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National Research Council (US) Committee on Diet and Health. Diet and Health: Implications for Reducing Chronic Disease Risk. Washington (DC): National Academies Press (US); 1989.
Lipids are compounds that are insoluble in water but are soluble in organic solvents such as ether and chloroform. Lipids that are important to our discussion include fats and oils (triglycerides or triacyglycerols), fatty acids, phospholipids, and cholesterol.
Fats and oils are esters of glycerol and three fatty acids. They are important in the diet as energy sources and as sources of essential fatty acids and fat-soluble vitamins, which tend to associate with fats. They also contribute satiety, flavor, and palatability to the diet.
Fatty acids generally consist of a straight alkyl chain, terminating with a carboxyl group. The number of carbons in the chain varies, and the compound may be saturated (containing no double bonds) or unsaturated (containing one or more double bonds). Short- and medium-chain saturated fatty acids (SFAs) (4 to 12 carbons in length) are found in milk fat, palm oil, and coconut oil. Other animal and vegetable fats contain predominantly longer-chain SFAs (more than 14 carbons in length) and are found chiefly in meats, butterfat, and some vegetable oils. Monounsaturated fatty acids (MUFAs), such as oleic acid, contain one double bond per molecule, whereas polyunsaturated fatty acids (PUFAs), such as linoleic acid, contain more than one. Linoleic acid is classified as an essential nutrient, since the body requires it but cannot synthesize it. Arachidonic acid is also required by the body but can be synthesized from linoleic acid, which is abundant in oils from corn, soybeans, and safflower seeds.
Linoleic acid (18 carbons with 2 double bonds) and arachidonic acid (20 carbons with 4 double bonds) belong to the omega(ω)-6 group of fatty acids, since the first double bond, counting from the methyl end of the molecule, occurs at carbon number 6. Since linoleic acid has 18 carbon atoms and 2 double bonds, it is usually represented in shorthand as C18:2, ω-6. Under this classification system, oleic acid (C18:1, ω-9) belongs to the ω-9 group, and the PUFAs in fish oils currently receiving much attention belong to the ω-3 group. Chief among these ω-3 fatty acids are eicosapentaenoic acid (EPA), which has 20 carbons and 5 double bonds (C20:5, ω-3), and docosahexaenoic acid (DHA), which has 22 carbons and 6 double bonds (C22:6, ω-3).
A growing body of evidence from studies in animals, including nonhuman primates, indicates that α-linolenic acid, or its longer-chain derivates EPA and DHA, are essential in the diet. These fatty acids appear to play distinctive roles in the structure and function of biologic membranes in the retina and central nervous system (Neuringer and Connor, 1986).
Unsaturated fatty acids form geometric isomers, i.e., the carbon chains are on the same side of the double bond in a cis isomer and on opposite sides of the bond in a trans isomer. Naturally occurring geometric isomers in food are mainly cis isomers, but hydrogenation of oils in the manufacture of margarine and shortening results in formation of some trans isomers. This latter process occurs naturally in the rumen of ruminants.
Phospholipids contain glycerol, fatty acids, phosphate, and, with such exceptions as phosphatidylglycerol and phosphatidylinositol, a nitrogenous component. Lecithin, for example, is made up of glycerol, two fatty acids (one saturated, usually), phosphate, and choline. Phospholipids are important structural components of brain and nervous tissue, of membranes throughout body tissues, and of lipoproteins—the carriers of cholesterol and fats in the blood.
Cholesterol and plant sterols, such as sitosterol, are high-molecular-weight alcohols with a characteristic cyclic nucleus and are unrelated to the structure of fats or phospholipids. Cholesterol frequently exists in foods and body tissues esterified to one fatty acid per molecule. It is a component of membranes in body cells and is required for normal development of the brain and nervous tissue. Furthermore, it is the precursor to bile acids, steroid hormones, and 7-dehydrocholesterol in the skin, which in turn is the precursor to vitamin D.
Cholesterol occurs naturally only in foods of animal origin. The highest concentrations are found in liver and egg yolk, but red meats, poultry (especially the skin), whole milk, and cheese make significant contributions to the diet.
Trends in the Food Supply
Trends in the quantities of lipids present in the food supply have been recorded by the U.S. Department of Agriculture (USDA) since 1909. These data represent amounts of lipids that "disappear" into wholesale and retail markets. No account is taken of amounts wasted, and no effort is made to measure intakes by individuals. Thus, food supply data do not represent amounts of lipids actually consumed and are referred to here as amounts available for consumption (see Chapters 2 and 3). Total amounts available are divided by the U.S. population to obtain amounts per capita. The following data on time trends were obtained from Marston and Raper (1987).
Fat available in the food supply increased from an average of 124 g/day per capita in 1909 to 172 g/day in 1985. Although the chief sources of fat during that time have been fats and oils; meat, poultry, and fish; and dairy products, great changes within each of these groups have occurred. The proportion of animal fat declined from 83 to 58% as butter and lard use declined, whereas the proportion of vegetable fat (in margarines and in salad and cooking oils) rose from 17 to 42%. Pork and beef have been major sources of fat in the food supply since 1909, but supplies of beef have declined somewhat recently from 90.7 lb/year per capita in 1975 to 79 lb/year in 1985. The supply of poultry has increased spectacularly since 1940 and continues to increase. In 1985, 70 lb per capita were available compared with 46 lb per capita from 1967 to 1969. The per-capita availability of whole milk dropped from 232 lb during 1967-1969 to 122 lb in 1985, whereas skim and low-fat milks increased from 44 to 112 lb (see Chapter 3).
Fatty acids available in the food supply have all increased since 1909, but the relative contributions of specific fatty acids have changed. The percentage of calories contributed by linoleic acid to total fat intake increased from 7% during 1909-1913 to about 16% in 1985, whereas the corresponding percentage from SFAs declined from approximately 42 to 34% (Figure 3-5). In 1985, linoleic acid was available at 7% of total calories, SFAs at 15%, and oleic acid at 17%.
Cholesterol availability reached its lowest levels of 464 mg/day per capita in 1917 and 1935, and its highest level of 596 mg/day in 1945. The supply declined to 480 mg/day per capita during 1977-1979, when it plateaued; the decline was due to diminished use of whole milk, butter, eggs, and lard. Food sources of cholesterol have changed somewhat over the century. In 1909, meat, poultry, and fish furnished 28% of the cholesterol in the food supply; in 1985, they supplied 40%. Fats and oils supplied 12% of the total cholesterol in 1909, but only 5% in 1985. Egg use has declined, but in 1985 still supplied 40% of the cholesterol in the food supply (see Chapter 3).
Lipid Intake: National Surveys
Actual intakes of various lipids have been estimated in national surveys, but the different surveys fail to agree on trends in actual consumption of fat. Data from the USDA"s Nationwide Food Consumption Surveys (NFCS) of 1955, 1965, and 1977-1978 show little change in fat levels used by households, but mean individual intakes were lower during 1977-1978 than in 1965 (USDA, 1984). Furthermore, compared with 1977-1978, a decline in fat intake was indicated in the 1985 and 1986 USDA Continuing Survey of Food Intakes of Individuals (CSFII) (USDA 1986, 1987). On the other hand, data from the National Health and Nutrition Examination Surveys (NHANES) do not support a decline in fat intake. For example, data from the first and second NHANES (19711974 and 1976-1980, respectively) indicate that for women 19 to 50 years of age, mean fat intakes remained stable during the 1970s and early 1980s (see Table 3-4). Systematic biases due to methods used in the surveys appear to explain these differences in estimates of fat intake. For example, in the 1985 and 1986 CSFIIs, interviewers tried to determine whether or not fat was trimmed from meat and the skin removed from poultry before these foods were consumed, but this was not done in the 1977-1978 CSFII.
The 1985 and 1986 CSFIIs indicated that fat provided an average of 36 to 37% of total calories for men and women and 34% for children. The 1977-1978 NFCS reported an average of 41% of total calories as fat for women in this age group, but as noted above, the results of this survey were higher than those of other surveys.
On the basis of 4 nonconsecutive days of intake by women and their children, and on 1 day of intake by men, men and women 19 to 50 years of age consumed a mean of 13% of total calories from SFAs, 14% from MUFAs, and 7% from PUFAs. Children 1 to 5 years old consumed a mean of 14% of calories as SFAs, 13% as MUFAs, and 6% as PUFAs (USDA, 1986, 1987).
The daily intake of cholesterol averaged 280 mg for women 19 to 50 years old (187 mg/1,000 kcal) and 223 mg for children 1 to 5 years old (156 mg/ 1,000 kcal) (USDA, 1987). Intakes for men 19 to 50 years old averaged 439 mg/day (180 mg/1,000 kcal) (USDA, 1986). Cholesterol intake was higher in low-income groups than in high-income groups; black women had higher intakes than white women, but white men had higher intakes than other men.
In the 1977-1978 NFCS, people from infancy to 75 years of age and older averaged 385 mg of cholesterol per day (USDA, 1984). Dietary cholesterol levels, in absolute amounts and in mg/ 1,000 kcal, were higher for blacks, for those below the poverty level, for those living in the South and West, and for those living in inner cities.
In the 1985 CSFII, dietary cholesterol came chiefly from meat (48% for men and 45% for women). Eggs provided 18% of the cholesterol intake for men and 15% for women, and grain products furnished 17% of the cholesterol intake for women and 14% for men, but these figures are somewhat misleading in that grain products furnished cholesterol only because they contained milk, butter, and eggs. The milk group provided 14% of the cholesterol intake for men and 16% for women.
Atherosclerosis and Cardiovascular Disease
Arterial lesions characterized by intimal thickening, lipid accumulation, and calcification in humans were identified and described at least as early as the seventeenth century. The lesions were named arteriosclerosis in 1829, and the distinctive form associated with lipid deposition was named atherosclerosis in 1904. However, atherosclerosis was not considered a common cause of death until decades after Herrick (1912) linked coronary atherosclerosis to thrombosis and myocardial infarction. Coronary heart disease (CHD) reached epidemic proportions in the United States before dietary fats were seriously suspected of being causative agents around 1950.
The first recorded evidence that diet had any association with atherosclerosis was the observation by Ignatovski (1908) that rabbits fed meat, milk, and eggs developed arterial lesions resembling atherosclerosis in humans. Anitschkow and Chalatow (1913) then identified cholesterol as the dietary component responsible for hypercholesterolemia and atherosclerosis in rabbits. In subsequent years, investigators demonstrated that many animal species were susceptible to dietary cholesterol, but this phenomenon was considered a laboratory curiosity that had no relevance to human nutrition nor to the rising incidence of CHD and related diseases in the Western world during the first half of the twentieth century.
De Langen, a Dutch physician working in Java, reported in 1916 that native Indonesians had lower levels of plasma cholesterol than did colonists from the Netherlands and associated this observation with a much lower frequency of CHD in the natives. He also observed that Javanese stewards on Dutch passenger ships who ate typical Dutch food had high plasma cholesterol levels and precocious CHD. These observations, published in Dutch in an obscure journal (De Langen, 1916, 1922), lay unnoticed for more than 40 years. In 1934, Rosenthal noted that the distribution of atherosclerosis and atherosclerotic diseases in many parts of the world corresponded to the consumption of fats and cholesterol (Rosenthal, 1934a,b,c).
The next published association of dietary fats with atherosclerosis and cardiovascular disease was the comment by Snapper (1941), based on his experience at Peking Union Medical College, that the high unsaturated fatty acid and low cholesterol content of the Chinese diet might be responsible for the remarkable scarcity of arteriosclerosis in China. This observation also lay unnoticed until after World War II, when reports that deaths from cardiovascular disease, especially those due to arteriosclerosis, declined dramatically in Scandinavia during the war when meat, eggs, and dairy products were scarce (Biörk, 1956; Malmros, 1950; Strøm and Jensen, 1951; Vartiainen, 1946; Vartiainen and Kanerva, 1947).
During the same period, a number of case-control studies of patients with myocardial infarction showed that affected people had higher serum cholesterol levels than did controls (Davis et al., 1937; Gertler et al., 1950b; Lerman and White, 1946; Morrison et al., 1948; Poindexter and Bruger, 1938; Steiner, 1948). The association of serum cholesterol concentrations with atherosclerosis and myocardial infarction was widely recognized by 1946 (Dock, 1946). The predictive value of serum cholesterol concentration for CHD was firmly established by the Framingham Study in 1957 (Dawber et al., 1957) and was confirmed by many similar longitudinal studies in the 1950s and 1960s (Pooling Project Research Group, 1978).
Nevertheless, appreciation of the relationship of diet to serum cholesterol levels, and thereby to CHD, developed more slowly. Although there had been an accumulation of epidemiologic evidence (mainly ecological correlations) supporting the concept that diet, especially dietary fat, was associated with elevated serum cholesterol concentrations and with CHD (Keys, 1957; Keys and Anderson, 1954), there also was much skepticism, as illustrated by the comments of Yudkin (1957), Yerushalmy and Hilleboe (1957), and Mann (1957).
Early in the 1950s, the serum-cholesterol-lowering effects of PUFAs were discovered, and epidemiologic and human experimental studies were focused on this issue. The role of dietary cholesterol remained uncertain until the 1960s, when several careful experiments in humans showed that it had a modest but definite effect. The early development of these concepts, along with the controversies, are found in reviews of the topic by Keys (1957, 1975) and Ahrens (1957). Subsequent sections of this chapter review in detail the epidemiologic and experimental evidence on the relationship between serum cholesterol and CHD, between diet and serum cholesterol, and between diet and CHD.
Functions and Transport Mechanisms"
Lipids are insoluble in water and circulate in plasma in association with certain specific proteins called apolipoproteins. The lipoproteins are large, macromolecular complexes of apolipoproteins and lipids in varying proportions. The four classes of specific lipoproteins that circulate in plasma are called chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
The primary function of plasma lipoproteins is lipid transport. The major lipid transported in lipoproteins—triglyceride—is only slightly soluble in water, yet up to several hundred grams must be transported through the blood daily. Hence, transport mechanisms have evolved to permit the packaging of thousands of triglyceride molecules in individual lipoprotein particles, which deliver the transported lipid to specific cells. Fatty acids esterified to glycerol constitute approximately 90% of the mass and about 95% of the potential energy of the triglyceride molecule. Free fatty acids are transported in noncovalent linkage as albumin-fatty acid complexes. This latter mode of transport does not permit the high degree of selective targeting of fatty acids to specific sites that is permitted by transport in lipoproteins, but these two modes of fatty acid transport together provide a more versatile system for bulk movement of a major substrate for energy metabolism.
Cholesterol is the other major lipid transported in lipoproteins. It is not used for energy; it is the precursor of steroid hormones and bile acids and is a structural component of cellular membranes. In higher animals, including all mammals, it is transported mainly in the form of cholesteryl esters, which are synthesized in cells or in the plasma compartment itself. As with triglycerides, the transport of cholesteryl esters in lipoproteins permits specific targeting of cholesterol to tissues that require it for structural purposes or for making its metabolic products.
Two of the lipoprotein classes, chylomicrons and VLDL, are composed primarily of triglyceride.
Chylomicrons transport exogenous (dietary) triglyceride, and VLDLs transport endogenous triglyceride. Chylomicrons are not normally present in postabsorptive plasma after an overnight fast. The VLDLs normally contain 10 to 15% of the plasma total cholesterol. LDLs contain cholesterol as their major component and normally contain most (60 to 70%) of the plasma cholesterol. HDLs are approximately half protein and half lipid and usually contain 20 to 30% of the total plasma cholesterol. Lipoproteins are lighter than the other plasma proteins because of their high lipid content. This characteristic permits both the operational classification and the ultracentrifugal separation of the different classes of lipoproteins.
Each lipoprotein class is heterogeneous in its protein constituents. Nine distinct apolipoproteins have been separated and described. Most investigators group the apolipoproteins into five families (designated apo A, apo B, apo C, apo D, and apo E) on the basis of their chemical, immunologic, and metabolic characteristics. Apo A refers to the apolipoproteins (apo A-I and apo A-II) that are primarily, but not exclusively, found in HDL. A third member of the apo A family, apo A-IV, is a minor component of chylomicrons. Apo B is the major apoprotein of LDL but also comprises about 35% of VLDL protein. There are two forms of apo B: a large form called apo B-100 and found in LDL and a smaller form called apo B-48 and produced mainly in the intestine. Apo C represents a group of apoproteins (apo C-I, apo C-II, apo C-III) that were originally described as major components of VLDL but that are also present as minor components in HDL. Apo D is a minor component of HDL. Apo E is a major component of VLDL and a minor one of HDL. The apolipoproteins serve both structural and functional roles. Some apoproteins are ligands for specific cell surface receptors, e.g., apo B-100 and apo E for the LDL (or apo B/E) receptor (Brown and Goldstein, 1986); others are cofactors for enzymes, e.g., apo C-II is a necessary activating cofactor for lipoprotein lipase. For reviews of lipoprotein structure and metabolism, see Havel (1987) and Stanbury et al. (1983).
Epidemiologic Evidence for CHD
Most major epidemiologic studies have focused on white men, but a few have provided information about women and nonwhites of both sexes.
Total Cholesterol (TC)
TC is used in this chapter as an abbreviation for the total cholesterol in either serum or plasma. TC concentration is usually expressed as milligrams of cholesterol per 100 ml of serum or plasma (mg/dl). TC concentrations in serum are about 2% higher than those measured in corresponding plasma (Folsom et al., 1983). Although this difference should be considered in comparing the results of studies with one another when numbers of subjects are large and small systematic biases might affect the comparison, it does not affect the major results or conclusions of studies discussed in this report in which serum or plasma is used in analyses of cholesterol. Thus, TC is used interchangeably for both serum and plasma total cholesterol.
Until the past decade, TC, rather than lipoprotein cholesterol, was measured in most epidemiologic studies because reliable methods for measuring lipoprotein cholesterol in large numbers of people were not available. Therefore, most data on disease risk are based on TC level.
Variation in Mean TC Among Populations
Meanlevels of TC vary widely among populations. In the Seven Countries Study, investigators studied 16 populations of middle-aged men residing in seven countries: Finland, the Netherlands, Italy, Yugoslavia, Greece, the United States, and Japan (Keys, 1970, 1980b). Examination methods, laboratory procedures, and quality control procedures were standardized. Mean TC for men ages 50 to 54 years varied from 157 mg/dl in a Japanese population to 262 mg/dl in eastern Finland (Keys, 1980b). In the Ni-Hon-San Study, three population-based samples of men of Japanese ancestry were compared. Mean TC levels for men ages 50 to 54 were 182, 219, and 228 mg/dl in Japan, Hawaii, and California, respectively (Nichaman et al., 1975). In the Israel Ischemic Heart Disease Study, the age-adjusted mean TC level in male civil servants age 40 and older varied from 195 mg/dl for those born in Africa to 219 mg/dl for those born in Central Europe (Kahn et al., 1969). Similar differences were found some 15 years later for male and female adolescents and adults in the Jerusalem Lipid Research Clinics Prevalence Study (Halfon et al., 1982a,b).
Other differences among populations have been observed for men in Puerto Rico, Hawaii, and Framingham, Massachusetts (Gordon et al., 1974), and for men and women in London, Naples, Uppsala, and Geneva (Lewis et al., 1978). Some of this evidence is reviewed in the report of a Conference on Health Effects of Blood Lipoproteins (1979). The results of these various studies, particularly the studies of migrants, indicate that the differences in mean TC levels among populations are due largely to environmental factors, principally diet, rather than to constitutional factors.
Large population differences in mean TC levels have also been observed among children and adolescents; the pattern of variation in these means closely parallels that of the adult values, but at lower absolute values (Conference on Blood Lipids in Children, 1983).
Variation in CHD Rates Among Populations
Large differences also exist among populations in the incidence of and mortality from CHD and in the prevalence and severity of atherosclerosis. For example, in the Seven Countries Study, age-standardized, 10-year incidence of first major CHD events (myocardial infarction and coronary death) among men free of CHD at entry varied from 3 in 1,000 on Crete to 107 in 1,000 in eastern Finland (Keys, 1980b). Corresponding figures for 10-year CHD mortality were 0 and 68 in 1,000, respectively. In the Ni-Hon-San Study, relative risks of first major CHD event were 0.46, 1.00, and 1.54 for the cohorts in Japan, Hawaii, and California, respectively (Kagan et al., 1981; Marmot et al., 1975; Robertson et al., 1977). Incidence of first major CHD events among middle-aged men in Framingham was twice that in Puerto Rico and Hawaii (Gordon et al., 1974).
Variation in Atherosclerosis Among Populations
In the International Atherosclerosis Project, the extent of atherosclerosis in the coronary arteries and aortas was measured in 23, 207 autopsied people from 19 populations in 14 countries (McGill, 1968b). The mean percentage of intimal surface with raised lesions varied from 6% in Durban Bantu to 18% in New Orleans whites. Differences among populations were noticeable at ages 15 to 24 and marked at ages 25 to 34. With few exceptions, ranking the populations according to extent of raised lesions corresponded closely to ranking them by CHD mortality rate.
Correlations Between Mean TC and CHD Rates Among Populations
Variation in mean TC levels among populations is highly correlated with variation in CHD incidence and extent of atherosclerosis. The correlation coefficient for median level of TC with age-standardized, 10-year CHD death rates for 16 cohorts in the Seven Countries Study wtogether .82 (Keys, 1980b). The correlations between median TC and national CHD death rates for these seven countries at 0, 5, 10, and 15 years after TC was measured to be .86, .90, .93, and also .96, respectively (Rose, 1982). In the International Atherosclerosis Project, there was a correlation of .76 between the extent of atherosclerosis and mean TC concentration in 19 populations (Scrimshaw and Guzman, 1968). Populations with mean TC levels less than 180 mg/dl are largely free of atherosclerosis and CHD, whereas those with mean TC levels above 220 mg/dl are characterized by high rates of CHD (Conference on Health Effects of Blood Lipoproteins, 1979). These results support the conclusion that variation in CHD rates among populations is determined predominantly by differences in levels of TC.
CHD Incidence and Mortality Among Individuals Within Populations
In prospective studies of middle-aged men, TC levels above 200-220 mg/dl are positively associated with risk of CHD in the United States (Pooling Project Research Group, 1978; Stamler et al., 1986) as well as in Norway (Holme et al., 1981), France (Ducimetiere et al., 1980), Japan (Johnson et al., 1968), Israel (Goldbourt et al., 1985), England (Rose and Shipley, 1980), Italy (Italian National Research Council, 1982), Finland, the Netherlands, Greece, and Serbia (Keys, 1980b). The association may be weak or absent in some populations with low mean levels of TC and low absolute risk of CHD, e.g., in rural areas of Bosnia and Croatia (Keys, 1980b; Kozarevic et al., 1976, 1981).
Results have been less consistent regarding the association of TC levels below 200 mg/dl with the risk of CHD. In fact, questions have been raised as to whether the association of serum TC with CHD risk is continuous or whether there is some level of serum TC below which it is not related to risk of CHD (e.g., Goldbourt, 1987). In four of the eight studies in the U.S. Pooling Project, age-standardized incidence of CHD for men ages 40 to 64 years was lower in the second quintile of serum TC (194 to 218 mg/dl) than in the first quintile (8194 mg/dl) (Pooling Project Research Group, 1978). In the Israel Ischemic Heart Disease Study of 9,902 male civil servants 40 or more years old, age-standardized 15-year CHD mortality rates according to quintile of serum TC (<176, 176 to 197, 198 to 216, 217 to 241, and >241 mg/dl) were 4.5, 4.9, 4.4, 6.7, and 10.2 per 100, respectively (Goldbourt et al., 1985). In the same study, however, the corresponding 7-year CHD mortality rates previously showed a steadily increasing pattern: 10, 12, 16, 17, and 30 per 1,000, respectively (Yaari et al., 1981). Also, in that study, the 5-year incidence rates for myocardial infarction were 29, 39, and 60 per 1,000 for men in the serum TC tertiles of 77 to 189, 190 to 219, and 220 to 500 mg/dl, respectively (Medalie et al., 1973).
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Many other large prospective studies have also shown a clear monotonic association of CHD with TC levels below 200 mg/dl. In the Hiroshima Adult Health Study of 4,256 men age 40 and older, 6-year age-standardized CHD morbidity ratios associated with three levels of TC (<180, 180 to 219, and >220 mg/dl) were 72, 162, and 333, respectively (100 representing risk for the whole group) (Johnson et al., 1968). Ten-year CHD mortality rates among 17,718 British civil servants ages 40 to 64 according to quintile of TC (<159, 159 to 183, 184 to 203, 204 to 233, and >233) were 28, 34, 36, 44, and 54 per 1,000, respectively (Rose and Shipley, 1980). In the Framingham Study, the 20-year CHD incidence for men ages 33 to 49 according to level of TC (114 to 193, 194 to 213, 214 to 230, 231 to 255, and 256 to 514 mg/dl) was 86, 153, 220, 268, and 306 per 1,000, respectively (Kannel and Gordon, 1982). Among 356,222 men ages 35 to 57 who were initially screened in the Multiple Risk Factor Intervention Trial, age-standardized 6-year CHD mortality increased steadily according to decile of TC from 3 per 1,000 for TC <168 mg/dl to 13 per 1,000 for TC >263 mg/dl (Stamler et al., 1986). The data for that trial are shown in Figure 7-1.