oreurrence dur- ing lipid-lowering inte,wention trials was increaseo h~,' -24% in the lipid-lowered groups. The post-trial experi- ence showed a comparative deficit of cancer occurrence in the control groups. The data suggest the presence of a small subgroup of subjects in whom the reduction of plasma cholesterol levels leads to increased risk of cancer. Earlier analyses ~ suggested that the observed low choles:erol values were due to the consequences of cancer, which was present but undiagnosed. Other analyses have taken that possibility into account and still find excess mortality from cancer 4~'~'~.

The field of cholesterol metabolism and atheroscler- osis has attracted some of our brightest intellects: perhaps they should begin to focus more attention on Ihe choles- terol-lowering paradox. It is small comfort to learn that one has proved the hypothesis but is still doomed. Not everyone subscribes to the lipid hypothesis. Rosenman ~ concluded that diet and cholesterol played a question- able role in tile history of cardiovascular disease in the 20th century and that the data are an insufficient basis to recommend gl.ass dietary changes. Stehbens ~'7 has writ- ten a book detailing the genesis, development and short- comings of the lipid hypothesis. There appears to be some unfinished business.

As stated at the outset, atherosclerosis is a life style disease in which blood cholesterol levels may play an important role, but it is as part of an ensemble of risk factors, not a solo performer. That part of the risk com- plex that can be addressed should be attended to. Life practices that include exercise and weight management will affect blood lipid levels as well. Many dietary guidelines have been promulgated for cardiovascular disease, cancer and other conditions. They usually begin by telling us to eat a varied diet and maintain a desirable weight. In most normal persons strict attention to these first two suggestions will be sufficient to promote better health. For most of us the answer is "moderation, not martyrdom'.

Trends in Food Science & Technology July 1994 ]Vol. 51 22~

Acknow ledgmen t 32 Supported, in pan , by a Research Career A w a r d 33

(HL-00734) f rom the Nat ional Inst i tutes o f Health. 34

References 35 1 Hopkins, P.N. and Williams, R.R. (1981) Atherosclerosis 40,1-52 2 Slender, D. and Zilversmit, D.B. (19811 Arteriosclerosis 1,38-49 36 3 Utermann, G., Heos, M. and Steinmetz, A. (19771 Nature 269,

604-507 4 Krilchevsky, D. (I 985) in Nutrition Update VI)L 2 (Weininger, J, and 37

Briggs, G.M., eds), pp. 91-103, John Wi)ey & Sons S Gordon, D.J., Hyde, J., Trost, D.C., Whaley, F.S., Hanan, P.J., Jacobs, 38

D.R. and Ekelund, E.G, (19881 J. Clin. EpidemioL 41,679..-689 6 Groover, M.E., Jr, Jemigan, J,A, and Martin, C.D. (1960) Am. I. Med.

Sci, 239,133-139 39 7 G~ler, M.M., Garn, S,M. and White, P.D. (19501 Circulation 2, 696-702 8 Kannel, W.B. and Gordon, T., eds (I 970) The Framinghem Study, 40

Section 24 The Framieghem Diet Study: Diet and the Regulation of Serum Cholesterol, US Department of Heallh, Education and Welfare, 41 Washington, DC, USA

9 Dawber, T.R., Nickerson, R.J., Brand, F.N. and Pool, J. (1982) Am. 1. 42 Clin. Nutr. 36, 617-625

10 Connor, W.E. and Connor, S.L (1994) in Pfinciples and Treatment of 43 Lipoprotein Disorders (Schenler, G, and Habenicht, A,J.R., eds), pp. 247-277, Springer-Verlag 44

I I McNamara, DJ. (1990) in Meat and Health (Advances in Meat Research, vol. 6) (Pearson, AM. and Dutson, T,R., edsL pp. 63.-87, 45 Elsevier

12 Quintao, E.C.R. andSperolto, G.(1987)Adv. LipidRes. 22,173-188 46 13 Blankenhorn, D.B. and Hod]s, H.N. (19941 in Principles and Treatment

of Lipoprotein Disorders (Schettler, G. and Habenichl, A.J.R., eds}, pp. 221-245, Springer-Verlag 47

14 Kritchevsky, D., Moyer, W.W., Tesar, W.G., Logan, J.B., Brown, RA., Davies, M.C. and Cox, H.R. (19541 Am. 1. PhysioL 178, 30-32 48

15 Kritchevsky, D., Tepper, S.A., Kim, H.K., Story, J.A., Vesselinovitch, D. and Wissler, R.W. (1976) Exp. Mol. Pathol. 24, 375-391 49

16 Hegsted, D,M., McGandy, R.B., Myers, M.L. and Stare, F.J. (19651 Am. 50 I. Clin. Nutr. 17, 281-295 51

17 Keys, A., Anderson, J.T. and Grande. F. (1965) Metabolism 14, 776-787

18 Derr, J., Kris-Etherton, P.M., Pearson, T.A, and Seligson, F.H. (1993) 52 Metabolism 42,130-134

19 Hegsted, D.M., Ausman, L.M., Iohnson, I.A. and Dallal, G.E. (1993) 53 Am. ]. Clin. Nutr. 57, 875483 54

20 Hayes, K.C. and Khosla, P. tl 992) FASEB J. 6, 2600-2607 21 Krilchevsky, D., Tepper, S.A., Vesselinovitch, D. and Wissler, R.W. 55

(1973) Atherosclerosis 17, 225-243 56 22 Kritchevsky, D. and Tepper, S.A. (1977) Atherosclerosis 27, 339-345 57 23 Cristophe, A., Marthys, F., Geers, R. and Verdonk, G. (1978) Arch. Int.

Physiol. Biochim. 86, 413-415 58 24 McNamara, D.I., Kolb, R, Parker, T.S., Batwin, H., Samuel, P., Brown,

C.D. and Ahrens, E.H., Jr (1987l 1. C/in. Invest. 79,1729-1739 59 25 Dutlon, H.). (1979) in Geometric and Positional FaG' Acid Isomers

(Emken, E.A. and Duilon, H.)., eds), pp. 1-16, American Oil Chemists 60 Society

26 McMillan, G.C., Silver, M.D. and Weigensberg, B.I. (1963) Arch. 61 Pathol. 76,105-112

27 Houtsmuller, U.M.T. (1978) Fette, Seifeo, Anstrichm. 80,162-169 62 28 Mensink, R.P. and Katan, M.B. (1990) New Engl. I. Med. 323,439-445 63 29 McOsker, D.E., Mattson, F.H., Sweringen, B. and Kligman, A.M. (19621 64

I. Am. Med. Assoc. 180, 380-385 65 Nestel, P., Noakes, M., Belling, B., McArthur, R., Clifton, P., Janus, E. and Abbey, M. l19921 L Lipid Res. 33,1029-1036 66 Lichtenstein, A.H., Ausman, LM,, Carrasco, W., Jenner, J.L., Ordovas, 67 I.M. and Schaefer, Eft. (19931Arterioscler. Thromb, 12,154-161

Ignatowski, A. (19081 Arch. Med. Exp. Anat. PatheL 20,1-20 Meeker, D.R. and Kesten, H.D. (19401 Pro(:. Soc. Exp. Biol. Med. 45, 543-545 Kfitchevsky, D., Tepper, S,A., Czarnecki, S.K., Kluffeld, D,M. and Story, J.A. (19811 Atherosclerosis 39,169-175 Hodges, R.E., Krehl, W,A., Stone, D.B. and Lopez, A. (1967) Am. I. Clin. Nutr. 20,198-208 Sirlori, C.R., Gaff], E., Mantero, O., Conti, F., Agradi, E., Tremoli, E., Sirtori, M., Fraterrigo, L, Tavazzi, h and Kritchevsky, D, (19791 Am. I. Clio. Nutr. 32,1645-1658 Holmes, W.L., Rubel, G.B. and Hood, S.S. (19801 Atherosclerosis 36, 379-387 TmsweJl, A.S. and Beynen, A.C, (19921 in Dietary Fibre- A Component of Fond (Schweizer, T.F. and Edwards, C.A., eds), pp. 295-332, Springer-Verlag Kritchevsky, D., Tepper, S.A. and Goodman, G. (19841 Am. I. Clin. Nutr, 40, 921-926 Humble, C.G.. Malarcher, A.M. and Tyroler, H,A. (1993) Am. I. Prey. Meal. 9,197-202 Ederer, F., Leren, P., Turpeinen, O. and Frantz, I.D. (1971) Lancet i, 203-206 Multiple Risk Factor Interveofon Trial Research Group (19821 J. Am. Med. ASsoc. 248,1465-1477 MultipJe Risk Factor Inte,"cenlion Trial Research Group (19901 I. Am. Med. Assoc. 263,1795-1802 Martin, MJ., Hutley, S.B., Browner, W.S, Kuller, LH., Wentworth, D. (1986) Lancet it, 933-936 Cowan, L.D., O'Conr~eU, D.I., Criqui, M.H., Barre0-Conner, E., Bush, T.L and Wallace, R.B. (1960) Am. I. Epidemiol. 131,468-482 Strandberg, T.E, Salomaa, V.V., Naukkarinen, V.A., Vanhanen, H.T., Sarna, S.J. and Miettinen, T.A. 119911/. Am. Meal. Assoc. 266, 1225-1229 Frantz, I.D., Jr, Dawson, E.A., Ashman, P.L, Gatewood, LC., Bartsch, C.E., Kuba, K. and Brewer, E.R. (1989) Arteriosclerosis 9,129-135 Muldcon, M.F., Manuck, S.B. and Matthews, K.A. (]990) Br. Med. 1. 301,309-314 Holme, I. (1993) Br. Heart]. 69, $42-$47 Ravnskov, U. (19921 Br. Med. ]. 305,15-19 ]acobs, D., Blackburn, H., Higgins, M., Reed, D., Iso, H., McMillan, G., Neaton, J., Nelson, J., Potter, F., Rifkind, B., Rossouw, J., Sbekelle, R. and Yusuf, S. (19921 Circulation 86,1046-1060 Hulley, S.B., Walsh, J.M.B, and Newman, T.B. (19921 Circulation 86,1026-1029 Barran, A. and Irwig, L. (1993) Med. J. Aust. 159, 644-647 Davey Smith, G., Song, F. and Sheldon, T.A. (19931 Br. Meal. J. 306,1367-1373 Opie, L.H. (19931 Cardiovasc. Drugs Thec 7, 779-784 Oliver, M.F. (1993) Cardiovasc. Drugs Ther. 7, 785-788 Denke, M.A., Sempps, C.T. and Grundy, S.M. (19931 Arch. Int. Med. 153,1093-1103 Grover, S., Abrahamowicz, M,, Joseph, L, Brewer, C., Coupal, L. and Suissa, S. (19921 I. Am. Med. Assoc. 267, 81,~822 Law, M.R., Wald, N.J., Wu, T., Hackshaw, A. and Bailey, A. (19941 Br. Med. J. 308, 363-366 Law, M.R., Wald, N.J. and Thompson, S.G. (19941 Br. Med. ]. 308, 367-373 Law, M.R., Thompson, S.G. and Wald, N.J. (1994) Br. Med. ]. 308, 373-379 McCormick, J. and Skrabanek, P. (19881 Lancet it, 839-841 Kritchevsky, S.B, and Kritchevsky, D. (1992)Annu. Rev. Nutr. 12, 391--416 Rose, G. and 5hipley, M.J. 11980) Lancet i, 523-526 McMichael, A,J., Jensen, O.M., Parker, D.M. and Zaridze, D.G. (19841 Epidemiol. Bey. 6,192-216 Rosenman, R.H. (1993) Homeostasis 34,1-44 Stehbens, W.E. (1993) The Lipid Hypothesis of Atherogenesis, R.G. Landes Co., Austin, TX, USA

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