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PLASMA CHOLESTEROL LEVELS AS RELATED TO DIET AND HEART DISEASE As has been indicated, cholesterol is a prominent constituent of atheromas. Experimental atherosclerosis was first induced by feeding rabbits rather large amounts of cholesterol (10). These studies were discounted for many years since cholesterol is a foreign food substance of the vegetarian rabbit. However, many investigators have found that certain disease states in which the plasma cholesterol is elevated (diabetes, familiar hypercholester- olemia, etc.) are associated with an increased susceptibility to atherosclerosis and ischemic heart disease (64, 106, 109). Briefly stated, the evidence implicating plasma cholesterol levels in the causation of ischemic heart disease is as follows: 1. Those populations in which coronary disease is an impor- tant cause of death have substantially higher plasma cholesterol levels than those in which this disease is rare (106). Thus, in the United States where coronary disease is a leading cause of death, the average plasma cholesterol level in middle-aged men is approximately 220-230 mg percent; whereas in Guatemala, among the Bantu of Africa and in similar groups, the average level is approximately 180 mg percent, or perhaps lower. 2. Within population groups such as in the United States, those with elevated plasma cholesterol levels have a greater risk of developing the disease. This has been most clearly shown in the Framingham study (105). In this population, the risk of developing coronary disease appears to be directly related to the plasma cholesterol, other things being equal. It is important to recognize that the data indicate no safe level of plasma cholesterol, but rather that each increment in the plasma cholesterol level above the lower levels encountered in the study appears to be associated with an increased risk. The same type of evidence is available from studies of patients who have had coronary disease. The average level is well above the levels in those who do not have evidence of the disease. However, it should be apparent that high levels of plasma cholesterol are not diagnostic of coronary disease. Some people with levels 32
Plasma Cholesterol in Diet and Heart Disease below the average in the United States do develop the disease and high levels do not inevitably result in a coronary attack. 3. In all experimental animals in which elevated plasma cholesterol levels have been produced by various means, athero- matous lesions develop. Such evidence does not prove that an elevated level of plasma cholesterol is the cause of atherosclerosis or of coronary disease. The elevated plasma cholesterol might be simply associated with the disease or with some other causal factor. For example, it has been claimed that elevated plasma triglycerides are more characteristic of patients with coronary disease than is a high plasma cholesterol (6). Since both the triglycerides and the cholesterol are carried in the various lipoprotein fraction, these two lipid fractions are associated and the significance of this conclusion is as yet unknown. It had been previously suggested (66) that the low-density lipoproteins, richer in triglycerides than cholesterol, were more closely associated with coronary disease. However, no epidemiologic studies are yet available to suggest that plasma triglycerides are a more likely causal factor than plasma cholesterol. Proof that a high plasma cholesterol level is causative of coronary disease in man can probably only come from experi- mental manipulation of the plasma cholesterol level in a sizable group of men and the demonstration that such treatment will lessen the incidence of the disease. Such evidence is not yet available, although some (11) is at least suggestive that this may be true. It becomes of great interest, therefore, to develop feasible methods of lowering the plasma cholesterol. Manipula- tion of the diet is a possibility and the role of the several dietary and pharmacological factors that may influence plasma cholesterol is discussed below. Effect of Dietary Cholesterol on Plasma Cholesterol Level The various animal species in which the effects of dietary chol- esterol have been studied respond in widely different fashion. Some species, such as the rabbit and chicken, are very sensitive, and moderate increases in the level of cholesterol in the diet cause pronounced raises in the amount of the plasma. Other species, such as the rat and the dog, show little response to diet- ary cholesterol alone (110). 33
Dietary Fat and Human Health Early studies in man suggested that dietary cholesterol was of little importance since fairly large doses of cholesterol produced little change in the plasma level (117). It now appears that as the food cholesterol is increased from 0 to perhaps 0.8 gm per day, other things being equal, the plasma cholesterol progressively increases, but further increases in intake provoke relatively little further increase in the plasma level (19, 20, 37, 38, 92, 112). The situation is complicated, however, by evidence that the dietary source of the cholesterolâthe form of the dietary chol- esterolâmay be important. Some natural sources of cholesterol may produce more substantial increases in the plasma than does crystalline cholesterol. Thus, the intake of cholesterol must be considered in devising diets that lower cholesterol levels, but more substantial changes in the plasma cholesterol may be pro- duced by manipulation of the dietary fat. Effect of Kind of Dietary Fat on Plasma Cholesterol Level The observations (81) that substitution of unsaturated vegetable oils for animal fats in the diet produced a substantial lowering of the plasma cholesterol level have been confirmed by many in- vestigators. It would appear obvious that a sustained change in the level of plasma cholesterol must reflect either a change in the rate of synthesis in the body or its degradation and excretion if the cholesterol content of the diet is not modified. The dietary fat might also affect the distribution of cholesterol within the vas- cular and cellular compartments of the body. Although there is general agreement that unsaturated vegetable oils tend to lower the plasma cholesterol levels while diets high in the ordinary saturated animal fats have the opposite effect, there is as yet no agreement upon fatty acid components presumed to be effective in raising or lowering the plasma chol- esterol level. One group of investigators (3) concluded that the plasma cholesterol level induced by a dietary fat was related to the degree of unsaturation of the fat, thus implying that oleic acid was about half as effective as linoleic acid. Another group (115) concluded that the monounsaturated acids have no effect. Rather, they have concluded (116) that the plasma cholesterol is a function of the total saturated fatty acid and the polyunsaturated acid con- tent of the dietary fat, the saturated fatty acids being approxi- mately twice as active in elevating the plasma cholesterol as the
Plasma Cholesterol in Diet and Heart Disease polyunsaturated acids are in lowering it. From more recent work (92, 112), it appears that the saturated fatty acids are not all equally active in elevating plasma cholesterol. Others (91) have also concluded that the chain length of the saturated fatty acids may be important in determining their effect. Various other parameters of fat composition (82, 101, 118) have been suggested as a means of predicting the effect of the dietary fat. Contrary to expectations (53, 144), hydrogenation of some vege- table oils was not found to influence their effect upon plasma cholesterol. It appears impossible at this time to arrive at any consensus of opinion as to the most important factors in dietary fats that control plasma cholesterol levels or upon the mechanism of action. This does not, however, modify the conclusion that large and sustained decreases in the circulating cholesterol can be easily induced by substitution of highly unsaturated vegetable oils in the diet in place of most of the saturated fats ordinarily pres- ent in the American diet. Effect of Dietary Carbohydrate on Plasma Cholesterol Level Those populations that experience little atherosclerosis generally consume diets that are not only low in fat but also high in starch and other forms of complex carbohydrates. It appears to be charac- teristic that, as the societies become more affluent, the consump- tion of both fat and sugar increases. It has been suggested that high sugar intakes may be a causal factor in the development of atherosclerotic heart disease (36, 208). Little evidence is avail- able to support this contention. In the few carefully controlled studies that have been reported (77, 114, 142), substitution of various complex forms of carbohydrate for sugar has resulted in only moderate lowering of the level of cholesterol in the plasma, much less than can be achieved by modification of the dietary fat. Since the consumption of animal fats and of sugar is highly correlated in most countries, epidemiologic data are not helpful in distinguishing between the possible effects of these two dietary factors. Although, as discussed elsewhere, the consumption of very low-fat high-carbohydrate diets may induce hyperglyceridemia, this condition does not appear to be characteristic of populations consuming low-fat diets (11). 35
Dietary Fat and Human Health Pharmacological Control of Plasma Cholesterol Plasma cholesterol concentration can be influenced by changing cholesterol degradation and excretion, its biosynthesis, or its distribution in the vascular and cellular compartments of the body. Several pharmacological agents that influence plasma cholesterol concentration are noted below. The oral administration of neomycin induces a reduction in plasma cholesterol concentration and a considerable increase in the fecal excretion of bile acids (69). These findings were in- terpreted to suggest that "neomycin lowers plasma cholesterol levels primarily by an increase in fecal excretion of sterols and bile acids." Presumably, neomycin is effective, at least in part, by inducing a change in the intestinal flora which alters the structure of sterols and bile acids and thus changes their absorp- tion. Cholesterol synthesis and degradation probably are in- creased during neomycin administration, but whether the regimen effects an over-all loss of cholesterol from the body is uncertain. When the enterohepatic circulation of the bile acids is inter- rupted by cannulation of the bile duct and the formation of an ex- ternal fistula, a greatly increased synthesis of bile acids from cholesterol occurs (193). This and other work suggests that feedback mechanisms regulate bile acid formation and, simul- taneously, the degradation of cholesterol. Oral administration of cholestyramine, an insoluble anion ex- change resin that will bind bile acids ^n_ vitro and in the intestinal tract, has been observed to decrease the plasma cholesterol in man by about 20 percent (range: 6-38 percent in 26 patients) (16). The largest decreases usually occurred in those patients with the highest initial cholesterol concentrations. Although side effects (impairment of fat and fat-soluble vitamin absorption) have not been a problem, further work is needed to establish the effective- ness and safety of this drug. Large doses of nicotinic acid by mouth also will lower the blood cholesterol concentration in many individuals (69). The mechanism for this is not understood, but it appears probable that nicotinic acid in some way interferes with the hepatic synthesis of lipids, particularly cholesterol. Nicotinic acid is presently being used in the treatment of hypercholesterolemia, but whether it has any effect on atherosclerosis, either in pre- vention or treatment, is unknown. 36
Plasma Cholesterol in Diet and Heart Disease Epidemiologic and Other Population Studies of Diet, Plasma Lipids, and Heart Disease Studies of populations by epidemiologic methods, in which, for example, differences in diet are correlated with the incidence of coronary heart disease, do not in themselves prove cause and effect. Nevertheless, if carefully done, they provide much collateral and confirming evidence about the setting in which this disease occurs, and often such studies act as stimuli to further research. Many epidemiologic studies concerning the relationships between diet, plasma lipids and atherosclerosis have been done. Some of these are poorly controlled, and in others the data are, for other reasons, inconclusive. A few of the more thought-provoking or better controlled studies are noted here. People who live on extremely low fat intakes have been investi- gated in many parts of the world. In one such study, 440 Koreans were eating approximately 7 percent of their 2,900 calories as fat. Although they were ingesting only about half as much linoleic acid as in the usual American diet, their adipose tissue had almost twice as much linoleic acid as is found in Americans (125). The occurrence rate of coronary artery disease in most oriental countries is though to be very much lower than in Western countries. This has been reasonably well documented for the Japanese and for the Koreans and has been associated with low plasma lipid, especially cholesterol, concentrations. Several studies have emerged from these observations. In one, a group of Korean soldiers who had been eating their low-fat army diet were attached to U.S. Army units. Within a few weeks, the change to the American diet, with nearly half the calories coming from fat, was associated with a considerable increase in concentration of plasma lipids in the Korean soldiers. Other environmental factors also changed, but the probability remains that the diet was the most important factor (124). It has been pointed out that Japanese men between the ages of 40 and 49, all with a common ancestry but presently living in three different environmentsâKyushu, Hawaii, or Los Angeles- had a greatly different incidence of coronary heart disease. As expected, it was very low in Kyushu, higher in Hawaii, and higher still in Los Angeles. These differences were parallel to average plasma cholesterol concentrations which were proportional to the percentage of calories from fat in the diet. The intake of 37
Dietary Fat and Human Health polyunsaturated fatty acids in Japan was said to be much the same as in Hawaii and in the continental United States (109). Additional evidence that race is not the important factor in influencing plasma cholesterol concentration comes from a study in Hawaii of the plasma cholesterol concentration among adult Honolulu men who were of Caucasian, Chinese, Philippine, Japanese, and Hawaiian extraction. The results of the study were consistent with the view that race is of negligible influence upon the plasma cholesterol concentration, but that environmental factors are influential (1). Further inspection of the literature substantiates the concept that race is not important. Studies among the Bantu of South Africa have, for many years, established that their habitual diet is very low in fat, that the plasma cholesterol concentration tends to be lower than in most Western countries, particularly after the age of 40, and that severe atherosclerosis and coronary artery disease are less common among the Bantu, for example, than among Europeans and Indians living in the same area but with different dietary (and other) habits. Moreover, Bantu living in cities and eating food more like that of a European, with a higher fat content, do have a considerably higher plasma cholesterol concentration (93, 195, 196, 197). A careful study of the disease patterns in autopsied individuals in Central Africa and Albany, New York, demonstrated a striking difference in the occurrence rate of myocardial infarction. This disease is almost nonexistent among the Africans studied, even in the older age groups, and is relatively common among the New Yorkers studied. The study was carefully corrected for age (70, 123). The African parts of this study were done in Ibadan, Nigeria, where the fat content of the diet is low and most of it is polyunsaturated, and in East Africa where various pastoral tribes live mostly on milk, blood, or meat; that is, a high saturated- fat diet. Thus, the differences in myocardial infarction rate could not be related to quantity or quality of dietary fat. Other environ- mental factors presumably are effective. The Masai, another pastoral tribe, who live almost entirely on milk and blood, also have a high saturated-fat intake. Never- theless, their blood cholesterol concentrations are relatively low and, as far as can be determined, atherosclerosis and coronary heart disease are infrequent. The Samburu people of nothern Kenya have a particularly low plasma cholesterol concentration (mean for males: 166 mg/100 ml) despite a diet usually made up of milk, meat when it is available, 38
Plasma Cholesterol in Diet and Heart Disease and small quantities of vegetables. In fact, when milk is plenti- ful, a warrier may drink 10 liters a day. The habitual diet is, thus, high in fat, most of which is saturated. Moreover, this group of people shows no increase in total cholesterol concentra- tion with age. They are generally very active physically (177). Another tribe, living largely on camel milk rather than cow's milk had a considerably higher plasma cholesterol concentra- tion (178). In general, then, pastoral tribes like these have a moderately low or very low plasma cholesterol concentration and probably a low incidence of coronary heart disease despite their high, usually animal, fat intake. These studies in Africa, where diet is so completely different for different areas, yet where plasma lipids are similar and atherosclerosis presumably low in frequency, point out clearly that environmental factors other than diet are undoubtedly influential; physical exercise may be the most impor- tant of these. Population studies are by no means confined to those done abroad. Many longitudinal diet and serum lipid studies have been done in the United States. In a study of 280 Minnesota businessmen, aged 45 to 55, only the plasma cholesterol concentration proved to be statistically significant in predicting risk of future coronary artery disease (109). Although overweight, overfatness, and elevated blood pressure were associated with greater risk, their predicting value was far below that for plasma cholesterol. These findings are much the same as those of the Framingham study. Further evidence that the plasma cholesterol concentration has value in predicting risk of clinically manifest heart disease is indicated by the U.S. Public Health Service prospective study in Framingham, Massachusetts (105). This study showed that incidence of new coronary disease in a group of men in early middle age, followed over an 8-year period, was more than four times as great among those with plasma cholesterol concentra- tions of 240 mg/100 ml or above as among men in a similar age category with cholesterol concentrations lower than 220 mg/100 ml. The risk of developing new heart disease was compounded by such additional factors as obesity, hypertension, and heavy cigarette smoking. Extensive experience with the effects on plasma cholesterol concentration of a diet rich in polyunsaturated fatty acids is provided by the Diet and Coronary Heart Disease Study begun in New York City early in 1957 and still continuing (103). This 39
Dietary Fat and Human Health regimen was associated with reduction in plasma cholesterol concentrations in many of the subjects, particularly those with the highest initial values. An analysis was made of the prevalence of heart attacks in the subjects who received this polyunsaturated- fatty-acid-rich regimen, and the results for the men aged 40 to 59 were compared with the incidence rates reported from the Framingham study in which the subjects continued to eat their usual diet, containing a high proportion of saturated fat. The rate of new coronary events per 1,000 men in New York was 3.4 as against 14.5 per 1,000 in Framingham. Thus, the ratio of actual to expected events in the New York study proved to be remarkably low. Problems involved in comparing the data from the New York and Framingham studies must be pointed out, however. For example, the New York subjects displayed a high degree of health consciousness, and differed sociologically and ethnically from the Framingham subjects. Moreover, the Framingham report was based on a different method of accumulation of persons-years of experience. The absence of a suitable control group makes it difficult to interpret the results obtained in the New York study. A somewhat different answer follows from a small study in London (172). Here 31 patients with a recent myocardial infarc- tion and 49 with angina were followed for 2 years while they con- sumed their usual diet or substituted olive oil or corn oil for much of their saturated fat. The plasma cholesterol concentra- tions were unchanged except for those who took the corn oil, in whom it was reduced. Fresh myocardial infarctions, however, were not reduced by either the olive oil or corn oil substitutions. In fact, if anything, the risk of a new infarction was increased in those taking the corn oil. The possibility, however, that the cholesterol-lowering diet may have had a favorable influence on morbidity and mortality from coronary heart disease underlines the urgent need for obtaining a more definitive answer. A controlled study of the immense size necessary to provide reliable answers to the questions posed will be extremely difficult. To test the feasibility of such large-scale field trials, a "National Diet-Heart Study," supported by the National Heart Institute, has been conducted in several large cities in the United States. Some 1,500 healthy male volunteers, aged 45 to 54, and their families have been entered in the study after being carefully examined medically, with particular emphasis on the cardiovascular system. These families followed diets that were changed from the usual American diet to be lower in saturated 40
Plasma Cholesterol in Diet and Heart Disease and higher in unsaturated fat. Careful follow-up is being continued with biochemical studies as well as medical evaluations. The results of the feasibility study will at least give an indication as to whether a large field trial can or should be undertaken. These worldwide population and epidemiologic studies, thus, do not decide the problems of dietary fats, blood lipids, and atherosclerosis. Diets very low and, conversely, those high in fat are compatible with low plasma cholesterol concentrations. Even diets high in saturated fats are associated with low chol- esterol, in spite of the careful clinical and metabolic studies in this country that seem to show the opposite. Undoubtedly, other environmental conditions must be taken into account, especially energy expenditure (physical exercise). Genetic influences, although unlikely, are not so far excluded. 41
