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Page 159 7 Fats and Other Lipids 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(w)-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, w-6. Under this classification system, oleic acid (C18:1, w-9) belongs to the w-9 group, and the PUFAs in fish oils currently receiving much attention belong to the w-3 group. Chief among these w-3 fatty acids are eicosapentaenoic acid (EPA), which has 20 carbons and 5 double bonds (C20:5, w-3), and docosahexaenoic acid (DHA), which has 22 carbons and 6 double bonds (C22:6, w-3). A growing body of evidence from studies in animals, including nonhuman primates, indicates that a-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
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Page 160 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 lipoproteinsthe 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
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Page 161 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. Evidence Associating Dietary Fats and Other Lipids with Chronic Diseases 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
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Page 162 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. Plasma Lipids and Lipoproteins 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 lipoproteinstriglycerideis 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.
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Page 163 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). Relationship of Plasma Lipid and Lipoprotein Levels to Atherosclerotic Cardiovascular Diseases 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
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Page 164 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 Inthe 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 was .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 were .86, .90, .93, and .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 (<194 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, how-
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Page 165 ever, 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). 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. In that trial the 6-year mortality rate doubled between 153 and 226 mg/dl (3.16 to 6.94 per 1,000) and doubled again between 226 and 290 mg/dl (6.94 to 13.05 per 1,000). The weight of evidence supports the idea that TC level, at least from 150 mg/dl upward, is positively associated in a continuous fashion with CHD risk. Because the incidence of CHD is low at TC levels under 200 mg/dl, occasional exceptions to this rule are more likely due to statistical artifact than to biologic diversity. Results from the observations of screenees in the Multiple Risk Factor Intervention Trial also indicated that the association between TC and 5-year risk of CHD death for 23,490 black men was similar to that for 325,384 white men (Neaton et al., 1984). The association between TC and the relative risk of CHD declines with age. In the pooled results of five U.S. studies, the relative risk of CHD in the highest quintile of TC (>256 mg/dl) compared to FIGURE 7-1 Relationship of serum cholesterol to CHD death in 361,662 men ages 35 to 57 during an average followup of 6 years. From Martin et al. (1986). Each point represents the median value for 5% of the population. the lowest quintile (<194 mg/dl) (defined as the ratio of the risks in these two groups) was 3.6, 1.9, 1.8, and 1.5 for men ages 45 to 49, 50 to 54, 55 to 59, and 60 to 64, respectively (Pooling Project Research Group, 1978). This observation has sometimes been misinterpreted to mean that the level of TC is relatively unimportant in elderly people. The committee believes that this misinterpretation may arise from failure to distinguish between the concepts of relative risk (the ratio between two risks) and attributable risk (the difference between two risks). The former is commonly used to evaluate the magnitude of an epidemiologic association; the latter is commonly used to evaluate its public health importance. In fact, in the set of studies cited above, the attributable risk (calculated as the difference in risk between the highest and lowest quintiles) did not vary consistently with age. Thus, the corresponding attributable risks were 46, 28, 40, and 42 per 1,000 in 8 years for men ages 45 to 49, 50 to 54, 55 to 59, and 60 to 64, respectively. Atherosclerosis at Autopsy TC measured by standardized procedures in apparently healthy men was strongly associated with extent of atherosclerosis at autopsy in the Hiroshima Adult Health Study (Rickert et al., 1968), Honolulu Heart Program (Reed et al., 1987; Rhoads et al., 1978),
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Page 166 the Framingham Study (Feinleib et al., 1979), the Oslo Study (Holme et al., 1981), and the Puerto Rico Heart Study (Sorlie et al., 1981). There are few data on women. In the Framingham Study, the extent of coronary atherosclerosis in men was positively correlated with TC measured 1, 5, and 9 years before death; in women, only TC measured 9 years before death but not TC measured 5 and 1 years before death correlated significantly (Feinleib et al., 1979). In the Bogalusa Heart Study, TC measured at 3 to 18 years of age was correlated (R = .67) with percentage of aortic intimal surface involved with fatty streaks as measured during the autopsies of 35 people who died between 7 and 24 years of age (Newman et al., 1986; Strong et al., 1986). Correlations with raised lesions and with lesions in the coronary arteries could not be reliably determined in this series because only 6 people had fibrous plaques and the extent of coronary intimal surface involved in fatty streaks was small, varying only from 0 to 6% (mean, 1%). In a follow-up of the initial report, Freedman et al. (1988) increased the number of cases to 44 and examined the relationship within races. As anticipated, blacks had more extensive fatty streaks than did whites, but there also was a strong positive association between the extent of aortic fatty streaks and the LDL cholesterol concentration within each race group. In summary, epidemiologic findings among populations and for individuals within populations consistently indicate a strong, continuous, and positive relationship between TC levels and the prevalence and incidence of, as well as mortality from, atherosclerotic CHD. This relationship has been confirmed in autopsy studies. LDL and HDL Cholesterol There is less epidemiologic evidence on lipoprotein cholesterol than on TC. Few early studies included measurements of lipoprotein cholesterol because of technical difficulties and cost. Differences Among Populations Lipoprotein cholesterol was not measured in the Seven Countries Study; thus, variation among populations is less well characterized for LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) than for TC. Apparently, average values of LDL-C vary widely among populations, but the evidence is less clear for HDL-C. In the Four European Communities Study, mean LDL-C varied from 116 to 168 mg/dl for men and from 114 to 146 mg/dl for women; in contrast, mean HDL-C varied only from 52 to 55 mg/dl for men and from 60 to 64 mg/dl for women (Lewis et al., 1978). In the 1950s, studies of three groups of sedentary Japanese men matched for fatness showed that mean b-lipoprotein cholesterol (LDL-C) was 120, 183, and 213 mg/dl for those residing in Shime, Honolulu, and Los Angeles, respectively; corresponding mean values for a-lipoprotein cholesterol (HDL-C) were 40, 40, and 35 mg/dl (Keys et al., 1958b). Results from the Jerusalem Lipid Research Clinic Study showed that differences in mean TC according to place of birth (Asia, North Africa, Europe, and Israel) were due mainly to differences in LDL-C (Harlap et al., 1982). On the other hand, a preliminary report of a survey of men in 13 countries indicated that mean HDL-C varied from 27 mg/dl in an African population to 58 mg/dl in eastern Finland (Knuiman and West, 1981). In a study of schoolboys 6 to 7 years old selected from 26 rural and urban populations in 16 countries (Knuiman et al., 1980), mean HDL-C varied from 31 mg/dl in rural Nigeria to 65 mg/dl in rural Finland and correlated (.90) with mean TC. The basis for these different results is not clear. There is no firm evidence regarding the ecological association of mean HDL-C to risk of CHD. In one study, a correlation of -.57 was found between mean HDL-C and CHD mortality for 19 countries (Simons, 1986), but these results were based on nonstandardized measurements of undefined samples of people. Knuiman and West (1981) obtained standardized measurements of HDL-C in a survey of small samples of men in 13 countries and found a correlation of .57 with national CHD mortality in those countries. One of the lowest population mean values for HDL-C was found in Mexico in Tarahumara Indians, who also had very low values of LDL-C and TC (Connor et al., 1978). Thus, the extent to which variation among populations in CHD rates may be affected by (associated with) variations in mean HDL-C levels is uncertain. Clearly, the association is substantially less than that between population CHD rates and mean LDL-C levels. Differences Among Individuals Baseline levels of LDL-C were positively associated with risk of CHD in men and women ages 50 to 79 years in the Framingham Study (Gordon et al., 1977), in Israeli male civil servants age 40 and older (Medalie et al., 1973), and in men ages 35 to 57, black and white, separately identified, who were assigned to the Usual-Care Group in the Multiple Risk
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Page 167 Factor Intervention Trial (Watkins et al., 1986). Change in LDL-C level has also been related directly to change in CHD risk; among hypercholesterolemic men treated with cholestyramine, reduction of 11% in LDL-C was associated with a decrease of 19% in risk of CHD (Lipid Research Clinics Program, 1984b). In the Framingham Study, HDL-C was inversely related to incidence of CHD in men and women ages 49 to 82 years (Castelli et al., 1986; Gordon et al., 1977); an increment in HDL-C of 25 mg/dl was associated with nearly a 50% decrement in risk of CHD for men and women after adjustment for age, body mass index (see Chapter 21 for definition), cigarette smoking, systolic blood pressure, and TC (Castelli et al., 1986). Among the hypercholesterolemic men treated with cholestyramine in the Lipid Research Clinics Coronary Primary Prevention Trial, 1 mg/dl increments in HDL-C at baseline and afterward were associated with decrements of 5.5 and 4.4% in risk of CHD, respectively (Gordon et al., 1986). Baseline level of HDL-C was inversely associated with risk of CHD among men assigned to the Usual-Care Group in the Multiple Risk Factor Intervention Trial (Watkins et al., 1986), but the association was weaker than that observed in the Framingham Study or the Lipid Research Clinics Program. These findings of an inverse relationship between HDL-C and CHD have been supported by observations in the Israel Ischemic Heart Disease Study (Goldbourt et al., 1985; Medalie et al., 1973) and in prospective case-comparison studies of frozen serum samples in Oslo (Enger et al., 1979) and in Tromsö, Norway (Miller et al., 1977). HDL-C was not significantly associated with the 24-year CHD death rate in a cohort of 526 Finnish men ages 36 to 61 (Keys et al., 1984) and was only weakly associated with CHD death rate in a cohort of 284 Minneapolis business and professional men ages 45 to 55 at entry into the study (Keys, 1980a; Keys et al., 1963). HDL-C was weakly and not significantly (inversely) associated with the incidence of CHD after adjustment for age, body mass index, blood pressure, cigarette smoking, and non-HDL cholesterol in the British Regional Heart Study (Pocock et al., 1986). A study of men in the USSR also failed to find an inverse association between HDL-C and CHD (Levy and Klimov, 1987). In the Oslo Study of men ages 40 to 49 years at entry in 1972 and 1973, antemortem measurements of plasma lipids and other characteristics were available for 129 men for whom there were also postmortem measurements of the extent of atherosclerosis. The percentage of the coronary intimal surface involved with raised lesions was positively correlated with TC (.32) and negatively correlated with HDL-C (-.25) (Holme et al., 1981). Although changes in HDL-C are related to changes in CHD risk in most populations, the benefit that can be expected from raising HDL as a preventive strategy in itself is not entirely clear. Added benefit, over that derived from lowering LDL, is suggested, however, by the long-term results of the Coronary Drug Project (Canner et al., 1986), by the results of the Cholesterol Lowering Atherosclerosis Study (Blankenhorn et al., 1987), and by those of the Helsinki Heart Study (Frick et al., 1987; Manninen at al., 1988), in which HDL-C was raised and TC, LDL-C, and VLDL-C were lowered. Among people ages 50 to 79 years in the Framingham Study, the ratio of TC to HDL-C was strongly associated with risk of CHD in men and women. The strength of the association was not significantly improved by adding TC or HDL-C to the equation containing this ratio (Castelli et al., 1983). A similar result was obtained with the ratio of LDL-C to HDL-C for women, but information about the level of LDL-C did add to the strength of the association in men. The authors concluded that ratios can be useful predictors of risk, but warned that they may not always be as informative as the joint use of the two individual figures used to calculate the ratio. It seems reasonable to expect that increasing knowledge about the various classes and subclasses of lipoproteins will lead to improved ability to predict risk of atherosclerotic diseases. Whether these prediction formulas will take the form of ratios or more detailed specifications of lipoprotein levels is uncertain. Although the ratio of TC or LDL-C to HDL-C may be a very good predictor of CHD risk in the U.S. population, it is probably not the best target for clinical management or therapy. The recent report of the National Cholesterol Education Program (1988) identified the absolute level of LDL-C as the key index for clinical decision-making about cholesterol-lowering therapy and as the specific target for therapy. The authors of the report stated, ''Reliance on a ratio of either total or LDL-cholesterol to HDL-cholesterol as a key factor in decisions regarding treatment is not a practice recommended in this report. Blood pressure and smoking are not combined into a single number because the clinician needs to know both facts
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Page 168 separately in order to recommend an intervention. Similarly, HDL-cholesterol and LDL-cholesterol are independent risk factors with different determinants, and combining them into a single number conceals information that may be useful to the clinician" (National Cholesterol Education Program, 1988). In summary, of the lipoprotein fractions, LDL has the strongest and most consistent relationship to individual and population risk of CHD. HDL has generally been found to be inversely associated with risk of CHD in individuals within a population, but in at least three long-term population studies, this inverse association was not seen (Keys et al., 1984; Levy and Klimov, 1987; Pocock et al., 1986). Population rates of CHD are much more strongly related to average TC and LDL-C values than to HDL-C. These findings (together with the results of animal experiments and clinical research reviewed later in this chapter) strongly support the conclusions that LDL-C is centrally and causally important in the pathogenic chain leading to atherosclerosis and CHD. Variation in LDL-C levels explains a large part of individual risk within high-risk cultures and explains almost all the differences in CHD rates among populations. HDL-C is associated inversely with individual susceptibility to CHD within populations where there is widespread elevation of LDL-C and TC. Data are inadequate to characterize ratios of LDL to HDL as a major determinant of the atherosclerotic disease burden among populations; however, the ratio provides improved individual prediction, again within high-risk, high-LDL cultures. Apolipoproteins Apolipoproteins play key roles in both the structure and function of plasma lipoproteins. Research on the molecular structure, genetic variability, and metabolism of plasma apolipoproteins has progressed rapidly in recent years, particularly with the application of the new techniques of molecular biology. Knowledge about apolipoproteins has added greatly to our understanding of lipoprotein metabolism and how it is related to atherosclerosis. In a number of instances, genetically controlled variations in apolipoproteins affect lipoprotein structure, composition, and metabolism. For example, polymorphic forms of apolipoprotein E (apo E) interact with dietary fats to influence plasma lipoprotein concentrations, and assessment of apo E phenotypes is an essential procedure in the diagnosis of familial dysbetalipoproteinemia. However, the evidence currently available does not clearly show that plasma apolipoprotein levels are better predictors of CHD than are the plasma levels of cholesterol in the major lipoprotein classes. Apo E Polymorphism and Hyperlipidemia In 1977, Utermann et al. (1977, 1979) demonstrated that genetic polymorphisms in apo E were associated with different plasma cholesterol, LDL-C, and b-VLDL concentrations. The apo E phenotypes were shown to be due to segregation of three alleles at a single locus (Zannis and Breslow, 1981) and the major isoforms to be determined by substitution of the amino acid cysteine for arginine (Weisgraber et al., 1981). The three major isoforms are called apo E2, E3, and E4. If the most common phenotype, designated E3/3, is considered to be normal, women who are heterozygous, with phenotype E3/2, have more than 40% higher plasma VLDL-C and intermediate-density-lipoprotein (IDL)-C levels, and 12% lower LDL-C levels (Robertson and Cumming, 1985). Men with the E3/2 phenotype have an approximately 15% increase in plasma VLDL-C and IDL-C concentrations and 20% lower LDL-C concentrations. The E2/2 phenotype is uncommon but is associated with extreme variations in plasma lipoprotein levels. Patients with familial dysbetalipoproteinemia (type 3 hyperlipoproteinemia) generally have the E2/2 phenotype. Most people with this phenotype do not have familial dysbetalipoproteinemia, however, and in fact have lower plasma cholesterol levels than the general population (see Davignon et al., 1988). In contrast, the presence of the E4 allele (and the E4/3 or 4/4 phenotype) appears to be associated with an increased level of LDL and an increase in coronary risk. Thus, a single amino acid substitution in one apolipoprotein can have a substantial effect on plasma cholesterol concentrations and on the plasma lipoprotein profile. This topic has been reviewed thoroughly by Davignon et al. (1988). The Apolipoproteins and Atherosclerosis In the 1980s, the availability of better methods for fractionating lipoproteins, for measuring serum apolipoproteins, and for detecting apolipoprotein variants made possible a new series of studies that sought relationships among lipoproteins, apolipoproteins, and atherosclerosis. This topic was reviewed by Brunzell et al. (1984) and by Wallace and Anderson (1987). Ishikawa et al. (1978) were among the first to examine the relationship of plasma apolipoprotein concentrations to CHD. In the Tromsö Heart
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Page 169 Study, apo A-I levels were associated inversely with CHD, but were less powerful predictors than HDL-C levels. A number of investigators subsequently compared CHD patients with controls and generally found apo B levels higher and apo A-I and apo A-II levels lower in diseased subjects (DeBacker et al., 1982; Fager et al., 1980, 1981; Franceschini et al., 1982; Maciejko et al., 1983; Naito, 1985; Onitiri and Jover, 1980; Riesin et al., 1980; Sniderman et al., 1980; Whayne et al., 1981). However, these investigators were not in agreement about whether apolipoprotein levels or lipoprotein cholesterol levels were better indicators of CHD. Pilger et al. (1983) used stepwise discriminant analysis to determine which measures best differentiated subjects with and without peripheral vascular disease. The best model included 14 variables, among which, in addition to HDL-C and LDL-C, were apo B, apo A-I, and apo A-II concentrations. Menzel et al. (1983) examined the relationship of six different apo E phenotypes to coronary lesions assessed by angiography in 1,000 patients. Heterozygotes (E3/2) were more frequent in patients with little or no coronary atherosclerosis, but E2/2 homozygosity, despite the presence of b-VLDL in the plasma, was not associated with more severe coronary lesions. Wallace and Anderson (1987) concluded their review by stating that apolipoprotein levels appeared promising as predictors of CHD, but that large cohort studies would be required to determine whether they are better predictors of atherosclerotic disease than plasma lipoprotein lipid levels and whether they are useful clinically. Lp(a) and Human Atherosclerosis The role of lipoprotein(a) [Lp(a)] in atherosclerosis and atherosclerotic heart disease has been controversial ever since Lp(a) was discovered by Berg (1963). The apoprotein of Lp(a) has been shown to consist of two peptidesapo(a) and apo Blinked by one or more disulfide bonds (Gaubatz et al., 1983). The recent sequencing of a cloned apo(a) complementary DNA (cDNA) showed that apo(a) is very similar to plasminogen (McLean et al., 1987). Several studies have shown a relationship between serum Lp(a) levels and CHD (Berg et al., 1974; Dahlén et al., 1975). High scores for coronary arteriosclerosis on angiography were correlated with serum Lp(a) levels (Dahlén et al., 1976). Walton et al. (1974) demonstrated Lp(a) in arterial lesions by immunofluorescence. Overall, the evidence concerning the association of Lp(a) with atherosclerosis is rather scanty, but highly suggestive. Lp(a) levels in plasma are generally believed not to be affected by diet. Lipoproteins and Apolipoproteins in Atherosclerotic Lesions Kao and Wissler (1965) demonstrated the presence of LDL in human lesions by immunofluorescence with rabbit antisera to LDL. Hoff and associates have demonstrated the presence of apo B, apo A-I, and apo C in the arteries of humans and several animal species (Hoff and Gaubatz, 1975; Hoff et al., 1974, 1975a,b,c; Yomantas et al., 1984). The same investigators quantified apo B in lesions (Hoff et al., 1977a,b, 1978, 1979b; reviewed by Hoff and Morton, 1985) and showed that LDL in lesions differed from plasma LDL (Hoff and Gaubatz, 1982; Hoff et al., 1979a). LDL in lesions stimulated the production of cholesteryl esters by macrophages (Clevidence et al., 1984; Goldstein et al., 1981). Apo A-I-containing lipoprotein extracted from arteries also differed in composition from plasma HDL (Heideman and Hoff, 1982). These studies clearly show that apo B-containing lipoproteins accumulated in atherosclerotic lesions. LDL from atherosclerotic lesions contained particles larger than those found in plasma LDL, was more electronegative, and stimulated cholesterol esterification in mouse peritoneal macrophages. The extent to which these alterations in LDL occurred in the arterial intima, after the LDL had entered the vessel wall, is not clear. This combined evidence implicates apo B-containing lipoproteins in the pathogenesis of atherosclerosis. Apolipoproteins and Dietary Responsiveness In view of the critical roles of apolipoproteins in lipoprotein metabolism, genetic variants in addition to those of apo E probably influence the lipemic responses of individuals to dietary fats and thereby affect the risk of CHD. This research area is quite active, and new findings are likely to be available in the near future. Summary Apolipoproteins show promise of helping us to understand the mechanisms linking diet to atherosclerosis and cardiovascular disease, but as yet they have not provided predictive power for atherosclerotic diseases beyond that provided by plasma lipid and lipoprotein cholesterol concentrations. They are not now useful in assessing the relationship of dietary fats to atherogenesis or
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Representative terms from entire chapter: