Symposium on Pediatric Cardiology

Pediatric Aspects of Atherosclerosis and Hypertension Julia Lee, M.D., * and Ronald M. Lauer, M.D. t

In modem societies, morbidity and mortality from infectious diseases and malnutrition have been greatly diminished. Chronic diseases, particularly arteriosclerosis and hypertension with their complications, now emerge as the most serious health problems. These processes take a tremendous toll in premature sickness, disability, and death, and have a major economic impact on its victims and upon the health care delivery system. In recent years, efforts to understand the origins and prevention of atherosclerosis and hypertension have developed in the disciplines of internal medicine, cardiology, epidemiology, preventive medicine and, more recently, pediatrics.

The Pediatric Problem It is estimated that one out of every five male children in the United States will develop coronary artery disease before the age of 60. The disease of atherosclerosis has an extremely long and silent latency before the first symptoms of angina pectoris, myocardial infarction or, not uncommonly, sudden death occur. A large proportion of the adult population is affected by hypertension and the prevalence rises steadi"Fellow in Pediatric Cardiology, University of Iowa Hospitals, Iowa City, Iowa tProfessor of Pediatrics, University of Iowa College of Medicine, Iowa City; Director, Division of Pediatric Cardiology, University of Iowa Hospitals, Iowa City, Iowa The investigations cited from the Muscatine Study are supported by a Specialized Center of Research Grant in Atherosclerosis (HL14230) from the National Heart, Lung and Blood Institute. Dr. Lee is supported by a Training Grant (HL05700) from the National Heart, Lung, and Blood Institute.

Pediatric Clinics of North America - Vol. 25, No.4, November 1978

909

910

JULIA LEE AND RONALD

M.

LAUER

ly with age. The primary expression of morbidity and mortality is stroke, and lesser but significant expression as cardiac and renal failure. IOO There is a growing conviction that the only way to significantly alter the course of atherosclerosis and hypertension is to attack the constitutional and environmental precursors long before the overt symptoms become manifest. As our knowledge of epidemiology, pathogenesis, and natural history of these processes has grown, the pediatrician has again come into the prime position to practice preventive medicine against diseases of major social, economic, and medical importance.

The Development of Atherosclerosis Historically, the concept of atherosclerosis dates back at least 200 years.'4 In 1727, Brunner described the necropsy findings in the aorta of his 75 year old father-in-law. In the second half of the nineteenth century, microscopic studies of the cellular pathology were initiated by Virchow and his contemporaries. 14 The atheromatous material was recognized to be an accumulation of lipids including cholesterol. The identification of the nature of the plaque contents inevitably imposed critical questions regarding the pathogenesis and etiology of the deposits. The earliest recognizable lesion in the vascular system is the fatty streak which is an accumulation of lipids in the intima of large muscular and elastic arteries. It has been described to be present in the vessels of young children and infants. Whether all fatty streaks invariably progress to more complex lesions has not been clarified. A more advanced lesion is the fibrous plaque, a raised lesion consisting of a central core of extracellular lipid covered on the luminal side of the vessel by a cap of fibromuscular tissue. These appear frequently by 15 years of age. It is the nidus for the development of complicated lesions of arterial stenosis, occlusion, and ischemia of vital tissues. Autopsies performed on young American soldiers killed in the Korean and Viet Nam conflicts substantiate the presence of advanced coronary atherosclerosis in 77 and 45 per cent respectively of the young casualties. 24 • 71 Thus, it appears that atherosclerosis has its silent beginnings in childhood.

DETERMINANTS OF HYPERCHOLESTEROLEMIA Factors that determine the level of serum cholesterol have not been fully delineated, but several important observations have been made. Among them is the relationship of diet to blood cholesterol levels. Animal studies by Wissler and Vesselinovitch 103 have shown that hypercholesterolemia and accelerated atherosclerosis could be induced in Rhesus monkeys fed the "Typical American Diet" as compared with monkeys fed the low cholesterol American Heart Association diet.

ATHEROSCLEROSIS AND HYPERTENSION

911

Epidemiologic studies have shown major correlations between habitual diet, plasma cholesterol levels, and the prevalence of atherosclerotic disease. 32 , 9:1 These contrasts are particularly striking if one compares the United States with its high coronary heart disease rate and a diet which is characterized by a high caloric intake, high total fat, high saturated fat and high cholesterol, to other countries with low coronary heart disease rates who subsist mainly on diets which are lower in total calories, total fat, saturated fat, and cholesterol. If one can extrapolate this observation from the adult population to the pediatric population, it suggests the existence of different degrees of risk for coronary artery disease among pediatric populations. Of interest is the observation of Golubjatnikov et al. ,36 which compared cholesterol levels of children from Wisconsin to a siInilar group of children from Mexico. The mean serum cholesterol level in the Wisconsin children was 188 mg per 100 mI, whereas the mean serum cholesterol in the Mexican children was considerably lower at 100 mg per 100 ml, with only 4 per cent of those children having serum cholesterols greater than 140 mg per 100 ml. Thus, it appears that the dietary habits of affluent societies are contributory to hypercholesterolemia and are reflected in the increased prevalence of coronary heart disease. This is not to say that diet causes atherosclerosis. Rather, there is a complex interplay of many physiologic, genetic, and environmental factors, and diet may have a role in augmenting the overall expression of serum cholesterol levels. Primary Versus Secondary Hypercholesterolemia The distinction between primary and secondary hypercholesterolemia is important. Secondary hypercholesterolemia is associated with hypothyroidism, diabetes mellitus, chronic renal failure, the nephrotic syndrome, obstructive liver diseases, exogenous steroid therapy, alcoholism, and oral contraceptive intake. A very small proportion of the total population with hyperlipidemia have a specific inherited form of hyperlipidemia. The majority of people who have serum cholesterol levels at or above the 95th percentile represent subjects with various dietary, polygenic, metabolic and other yet unidentified factors. Five types of hyperlipidemia based on the ultracentrifugation properties of lipoproteins have been identified. Detailed descriptions of these primary hyperlipoproteinemias and, specifically, the familial hyperlipoproteinemias, are well described in the,pediatric literature. 30 Type II hyperlipoproteinemia, also known as familial hyperbetalipoproteinemia or familial hypercholesterolemia is the major inherited hyperlipoproteinemia of significance in the pediatric population. Children with this disorder have difficulty in clearing cholesterol from their plasma. Type II familial hyperlipoproteinemia has two subtypes, Type IIa and lIb. Type lIa is characterized by elevation of low density lipoprotein, whereas Type lIb is characterized by elevations of low density lipoprotein and very low density lipoprotein. This genetic disorder may be present in either the heterozygous or homozygous form. The types differ dramatically in the clinical expression and prognosis. Heterozygotes are char-

912

JULIA LEE AND RONALD

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LAUER

acterized by hypercholesterolemia of usually less tl!an 500 mg per 100 ml. They often have premature atherosclerotic coronary heart disease between the ages of 35 and 55 years. There is a large degree of variability in the expression of cardiac disease in the heterozygote. In contrast, the homozygote has a more uniform course of accelerated cardiac disease with symptoms of angina pectoris, myocardial infarction, or sudden death occurring in late childhood or early adulthood. The most helpful clinical clue is the identification of cutaneous planar xanthoma, which are uniformly present in the homozygote within the first decade of life and not infrequently are present llt birth.

DETERMINANTS OF HYPERTENSION Hereditary and Environmental Influences Blood pressure appears to be influenced by genetic and environmental factors. Feinleib et al. 28 demonstrated that monozygotic twins have higher correlations for blood pressure than other relatives, including dizygotic twins. Dizygotic twins, however, have higher correlations than other siblings or parents to their offspring. Biron et al. 7 examined the familial similarity of blood pressure in adopted and natural children and concluded that blood pressure was largely hereditary. In contrast, migrant studies have demonstrated a strong environmental influence. CasseP2 summarized several studies which showed when certain populations with low incidence of hypertension migrate, the incidence of hypertension increases to levels resembling the population of their new homeland. It appears that blood pressure is genetically determined, but it is altered by environmental influences. Familial Aggregation of Blood Pressure Ayman et al. 4 reported elevation of blood pressure in 28 per cent of childreQ. in families with one hypertensive parent and 41 per cent of children with two hypertensive parents. In addition, elevated blood pressure occurs in 65 per cent of siblings of hypertensive subjects. Miall at al. 72 described familial aggregation of blood pressure in adults compared with that of first degree relatives. Similarly, Plate9 found a greater incidence of hypertension in the siblings of patients with severe hypertension than in the general population. Zinner104 described familial aggregation of blood pressure in children (2 through 14 years) with their siblings and their mothers. Heyden et al. 44 in the Evans County Study described similarities in blood pressure among first degree relatives to be of the same magnitude for blacks and whites. The phenomenon of familial aggregation of blood pressure between mother and child has been described to be present as early as 2 months of age. 55 These studies suggest that genetic and environmental influences are in effect even at a very early age. Although hyperten-

ATHEROSCLEROSIS AND HYPERTENSION

913

sion appears statistically to aggregate in families, the degree of correlation is not strong enough to allow the identification of a hypertensive family by the examination of a single family member.

Obesity Obesity and hypertension are positively correlated in adults. 60 • 74, 93 A similar relationship exists in chidren. Johnson et al. 48 studied a group of adolescents in Evans County, Georgia, and found that obese individuals in this group had a greater incidence of hypertension; those who experienced a rapid weight gain during the study were most likely to have sustained hypertension. Similarly, Rames et al. 82 in a study of Muscatine, Iowa school children found that more than half of the children investigated for sustained hypertension were obese with relative weights in excess of 120 per cent. Some had significant reduction of their blood pressures concomitant with weight loss. The elevated blood pressure associated with obesity was not an artifact resulting from the subject's fat arm, but true arterial hypertension confirmed by direct measurement of intra-arterial pressure. Dietary Salt and Hypertension in Human and Animal Models The relationship between salt intake and hypertension raises many provocative questions. Epidemiologic studies in the South Sea Islands noted that adults had low blood pressure that did not rise with age. 66, 76,90 Analysis of their diet revealed a very low salt intake of 5 gm per day or less. Conversely, hypertension occurs in 84 per cent of Northern Akita Japanese farmers 93 who consume up to 25 to 30 gm of salt per day as a part of their dietary custom. However, observations have been made describing people who consume large amounts of salt and do not develop hypertension. These conflicting observations may be reconciled by postulating the existence of other determinants such as a hereditary sensitivity to salt. Dahl et al. 15 were able to selectively breed salt-resistant and salt-sensitive strains of rats, When fed a low sodium diet, the blood pressures were similar when young; however, the hypertensive-prone strain spontaneously developed mild hypertension as adults. When the hypertensive-prone rats were fed a high salt diet, they developed accelerated hypertension. Mark et al. 68 studied a group of human subjects with borderline hypertension and found that a high sodium intake induced an increase in forearm vascular resistance, neurogenic vasoconstriction, and increased arterial pressure as opposed to normotensive control subjects. It may be postulated that "resistant" individuals do not develop elevated blood pressure when exposed to a similar amount of dietary salt. If susceptible individuals could be identified, the development of hypertension might be prevented by the lifelong practice of low salt intake.

CORONARY RISK FACTORS Coronary risk factors are characteristics whose presence in adults is associated with an increased likelihood that a myocardial infarction

914

JULIA LEE AND RONALD

M.

LAUER

will develop at a later time. They have been identified through prospective epidemiologic studies on large groups of healthy adults. 50. 87. 9;) The following risk factors for coronary heart disease have been identified: increased serum cholesterol, hypertension, cigarette smoking, obesity, family history of premature arteriosclerotic cardiovascular disease, diabetes mellitus, lack of physical activity, and psychological behavioral profile. Coronary risk based on these factors give an index of the probability of developing future coronary artery disease. 96 For example, a normotensive 35 year old white male who is a nonsmoker and has a serum cholesterol of 185 mg per 100 ml and no other major abnormalities has an 0.4 per cent probability of having coronary artery disease within the next 6 years. In contrast, the same 35 year old white male will have a 16.9 per cent probability of having coronary artery disease within the next 6 years if he has hypercholesterolemia, hypertension, is a cigarette smoker, and exhibits electrocardiographic evidence of left ventricular hypertrophy and has an abnormal glucose tolerance test. Thus, a greater than 40-fold increase in risk can be brought about by changes in the risk factors present. The individual risk factors are not of equal importance and it appears that hypercholesterolemia, hypertension, and the smoking habit have the greatest predictive value. Although one or more of these factors are present in a high percentage of people with atherosclerotic heart disease, there remains a sizeable proportion of those with occlusive atherosclerotic disease in whom the risk factors are not present, suggesting the existence of other factors which are yet to be identified. 20 , 21 Cholesterol Cholesterol levels in adults have been shown to be one of the best predictors for the development of coronary heart disease. 96 Cholesterol can be separated by ultracentrifugation into several fractions. These fractions are VLDL (very low density lipoprotein), LDL (low density lipoprotein), and HDL (high density lipoprotein). Excessive amounts of VLDL and LDL or combinations of these with each other or other lipids characterize one of the five recognized clinical patterns of the hyperlipoproteinemias. 30 There is recent evidence which suggests the proportion of the fractions, HDL in particular, to be a better index or risk than total cholesterol. 57 It appears that increased HDL is associated with decreased coronary risk, whereas decreased HDL is associated with increased risk. 13 Lower than average levels for HDL have been reported in up to 40 per cent of male adults with coronary artery disease. Similarly, type II familial hyperlipidemia is associated with abnormally high levels of LDL and also low levels of HDL. Thus, the total cholesterol to HDL ratio may become the more useful predictive index. 13 The precise mechanism by which HDL performs its beneficial role has not been fully delineated. It appears that it may playa role in limiting the rate of cholesterol deposition and/or promoting its removal.

ATHEROSCLEROSIS AND HYPERTENSION

915

Hypertension Hypertension in adults is known to be associated with serious consequences of coronary artery disease, congestive heart failure, renal insufficiency, and stroke. In animal studies, hypertension is known to aggravate and accelerate the development of atherosclerosis. The impact of hypertension on morbidity, mortality, and productivity is documented by life insurance statistics. 61 The cooperative study of the Veterans Administration has shown that there is a reduction in morbidity and mortality following the identification and treatment of adult males with essential hypertension. 101 There are little clinical data available of serial measurements of blood pressure from childhood through adulthood. Thus, the predictive value of childhood blood pressure is somewhat uncertain. However, several pertinent observations have been made. First is the phenomenon of tracking of blood pressure or the stability of blood pressure rank over time. Zinner found significant tracking of blood pressure in a group of children in whom initial measurements were compared with those taken four years later. l04 Similarly, Buck described the persistence of elevated blood pressure first observed at age 5 and at followup at age 12 years. to Data from the study of children in Muscatine, Iowa showed that while there was a relationship between initial blood pressure measurements and subsequent annual measurements over six years, there was marked variability in individual blood pressure measurements. 58 This stresses the importance of serial measurements to identify accurately children with sustained blood pressure elevation. In addition, longer periods of observation of groups of children will be required to know if high childhood blood pressure levels relate to the development of adult hypertension. Cigarette Smoking The risks that have been most emphasized for cigarette smokers are lung cancer and chronic bronchitis; but in fact about half of the excess mortality in smokers is due to cardiovascular disease. 85 It has also been established that cigarette smoking significantly enhances the effect of other coronary heart disease risk factors and, at any given level of risk, the habit of cigarette smoking almost doubles the risk. 5 It appears that the risk is greatest in heavy smokers (more than 20 cigarettes per day). It is proportional to the duration of smoking and is highest in those who started smoking before the age of 20 years. This is especially important in view of the fact that the majority of teenagers who smoke become established adult smokers. The incidence of coronary heart disease in women has risen in the past 20 years. During this same period of time, the cigarette smoking habit has increased by 35 per cent. Several studies have shown that women who smoke and also use oral contraceptives are at even greater risk for developing coronary heart disease. 67 These three important facts about smoking have been established: the cigarette smoking habit constitutes a major coronary risk factor; the habit is potentially alterable; and abandoning the habit will reduce

916

JULIA LEE AND RONALD

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LAUER

the risk. 21, 49. 81 These facts make it clear that every effort should be made to discourage the initiation and continuation of the cigarette smoking habit.

Family History Individuals with a family history of coronary heart disease are at an increased risk themselves. lB. 31 The association is greatest for those who have first degree relatives (parents, siblings, or children) who have recognized coronary heart disease before age 50 years. s The magnitude of this association is two to five times greater than the risk of individuals with no known coronary heart disease among relatives. The familial patterns of coronary heart disease may be a reflection of the familial patterns which exist in the major risk factors of plasma cholesterol, blood pressure, cigarette smoking habit or blood glucose levels. 92 ,93 Plasma cholesterol levels have been shown to have familial patterns of similarity.IB Similarly, Pickering 7H and MialF2 have described familial patterns for blood pressure among adults, and Zinner et al. 'OO have described familial similarities for blood pressure in children. Hennekens et al. 42 compared the plasma cholesterol levels of children of men with premature myocardial infarction with the plasma cholesterol levels of children of healthy men. It was found that the relative risk for having cholesterol levels in excess of 230 mg per 100 ml was 3.6 times greater for children of affected men. In a study of Muscatine, Iowa school children, Schrott et al. B9 found an increased frequency of coronary heart disease in relatives of hyperlipidemic school children. A family history of coronary heart disease, particularly occurring prematurely in first degree relatives, appears to be a significant factor in the risk of developing coronary heart disease. Obesity Life insurance statistics have shown that obesity is associated with a shortened life expectancy.69 However, its role as a coronary risk factor is less clear. It appears that the relationship between obesity and angina pectoris and sudden death is stronger than for nonfatal myocardial infarction. The Framingham Study has shown an increased risk for coronary heart disease with obesity but the effect was less than the effect of elevated plasma cholesterol or hypertension. 50 Obesity is frequently associated with the presence of other risk factors such as hypertension, elevated plasma lipids, glucose intolerance,. or diabetes mellitis. The correction of obesity may improve elevated blood pressure, hyperlipidemia, and glucose intolerance, thus resulting in an overall reduction of risk. 80

Psychological Factors It is a common belief that nervous tension and emotions aroused by situational circumstances can contribute to factors causing heart attacks. The Western Collaborative Group Study86 popularized the con-

ATHEROSCLEROSIS AND HYPERTENSION

917

cept of Type A and Type B personalities and the possible relationship of behavior to risk of development of coronary heart disease. Type A behavior, characterized by excessive sense of time urgency, preoccupation with deadlines, aggressiveness, and competitive drive was claimed to be associated with coronary heart disease twice as often as Type B behavior which had the opposite characteristics. The Jenkins Activity Survey, a self-administered, machine scored questionnaire, has been designed to assess the Type A behavior pattern as a predictor of coronary riskY These authors suggest that the recognition of the Type A personality may be used in the counseling of particular individuals. Whether intervention can be successfully achieved in such individuals has yet to be established. Physical Activity It is generally accepted that man derives benefit from habitual exercise, and in more recent years, there has been considerable interest in the role of a sedentary life in the development of coronary heart disease. Paffenbarger77 reported the relationship between work activity and incidence of coronary heart disease in dock workers. The workers are classified into high, medium, or low calorie output jobs. He found the high activity workers to have coronary heart disease rates almost half as often as those found in the medium and low category workers. Differences persisted even when the effects of other risk factors were taken into account. The Framingham Study 51 examined the activity level independently of other coronary risk factors and found an association of higher incidence of ischemic heart disease in sedentary subjects. There was also evidence of lower mortality rates among the post-myocardial infarction patients who had a higher activity level in comparison to sedentary patients. There is some evidence that physical activity enhances production of high density lipoprotein, which may playa protective role in ischemic heart disease. 57 These observations suggest that exercise enhances factors such as cardiopulmonary fitness and metabolic mechanisms such as increased production of high density lipoprotein. These may play a role in curbing the development of coronary heart disease. Since habits established in childhood are often maintained into adulthood, a program promoting regular physical exercise and physical fitness seems appropriate.

THE CHALLENGE OF PREVENTION IN CHILDHOOD Modification of Cholesterol Levels in Children There are certain groups of children who appear to be at greater risk for the development of occlusive atherosclerotic disease and who might benefit from lowering of their plasma cholesterol. These include

918

JULIA LEE AND RONALD

M.

LAUER

children with familial hyperlipidemia, the progeny of young victims of myocardial infarction,32 and children with persistent hypercholesterolemia greater than 220 mg per 100 ml. The objective of treatment is to lower the cholesterol and concentration of low density lipoprotein into the normal range. 20. 34 Therapy usually begins with dietary intervention. It has been observed that children with mild hypercholesterolemia (in the range of 225 to 250 mg per 100 ml) have the most satisfactory response to diet alone. The diet alteration depends on the age of the child. The infant from newborn through 6 months of age can be easily managed by use of standard formulas which are higher in polyunsaturated fats and lower in cholesterol than breast milk or cow's milk. After 6 months of age, the diet must be modified by selection of solids which are low in cholesterol. The recommended diet from the American Heart Association for older children and adults is to maintain a diet providing 150 mg cholesterol with 25 to 30 per cent of calories from fat and a PIS ratio of 1.1. Carbohydrates and protein would constitute the remaining 60 per cent and 15 per cent respectively.2 Older children are a greater challenge because of their more particular food preferences. Active participation by an interested nutritionist can be very helpful in providing recipes and the encouragement needed for permanent adherence to the diet. Children who do not start on dietary intervention from infancy or early childhood need special attention to make the transition. Low cholesterol diet recipies are available from the American Heart Association. 3 It has been shown that diet alone can bring about a 10 to 15 per cent reduction in plasma cholesterol in an out-patient population. There are a number of children who do not respond to diet at all or the reduction in plasma cholesterol is not- adequate. In general, these are children with the higher ranges of plasma cholesterol (250 mg per 100 ml and above). They may require drug intervention. 34 At the present time, the most widely used drug is cholestyramine. It is an anionexchange resil'l which binds bile acids and reduces their reabsorption. The dose is titrated to the response (8 to 16 grams per day in two divided doses). Measures must be taken to monitor their side effects, usually gastrointestinal symptoms. It may be necessary to supplement fat soluble vitamins, especially in children who develop steatorrhea. Clofibrate and nicotinic acid have also been used. They act by altering lipoprotein production in the liver. Para-aminosalicylic acid has also been used. Drugs which directly block cholesterol synthesis have more severe, toxic side effects and are not usually used in children. A limited number of children with hyperlipidemia have undergone surgical procedures, namely partial ileal bypass 9 and portacaval shunts. Further evaluation of these procedures are needed. Although not enough time has elapsed to evaluate the long-term benefits of such measures, there is sufficient evidence pointing to the detrimental effects of hypercholesterolemia. Thus, it seems justified to initiate intervention in these high risk groups.

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ATHEROSCLEROSIS AND HYPERTENSION

Ranges of Serum Cholesterol in Children The ranges of serum cholesterol have been measured in neonates (cord blood), infants, and school age children. The mean serum or plasma lipid concentration for infants is summarized in Table 1 and for older children in Table 2. Several investigators have examined cord blood levels of cholesterol in an attempt at early identification of hyperlipidemia. 6 • 16. 33, IJ8. 97 It has been questioned whether cholesterol levels measured at birth are predictive of levels after age 1 year. Kwiterovitch et al,36 has suggested that low density lip()protein cholesterol leyels may be of more reliable predictive value than total plasma cholesterol. It is evident from the lipid values given in Tables 1 ana 2 that variability exists in these measurements. Plasma cholesterol is generally slightly lower than serum, Laboratories also differ in their techniques. Attempts are being made to standardize techniques among the Lipid Research Centers. To minimize biologic variations, it is advisable to collect the blood sample after a 12-hour overnight fast. Recent food intake does not have much effect on blood levels of cholesterol but triglycerides are greatly altered by recent dietary intake. Specimens from ambulatory patients should ideally be drawn shortly after assuming the supine position. A prolonged period of recumbency can lower the cholesterol level. The diagnosis of hypercholesterolemia should not be made on a single determination. In the Muscatine Study 58 examination of chilTable 1.

Low Density Lipoprotein and Lipid Concentrations in Infants" BIRTH

REFERENCE

SOURCEt

NUMBER

C

Glueck et al. 1971'" Darmady et al, 1972 '6 Barnes et al, 1972 6 Greten et al, 1973 38 Kwiterovich et al, 1973'" Goldstein et al, 1974" Tsang et al, 1974 97

P

1800

64 ± 19

S

302

78 ±23

P

747

76 ± 19

S

1323

60 ±20

P

36

74 ± 11

37 ± 15

P

2000

82 ±20

42 ±25

P

56

T

ONE YEAR

LDL

C

37 ±21 191 ± 36 52 ± 18 35 ± 12 31 ±6

138 ± 29

*C, cholesterol; T, triglyceride; LDL, low density lipoprotein; lipid levels in mg/dl (mean ±SD), ts, serum; P, plasma, Both serum and plasma can be used for cholesterol determinations, Plasma levels are usually slightly lower, Different laboratories may employ different methods and the degree of correspondence may depend on the technique used,

Table 2.

Lipid Concentrations in Children* SCHOOL AGE CHILDREN COMBINED

5 TO 7 YEARS REFERENCE

SOURCEt

Drash and Hengstenberg 1972 22 Lauer et al. 1975 58 Wilmore and McNamara 1974 '02 Lee 1967"

81 82 81 81

8tarr

81

1971 94

Carter 1976"

P

NUMBER 203 4829 95 55 boys 66 girls 291 58 4297

C

T

171 ± 27

72 ±36

C 170 ±35 182 ±29 178 ±27 164.2 166.1 177 ±25

T

16 TO 17 YEARS C

T

177 ± 26

108 ±46

60.6 ±38

175.7 ±25.8 158.7 ±25.7

53.4

'C, cholesterol; T, triglyceride; lipid levels in mg/dl (mean ± 8D). t81, serum; 82, AAI serum; P, AA2 plasma Both serum and plasma can be used for cholesterol determinations. Plasma levels are usually slightly lower. Different laboratories may employ different methods and the degree of correspondence may depend on the technique used.

ATHEROSCLEROSIS AND HYPERTENSION

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dren whose levels exceeded the 95th percentile for age, 70 per cent were significantly lower on second deterInination. Therefore, repeated samples, preferably three measurements, should be obtained to confirm the presence of an abnonnally high level of cholesterol before any therapy is instituted. Needless to say, causes for secondary hypercholesterolemia should be excluded. Diets for Normal Infants and Children It has been observed that the serum cholesterol levels in nonnal infants fed commercial formulas are lower than those in infants fed breast milk. 29 However, there is no evidence that this is either beneficial or harmful in terms of growth and development or in terms of potential for subsequent development of atherosclerosis. There is some animal evidence that suggests the need for a high cholesterol load during early infancy to ind~ce the control to maintain cholesterol levels at a lower level in later life. 39 Therefore, the high cholesterol content of breast milk should not detract from its use as the major food source of infant feeding. Skim milk is not recommended for children under one year of age because it does not meet the infant's caloric requirements. A useful dietary guideline at the present time would include breast milk or fonnula during the first six months of life to be continued- as the predominant source of nutrient until one year of age. When foods are added after six months of age, it may be prudent to limit the intake of cholesterol, saturated fats, and total fat.!9 The 1961 American Heart Association statement on diet! recommended the adult diet contain less than 300 mg of cholesterol per day, with fat constituting no more than 35 per cent of the total calories and saturated fats less than 10 per cent. One of the major concerns for adoption of the diet by all age groups is for possible unseen hazards. Although healthful diets fufilling these requirements have been the practice for centuries in the Mediterranean and Far Eastern cultures, it may be less easily attainable in Western cultures. Major dietary changes in the United States are likely to involve the widespread use of fabricated or substitute foods which may carry the hazard of vitamin and mineral imbalance.

BLOOD PRESSURE CONTROL IN CHILDREN Hypertension in Children The prevalence of hypertension in the pediatric population has been reported to vary from 1.4 to 11 per cent. 52. 64. 65 There is even greater variability in the reported proportion of primary versus secondary hypertension. Some studies report 100 per cent of childhood hypertension to be primary. 23. 64 In contrast, other studies report 85 per cent of childhood hypertension to be secondary. 62. 63. 70. 83. 84 These differences may be accounted for partly by the pediatric populations selected for the studies. Data from healthy children58. 64. 70. 84 will differ from data from children referred to medical centers for investigation of recog-

1

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JULIA LEE AND RONALD

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LAUER

nized hypertension. 63 . 70, 83 In the Muscatine Study, 58 13.4 per cent of school children were found to be hypertensive, defined as blood pressure in excess of the 95th percentile for age or greater than 140/90 mm Hg, on initial examination. After four screenings, only 0.6 per cent had persistence of hypertension. Half of these children were obese and some had reduction of blood pressure with weight reduction. Approximately 0.2 per cent had secondary hypertension attributed to coarctation of the aorta, birth control contraceptive intake, renal artery stenosis, or hydronephrosis. Only 0.11 per cent of the persistently hypertensive children were without identifiable cause. Londe et al. 65 described the prevalence of hypertension in a population of apparently healthy children with a similar observation that many became normotensive upon rescreening. These studies confirm the labile nature of blood pressure, especially in adolescents. The diagnosis of hypertension, therefore, should not be made on a single measurement because few have persistence of elevated blood pressure on successive examinations. Unjustified labeling can create anxiety and compromise future employability and insurability. These studies also show that mass screening programs of blood pressure in children is not cost effective for the purpose of detection because of the extremely low yield. However, they emphasize the need to include blood pressure measurements as a routine procedure during the continuing care of children. Methods of Measuring Blood Pressure in Children Blood pressure measurements obtained by indirect methods can be reliable and consistent if recorded under standardized conditions using well functioning equipment. Blood pressure measurement should be a routine part of examination of all children and should be repeated over a period of time in order to determine a significant pattern of blood pressure. Equipment should include a variety of cuff sizes to accommodate the various arm sizes. Reference to cuff size is to the inflatable bladder and not to the cloth covering. It should be of sufficient width to cover at least two-thirds of the upper arm and of sufficient length to encompass the circumference of the arm. 54 Cuffs which are too narrow or too 'short will result in artifactually high measurements. Mercury-gravity manometers may be more desirable than aneroid types because they do not require recalibration. The older child should be seated in a relaxed, quiet environment. The first, fourth, and fifth Korotkoff sounds should be recorded. The fourth and fifth sounds may occur simultaneously. In children it is not unusual to find the Korotkoff sounds persisting until the cuff is completely deflated. Thus, the fourth Korotkoff sound is recommended as an index of diastolic pressure measurement in children. The deScribed method can usually be satisfactorily employed in children 3 years of age and older. The measurement of blood pressure in infants requires special techniques. The flush method will give an estimate of mean pressure which is of limited utility. A more useful and accurate assessment of systolic blood pressure in infants can be

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ATHEROSCLEROSIS AND HYPERTENSION

obtained by the use of one of the Doppler devices. It has been shown that there is good correlation between Doppler measurements and intra-arterial recordings. 43 Hospitals providing care for infants should be equipped with Doppler devices to monitor blood pressures of critically ill infants. Some portable models that are more convenient for office use are available. Standards for Blood Pressure in Children The National Heart, Lung and Blood Institute of the National Institutes of Health recently appointed a Task Force on Blood Pressure Control in Children for the purpose of providing much needed specific guidelines for blood pressure parameters in children. 73 As a part of this effort, charts illustrating selected percentiles of seated blood pressure for children ages 2 through 18 years were established from studies of three institutions in the Specialized Centers of Research in Atherosclerosis programs located in Muscatine, Iowa, Rochester, Minnesota and Miami, Florida (Fig. 1). These charts provide a means for serial recording of a child's blood pressure over time in a manner siInilar to the plotting of weight and height. However, due to the labile nature of children's blood pressures, the measurements will not follow the percentile tracks as closely as height and weight. Evaluation of Hypertensive Children A scheme developed by the task force for the identification and evaluation of children with elevated blood pressure is shown in Figure 2. Asymptomatic subjects who are found to have blood pressures above the 95th percentile for age on three occasions should be further evaluated. A medical history and a physical examination may reveal PRE~~

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12

14

16

18

AGE

Figure 1. Standards for children's blood pressure. A, Percentiles of blood pressure measurement in boys (right arm, seated). B, Percentiles of blood pressure measurement in girls (right arm, seated). (Printed with permiSSion of the American Academy of Pediatrics: Report of the Task Force on Blood Pressure Control in Children. Pediatrics 59(Suppl.): 797-820, 1977.)

.i

!,I

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JULIA LEE AND RONALD

Initial Blood Pressure Measurement' Medical History Physical Exam

M.

LAUER

'_.95%2

1>95% 95%

+-

1>95% Repeat Blood Pressure Measu rement

}

95%

Investigation Repeat Medical History Repeat Physical Exam Creatinine; BUN' Urinalysis

·~95%

..................

• · · --+;· ··..................··· r--t ....•.•..........• ·· 4=·• Test and Exams Normal Diastolic BP ._ 90 ages 3-12 90ages 3-12 >100 ages 13-18

Annual Reevaluation, Counseling, and Su rveiliance

:

Further Investigation

.......•....•...•. Blood pressure measurements should be made at 1-4 week intervals 1

If initial blood pressure measurement taken at school or other community center. two subsequent blood pressure measurements should be made prior to referral of patient. If feasible

2 The 95 percentile is an arbitrary statistical cutoff pOint. children with blood pressure at the 95 percentile should be labeled as having high normal pressure rather than being hypertensive. J

Optional- If patient IS obese or a cause Identified for hypertension. BUN Or creatinine may not

be indicated.

Figure 2. Identification and evaluation of asymptomatic children with elevated blood pressure. (Printed with permission of the American Academy of Pediatrics: Report of the Task Force on Blood Pressure Control in Children. Pediatrics, 59(Suppl.): 797-820, 1977.)

conditions such as obesity, coarctation of the aorta, renal disease, and drug ingestion. When the hypertension is severe, special attention should be focused on the target organs, looking for evidence of abnormalities in the fundus of the eye and in cardiovascular and renal systems. The preliminary evaluation would not be complete without the assessment of other risk factors such as obesity and cigarette smoking. For further discussion on the treatment of hypertension, the reader is referred to the Report of the Task Force on Blood Pressure Control in Children. 73

Control of Smoking The strong evidence associating cigarette smoking to cancer of the lung, chronic bronchitis, and cardiovascular diseases has resulted in

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some decline in cigarette smoking among adults; but there is a disturbing increase among pre-teens and teenagers. 99 It has been observed that the smoking habit is extremely addicting, and the younger the onset of smoking, the stronger the addiction. This has prompted interest to investigate the habits and beliefs of children about smoking and possible deterrents to establishment of the smoking habit. Evans 26 described some features of a social-psychological survey to deter smoking in children. In a survey of fifth, sixth, and seventh grade school children and teachers, it was determined that children entering junior high school were the most susceptible age to the social influences to begin smoking. This implies that education should be initiated before this age and perhaps reinforced again upon entry into junior high schooL The primary sources of influence were peers, parents, and the advertising media. Thus, the strategy should be directed at familiarizing children with the nature of these influences and teaching them how to cope effectively with pressures from these three sources. Evans et al. 25 also noted that although children recognized smoking to be a health hazard, the concept of the future consequences of pulmonary or circulatory disease was remote in terms of a child's perception of time. Thus, children should be oriented with explanations of the immediate physiologic effects of smoking which include heart rate and carbon monoxide effects. A smoking study carried out in Saskatoon, Saskatchewan surveyed the habits and beliefs of Canadian seventh and eighth graders.88 It confirmed the observation that a student's smoking habit reflected the habits of those about him. Smokers tended to have friends who were smokers and they perceived themselves living in a society of smokers. Taking up smoking was encouraged or discouraged by factors such as the smoking habit of parents, siblings, socioeconomic status, academic expectations and religious observance. It is of interest that 80 per cent of nonsmokers and nearly 50 per cent of ex-smokers and current smokers did not expect to be smokers in five year's time. This reflects their general optimism about the ease of giving up smoking. In reality, fewer than 15 per cent of established smokers give up the habit. However, the fact that these children did not intend to commit themselves to a lifetime of smoking may provide an opportunity for health education programs to intervene. A proportion of eighth graders indicated a desire for help to stop smoking. The mass media is a powerful and effective means of disseminating information that has the ability to influence the habits and behavior of its audience. It has been'determined that by the time 10 per cent of the target group has adopted a new product or practice, the adoption process has gained sufficient momentum to proceed to its fullest potential without further intervention by the marketing agent. RR The tobacco industry has fully exploited the mass media to project various attractive images of the smoker to entice new smokers. Farquhar et al. 27 explored the use of the mass media for the purpose of community education for cardiovascular health, which included information about the detrimental effects of cigarette smoking. It was found that this

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was an effective method of reducing cigarette smoking and mass media educational campaigns directed at entire communities can be useful in health education. The method has not been assessed in children, but with modification it has potential utility. Parents can be a powerful source of influence of childhood smoking attitudes. It appears that a parent's verbal attitude has little effect but parental behavior has a strong influence. 88 The behavior of teachers and members of the health profession are also highly regarded by children. Thus, people in these positions should attempt to influence, by their actions, children's attitudes and life styles.

REFERENCES 1. American Academy of Pediatrics: Committe on Nutrition, Childhood Diet and Coro-

nary Heart Disease. Pediatrics, 49:305-507, 1972. 2. American Heart Association: A statement for physicians: The value and safety of diet modifications to control hyperlipidemia in childhood and adolescence. Unpublished. 3. American Heart Association Cookbook: American Heart Association, Inc. New York, David McKay Co., 1973. 4. Ayman, D.: Heredity in arteriolar (essential) hypertension. A clinical study of blood pressure of 1,524 members of277 families. Arch. Intern. Med., 53:792-802,1972. 5. Barham, M. 0.: PrinCiples of prevention of coronary heart disease: A critique. Am. J. Cardiol.,40:251-260, 1977. 6. Barnes, K., Nestel, P. J., Pryke, E. S., et al.: Neonatal plasma lipids. Med. J. Aust., 2:1002-1005,1972. 7. Biron, P., Mongeau, J., and Bertrand, J.: Familial aggregation of blood pressure in adopted and natural children. In Paul, O. (ed.): Epidemiology and Control of Hypertension. New York, Stratton Medical Books, 1975, pp. 397-405. 8. Blumenthal, S., Jesse, M. J., Hennekens, C. H., et al.: Risk factors for coronary heart disease in children of affected families. J. Pediat., 87:1187-1192, 1975. 9. Buchwald, H.: Surgical risk of the hyperlipidemic states by partial ileal bypass. In Casdorph, H. R. (ed.): Treatment of the Hyperlipidemic States. Springfield, Charles C Thomas, 1971. 10. Buck, S. W.: The presistence of elevated blood pressure first observed at age 5. J. Chron. Dis., 26: 101-104, 1973. 11. Carter, G. A., Clarke, W., Schrott, H., et al.: Plasma cholesterol, triglycerides and the lipoprotein fractions in school age children: The Muscatine Study. J. Lipid Res., unpublished data. 12. Cassel, J.: Studies of hypertension in migrants. In Paul, O. (ed.): Epidemiology and Control of Hypertension. New York, Stratton Medical Books, 1975, pp. 41-61. 13. Castelli, W. P., Doyle, J. T., Gordon, T., et al.: Cholesterol and other lipids in coronary heart disease. Circulation, 55 :767-772, 1977. 14. Cowdry, E. V.: Arteriosclerosis. New York, MacMillan and Co., 1933. 15. Dahl, L. K., Heine, M., and Lassinari, L.: Effects of chronic excess salt ingestion: Role of genetic factors in both DOCA-salt and renal hypertension. J. Exp. Med., 118:605-617,1963. 16. Darmody, J. M., Fasbrooke, A. S., and Lloyd, J.: Prospective study of serum cholester01 levels during the first year of life. Brit. Med. J., 2:685-688, 1972. 17. Deutcher, 1., Ostrander, L. D., and Epstein, F. H.: Familial factors in premature coronary heart disease - A preliminary report from the Tecumseh Community Health Study. Am. J. Epidemiol., 91 :233-237, 1970. 18. Deutcher, S., Epstein, F. H., and Keller, J. B.: Relationships between familial aggregation of coronary heart disease and risk factors in the general population. Am. J. Epidemiol., 89:510-520, 1969. 19. Dialogues in Infant Nutrition. In Blumenthal, S. (ed.): Infant Nutrition and Atherosclerosis. Bloomfield, New York, Health Learning Systems, Inc., Vol. 1, No.3, October 1977. 20. Dietary Management of Hyperlipoproteinemia. A Handbook for Physicians. Office of Heart and Lung Information, Bethesda, Maryland, 1970, pp. 14-23. 21. Doll, R., Hill, A. B.: Mortality of British doctors in relationship to smoking. Observations in coronary thrombosis. Nat. Cancer Inst., 19:205-268, 1966.

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22. Drash, A., and Henzstenberg, F.: The identification of risk factors in normal children in the development of arteriosclerosis. Ann. Clin. Lab Sci., 2:348-359, 1972. 23. Dube, S. K., Dapoor, S., Ratner, H., et al.: Blood pressure studies in black children. Am. J. Dis. Child., 129:1177-1180,1975. 24. Enos, W., F., Holmes, R. H., and Beyer, J.: Coronary heart disease among U.S. soldiers killed in action in Korea. J.A.M.A., 152:1090--1093,1953. 25. Evans, R. 1., Rozelle, R. M., Mittelmark, M. B., et al.: Deterring the onset of smoking in children: Knowledge of immediate physiological effects and coping with peer pressure, media pressure and parent modeling. J. Appl. Soc. Psycho!., in press. 26. Evans, R. 1.: Smoking in children: Developing a social-psychological strategy of deterrance. Prevent. Med., 5:122-127,1976. 27. Farquhar, J. W., Wood, P. D., Breitrose, H., et al.: Community education for cardiovascular health. Lancet, 1192-1195, 1977. 28. Feinlieb, M., Garrison, M. S., Barhani, M., et al.: Studies of hypertension in twins. In Paul, O. (ed.): Epidemiology and Control of Hypertension. New York, Stratton Medical Books, 1975, pp. 3--20. 29. Fomon, S. J.: Infant Nutrition. Edition 2. Philadelphia, W.B. Saunders Co., pp. 172173, 1974. 30. Fredrickson, D. S., Gotto, A. M., and Levy, R. 1.: Familial lipoprotein deficiency. In Stansbury, J. B., et al. (eds.): The Metabolic Basis of Inherited Disease. Edition 3. New York, McGraw-Hill, 1972, p. 545. 31. Gertler, M. M., and White, P. D.: Coronary heart disease in young adults: A multidisciplinary study. Cambridge, Harvard University Press, 1954. 32. Glueck, C. J., Fallot, R. W., Tsang, R., et al.: Hyperlipidemia in progeny of parents with myocardial infarction before age 50. Am. J. Dis. Child., 127:70--75,1974. 33. Glueck, C. J., Heckman, F., Schoenfeld, M., et al.: Neonatal familial type II hyperlipoproteineInia: Cord blood cholesterol in 1800 births. Metabolism, 20:597-608, 1971. 34. Glueck, C. J., Fallot, R., and Tsang, R.: Pediatric familial type II hyperlipoproteineInia treatment with diet and cholestyramine resin. Pediatrics, 52 :669-679, 1973. 35. Goldstein, J. L., Albers, J. J., Schrott, H. G., et a!.: Plasma lipid levels and coronary heart disease in adult relatives of newborns with normal cord blood lipids. Am. J. Human Genet., 26:727-735, 1974. 36. Golubjatnikov, R., Paskey, T., and Inborn, S. 1.: Serum cholesterol levels of Mexican and Wisconsin school children. Am. J. Epidemiol., 96:36-39, 1972. 37. Gordon, T., and Kannel, W. R.: The effects of overweight on cardiovascular disease. Geriatrics, 28 :80--88, 1973. 38. Greten, H., Wengreen, H., and Ungner, H.: Early diagnosis of familial type II hyperlipoproteinemia. Nutr. Metab., 15:128-131, 1973. 39. Hahn, P., and Kirby, L.: Immediate and late effects of premature weaning on feeding a high fat or high carbohydrate diet to weanling rats. J. Nutr., 103 :690--696, 1973. 40. Hames, C. G., and Greenberg, B. G.: A comparative study of serum cholesterol levels in school children and their possible relationship to atherogenesis. Am. J. Pub. Health, 51 :374--385, 1961. 41. Health Consequences of Smoking - A Report of the Surgeon General. Washington, D.C., Government Printing Office, 1971. 42. Hennekens, C. H., Jesse, M. J., Klein, B., et al.: Cholesterol among children of men with myocardial infarction. Pediatrics, 58 :211-217, 1976. 43. Hernandez, A., Goldring, D., and Hartman, A. F.: Measurement of blood pressure in infants and children by the Doppler ultrasonic technique. Abstracts of Midwest Soc. Ped. Res., November, 1977. . 44. Heyden, S., Bartel, A., Hames, C., et al.: Elevated blood pressure levels in adolescents, Evans County, Georgia, seven year follow-up of 30 patients and 30 controls. J.A.M.A., 209:1683-1689, 1969. 45. Holman, R. L., McGill, H. C., Strong, J. P., et al.: The natural history of atherosclerosis. Am. J. Pathol., 34:209-235, 1958. 46. Jenkins, C. D.: Psychological and social precursors of coronary heart disease. New Engl. J. Med., 284:244--307, 1971. 47. Jenkins, C. D., Rosenman, R. H., and Friedman, M.: Development of an objective psychological test for the deterInination of the coronary prime behavior pattern in employed men. J. Chron. Dis., 20:371-379, 1967. 48. Johnson, S., Coroni, J. C., Cassel, J. C., et al.: The influence of race, sex, and weight on blood pressure behavior in young adults. Am. J. Cardio!., 35:523-530, 1975. 49. Kahn, H. A.: The Dorn study of smoking and mortality among U.S. veterans. Nat. Cancer Center Monograph, 19:1-125, 1966. 50. Kannel, W. B., McGee, T., and Gordon, R.: A general cardiovascular risk profile: The Framingham Study. Am. J. Cardiol., 38:46-51, 1976.

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51. Kannel, W. B.: Physical exercise and lethal atherosclerosis disease. New Engl. J. Med., 282:1153-1154, 1970. 52. Keys, A.: The role of the diet in human atherosclerosis and its complications. In Sander, M., and Bourne, O. H. (eds.): Atherosclerosis and Its Origins. New York, Academic Press, 1963, p. 263. 53. Kilcoyne, M., Ritcher, R, and Alsup, P.: Adolescent hypertension. I. Detection and Prevalence. Circulation, 50: 758-764, 1974. 54. Kirkendall, W. M., Burton, A. C., Epstein, F. H., et al.: Recommendations for human blood pressure determination by sphygmomanometer. Circulation, 36:980-988, 1967. 55. Klein, B. E., Hennekens, C. H., Jesse, M. J., et al.: Longitudinal studies of blood pressure in off-spring of hypertensive mothers. In Paul, O. (ed.): Epidemiology and Control of Hypertension. New York, Stratton Medical Books, 1975, p. 387. 56. Kwiterovich, P.O., Levy, R. K., and Frederickson, D. S.: Neonatal diagnosis of familial type II hyperlipoproteinemia. Lancet, 1: 118-121, 1973. 57. Lancet: HDL and coronary heart disease. Lancet, 2: 131-132, 1976. 58. Lauer, R M., Connor, W. E., Leaverton, P. E., et al.: Coronary heart disease risk factors in school children: The Muscatine Study. J. Pediat., 86:697-706,1975. 59. Lee, V. A.: Individual trends in the total serum cholesterol of children and adolescents over a ten year period. Am. J. Clin. Nutr., 20:5-12, 1967. 60. Levy, R L., et al.: Overweight: Its prognostic significance in relationship to height and cardiovascular-renal disease. J.A.M.A., 131 :951-953, 1946. 61. Lew, E. A.: High blood pressure and other risk factors and longevity: The insurance viewpoint. Am. J. Med., 55:281-294,1973. 62. Lieberman, E.: Essential hypertension in children and youth: A pediatric perspective. J. Pediat., 85 :1-11, 1974. 63. Loggie, J., and Rauh, L.: Persistent hypertension in the adolescent. Med. Clin. North Am., 59: 1371-1383, 1975. 64. Loggie, J.: Systemic hypertension in children. Pediat. Clin. North Am., 18:1273-1310, 1971. 65. Londe, S., Bourgoignie, J., Robson, A., et al.: HypertenSion in apparently normal children. J. Pediat., 78:569-577, 1971. 66. Maddachs, I.: Possible absence of essential hypertension in two complete Pacific Island populations. Lancet, 2:396-399, 1961. 67. Mann, J. I., and Inman, W. H. W.: Oral contraceptives and death from myocardial infarction. Brit. Med. J., 2:245-248, 1975. 68. Mark, A. L., Lawton, W. J., Abboud, F. M., et al.: Effects of high and low sodium intake on arterial pressure and forearm vascular resistance in borderline hypertension. Circ. Res. 36 and 37(Suppl. 1):1-198, 1975. 69. Marks, H. H.: Influence of obesity on morbidity and mortality. Bull. New York Acad. Med., 36:296-312, 1960. 70. M~Crory, W., and Noonan, J.: Hypertension in childhood: Disease of complication. J. Iowa State Med. Soc., 50:188-192, 1960. 71. McNamara, J. J., Molar, M. A., Stremple, J. F., et al.: Coronary artery disease in combat casualties in Vietnam. J.A.M.A., 216:1185-1187, 1971. 72. Miall, W. E.: Follow-up study of arterial pressure in the population of a Welsch mining valley. Brit. Med. J., 2:1204-1210,1959. 73. National Heart, Lung and Blood Institute: Report of the Task Force on Blood Pressure Control in Children. Pediatrics, 59(Suppl):797-820, 1977. 74. Oberman, A., et al.: Trends in systolic blood pressure in the thousand aviator cohort over a twenty-four year period. Circulation, 36:812-822, 1967. 75. Oliver, M. F.: Ischaemic heart disease in. young women. Brit. Med. J., 4:253-259, 1974. 76. Page, L. B., Damen, A., and Mollering, R C.: Antecedents of cardiovascular disease in six Solomon Island societies. Circulation, 49:1132-1146, 1976. 77. Paffenbarger, R S., and Hale, W. E.: Work activity and coronary heart mortality. New Eng!. J. Med. 292 :545-550, 1975. 78. Pickering, G.: High Blood Pressure. London, Churchill, 1968. 79. Platt, R: Heredity in hypertension. Lancet, 7 :899-904, 1963. 80. Prevention of coronary heart disease. J. Royal ColI. Phys., 10:213-275, 1976. 81. Primary Prevention of Atherosclerotic Disease: Report of the Inter-Society Commission for Heart Disease Resources. Circulation, 42:A-55-A-95, 1970. 82. Rames, L., Clarke, W. R, Connor, W. E., et al.: Normal blood pressures and the evaluation of sustained blood pressure elevation in childhood: The Muscatine Study. Pediatrics, 61 :245-251, 1978. 83. Rance, C. P., Arbu, G. S., Balfe, J. W., et al.: Persistent systemic hypertension in infants and children. Pediat. Clin. North Am., 21 :801-824, 1974.

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84. Reichman, L. B., Cooper, B., Blumenthal, S., et al.: Hypertension testing among high school students. I. Surveillance procedures and results. J. Chron. Dis., 23:161-171, 1975. 85. Reid, D. D.: Smoking and ischemic heart disease prevention - Problem and potential. Prevent. Med., 1 :84-91, 1972. 86. Rosenman, R. H., Brand, R. J., Jenkins, O. D., et al.: Coronary heart disease in the Western Collaboratory Group Study. J.A.M.A., 233:872-877, 1972; 195:86-92, 1966. 87. Rosenman, R. H., Friedman, M., Straus, R., et al.: Coronary heart disease in the Western Collaborative Study Group - A follow-up example of 4% years. J. Chron. Dis., 23:173-190, 1970. 88. Saskatoon Smoking Study. Prepared by Department of Social and Preventive Medicine, College of Medicine, University of Saskatchewan, May, 1974. 89. Schrott, H. G., Lauer, R. M., and Clarke, W. R.: Increased frequency of coronary heart disease in relatives of hyperlipidemic school children. Circulation, 52(Suppl. II): A-43, 1975. 90. Shaper, A. G.: Cardiovascular disease in the tropics. III. Blood pressure and hypertension. London, Brit. Med. Assoc., 1974. 91. Stamler, J.: The natural history and epidemiology of hypertensive disease. In Cart, J. H. et al. (eds.): Pathogenesis of Essential Hypertension. Proc. Prague Symp. Prague, State Medical Publishing House, 1960, pp. 67-107. 92. Stamler, J., and Epstein, F. H.: Coronary heart disease: Risk factors as guides to preventive action. Prevent. Med., 1 :27-48, 1972. 93. Stamler, J.: Epidemiology of coronary heart disease. Med. Clin. North Am., 57:5--46, 1973. 94. Starr, P.: Hypercholesterolemia in school children. Am. J. Clin. PathoI. 56:515-522, 1971. 95. Tahahosi, E., et al.: The geographical distribution of cerebral hemorrhage and hypertension in Japan. Hum. BioI., 29:139--166, 1967. 96. Truett, J., Cornfield, J., and Kannel, W.: A multivariate analysis of the risk of coronary heart disease in Framingham. J. Chron. Dis., 20:511-524, 1967. 97. Tsang, R. C., Fallat, R. W., and Glueck, C. J.: Cholesterol at birth and age 1: Comparison of normal and hypercholesterolemic neonates. Pediatrics, 53 :458-470, 1974. 98. U.S. Department of Health, Education and Welfare: Blood pressure levels in children 6-11 years. U.S. Publication Services 11, No. 135: 1-24, 1973. 99. U.S. Department of Health, Education and Welfare. Cigarette smoking among teenagers and young women. DHEW Publication No. (NIH)77-1203, 1977. 100. U.S. Department of Health, Education and Welfare: Hypertension and hypertensive heart disease in adults, U.S. 1960-1962. National Health Survey. National Center for Health Statistics. Series 11: No. 13, 1966. 101. Veterans Administration: Cooperative study group on hypertensive agents: Effects of treatment on morbidity of hypertension. J .A.M.A., 202: 1028-1034, 1967. 102. Wilmore, J. H., and McNamara, J. J.: Prevalence of coronary heart disease risk factors in boys 8-12 years of age. J. Pediat., 84:527-533,1974. 103. Wissler, R. W., and Vesselinovitch, D.: The effects of feeding various dietary fats on the development and regression of hypercholesterolemia and atherosclerosis. In Sirlari, C., Ricci, G., and Garim, G. (eds.): Diet and Atherosclerosis. New York, Plenum Press, 1973, pp. 66-76. . 104. Zinner, S. H., Levy, P. S., and Kass, E. H.: Familial aggregation of blood pressure in children. New EngI. J. Med., 284:401-404, 1971. Department of Pediatrics University of Iowa Hospitals Iowa City, Iowa 52242