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Atherosclerosis as a pediatric problem
MEDICAL
PROGRESS
Atberosclerosis as a pediatric problem Atherosclerosis, most [requently mani]ested as coronary heart disease, is the major health concern in the United States. This disease o[ adulthood has its origins in in[aney and childhood. Genetically determined lipid abnormalities account [or a distinct but small segment o[ highly susceptible persons. Early detection of such individuals and correction of their lipid dejects would appear to be indicated in an effort to delay the atherosclerotie process. Other more common traits also having origins early in li[e are hypertension, acquired lipid dejects, diabetes meJlitus, obesity, the smoking habits and a sedentary way o[ [i]e. Attention by the pediatrician to the prevention and early treatment o[ these "de/ects" is urged.
William B. Kannel, M.D., M.P.H., F r a m i n g h a m , Mass., and Thomas R. Dawber, M.D., M.P,H., Boston, Mass.
T I-I E R E I S A growing conviction that the only way to substantially reduce the toll from atherosclerotic disease is to attack its constitutional and environmental precursors long before overt symptoms occur. Epidemiologic and pathologic studies suggest that only early intervention is likely to have a major impact on the evolution of the disease. The pathologic changes which lead to atheroscterosis begin in infancy and progress during childhood. Consideration of the possible value of prophylaxis beginning in childhood is therefore in order. NATURAL HISTORY OF A T H E R O S C L E R O S I S
The study of atheroselerosis in human subjects is necessarily confined to pathologic examination of the lesions at autopsy and to investigation of the clinical manifestaFrom the National Heart and Lung Institute and Boston University School o[ Medicine. Reprint address: 123 Lincoln St., Framingham, Mass. 01701.
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tions produced by this disorder. Much information has been accumulated about the most common diseases resulting from atherosclerotic narrowing and obstruction of the coronary arteries, the arteries of the neck and brain, and those of the lower extremities. Because of its frequency and serious consequences, the most extensively investigated disorder has been coronary heart disease. 1-6 More recently cerebrovascutar disease has come under increased scrutiny. See related text, pp. 683 and 693. Except in rare instances, none of the three major clinical manifestations of atherosclerosis is a disease of infancy and childhood. Only the premature atherosclerotic changes of progeria are comparable to adult coronary artery disease. Nevertheless, the pediatrician should be aware that the precursors of atherosclerosis may become established in childhoodY, s
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EVOLUTION OF THE ATHEROSCLEROTIC PLAQUE Autopsies of men in their twenties killed during wartime indicated that 70 per cent already had at least moderately advanced coronary athe rosclerosis2"l~ More recent studies in Vietnam, while revealing some evidence of atherosclerosis in 45 per cent, showed gross, severe coronary atherosclerosis in only 5 per cent. 52 These findings suggest that although the clinical disease becomes manifest in adult life, the underlying atherosclerotic process begins much earlier. The hallmark of the early lesion is an accumulation of lipid in the intima of mediumsized and large arteries. The earliest grossly visible lesion is the "fatty streak" resulting from the accumulation of lipid, predominantly cholesterol, both extracellularly in the intima and intracellularly in foam ceils. This lipid deposit, remarkably' similar in composition to lipids in the blood, appears to migrate from the blood into the vessel wall. The cells in the arterial wall do not seem to enter into the production of the lipid since plaques have been observed to form on synthetic vascular prostheses. Lipid deposits (fatty streaks) are common in children by the age of 3 to 5 years, yet there is considerable geographic variation in mortality rate from the late consequences of such lesions. In general, the deposits increase in size and number as the child grows older; in later years a number of fatty streaks are observed in varying stages of progression. It is also conceivable that some deposits are resorbed; regression of experimentally induced fatty plaques has been demonstrated in animals, including the monkey. 12 Although the progression from fatty streaks through fibrous plaques to atheromatous ulceration cannot be documented by longitudinal studies in human subjects, there are enough cross-sectional observations to permit the assumption that such progression does occur. If the progression from fatty streak to atheromatous ulcer could be materially slowed, atherosclerotic disease would cease to be a major cause of death or dis-
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ability. This consideration makes atherosclerosis a concern of pediatrics. Whereas much is known about the pathology of atherosclerosis and its evolution in adults, there is still much to be learned about its earlier stages. Factors initiating the process remain uncertain, as do those influencing progression. Endothelial injury and platelet adhesion, ground substance alteration, lipid accumulation, local metabolic aberration of the arterial wall, and reaction to injury have all been implicated. 3-17 The productive, proliferative lesion involving the reticuloendothelial cells, elements of the mesenchymal connective tissue, and smooth muscle cells is indeed a complex one. The role of platelets and fibrin in the pathogenesis of the atherosclerotic lesion is still unclear38-2~ Rich in lipids, vasoactive substances, and enzymes, the platelets adhere to the vascular intima when laminar flow is disturbed; thrombi initiated by their aggregation and adherence may become organized and incorporated. Early experimental lesions have been shown to regress almost completely, but if more lipid accumulates as time passes, an amorphous degeneration develops, producing a reaction to injury with cellular proliferation. The resulting fibrous plaques eventually become ulcerated, calcified, and vascularized by ingrowth of capillaries and are less likely to regress. This suggests that primary preventive measures would be more effective early in life. Since atherosclerosis can be fairly advanced by age 20, it would appear that such efforts must be applied well before that age. Atherosclerosis apparently proceeds from a complex interplay of many factors including the physical properties of the vessels and rheologic characteristics of the flow within them, as well as the lipid and other metabolic processes in the blood and the vessel wall. Propensity to this vascular affliction thus depends partly on the type of vasculature inherited. Local anatomical differences, as in arterial caliber or intimal integrity, can strongly influence the dynamics of flow and the sites where lesions develop. TM 22 Some individuals live to old age free of clinical
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atherosclerosis, presumably without ever trying to control their diet, physical activity, and other habits. Some very old persons have little evidence of atherosclerosis at autopsy. Inherited variations in vascular structure and metabolism are surely major determinants of individual ability to cope with atherogenic influences. Atheroma tend to form at certain sites which may largely be determined by hemodynamic effects. Angulation producing turbulence and impingement of the bloodstream on the arterial wall favors early development of lesions, but the architecture of the arterial circulation is not the sole or even the chief determinant of atheroma formation. 21 Tortuous veins and pulmonary arteries may escape atheromatosis entirely even though they are bathed by the same lipidladen blood. Pressure also appears to be crucial; below some critical level of blood pressure, as in the pulmonary arterial circuit, atheromatosis does not develop. Even above such pressure, certain arteries (e.g., the internal m a m m a r y and radial arteries) remain relatively free of this disorder for reasons which are not clear. This phenomenon could be a function of dynamics of flow and pressure since propensity to atherosclerosis is generally proportional to arterial caliber. 22 Both the atherosclerotic process in the vessels and the clinical manifestations thereof differ according to age. Although there are many exceptions, the development of disabling and fatal infarctions is proportional to the severity of the underlying atherosclerosis. Women are less prone than men to clinical atherosclerosis, particularly under the age of 50. 23 Age and sex are among the most powerful determinants of atherosclerosis, whether through altered tissue responses to atherogenic influences, vascular wear and tear, or exposure to various noxious influences. For adults at any age vulnerability varies over a wide range and relates to a number of readily identifiable "risk factors." Epidemiologic studies in Framingham are in agreement with those of a number of similar investigations, s, 5, 6, s The ingredients of a coronary profile, which alIow estimation of the probability of a coronary attack
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many years hence, are now well known. 24 Similar profiles can be described for cerebral infarction and occlusive disease of the peripheral arteries.2~, 26 Such "atherogenic profiles" can readily be constructed for adults from simple observations which are not hazardous, invasive, costly, or unpleasant; this makes it possible to identify years in advance persons who are highly vulnerable to coronary attacks. Preventive efforts can then be focused on such susceptible individuals. 27 The earlier in life tile coronary risk factors are assessed, the stronger their impact. 2~ The Framingham experience involves persons 30 or more years of age; extrapolation to earlier ages is speculative. However, studies of college students suggest that coronary and stroke mortality rates can be predicted at this stage in life. a, 6, s We lack prospective data on the predictability of coronary events at still earlier ages, but it is reasonable to suppose that such data would identify some potential coronary and stroke candidates even in infancy. Of all the factors implicated in coronary disease, abnormalities of blood lipids and blood pressure are most important. While both may influence cardiovascular disorders in other ways, it appears that they exert their most deleterious effects by producing or accelerating atherosclerosis. These factors must be sought out through periodic examination and should be made known to the parents of the potential victim. SERUM
LIPIDS
Most atherogenic serum lipid disorders appear to have their roots in childhood. Some are inborn errors of lipid metabolism. Others are acquired or associated with various disease processes. The habits of diet and sedentary living, which contribute to the acquired hyperlipoproteinemias, may also be formed in childhood. It is not yet clear whether adult blood lipid values can be predicted from analysis of blood during infancy or childhood. It is unlikely that genes are the sole determinants of the generally high serum lipid values encountered in western civilization. Nutrition,
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physical activity, and many other environmental factors undoubtedly play important roles in determining the lipid levels found in the general population, as well as in inherently vulnerable individuals. Genetically determined lipid disorders. I-Iyperlipemia and hyperlipoproteinemia have been implicated as major contributors to atherogenesis. Inherited hypercholesterolemia with xanthomatosis is a lipid disorder long recognized as associated with premature and severe atherosclerosis. This disorder is genetically determined as a dominant trait. In the adult it is characterized by the frequent appearance of tuberous and tendonous xanthomata, in association with high plasma values for cholesterol (usually above 300 rag. per 100 ml.) and by cholesterol-rich beta lipoproteins in the presence of normal triglyceride concentration. Although this type I I hyperbetalipoproteinemia . may occasionally be recognizable in chiIdhood by some of its clinical stigmata, reliance on these alone will detect only a fraction of affected children. Serum lipid analysis early in life, even at birth, will frequently detect this abnormality. Total serum cholesterol values in young children average approximately 160 mg. per 100 ml. with a range of 105 to 215 rag. per 100 ml.2S; above these levels the probability of an inborn error of lipid metabolism is very high. In the upper range of normal, i.e., above 200 rag. per milliliter, the distinct possibility of an underlying lipid abnormality must be considered. Infants born into families with any history of "familial hypercholesterolemia" or precocious atherosclerotic disease should be studied for a lipid abnormality and, if negative, tested periodically into adulthood to exclude a possible heterozygous state in which the appearance of the abnormality may be delayed. Ideally, assessment of children for this type of hyperbetalipoproteinemia requires precise measurement of low-density Iipoprotein (Sf0-20) cholesterol. This necessitates a series of tests including alpha, beta (LDL), and total cholesterol and triglyceride determinations, and lipoprotein electrophoresis of the total plasma and of the top and bottom fractions after ultracentrifugationY ~ The last
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is required to exclude type III dyslipoproteinemia. Acquired hyperlipoproteinemia should be excluded by tests of glucose tolerance, renal and hepatic function, and uric acid concentration. Other family members should also have lipid determinations to establish whether the child has familial xanthomatosis as well as to identify members with undiagnosed hyperlipoproteinemia. In summary, the biochemical hallmarks of this dominant inherited trait are the extraordinarily high levels of plasma cholesterol (more than 230 rag. per 100 ml.) and beta lipoprotein with normal triglyceride and glucose tolerance values. Xanthomata may be seen early but not in all cases. The goal of treatment is to reduce plasma cholesterol concentration, preferably below 200 rag. per 100 ml. In very young children, still lower values should be sought. Xanthomata rarely a p p e a r when the plasma cholesterol level is within the range of normal. Their appearance and disappearance is closely related to the level of plasma cholesterol, so Further experience will be required to ostablish the optimum diet and drug regimen for children with hyperlipoproteinemia, especially type II. A diet low in cholesterol (under 200 rag. daily), with polyunsaturated exceeding saturated fatty acids by a ratio of more than 2: 1, is currently advocated in this disorder. Saturated fat should provide no m o r e than 10 per cent and total fat no more than 35 per cent of all food calories. Type II heterozygous persons will probably respond to this dietary regimen. Some will also require administration of a drug such as cholestyramine. Type II homozygous persons generally obtain very little reduction in serum cholesterol levels with dietary management alone and require additional therapy after the maximum dietary effect has been reached. Administration of multiple drugs is usually necessary for this purpose. Unfortunately, some patients are quite resistant to all drug combinations. When all else fails, the somewhat drastic procedure of ileal bypass may be considered; some have found it successful in lowering lipid values well beyond those achieved with dietary management alone. ~1' ~2 Others, perhaps less ex-
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pert in its application, have found it less effective than diet and drugs. Side effects including diarrhea, partial intestinal obstruction, and intussusception may occur2 B All children of persons with type I I hyperlipoproteinemia should be tested, and those with this trait should be treated very early in life. Until more is known of the longterm effects of drug therapy, the pediatrician may feel constrained to rely on dietary management, but the hazards of premature atherosclerotic disease in the homozygotic child are formidable and may warrant drug therapy despite the uncertainty. For the heterozygotic child with type I I hyperbetalipoproteinemia, drug therapy can be delayed until about age 14. Dosages of antilipemic drugs for children and infants are not well established, are certainly not a simple fraction of the adult dose, and must be carefully adjusted to obtain maximal efficacy without incurring dangerous or unpleasant side effects. Of the other types of hyperlipoproteinemia, type I (chylomicronemia) is genetically determined but is extremely rare and not a precursor of atherosclerotic diseaseY 3 It is inherited as a Mendelian recessive gene, also often determinable in infancy. Correction of the severe hyperlipemia will eliminate abdominal pain and pancreatitis. Types I I I , IV, and V hyperlipoproteinemia cannot be detected until later in life. Type I I I lipoproteinemia, which may also be associated with accelerated atherogenesis, is apparently inherited as a recessive trait. It has thus far not been identified prior to age 20, but it would seem prudent to look for it periodically, beginning in childhood, in offspring of affected parents. Type I V prebetahyperlipoproteinemia is only rarely detected before age 25. Although it is very likely an acquired disorder in m a n y persons, it is believed to be inherited as a dominant trait with delayed expression. Although type I V is not manifest until adulthood, its possible precursors of obesity, impaired glucose tolerance, and excessive dietary carbohydrate intake m a y be present earlier in life. Some of the inherited lipid
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abnormalities may appear only after a period of excessive dietary intake of saturated fats, cholesterol, and calories. Acquired lipid disorders. Children born into families with a tendency to premature atherosclerotic disease should be considered at high risk whether or not they have a demonstrable error of lipid metabolism. A good case can also be made for periodic blood cholesterol monitoring and for diet and weight control in all infants and children whose plasma cholesterol values exceed 160 mg. per 100 ml. The trend of cholesterol levels in relation to age in children is still not fully known. The prognostic significance of moderate plasma cholesterol elevations in infants and children is not known and can only be inferred from prospective studies in young adults. In view of the fact that the risk of coronary artery disease rises in proportion to the plasma cholesterol concentrations, an ideal cholesterol value would appear to be the lowest one achievable without illness. ~4 Most atherosclerotic disease in the general population does not result from the aforementioned inborn errors of metabolism but occurs in those persons who as adults have serum cholesterol elevations in the less dramatic range of 250 to 350 rag. per 100 ml. Some of these "moderate" elevations may represent a heterozygous state for an inborn error of lipid metabolism, but most probably represent the environmental effect of excess intake of saturated fat, cholesterol, and refined carbohydrate by persons in positive energy balance, a5 BLOOD
PRESSURE
Elevated blood pressure is one of the most common and potent elements predisposing to coronary artery disease. A familial tendency toward hypertension has long been suspected by clinicians and confirmed by population studies. A significant correlation of the blood pressures of siblings has been demonstrated. Studies of twins have suggested a genetic explanation by revealing a closer correspondence of pressures among identical than among fraternal twins; the
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latter, in turn, correlated more closely than those of other siblings. The repeatedly demonstrated familial aggregation of blood pressure has been variously interpreted as supporting either a polygenic or single gene inherited mechanism of blood pressure regulation?G, a7 However, environmental factors could explain the clustering of hypertension in families. Families share more than genes; even spouses tend to share blood pressures to some extent, and this in proportion to the duration of the marriage? s Parent-child correlation of blood pressures tends to be greatest in families in which spouse aggregation is also present. Furthermore, there has been no convincing demonstration of bimodality in the distribution of blood pressure. Recently Zinner and associates 39 have extended the finding of familial aggregation of blood pressure .to include children in the range of 2 to 14 years. Although this tends to favor a genetic explanation, early environmental influences of relatively short duration could also start the potential hypertensive patient on the road to overt disease. Proof of the existence of environmental determinants of familial aggregation of Mood pressure must still be awaited. The findings of Zinner and associates 39 suggest that the process of essential hypertension, and ultimately its influence on the rate of atherogenesis, has its roots very early in life. Most prospective studies of hypertension in adults also reveal that, despite its high prevalence, few entirely new cases evolve among normotensive persons after age 30. The report o f Zinner and coworkers a9 suggests that hypertension in adult life could possibly be predicted from the blood pressure pattern in youth. Direct evidence bearing on this should be sought. There is some suggestion that the level of pressures achieved early in life tends to determine the subsequent level of pressure obtained in adult life. Physicians have long suspected that modest and labile pressure elevations precede severe fixed diastolic hypertension. Hypertension may be a self-prepetuating vicious cycle. Long-standing hyper-
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tension appears to alter arteriolar structure so as to increase peripheral resistance; it may also reset "barostats" at a higher level. Many clinicians believe that the rate of rise in pressure with age or time is steeper in those with high than with low pressures. Whether this is a biological fact, statistical artifact, or unsubstantiated clinical folklore is difficult to decide. 4~ The incidence of elevated blood pressure certainly increases with age in most populations. The causes of so-called essential hypertension will be more readily identified by investigations closer to the time of onset. Factors initiating hypertension may differ from those which sustain it. Intensive study of the children of hypertensive parents may reveal the causes of hypertension in the adult. Hypertension promotes atherogenesis, myocardial failure, and strokes. No means of preventing hypertension other than the avoidance of obesity is currently known. Presently we can only attempt to control established hypertension in order to d e l a y its cardiovascular sequelae. We can no longer doubt that persons with severe or moderate hypertension benefit from having their pressures lowered. 41 We lack concrete evidence that the same benefits accrue to mildly hypertensive patients without organ damage. Such evidence is urgently needed. The risk of atherosclerotic and other cardiovascular sequelae varies widely with blood pressure even in the "borderline" range of elevations. In adults of any age and either sex, even modest elevations of pressure--systolic or diastolic, casual or b a s a l - a r e associated with a substantial increase in risk of coronary heart diseaseY a When associated with elevated blood lipid levels or electrocardiographic abnormalities, this risk is formidable. Since few risk factors in the make-up of the potential victim of atherosclerosis are more easily detected and controlled, essential hypertension is more deserving of attention than any other factor. It would seem that the earlier in life this prophylaxis is implemented the better. Fear of the possible hazards of long-range use of antihypertensive agents need not deter
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such an endeavor, since the modest, labile pressures of incipient hypertension may for a long time require nothing more than weight reduction, salt restriction, and administration of tranquilizers for their control. The pediatrician may ask what concrete steps he should take to prevent the development of hypertension. Elevated blood pressure in the young may result from renal disease, coarctation, or other "specific" causes; these should be sought and treated appropriately. Since many adults with "essentiaF' hypertension had blood pressure levels at the upper limit of "normal" as children, this measurement is an important part of the physical examination. Children with blood pressure values in the upper 20 per cent of the distribution curve merit periodic re-examination. In such children the prevention and correction of obesity is important since obesity is the single most important environmental factor clearly related to elevated blood pressure. 42 The other major environmental factor is the sodium content of the diet. Marked lowering of sodium intake to 200 mg. per day or less has an important hypotensive effect. A similar effect can be obtained by "washing out" sodium with natriuretic drugs. Limiting the sodium content of baby foods and of children's diets is still the safest effective procedure for lowering blood pressure. Studies which suggested that relatively low sodium intake might have some beneficial effect have not been confirmed. It is nevertheless still possible that a low intake of sodium throughout life might have an important effect in preventing hypertension in adult years. The habit of adding salt to practically all foods is learned early in life. Commonly encountered daily intakes of 4 to 12 Gm. are far in excess of the daily need for this electrolyte. The pediatrician should discourage the common habit of adding salt to childhood diets. IMPAIRED
GLUCOSE T O L E R A N C E All children of diabetic parents merit careful monitoring, not only of their carbo-
The ]ournal o[ Pediatrics April 1972
hydrate tolerance, but of their blood lipids, blood pressure, and weight pattern as well. Although the acute metabolic consequences of diabetes have been controlled by administration of hypoglycemic agents, there is little evidence that the late cardiovascular sequelae have been similarly ameliorated. 4a Diabetes represents a more complex metabolic derangement than simply one of impaired carbohydrate utilization; metabolism of lipids is deranged as well. Obesity and impaired glucose tolerance are prominent features of types III, IV, and V hyperlipoproteinemia. Removal of very low-density (S,20-400) prebeta lipoprotein by adipose tissue appears to be impaired in the obese subject. The superfluous fat in obese adults is found in oversized fat cells which become relatively unresponsive to insulin. Removal of lipoprotein by adipose tissue depends on the action of insulin. Elevated endogenous triglyceride and prebeta lipoprotein are characteristic of the obese patient with adult-onset, keto-resistant diabetes. Data from Framingham have revealed that lipid abnormality may precede the onset of diabetes by a decade or more, suggesting that the lipid disorder is not merely a consequence of uncontrolled carbohydrate intolerance. ~4 Perhaps a broader concept of diabetes "control," including the return to normal of blood lipids, blood pressure, and body weight would retard the accelerated atherogenesis accompanying diabetes, which has not been accomplished by improvement of carbohydrate tolerance alone. It is entirely possible that adult-onset, keto-resistant, obesity-related diabetes may be a late sequela of childhood obesity which produces a lasting proliferation of enlarged adipose tissue cells relatively resistant to insulin. ~ In keeping with this hypothesis, data from Framingham demonstrated an increased risk of diabetes in proportion to the degree of adiposity. 4~ LIVING
HABITS
The chief determinants of plasma lipid values, blood pressure, and carbohydrate tolerance in the general population are still speculative. While an inherited predisposi-
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tion is suspected, it is likely that environmental influences play a large role in prorooting the appearance of these atherogenic traits later in life. There is mounting evidence that faulty living habits and the unrestricted application of modern technology are exacting an increasing toll in death from atherosclerotic disease. This technologic revolution has provided a surfeit of food at the same time that physical activity has been curtaiied. Eating habits, indolence and sedentary living habits, propensity to obesity, and possibly the cigarette habit are likely conditioned in childhood by the behavior and attitudes of the family group. Diet. The storage of calories derived from saturated fat and refined carbohydrate has in all likelihood contributed to the generally high blood lipid concentrations, the high prevalence of impaired, carbohydrate tolerance, and possibly to hypertension in the general population. There is reason to believe that the type of diet habitually eaten is to a large extent responsible for the levels of serum lipids observed in a population. Those who habitually eat a diet high in calories, saturated fat, cholesterol, and refined carbohydrate have substantially higher cholesterol values than those who do not. 84 The American type of diet has been demonstrated to produce atheroma in primates. 12 Lipid levels can be lowered in a predictable fashion by dietary manipulation. There is little question that food preferences and eating habits are conditioned in childhood. It would seem reasonable for pediatricians to counsel mothers on the feeding of a diet emphasizing skim milk, cottage cheese, and other dairy products derived from skimmed milk, legumes, fruits, starches, lean meats, poultry, and fish. Candies, pastries, egg yolks, animal fats (including dairy fats), and organ meats should be de-emphasized. The only vegetable fat that need be restricted is coconut oil, the only naturally occurring highly saturated vegetable oil. Overeating and overfeeding should be discouraged. Further experience will be required to establish the ideal diet to promote optimal
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cardiovascular health later in life. Infants a n d c h i l d r e n can thrive and develop normally on either a diet high in saturated fat and cholesterol or one that contains little of these nutrients. Only an adequate amount of high-quality protein, vitamins, polyunsaturated fatty acids, and calories appears essential. Although breast-fed infants have a relatively high level of serum cholesterol compared to others, it would not seem wise to recommend artificial feeding on this account. *s The diet composition considered most desirable for children should contain less than 35 per cent of calories from f a t - - a polyunsaturated/saturated ratio of 2 : 1--and less than 200 rag. of cholesterol. In those with a tendency to gain weight, refined carbohydrate should be restricted. Physical exercise. Although young children tend by nature to be physically active, they tend to become sedentary as society makes it increasingly difficult for them to remain active. Parents can set an example by encouraging youngsters to remain physically active and by participating in family outings, hiking, and sports whenever possible. Regular exercise will aid in avoidance of obesity and its attendant atherogenic effects. More important, it may set a pattern for a physically active way of life in adulthood. Persons who are sedentary have been found at Framingham and elsewhere to develop more myocardial infarctions and to have a higher mortality rate from coronary artery disease. Physical activity, possibly by promoting collateral blood supply in adults as the coronary vessels become increasingly stenotic, appears to protect against a lethal outcome in coronary attacks. 46 The amount of exercise required to accomplish this is apparently modest. 4~ Obesity. There is some evidence to suggest that obesity, by increasing the size and number of adipose tissue cells and altering the sensitivity to insulin, may be a self-perpetuating entity. However, while there appears to be a wide inherent variation in the tendency to store calories, obesity is generally the result of eating too much and exercising too little. Obese parents are
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more apt to have obese children. Equating leanness in childhood with ill health is an attitude which should be dispelled. The obese subjects in Framingham, particularly those with other risk factors, had an excess of angina and sudden death. Whereas adiposity may accelerate atherogenesis by promoting lipid abnormalities, impaired carbohydrate tolerance, and hypertension, it appears also to make a contribution per se. Its effect is apparent even after adjusting for these variables, suggesting that the increased cardiac work load imposed by obesity in persons with a compromised circulation may be an important mechanism. 4s The cigarette habit. The cigarette habit has been demonstrated to influence coronary death adversely, particularly in persons at known risk?, 49, ~0 Lethal coronary attacks appear to be triggered by cigarette smoking, the impact diminishing with advancing age. Research has shown that the smoking habit is usually acquired early in life. It is unlikely that the cigarette habit represents a serious threat to cardiovascular health in adolescence. The toll is exacted later in life after the habit becomes established and the cardiovascular system more vulnerable to its effects. The cigarette habit becomes established more readily in adolescents who are exposed to it by their peers, siblings, and parents? 1 The ready availability of cigarettes in the home and in vending machines places unnecessary temptation in the path of maturing children. Seductive advertising to which children are exposed should be discouraged. Smoking in public buildings and vehicles should be prohibited. CONCLUSIONS
In the United States coronary heart disease and the other clinical manifestations of atherosclerosis are the major causes of illness and death. Atherosclerosis, although uncommonly observed before age 40, has its onset in infancy and childhood. Some of the factors predisposing to this disorder, e.g., genetically determined lipid abnormalities and hypertension, may be detected
The ]ournal o[ Pediatrics April 1972
early in life. Other factors which represent life habits are also frequently established as a result of childhood environment. Only by controlling constitutional traits and environmental influences early in life does it appear likely that an important beneficial effect on coronary heart disease mortality and morbidity rates will be brought about. The pediatrician has a long tradition in health maintenance and preventive medicine. More than any other medical specialist he has adopted the prophylactic approach in everyday medical practice. Although his direct responsibility for medical care arbitrarily ends with adolescence, the pediatrician has an opportunity to markedly affect the development of diseases of later life. He therefore has a responsibility not only to be concerned about diseases which become clinically manifest during infancy and childhood but about those which, although not appearing until later in life, may be prevented or delayed by health practices during the first two decades of life. At the present time the pediatrician may expect that one in every five male patients under his care will develop coronary heart disease before the age of 60. There is every likelihood that the pediatrician can play a crucial role in favorably changing these statistics. Promotion of cardiovascular health should be one of the chief concerns of the conscientious pediatrician. Although proof of the efficacy of prophylactic measures aimed at preventing atherosclerotlc disease is lacking, it is reasonable to believe that the approach advocated will materially lower the morbidity and mortality rates from this disorder. This approach calls for (1) the prevention of obesity, (2) the early determination of any lipid abnormalities and their correction by diet or other procedures if necessary, (3) careful surveillance for early evidence of hypertension and the institution of corrective measures, (4) the promotion of high-energy output physical activity, and (5) discouragement of the cigarette smoking habit.
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Atherosclerosis in pediatrics
REFERENCES
1. Gordon, T., and Kannel, W. B.: Premature mortality from coronary heart disease. The Ft;amingham Study, J. A. M. A. 215: I617, 1971. 2. Kannel, W. B., McNamara, P. M., Feinlaib, M., and Dawber, T. R.: The unrecognized myocardial infarction. Fourteen year followup experience in the Framingham Study, Geriatrics 25: 75, 1970. 3. Doyle, J. T., Heslin, A. S., I-Iilleboe, H. E., and Formel, P. F.: Marly diagnosis of ischemic heart disease, N. Engl. J. Med. 261: 1096, 1959. 4. Weinblatt, E., Shapiro, S., and Frank, C. W.: Prognosis of men after first myocardial infarction: Mortality and first recurrence in relation to selected parameters, Am. J. Public Health 58: i329, 1969. 5. Thomas, C. B.: Familial and epidemlologic aspects of coronary disease and hypertension, J. Chron. Dis. 7: 198, 1958. 6. Paffenbarger, R. S., Notkin, J., Krueger, D. E., Wolf, P. A., Thorne, M. C., LeBauer, E. J., and Williams, J. L.: Chronic disease in former college students. II. Methods of study and observations on mortality from coronary heart disease, Am. J. Public Health 56: 962, 1966. 7. Kannel, W. B.: An epidemiologic study of cerebrovascular disease, in Siekert, R. G., and Whisnant, J. P., editors: Cerebral vascular diseases--Transactions of the Fifth Conference, New York~ 1966, Grune & Stratton, Inc. 8. Paffenbarger, R. S., and Wing, A. L.: Characteristics in youth predisposing to fatal stroke in later years, Lancet 1: 753, 1967. 9. Enos, W. F., Holmes, R. H., and Beyer, J.: Coronary disease among U. S. soldiers killed in action in Korea, J. A. M. A. 152: 1090, 1953. I0. Rigal, R. D., Lovell, F. W., and Townsend, F. M.: Pathologic findings in the ca~rdiovascular systems of military flying personnel, Am. J. Cardiol. 6: 19, 1960. 11. Mason, J. K.: Asymptomatie disease of coronary arteries in young men, Br. Med. J. 2: 1234, 1963. 12. Wissler, R. W.: Recent progress in studies of experimental primate atherosclerosis, in Miras, C. J., Howard, A. N., and Paoletti, R., editors: Progress in Biochemistry and Pharmacology, Vol. 4, New York, 1968, S. Karger AG. 13. Holman, R. L., McGill, H. C., Strong, J. P., and Griffin, O. R.: The natural history of atherosclerosis, Trans. Assoc. Life Ins. Med. Directors of America, vol. 40, 1956, pp. 86114, 14. Gould, R. G.: Lipid metabolism and atherosclerosis, Am. J. Med. 11: 209, 1951. 15. Duncan, L. E., Jr.: Mechanical factors in the localization of atheromata, in Jones; R. J., editor: Evolution of the atherosclerotlc plaque, Chicago, 1963, University of Chicago Press. 16. Simonton, J. H., and Gofman, J. W.: Macro-
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33. 34.
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phage migration in experimental atherosclerosis, Circulation 4: 557, 1951. Cox, G. E., Truehart, R. E., and Kaplan, J.: Atherosclerosis in rhesus monkeys. IV. Repair of arterial iniury--an important secondary atherogenic factor, Arch. Pathol. 76: 166, 1963. Duquid, J. B.: Thrombosis as a factor in the pathogenesis of coronary atherosclerosis, J. Pathol. 58: 207, 1946. Patterson, J. C., Moffat, T., and Mills, J.: Hemosiderin deposition in early atherosclerotic plaques, Arch. Pathol. 61: 496, 1956. Lyford, C. L., Connor, W. E., Hoak, J. C., and Warner, E. D.: The coagulant and thrombogenic properties of human atheroma, Circulation 36: 284, 1967. Texon, M.: The hemodynamic concept of atherosclerosis, Am. J. Cardiol. 5: 291, 1960. Young, W., Gofman, J. W., Tandy, R., Malamud, N., and Waters, E. S.. The quantitation of atherosclerosis. I. Relationship to artery size, Am. J. Cardiol. 6: 288, 1960. Kannel, W. B., Dawber, T. R., and McNamara, P. M.: Detection of the coronary-prone adult: The Framingham Study, J. Iowa IVied. Soc., 1966, pp. 26-34. Truett, J., Cornfield, J., and Kannel, W. B.: A multivariate analysis of the risk of coronary heart disease in Framingham, J. Chron. Dis. 20: 511, 1967. Framingham Monograph No. 27: U. S. Government Printing Office, Washington, D. C., 1971. Kannet, W. B., and Shurtleff, D.: The natural history of arteriosclerosis obliterans, Cardiovasc. Clin. 3: 38, 1971. Dawber, T. R., and Thomas, H. E., Jr.: Prevention of myocardial infarction, Progr. Cardiovasc. Dis. 13: 343, 1971. Baker, H., Frank, O., Feingold, S., Christakis, G., and Ziffer, H.: Vitamins, total cholesterol and triglycerides, Am. J. CIin. Nutr. 20: 850, 1967. Fredrickson, D. S., Levy, R. I., and Lees, R. S.: Fat transport in lipoproteins----an integrated approach to mechanisms and disorders, N. Engl. J. Med. 276: 34, 94, 148, 215, 273, 1967. Roe, D. A.: Essential hyperlipemia with xanthomatosis, Arch. Dermatol. 97:436, 1968. Buchwald, H., Moore, R. B,, Frantz, I. D., and Varco, R. L.: Proceedings of the Second International Symposium on Atherosclero~is, 1970, p. 464. Buchwald, H., Lee, G. B., Amplatz, K., Moore, R. B., Frantz, I. D., and Varco, R. L.: Severe atheroselerotic cardiovascular disease in a 14-year-old homozygous familial hypercholesterolemic, Minn. Med. 51: 477, 1968. Lees, R. S., and Wilson, D. E.: The treatment of hyperlipidemia, N. Engl. J. Med. 284: 186, 1971. Keys, A., editor: Coronary heart dise~ge in seven countries, Circulation 41: 162, 1970. (Suppl. 1.)
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35. Kannel, W. B., Castelli, W. P., Gordon, T., and McNamara, P. M.: Serum cholesterol, lipoproteins and the risk of coronary heart disease, Ann. Intern. Med. 74: 1, 1971. 36. Pickering, G. W.: The inheritance of arterial pressure, in Stamler, J., Stamler, R., and Pullman, T. N., editors: The epidemiology of hypertension, New York, 1967, Grune & Stratton, Inc. 37, Platt, R.: Heredity in hypertension, Quart. J. Med. 16: 111, 1947. 38. Winkelstein, W., Jr., Kantor, S., and Ibrahim, M.: Familial aggregation of blood pressure: Preliminary report, J. A. M. A. 195: 848, 1965. 39. Zinner, S. H., Levy, P. S., and Kass, E. H.: Familial aggregation of blood pressure in children, N. Engl. J. Med. 284: 401, 1971. 40. Miall, W. E.: Implications of the relation between blood pressure and age, Milbank Mere. Fund Quart. 47: 107, i969. (Part 2.) 41. Freis, E. D.: Effect of antihypertensive treatment on morbidity, Milbank Mere. Fund Quart. 47: 153, 1969. (Part 2.) 42. Dawber, T. R., Kannel, W. B., Kagan, A., Donabedian, R. K., McNamara, P. M., and Pearson, G.: Environmental factors in hypertension, in Stamler, J., Stamler, R., and Pullman, T. N., editors: The epidemiology of hypertension, New York, 1967, Grune & Stratton, Inc. 43. Dawber, T. R., and Thomas, H. E., Jr.: Prophylaxis of coronary heart disease, stroke
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44. 45. 46.
47. 48. 49. 50.
51.
52.
and peripheral atherosclerosis, Ann. N. Y. Acad. Sci. 149: 1038, 1968. Kannel, W. B.: The Framingham Study. Unpublished data. Krasilnikoff, P. A., and Vesterdal, J.: Serum lipids in premature infants on vegetable fat diet, Acta Paediatr. Stand. 55: 505, 1966. Kannel, W. B.~ Pearson, G., and McNamara, P. M.: Obesity as a force of morbidity and mortality, in Heald, F. P., editor: Adolescent nutrition and growth, New York, 1969, Appleton-Century-Crofts, Inc. Kannel, W. B.: Physical exercise and lethal atherosclerotic disease, N. Engl. J. Med. 282: 1153, 1970. (EditoriaI.) Seltzer, C. C.: Overweight and Obesity. The associated cardiovascular risk, Minn. Med. 52: 68, 1969. Kannel, W. B., and McNamara, P. M.: The evidence for excess risk in coronary heart disease, Minn. Med. 52: 1265, 1969. Kannel, W. B., Kagan, A., Dawber, T. R., and Revotskie, N.: Epidemiology of coronary heart disease. Implications for the practicing physician, Geriatrics 17: 675, 1962. Kahn, E. B., and Edwards, C. N.: Smoking and youth. Contributions to the study of smoking behavior in high school students, J. School Health 49: 561, 1970. McNamara, S. S., Molot, M. A., Stremple, J. F., and Cutting, R. T.: Coronary artery disease in combat casualties in Vietnam, J. A. M. A. 216: 1t85, 1971.
PROGRESS
Atberosclerosis as a pediatric problem Atherosclerosis, most [requently mani]ested as coronary heart disease, is the major health concern in the United States. This disease o[ adulthood has its origins in in[aney and childhood. Genetically determined lipid abnormalities account [or a distinct but small segment o[ highly susceptible persons. Early detection of such individuals and correction of their lipid dejects would appear to be indicated in an effort to delay the atherosclerotie process. Other more common traits also having origins early in li[e are hypertension, acquired lipid dejects, diabetes meJlitus, obesity, the smoking habits and a sedentary way o[ [i]e. Attention by the pediatrician to the prevention and early treatment o[ these "de/ects" is urged.
William B. Kannel, M.D., M.P.H., F r a m i n g h a m , Mass., and Thomas R. Dawber, M.D., M.P,H., Boston, Mass.
T I-I E R E I S A growing conviction that the only way to substantially reduce the toll from atherosclerotic disease is to attack its constitutional and environmental precursors long before overt symptoms occur. Epidemiologic and pathologic studies suggest that only early intervention is likely to have a major impact on the evolution of the disease. The pathologic changes which lead to atheroscterosis begin in infancy and progress during childhood. Consideration of the possible value of prophylaxis beginning in childhood is therefore in order. NATURAL HISTORY OF A T H E R O S C L E R O S I S
The study of atheroselerosis in human subjects is necessarily confined to pathologic examination of the lesions at autopsy and to investigation of the clinical manifestaFrom the National Heart and Lung Institute and Boston University School o[ Medicine. Reprint address: 123 Lincoln St., Framingham, Mass. 01701.
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tions produced by this disorder. Much information has been accumulated about the most common diseases resulting from atherosclerotic narrowing and obstruction of the coronary arteries, the arteries of the neck and brain, and those of the lower extremities. Because of its frequency and serious consequences, the most extensively investigated disorder has been coronary heart disease. 1-6 More recently cerebrovascutar disease has come under increased scrutiny. See related text, pp. 683 and 693. Except in rare instances, none of the three major clinical manifestations of atherosclerosis is a disease of infancy and childhood. Only the premature atherosclerotic changes of progeria are comparable to adult coronary artery disease. Nevertheless, the pediatrician should be aware that the precursors of atherosclerosis may become established in childhoodY, s
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EVOLUTION OF THE ATHEROSCLEROTIC PLAQUE Autopsies of men in their twenties killed during wartime indicated that 70 per cent already had at least moderately advanced coronary athe rosclerosis2"l~ More recent studies in Vietnam, while revealing some evidence of atherosclerosis in 45 per cent, showed gross, severe coronary atherosclerosis in only 5 per cent. 52 These findings suggest that although the clinical disease becomes manifest in adult life, the underlying atherosclerotic process begins much earlier. The hallmark of the early lesion is an accumulation of lipid in the intima of mediumsized and large arteries. The earliest grossly visible lesion is the "fatty streak" resulting from the accumulation of lipid, predominantly cholesterol, both extracellularly in the intima and intracellularly in foam ceils. This lipid deposit, remarkably' similar in composition to lipids in the blood, appears to migrate from the blood into the vessel wall. The cells in the arterial wall do not seem to enter into the production of the lipid since plaques have been observed to form on synthetic vascular prostheses. Lipid deposits (fatty streaks) are common in children by the age of 3 to 5 years, yet there is considerable geographic variation in mortality rate from the late consequences of such lesions. In general, the deposits increase in size and number as the child grows older; in later years a number of fatty streaks are observed in varying stages of progression. It is also conceivable that some deposits are resorbed; regression of experimentally induced fatty plaques has been demonstrated in animals, including the monkey. 12 Although the progression from fatty streaks through fibrous plaques to atheromatous ulceration cannot be documented by longitudinal studies in human subjects, there are enough cross-sectional observations to permit the assumption that such progression does occur. If the progression from fatty streak to atheromatous ulcer could be materially slowed, atherosclerotic disease would cease to be a major cause of death or dis-
Atheroscterosis in pediatrics
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ability. This consideration makes atherosclerosis a concern of pediatrics. Whereas much is known about the pathology of atherosclerosis and its evolution in adults, there is still much to be learned about its earlier stages. Factors initiating the process remain uncertain, as do those influencing progression. Endothelial injury and platelet adhesion, ground substance alteration, lipid accumulation, local metabolic aberration of the arterial wall, and reaction to injury have all been implicated. 3-17 The productive, proliferative lesion involving the reticuloendothelial cells, elements of the mesenchymal connective tissue, and smooth muscle cells is indeed a complex one. The role of platelets and fibrin in the pathogenesis of the atherosclerotic lesion is still unclear38-2~ Rich in lipids, vasoactive substances, and enzymes, the platelets adhere to the vascular intima when laminar flow is disturbed; thrombi initiated by their aggregation and adherence may become organized and incorporated. Early experimental lesions have been shown to regress almost completely, but if more lipid accumulates as time passes, an amorphous degeneration develops, producing a reaction to injury with cellular proliferation. The resulting fibrous plaques eventually become ulcerated, calcified, and vascularized by ingrowth of capillaries and are less likely to regress. This suggests that primary preventive measures would be more effective early in life. Since atherosclerosis can be fairly advanced by age 20, it would appear that such efforts must be applied well before that age. Atherosclerosis apparently proceeds from a complex interplay of many factors including the physical properties of the vessels and rheologic characteristics of the flow within them, as well as the lipid and other metabolic processes in the blood and the vessel wall. Propensity to this vascular affliction thus depends partly on the type of vasculature inherited. Local anatomical differences, as in arterial caliber or intimal integrity, can strongly influence the dynamics of flow and the sites where lesions develop. TM 22 Some individuals live to old age free of clinical
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atherosclerosis, presumably without ever trying to control their diet, physical activity, and other habits. Some very old persons have little evidence of atherosclerosis at autopsy. Inherited variations in vascular structure and metabolism are surely major determinants of individual ability to cope with atherogenic influences. Atheroma tend to form at certain sites which may largely be determined by hemodynamic effects. Angulation producing turbulence and impingement of the bloodstream on the arterial wall favors early development of lesions, but the architecture of the arterial circulation is not the sole or even the chief determinant of atheroma formation. 21 Tortuous veins and pulmonary arteries may escape atheromatosis entirely even though they are bathed by the same lipidladen blood. Pressure also appears to be crucial; below some critical level of blood pressure, as in the pulmonary arterial circuit, atheromatosis does not develop. Even above such pressure, certain arteries (e.g., the internal m a m m a r y and radial arteries) remain relatively free of this disorder for reasons which are not clear. This phenomenon could be a function of dynamics of flow and pressure since propensity to atherosclerosis is generally proportional to arterial caliber. 22 Both the atherosclerotic process in the vessels and the clinical manifestations thereof differ according to age. Although there are many exceptions, the development of disabling and fatal infarctions is proportional to the severity of the underlying atherosclerosis. Women are less prone than men to clinical atherosclerosis, particularly under the age of 50. 23 Age and sex are among the most powerful determinants of atherosclerosis, whether through altered tissue responses to atherogenic influences, vascular wear and tear, or exposure to various noxious influences. For adults at any age vulnerability varies over a wide range and relates to a number of readily identifiable "risk factors." Epidemiologic studies in Framingham are in agreement with those of a number of similar investigations, s, 5, 6, s The ingredients of a coronary profile, which alIow estimation of the probability of a coronary attack
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many years hence, are now well known. 24 Similar profiles can be described for cerebral infarction and occlusive disease of the peripheral arteries.2~, 26 Such "atherogenic profiles" can readily be constructed for adults from simple observations which are not hazardous, invasive, costly, or unpleasant; this makes it possible to identify years in advance persons who are highly vulnerable to coronary attacks. Preventive efforts can then be focused on such susceptible individuals. 27 The earlier in life tile coronary risk factors are assessed, the stronger their impact. 2~ The Framingham experience involves persons 30 or more years of age; extrapolation to earlier ages is speculative. However, studies of college students suggest that coronary and stroke mortality rates can be predicted at this stage in life. a, 6, s We lack prospective data on the predictability of coronary events at still earlier ages, but it is reasonable to suppose that such data would identify some potential coronary and stroke candidates even in infancy. Of all the factors implicated in coronary disease, abnormalities of blood lipids and blood pressure are most important. While both may influence cardiovascular disorders in other ways, it appears that they exert their most deleterious effects by producing or accelerating atherosclerosis. These factors must be sought out through periodic examination and should be made known to the parents of the potential victim. SERUM
LIPIDS
Most atherogenic serum lipid disorders appear to have their roots in childhood. Some are inborn errors of lipid metabolism. Others are acquired or associated with various disease processes. The habits of diet and sedentary living, which contribute to the acquired hyperlipoproteinemias, may also be formed in childhood. It is not yet clear whether adult blood lipid values can be predicted from analysis of blood during infancy or childhood. It is unlikely that genes are the sole determinants of the generally high serum lipid values encountered in western civilization. Nutrition,
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physical activity, and many other environmental factors undoubtedly play important roles in determining the lipid levels found in the general population, as well as in inherently vulnerable individuals. Genetically determined lipid disorders. I-Iyperlipemia and hyperlipoproteinemia have been implicated as major contributors to atherogenesis. Inherited hypercholesterolemia with xanthomatosis is a lipid disorder long recognized as associated with premature and severe atherosclerosis. This disorder is genetically determined as a dominant trait. In the adult it is characterized by the frequent appearance of tuberous and tendonous xanthomata, in association with high plasma values for cholesterol (usually above 300 rag. per 100 ml.) and by cholesterol-rich beta lipoproteins in the presence of normal triglyceride concentration. Although this type I I hyperbetalipoproteinemia . may occasionally be recognizable in chiIdhood by some of its clinical stigmata, reliance on these alone will detect only a fraction of affected children. Serum lipid analysis early in life, even at birth, will frequently detect this abnormality. Total serum cholesterol values in young children average approximately 160 mg. per 100 ml. with a range of 105 to 215 rag. per 100 ml.2S; above these levels the probability of an inborn error of lipid metabolism is very high. In the upper range of normal, i.e., above 200 rag. per milliliter, the distinct possibility of an underlying lipid abnormality must be considered. Infants born into families with any history of "familial hypercholesterolemia" or precocious atherosclerotic disease should be studied for a lipid abnormality and, if negative, tested periodically into adulthood to exclude a possible heterozygous state in which the appearance of the abnormality may be delayed. Ideally, assessment of children for this type of hyperbetalipoproteinemia requires precise measurement of low-density Iipoprotein (Sf0-20) cholesterol. This necessitates a series of tests including alpha, beta (LDL), and total cholesterol and triglyceride determinations, and lipoprotein electrophoresis of the total plasma and of the top and bottom fractions after ultracentrifugationY ~ The last
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is required to exclude type III dyslipoproteinemia. Acquired hyperlipoproteinemia should be excluded by tests of glucose tolerance, renal and hepatic function, and uric acid concentration. Other family members should also have lipid determinations to establish whether the child has familial xanthomatosis as well as to identify members with undiagnosed hyperlipoproteinemia. In summary, the biochemical hallmarks of this dominant inherited trait are the extraordinarily high levels of plasma cholesterol (more than 230 rag. per 100 ml.) and beta lipoprotein with normal triglyceride and glucose tolerance values. Xanthomata may be seen early but not in all cases. The goal of treatment is to reduce plasma cholesterol concentration, preferably below 200 rag. per 100 ml. In very young children, still lower values should be sought. Xanthomata rarely a p p e a r when the plasma cholesterol level is within the range of normal. Their appearance and disappearance is closely related to the level of plasma cholesterol, so Further experience will be required to ostablish the optimum diet and drug regimen for children with hyperlipoproteinemia, especially type II. A diet low in cholesterol (under 200 rag. daily), with polyunsaturated exceeding saturated fatty acids by a ratio of more than 2: 1, is currently advocated in this disorder. Saturated fat should provide no m o r e than 10 per cent and total fat no more than 35 per cent of all food calories. Type II heterozygous persons will probably respond to this dietary regimen. Some will also require administration of a drug such as cholestyramine. Type II homozygous persons generally obtain very little reduction in serum cholesterol levels with dietary management alone and require additional therapy after the maximum dietary effect has been reached. Administration of multiple drugs is usually necessary for this purpose. Unfortunately, some patients are quite resistant to all drug combinations. When all else fails, the somewhat drastic procedure of ileal bypass may be considered; some have found it successful in lowering lipid values well beyond those achieved with dietary management alone. ~1' ~2 Others, perhaps less ex-
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pert in its application, have found it less effective than diet and drugs. Side effects including diarrhea, partial intestinal obstruction, and intussusception may occur2 B All children of persons with type I I hyperlipoproteinemia should be tested, and those with this trait should be treated very early in life. Until more is known of the longterm effects of drug therapy, the pediatrician may feel constrained to rely on dietary management, but the hazards of premature atherosclerotic disease in the homozygotic child are formidable and may warrant drug therapy despite the uncertainty. For the heterozygotic child with type I I hyperbetalipoproteinemia, drug therapy can be delayed until about age 14. Dosages of antilipemic drugs for children and infants are not well established, are certainly not a simple fraction of the adult dose, and must be carefully adjusted to obtain maximal efficacy without incurring dangerous or unpleasant side effects. Of the other types of hyperlipoproteinemia, type I (chylomicronemia) is genetically determined but is extremely rare and not a precursor of atherosclerotic diseaseY 3 It is inherited as a Mendelian recessive gene, also often determinable in infancy. Correction of the severe hyperlipemia will eliminate abdominal pain and pancreatitis. Types I I I , IV, and V hyperlipoproteinemia cannot be detected until later in life. Type I I I lipoproteinemia, which may also be associated with accelerated atherogenesis, is apparently inherited as a recessive trait. It has thus far not been identified prior to age 20, but it would seem prudent to look for it periodically, beginning in childhood, in offspring of affected parents. Type I V prebetahyperlipoproteinemia is only rarely detected before age 25. Although it is very likely an acquired disorder in m a n y persons, it is believed to be inherited as a dominant trait with delayed expression. Although type I V is not manifest until adulthood, its possible precursors of obesity, impaired glucose tolerance, and excessive dietary carbohydrate intake m a y be present earlier in life. Some of the inherited lipid
The Journal o[ Pediatrics April 1972
abnormalities may appear only after a period of excessive dietary intake of saturated fats, cholesterol, and calories. Acquired lipid disorders. Children born into families with a tendency to premature atherosclerotic disease should be considered at high risk whether or not they have a demonstrable error of lipid metabolism. A good case can also be made for periodic blood cholesterol monitoring and for diet and weight control in all infants and children whose plasma cholesterol values exceed 160 mg. per 100 ml. The trend of cholesterol levels in relation to age in children is still not fully known. The prognostic significance of moderate plasma cholesterol elevations in infants and children is not known and can only be inferred from prospective studies in young adults. In view of the fact that the risk of coronary artery disease rises in proportion to the plasma cholesterol concentrations, an ideal cholesterol value would appear to be the lowest one achievable without illness. ~4 Most atherosclerotic disease in the general population does not result from the aforementioned inborn errors of metabolism but occurs in those persons who as adults have serum cholesterol elevations in the less dramatic range of 250 to 350 rag. per 100 ml. Some of these "moderate" elevations may represent a heterozygous state for an inborn error of lipid metabolism, but most probably represent the environmental effect of excess intake of saturated fat, cholesterol, and refined carbohydrate by persons in positive energy balance, a5 BLOOD
PRESSURE
Elevated blood pressure is one of the most common and potent elements predisposing to coronary artery disease. A familial tendency toward hypertension has long been suspected by clinicians and confirmed by population studies. A significant correlation of the blood pressures of siblings has been demonstrated. Studies of twins have suggested a genetic explanation by revealing a closer correspondence of pressures among identical than among fraternal twins; the
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latter, in turn, correlated more closely than those of other siblings. The repeatedly demonstrated familial aggregation of blood pressure has been variously interpreted as supporting either a polygenic or single gene inherited mechanism of blood pressure regulation?G, a7 However, environmental factors could explain the clustering of hypertension in families. Families share more than genes; even spouses tend to share blood pressures to some extent, and this in proportion to the duration of the marriage? s Parent-child correlation of blood pressures tends to be greatest in families in which spouse aggregation is also present. Furthermore, there has been no convincing demonstration of bimodality in the distribution of blood pressure. Recently Zinner and associates 39 have extended the finding of familial aggregation of blood pressure .to include children in the range of 2 to 14 years. Although this tends to favor a genetic explanation, early environmental influences of relatively short duration could also start the potential hypertensive patient on the road to overt disease. Proof of the existence of environmental determinants of familial aggregation of Mood pressure must still be awaited. The findings of Zinner and associates 39 suggest that the process of essential hypertension, and ultimately its influence on the rate of atherogenesis, has its roots very early in life. Most prospective studies of hypertension in adults also reveal that, despite its high prevalence, few entirely new cases evolve among normotensive persons after age 30. The report o f Zinner and coworkers a9 suggests that hypertension in adult life could possibly be predicted from the blood pressure pattern in youth. Direct evidence bearing on this should be sought. There is some suggestion that the level of pressures achieved early in life tends to determine the subsequent level of pressure obtained in adult life. Physicians have long suspected that modest and labile pressure elevations precede severe fixed diastolic hypertension. Hypertension may be a self-prepetuating vicious cycle. Long-standing hyper-
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tension appears to alter arteriolar structure so as to increase peripheral resistance; it may also reset "barostats" at a higher level. Many clinicians believe that the rate of rise in pressure with age or time is steeper in those with high than with low pressures. Whether this is a biological fact, statistical artifact, or unsubstantiated clinical folklore is difficult to decide. 4~ The incidence of elevated blood pressure certainly increases with age in most populations. The causes of so-called essential hypertension will be more readily identified by investigations closer to the time of onset. Factors initiating hypertension may differ from those which sustain it. Intensive study of the children of hypertensive parents may reveal the causes of hypertension in the adult. Hypertension promotes atherogenesis, myocardial failure, and strokes. No means of preventing hypertension other than the avoidance of obesity is currently known. Presently we can only attempt to control established hypertension in order to d e l a y its cardiovascular sequelae. We can no longer doubt that persons with severe or moderate hypertension benefit from having their pressures lowered. 41 We lack concrete evidence that the same benefits accrue to mildly hypertensive patients without organ damage. Such evidence is urgently needed. The risk of atherosclerotic and other cardiovascular sequelae varies widely with blood pressure even in the "borderline" range of elevations. In adults of any age and either sex, even modest elevations of pressure--systolic or diastolic, casual or b a s a l - a r e associated with a substantial increase in risk of coronary heart diseaseY a When associated with elevated blood lipid levels or electrocardiographic abnormalities, this risk is formidable. Since few risk factors in the make-up of the potential victim of atherosclerosis are more easily detected and controlled, essential hypertension is more deserving of attention than any other factor. It would seem that the earlier in life this prophylaxis is implemented the better. Fear of the possible hazards of long-range use of antihypertensive agents need not deter
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such an endeavor, since the modest, labile pressures of incipient hypertension may for a long time require nothing more than weight reduction, salt restriction, and administration of tranquilizers for their control. The pediatrician may ask what concrete steps he should take to prevent the development of hypertension. Elevated blood pressure in the young may result from renal disease, coarctation, or other "specific" causes; these should be sought and treated appropriately. Since many adults with "essentiaF' hypertension had blood pressure levels at the upper limit of "normal" as children, this measurement is an important part of the physical examination. Children with blood pressure values in the upper 20 per cent of the distribution curve merit periodic re-examination. In such children the prevention and correction of obesity is important since obesity is the single most important environmental factor clearly related to elevated blood pressure. 42 The other major environmental factor is the sodium content of the diet. Marked lowering of sodium intake to 200 mg. per day or less has an important hypotensive effect. A similar effect can be obtained by "washing out" sodium with natriuretic drugs. Limiting the sodium content of baby foods and of children's diets is still the safest effective procedure for lowering blood pressure. Studies which suggested that relatively low sodium intake might have some beneficial effect have not been confirmed. It is nevertheless still possible that a low intake of sodium throughout life might have an important effect in preventing hypertension in adult years. The habit of adding salt to practically all foods is learned early in life. Commonly encountered daily intakes of 4 to 12 Gm. are far in excess of the daily need for this electrolyte. The pediatrician should discourage the common habit of adding salt to childhood diets. IMPAIRED
GLUCOSE T O L E R A N C E All children of diabetic parents merit careful monitoring, not only of their carbo-
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hydrate tolerance, but of their blood lipids, blood pressure, and weight pattern as well. Although the acute metabolic consequences of diabetes have been controlled by administration of hypoglycemic agents, there is little evidence that the late cardiovascular sequelae have been similarly ameliorated. 4a Diabetes represents a more complex metabolic derangement than simply one of impaired carbohydrate utilization; metabolism of lipids is deranged as well. Obesity and impaired glucose tolerance are prominent features of types III, IV, and V hyperlipoproteinemia. Removal of very low-density (S,20-400) prebeta lipoprotein by adipose tissue appears to be impaired in the obese subject. The superfluous fat in obese adults is found in oversized fat cells which become relatively unresponsive to insulin. Removal of lipoprotein by adipose tissue depends on the action of insulin. Elevated endogenous triglyceride and prebeta lipoprotein are characteristic of the obese patient with adult-onset, keto-resistant diabetes. Data from Framingham have revealed that lipid abnormality may precede the onset of diabetes by a decade or more, suggesting that the lipid disorder is not merely a consequence of uncontrolled carbohydrate intolerance. ~4 Perhaps a broader concept of diabetes "control," including the return to normal of blood lipids, blood pressure, and body weight would retard the accelerated atherogenesis accompanying diabetes, which has not been accomplished by improvement of carbohydrate tolerance alone. It is entirely possible that adult-onset, keto-resistant, obesity-related diabetes may be a late sequela of childhood obesity which produces a lasting proliferation of enlarged adipose tissue cells relatively resistant to insulin. ~ In keeping with this hypothesis, data from Framingham demonstrated an increased risk of diabetes in proportion to the degree of adiposity. 4~ LIVING
HABITS
The chief determinants of plasma lipid values, blood pressure, and carbohydrate tolerance in the general population are still speculative. While an inherited predisposi-
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tion is suspected, it is likely that environmental influences play a large role in prorooting the appearance of these atherogenic traits later in life. There is mounting evidence that faulty living habits and the unrestricted application of modern technology are exacting an increasing toll in death from atherosclerotic disease. This technologic revolution has provided a surfeit of food at the same time that physical activity has been curtaiied. Eating habits, indolence and sedentary living habits, propensity to obesity, and possibly the cigarette habit are likely conditioned in childhood by the behavior and attitudes of the family group. Diet. The storage of calories derived from saturated fat and refined carbohydrate has in all likelihood contributed to the generally high blood lipid concentrations, the high prevalence of impaired, carbohydrate tolerance, and possibly to hypertension in the general population. There is reason to believe that the type of diet habitually eaten is to a large extent responsible for the levels of serum lipids observed in a population. Those who habitually eat a diet high in calories, saturated fat, cholesterol, and refined carbohydrate have substantially higher cholesterol values than those who do not. 84 The American type of diet has been demonstrated to produce atheroma in primates. 12 Lipid levels can be lowered in a predictable fashion by dietary manipulation. There is little question that food preferences and eating habits are conditioned in childhood. It would seem reasonable for pediatricians to counsel mothers on the feeding of a diet emphasizing skim milk, cottage cheese, and other dairy products derived from skimmed milk, legumes, fruits, starches, lean meats, poultry, and fish. Candies, pastries, egg yolks, animal fats (including dairy fats), and organ meats should be de-emphasized. The only vegetable fat that need be restricted is coconut oil, the only naturally occurring highly saturated vegetable oil. Overeating and overfeeding should be discouraged. Further experience will be required to establish the ideal diet to promote optimal
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cardiovascular health later in life. Infants a n d c h i l d r e n can thrive and develop normally on either a diet high in saturated fat and cholesterol or one that contains little of these nutrients. Only an adequate amount of high-quality protein, vitamins, polyunsaturated fatty acids, and calories appears essential. Although breast-fed infants have a relatively high level of serum cholesterol compared to others, it would not seem wise to recommend artificial feeding on this account. *s The diet composition considered most desirable for children should contain less than 35 per cent of calories from f a t - - a polyunsaturated/saturated ratio of 2 : 1--and less than 200 rag. of cholesterol. In those with a tendency to gain weight, refined carbohydrate should be restricted. Physical exercise. Although young children tend by nature to be physically active, they tend to become sedentary as society makes it increasingly difficult for them to remain active. Parents can set an example by encouraging youngsters to remain physically active and by participating in family outings, hiking, and sports whenever possible. Regular exercise will aid in avoidance of obesity and its attendant atherogenic effects. More important, it may set a pattern for a physically active way of life in adulthood. Persons who are sedentary have been found at Framingham and elsewhere to develop more myocardial infarctions and to have a higher mortality rate from coronary artery disease. Physical activity, possibly by promoting collateral blood supply in adults as the coronary vessels become increasingly stenotic, appears to protect against a lethal outcome in coronary attacks. 46 The amount of exercise required to accomplish this is apparently modest. 4~ Obesity. There is some evidence to suggest that obesity, by increasing the size and number of adipose tissue cells and altering the sensitivity to insulin, may be a self-perpetuating entity. However, while there appears to be a wide inherent variation in the tendency to store calories, obesity is generally the result of eating too much and exercising too little. Obese parents are
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more apt to have obese children. Equating leanness in childhood with ill health is an attitude which should be dispelled. The obese subjects in Framingham, particularly those with other risk factors, had an excess of angina and sudden death. Whereas adiposity may accelerate atherogenesis by promoting lipid abnormalities, impaired carbohydrate tolerance, and hypertension, it appears also to make a contribution per se. Its effect is apparent even after adjusting for these variables, suggesting that the increased cardiac work load imposed by obesity in persons with a compromised circulation may be an important mechanism. 4s The cigarette habit. The cigarette habit has been demonstrated to influence coronary death adversely, particularly in persons at known risk?, 49, ~0 Lethal coronary attacks appear to be triggered by cigarette smoking, the impact diminishing with advancing age. Research has shown that the smoking habit is usually acquired early in life. It is unlikely that the cigarette habit represents a serious threat to cardiovascular health in adolescence. The toll is exacted later in life after the habit becomes established and the cardiovascular system more vulnerable to its effects. The cigarette habit becomes established more readily in adolescents who are exposed to it by their peers, siblings, and parents? 1 The ready availability of cigarettes in the home and in vending machines places unnecessary temptation in the path of maturing children. Seductive advertising to which children are exposed should be discouraged. Smoking in public buildings and vehicles should be prohibited. CONCLUSIONS
In the United States coronary heart disease and the other clinical manifestations of atherosclerosis are the major causes of illness and death. Atherosclerosis, although uncommonly observed before age 40, has its onset in infancy and childhood. Some of the factors predisposing to this disorder, e.g., genetically determined lipid abnormalities and hypertension, may be detected
The ]ournal o[ Pediatrics April 1972
early in life. Other factors which represent life habits are also frequently established as a result of childhood environment. Only by controlling constitutional traits and environmental influences early in life does it appear likely that an important beneficial effect on coronary heart disease mortality and morbidity rates will be brought about. The pediatrician has a long tradition in health maintenance and preventive medicine. More than any other medical specialist he has adopted the prophylactic approach in everyday medical practice. Although his direct responsibility for medical care arbitrarily ends with adolescence, the pediatrician has an opportunity to markedly affect the development of diseases of later life. He therefore has a responsibility not only to be concerned about diseases which become clinically manifest during infancy and childhood but about those which, although not appearing until later in life, may be prevented or delayed by health practices during the first two decades of life. At the present time the pediatrician may expect that one in every five male patients under his care will develop coronary heart disease before the age of 60. There is every likelihood that the pediatrician can play a crucial role in favorably changing these statistics. Promotion of cardiovascular health should be one of the chief concerns of the conscientious pediatrician. Although proof of the efficacy of prophylactic measures aimed at preventing atherosclerotlc disease is lacking, it is reasonable to believe that the approach advocated will materially lower the morbidity and mortality rates from this disorder. This approach calls for (1) the prevention of obesity, (2) the early determination of any lipid abnormalities and their correction by diet or other procedures if necessary, (3) careful surveillance for early evidence of hypertension and the institution of corrective measures, (4) the promotion of high-energy output physical activity, and (5) discouragement of the cigarette smoking habit.
Volume 80 Number 4, part I
Atherosclerosis in pediatrics
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