Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
ATHEROSCLEROSIS (ARTERIOSCLEROSIS) The Nature of Atherosclerosis Atherosclerosis is a disease that first involves the arterial intima. The early lesions consist of fatty changes in the arterial walls that may result in formation of atheromas. Advanced lesions of atheroma are composed of fibrous masses of lipid, collagen, hyalin, and fibrin, in which areas of recent and old hemorrhage abound in a vascularized tissue framework (204). Deposits of iron, cholesterol (both in free form and as esters), triglycerides, phospholipids, ceroid pigment, and calcium salts are prominent. The elastic elements in the intimal tissue are frayed or absent, and the medial layer may be replaced by sclerotic tissue. The latter changes appear to be secondary. Large atheromatous plaques in the aorta are more common in the abdominal portion than in the thoracic portion. They occur most frequently around orifices of branches and, accordingly, are more numerous in the posterior wall. Lesions are often less advanced in coronary arteries than in more distal arteries. The left coronary artery is more frequently affected than the right coronary artery. With ulceration of lesions, formation of a clot attached to the vessel wall (mural thrombosis) develops which, if it occurs in a coronary artery, may lead to occlusion and often fatal infarction. Occlusive thrombosis in coronary arteries occurs, however, more frequently than can be accounted for by ulceration. The precise morphologic counterpart of human atherosclerosis has not been produced in any experimental animal. In some experimental animals with lesions induced by cholesterol feeding, abnormal deposits of cholesterol are found not only in blood vessels but also to varying extent in liver, spleen, lung, kidney, and tongue (143). Such visceral deposits are absent in athero- sclerosis of man. Much experimental work centering on cardiovascular disease has dealt with atheroma and has not included its complications, such as thrombosis. Yet the factors that initiate atheroma may 23
Dietary Fat and Human Health not necessarily be identical with those responsible for its fatal complications. Myocardial infarction with formation of mural thrombi has been induced in rats on a drastically altered dietary regimen (89). Numerous hypotheses regarding the initiation of atheromatous lesions have been considered. Among these are: vascular injury, trauma or inflammation; abnormal lipid synthesis in the arterial tissue; abnormal plasma lipids; thrombus formation; degenerative change in the protein of the elastic membranes, media, or intimal tissue; prolonged hypertension; and abnormal activities of certain hormones. Thus, both chemical and mechanical factors have been postulated as causes of this cardiovascular disease. Many workers have pointed out that the variable focal distribution of atherosclerosis in the arterial system implies that some local factor or factors operate in initiation and development of the disease. Any hypothesis centering on an atherogenic toxin in the diet as the cause of atherosclerosis must recognize that atheroscler- osis is not a disease of modern man, but has been recognized in its present form for several thousand years (122) and in people existing on widely different diets. The abnormal lipid hypothesis regarding the development of atheroma pictures atherosclerosis as originating in some dis- order of lipid metabolism affecting the arterial wall either directly or indirectly and implicating dietary fats and changes in plasma lipids in the pathogenesis. The fact that iron deposits, red blood cells, and fibrous tissue or fibrin as well as lipids are found even in early lesions is sometimes forgotten. Another method of learning about early lesions and their pro- gression is the study of infants, children, and young adults. Only a few studies in children under the age of 15 years have been made, but they are noteworthy because the stage of the lesion can be dated more accurately than in the adult. Fatty streaks have been reported in coronary arteries and aortas at early ages- even a few days after birth. Lipid streaks and even early hyaliniza- tion in coronary arteries of infants and juveniles have been re- ported (155); completely uninvolved coronary arteries were found only in fetuses. Studies (57) of hearts and aortas of young American soldiers in Korea demonstrated that fatal coronary occlusion could occur between 18 and 21 years of age and, in cases of young soldiers killed in battle, advanced coronary lesions were frequently observed. Thus, lesions regarded as preather- omatous were found at an early age, and advanced lesions were found even in the late teens. 24
Atherosclerosis (Arteriosclerosis) Intensified study, with contemporary techniques, of these lesions in children would help to elucidate the true natural history of atheroma. The fact that lesions may have formed by the end of the pediatric period indicates that attention also should be focus- sed on the diet and other factors in this age group. Epidemic- logic factors related to atheroma, such as hypertension and smoking, are not prevalent in children and lesions might be more susceptible to reversal than those in the adult where calcifica- tion and fibrosis are present. Experimental Production of Atherosclerosis Knowledge concerning experimental atherosclerosis, from the standpoint of the pathologic anatomist, has been strengthened during the past decade by at least two major advancesâinvestiga- tions have been conducted on many species other than the chick and rabbit, and electron microscopy has permitted visualization and positive identification of structures in the arterial wall. Morphologic studies of cholesterol-induced atheroma have been reported in many speciesârabbit and chick (10, 39, 47, 106), dog (181), rat (54, 90, 205), mouse (42), guinea pig (7), hamster (68), domestic pig (169), monkey (41, 138, 186, 187), susceptible strain of pigeon (134), duck (106), and prairie gopher (9). From these studies and others, the following points have emerged: 1. Lipid in some form is a prominent feature of lesions in whatever artery (coronary, aorta, etc.) they develop. There is a disagreement, however, as to whether it appears before any other demonstrable change; whether it initially appears as tri- glyceride (or free fatty acid), cholesterol, or cholesterol esters ( at later stages all forms are present); or whether it enters the arterial wall directly, is carried by macrophages (foam cells), or enters by both methods. Some investigators (65) think the lipid may be synthesized in situ by myogenic foam cells in the subintima and inner portion of the media. Ceroid has been found in all models when searched for, as well as in man (87, 88). 2. The foam cell is present in lesions induced in all species. It is much more prominent in some, such as the rabbit, than in others, such as the monkey. The presence of the foam cell is regarded by many as the most important cytologic response of the arterial wall to atherogenic stimuli. A smaller but important body of opinion regards the reaction and modification of smooth muscle cells as an equally fundamental response (210). 25
Dietary Fat and Human Health 3. From studies of early lesions and other approaches (in- jection of thrombi with resultant pulmonary arterial atheroma) (48), intimal deposition of fibrin, platelets, and, in some instances, red blood cells is regarded as the primary and cardinal event by supporters of the thrombogenic theory of pathogenesis of atheroma. Lipid and foam cells are considered to be secondary subsequent additions to the lesion as the thrombus becomes organized and converted to a plaque. Changes occurring more deeply within the wall (intima and media) also are considered secondary to the initial thrombotic event. Most supporters of this hypothesis agree that the fibroblasts are derived from intimal endothelial cells, although certain forms of reticuloendothelial cells in the circu- lating blood have been considered possible precursors of fibro- blasts (8). 4. Edema and abnormal accumulation of mucopolysaccharides (151) have been considered as initiating pathogenic events, but evidence in support of either concept is still inadequate. 5. In all species studied, lesions consisting of foam cells and lipid, and with some proliferation of intimal cells and usually of smooth muscle cells as well (altered or not), can be readily produced. Fibrosis, hyalinization, calcification (egg-shelling), ulceration, and thrombosis are not consistently encountered. All of these features have been reported only in rabbits (39), although most of them have been seen in rats (90). 6. Some evidence suggests that dietary factors enhance blood coagulation and thus the formation of thrombi (see page 29) and that they may be different from those affecting atherogenesis. Relation of Lipids in Normal and Atherosclerotic Arteries to Plasma Lipids Evidence has accumulated indicating that an exchange between plasma lipids and lipids in atherosclerotic arteries exists in man. The deposition of 14 C- labeled dietary cholesterol in the atheromatous aorta, although slow, does occur (167). Plasma cholesterol, likewise, exchanges with arterial-wall cholesterol, although the rate is slower than in any other tissue except brain tissue (21, 35, 121). In normal intima, equilibration with plasma cholesterol probably occurs eventually (35), but the presence of atherosclerosis appears to delay the rate of reaching equilibrium. The factors that influence this rate are not known. 26
Atherosclerosis (Arteriosclerosis) On ordinary diets, the fatty acid composition of the arterial- wall lipids is similar to that in plasma(22, 25, 154, 184, 189). When polyunsaturated fat is substituted for saturated fat in the diet, the degree of unsaturation of the plasma lipids gradually rises and, ultimately, similar changes occur in the arterial wall. When normal aortic intima or media are compared with fatty deposits in the aorta, the only lipid class that showed changes in fatty acid composition were cholesteryl esters (154). The lipid composition in several areas of the aorta in patients with atherosclerosis has been reported (183). Both early and advanced plaques were found to have significantly less linoleic acid and more oleic acid in the cholesteryl ester fraction than plasma from the same individuals. An increase of lipid with age, both in the coronary arteries and in the aorta, has been found in subjects who died of causes unrelated to occlusive coronary disease and was accounted for by the deposition of cholesterol and cholesteryl esters (200). In contrast, in subjects who died from coronary heart disease, 60 percent more cholesteryl ester and 80 percent more cholesterol was found in their coronary arteries (201). No significant increase in triglycerides or phospholipids was found in the latter group, however, there was an increase in ash content of the coronary arteries of the coronary-occlusion group. These studies of atherosclerotic arteries do not support any cause-and-effect hypothesis relating diet to coronary artery disease or to atherosclerosis in general, but do provide evidence of a relationship, although not perfect, between plasma lipids and those in atherosclerotic plaques. Plasma Triglycerides, Obesity, Diabetes, and Atherosclerosis A large portion of plasma lipid is in the form of triglyceride, particularly after a meal. Patients with known coronary artery disease frequently have high plasma triglyceride concentrations (5, 6, 30, 176), and some investigators consider the correlation between increased triglyceride concentration and coronary artery disease to be better than the correlation with plasma cholesterol concentration. Elevated plasma triglyceride con- centration was found to be the most characteristic blood lipid change after myocardial infarction, in the age group between 27
Dietary Fat and Human Health 33 and 50 years (6, 30). The plasma triglycerides are mainly carried in the low-density lipoproteins, so that these recent reports confirm earlier data (66) that indicated that the con- centration of those lipoproteins rich in triglycerides (density 1.006-1.019) correlated more closely with the presence of coronary heart disease than did that of the cholesterol-rich lipoprotein (density 1.019-1.063). There is much evidence to suggest that obesity predisposes to coronary heart disease (203). The Framingham study, how- ever, has revealed only a small risk for obesity alone unless it was very marked or associated with high plasma cholesterol (105). Triglycerides in the plasma were not reported from the Framingham study. In other investigations, weight reduction of obese subjects, even to normal weights, did not correlate importantly with the plasma cholesterol concentration (28, 149). Atherosclerosis is common in individuals with diabetes, and in diabetes the plasma cholesterol and triglyceride concentra- tions are often increased. The concentration of the triglyceride is a well-recognized index of adequacy of control of the disease. Obesity is commonly seen in maturity-onset diabetes and the frequency of atherosclerotic complications in this situation is particularly high. These observations suggest that the metabolic defect or defects leading to diabetes and to high plasma cholesterol and triglyceride concentrations, as well as obesity, may be impor- tant in the pathogenesis of the atherosclerosis. It may be signifi- cant that levels of plasma triglycerides can be reduced in diabetics, overweight nondiabetic adults, patients with coronary artery disease, and most patients with hyperlipemia in a fasting state by the ingestion of diets reduced in calories and carbohydrates and relatively rich in fats, particularly polyunsaturated fats. High-carbohydrate diets, especially in populations that enjoy a sufficiency (if not an excess) of calories, promote lipogenesis which facilitates the manufacture of saturated fats and increases their plasma concentration. Plasma triglyceride concentration also can be lowered by weight reduction. Similarly, increased physical activity results in a reduction of plasma triglyceride concentration, presumably by means of the negative calorie balance. It is not known whether these plasma lipid changes are causally related to atherosclerosis. The plasma cholesterol concentration is still the most likely to correlate with coronary heart disease, perhaps, in part, because it has been studied much longer than the plasma triglycerides. Nevertheless, 28
Atherosclerosis (Arteriosclerosis) recommendations for dietary alterations designed to reduce plasma lipids or prevent rises should take into consideration the possible relationship of triglycerides and atherogenesis and the fact that plasma triglyceride and cholesterol concentrations respond to dietary manipulations somewhat differently. Vitamin E and Lipid Metabolism Vitamin E, or tocopherol, functions as a biological antioxidant (97); that is, it retards the undesirable oxidative rancidification of polyunsaturated fatty acids in tissues. One means of inducing tocopherol deficiency has been to overtax tissue supplies of the vitamin by feeding large amounts of highly unsaturated oils with- out tocopherol (97). Diets rich in polyunsaturated fatty acids must, therefore, contain and be protected by sufficient tocopherol or other biological antioxidants (185). In clinical studies, tocopherol deficiency has resulted from disorders of lipid absorption such as cystic fibrosis of the pancreas (72), chronic pancreatitis (25), sprue, or protein deficiency (45). Although the primary products of lipid autoxidation are dif- ficult to demonstrate in tissues, lipid polymers called ceroid or lipofuscins are relatively easy to demonstrate in human atheromatous lesions, in the smooth muscle of patients with cystic fibrosis of the pancreas (72), and in chronic pancreatitis in adults (26). In animals deprived of vitamin E, ceroid pigment is found in many tissues. Plant oils that have high amounts of linoleic and linolenic acids usually have high levels of total tocopherol (85). The pro- portion of a-tocopherol in the total tocopherols may vary greatly, and some tocopherol may be lost during refining, storage, and cooking. The utilization and storage of both vitamin A and carotene are affected by the amount of tocopherol supplied (150). Effects of Fats on Blood Coagulation and Thrombosis Despite much research, relationships between dietary or blood fats, blood clotting, and atherosclerosis remain uncertain (165). Most studies of this problem have dealt with effects of fats on coagulation mechanisms. It is well established that one or 29
Dietary Fat and Human Health perhaps several phospholipids are among the factors accelerating the first stage of clotting, but no implications with respect to atherosclerosis can be drawn from this information. In experi- mental models simulating the human artery, platelets are essential for thrombus formation. Moreover, diet may affect platelet metabolism (153). After ingestion of some types of fat, blood fibrinolysis may be inhibited but without any relationship to the degree of unsaturation of the fats (80). Exercise in conjunc- tion with a fatty meal decreases this antifibrinolytic activity (79). Thromboembolic phenomena in hospitalized patients (84) were found to be higher in those fed butter and margarine than in those fed vegetable oil with their meals. As a group, patients with ischemic heart disease show increased coagulability by_in vitro clotting tests (141). In vitro tests purporting to show increased coagulability are difficult to interpret at best and are not neces- sarily correlated with the key clinical problemâthat of throm- bosis (137). Alcohol, Blood Lipids, and Atherosclerosis Some clinicians have the impression that chronic alcoholic patients have less arteriosclerosis than nonalcoholic subjects; some believe that alcohol predisposes to atherosclerosis. There are no clinical studies that conclusively support either of these concepts. In experimental animals, alcohol has been found vari- ously to favor (73), protect against (49), or have no significant effect on (156, 158) atherosclerosis produced by experimental means. The carbon atoms of alcohol have been traced to a variety of body constituents, including lipids and glycogen, but most of the alcohol is oxidized in the body to carbon dioxide (199). Alcohol has been found to spare body fat (14), but whether or not it spares protein is questionable (152). When carbohydrates are replaced by alcohol (36 percent of the total calories), fatty infiltration of the liver develops in both man and rats despite ingestion of an otherwise adequate diet (133). Alcohol can increase hepatic fatty acid synthesis, but whether this or other mechanisms are res- ponsible for the production of the fatty livers common in alco- holics is still controversial (43, 131). On short-term alcohol administration (6-8 hr), a rise in circulating triglycerides without change in cholesterol has been reported (104). On more prolonged alcohol administration, plasma 30
Atherosclerosis (Arteriosclerosis) triglycerides increased during the first 8-10 days, but returned to normal thereafter (133). Alcoholics usually have either normal plasma lipids or various degrees of mild hyperlipemia, and the transient effect of alcohol suggests that the variable degree of lipemia of alcoholics may depend on the duration of the alcohol intake. The mechanism of this moderate alcoholic hyperlipemia has not yet been elucidated; it does not appear to be due solely to an increase in total caloric intake because a similar effect could not be reproduced by the administration of isocaloric amounts of fat or carbohydrate (104). On rare occasions, gross lipemia (up to 10 gm percent plasma glycerides) with marked lactescence has been observed in alcoholics. This is usually accompanied by symptoms associated with liver insufficiency (209). The excessive hyperlipemia could be due to the potentiating ef- fect of alcohol on lipoprotein lipase deficiency (136) or to an associated pancreatitis (4). In addition to its effect on circulating glycerides, alcohol also increases plasma cholesterol in both man (78, 133) and rats (49, 73, 158). Similar effects have been described for cir- culating phospholipids (133, 158). In man, acute administration of alcohol results in immediate short-time fall of circulating free fatty acids (FFA) (132). More prolonged alcohol administration, however, produces no deviation from normal plasma FFA concentration, but very large doses of alcohol (40 oz of 86 proof per day) increase FFA concentration (133). 31
