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Studies of the pathobiologic consequences of high blood pressure in childhood, as well as those following blood pressure levels into young adulthood, indicate that early intervention in the natural history of essential hypertension is warranted. In an exploratory study of the concept, 95 children out of 1604 (aged 8 to 18 years), who persistently scored higher than the 90th percentile for blood pressure over a 4-month period, considering the race, sex, and height of the children, were studied. Five series of replicate measurements with 30 total observations were obtained. Children with evidence of secondary hypertension were excluded. The study children were randomly divided into treatment (n = 48) and high-comparison (n = 47) groups. Treatment consisted of low-dose combined drug therapy (propranolol and chlorthalidone) with an educational program directed towards hypertension and dietary and exercise modification. Monthly follow-up was continued for 30 months. Significant systolic (-3.59 mm Hg) and diastolic (-1.73 mm Hg) changes were noted up to 30 months (p less than 0.05) with minimal side effects. Furthermore, analyses suggested that the blood pressure change, at least in the first month, was mostly attributable to drug therapy. Moreover, the mechanism of blood pressure change appeared to be race-specific, with whites having pulse rate changes and blacks having significant weight changes, which were associated with blood pressure change. This trial shows further research is warranted to determine optimum approaches for early treatment of essential hypertension to prevent future hypertensive disease.

Children initially aged 21/2 to 14 years living in Bogalusa, Louisiana (n = 2530) were examined twice, 3 years apart, for fasting serum pre-beta- and beta-lipoprotein cholesterol (beta-LPC) levels. Based on averages of these levels, the children were ranked for pre-beta- and beta-LPC in combinations of extreme quintiles (low-low, high-high) or quartiles (low-high, high-low), n = 388, and were reexamined for serum lipids, lipoprotein cholesterol, glucose tolerance, and anthropometry. Skinfolds were thicker in whites than in blacks except for subscapular skinfold. Children in the high-high stratum were heavier and more obese. The postglucose insulin level was positively correlated with fasting serum triglycerides and pre-beta-LPC. Compared with other strata, high-high strata showed more clustering among half-hour and 1-hour plasma insulin, serum triglycerides and pre-beta-LPC, and trunk skinfolds. We conclude that racial differences in lipid and carbohydrate metabolism occur in all four strata, and that a strong clustering occurs more in the high-high stratum, which may, in part, explain the coincidence of several high cardiovascular risk factor levels observed in the same children. These observations document in free-living children changes of obesity, plasma glucose, and insulin metabolism related to serum lipoproteins that are involved in the early natural history of atherosclerosis.

We explored the relation between amount of adipose tissue and maturation in 3,524 boys and girls ages 5–14 years examined in 1973–1974, and 4,074 children ages 5–17 years (re)examined in 1976–1977. Subjects were drawn from a total, geographically defined, biracial community as part of a cardiovascular risk factor screening. Height, weight, triceps skinfold thickness, external sexual maturation according to Reynolds—Tanner, status of menarche, and visible gynecomastia were assessed. We observed that adiposity was positively correlated with acceleration of maturation. This positive correlation was stronger in girls than boys, and stronger in whites than blacks. Visible gynecomastia was more prevalent at ages 13–15 years than other ages. These boys were markedly more obese than all others. Gynecomastia was negatively associated with sexual maturation (after controlling for the positive effect of adiposity), in white boys more than in black. Adiposity may have some feedback sex-hormonal effect, in girls more directly, toward accelerated maturation. In boys adiposity enhances gynecomastia which in turn is likely related to a deceleration in male maturation. The observed effects of adiposity on sex-hormonal function could have implications for the known association between adiposity and incidence of sex hormone-related female cancers, especially mammary cancer.

Resting heart rates were ascertained during the 1978-1979 school year in 3590 children aged 5-17 years in the biracial geographic population of Bogalusa, Louisiana. These rates were found to be relatively independent of the method of measurement, whether supine by physician's stethoscope or dressed sitting radial pulse taken by a nurse, and in either case adhering to a strict measurement protocol. Apart from the known influences of age and sex, the authors found a small but consistent racial influence, with whites having 3-4 beats/min higher rates than blacks. Controlling for age, the authors found heart rate to be positively correlated with blood pressure in whites and with subcapsular skinfold thickness in boys. No consistent relation between heart rate and amount of cigarettes smoked was observed. Boys in the upper five percentiles of blood pressure-heart rate ("double") product values were found to have about twice the subscapular skinfold thickness compared to the lower five percentiles. Likewise, boys in the upper five percentiles of subscapular skinfold thickness had significantly increased double products. Since the double product is an index of cardiac oxygen consumption, this finding could point to a possible etiologic link between obesity and chronic cardiac stress in males beyond the mediation of lipoproteins, cholesterol, and diabetes mellitus in contributing to atherosclerotic heart disease, but this issue needs further study. Ascertainment of resting heart rate provides an additional parameter in the study of cardiovascular risk factor variables, in youth as in adulthood, to supplement the natural history of the atherosclerosis-hypertension syndrome with its sequelae.

A model designed as primary hypertension prevention for children ranking high in blood pressure, selected from a total population, was applied to a semirural, biracial community. A Dietary/Exercise Alteration Program Trial (ADAPT), in combination with low-dose medication, was tested on 48 children aged 8-18 years who were randomly selected from 100 children consistently in the upper blood pressure decile. The interactive model a) focuses on a major public health problem that is measurable and modifiable, b) outlines a preventive approach to involve children and parents in establishing healthy life styles, and c) converts community limitations into resources. The comprehensive program was developed to support eating and exercise modifications accepted for hypertension treatment without placing children in a sick role. Sodium reduction, weight control, and regular exercise are the life-style changes promoted. Indicators for evaluating development and implementation of ADAPT are presented. The commitment to written pledges, ie, making simple behavioral changes, had a significant inverse association with post-treatment sodium and energy intakes in regression models that included the child's curriculum and physical activity class attendance. ADAPT represents an initial approach for developing primary preventive treatment of early essential hypertension in a pediatric population.

Using data from an autopsy series, we found a strong positive correlation between liver concentration of cadmium and death from heart disease. In view of recent experiments reported in the literature, the possibility that a low level of cadmium has a toxic effect on the cardiac conduction system is supported.

Since a positive association between blood pressure and plasma glucose level in child populations has been observed previously, we studied this relationship in a stratified random sample of children ages 7-15 years drawn from a total geographic population. We stratified this population (N = 3524) by diastolic blood pressure and weighted the extreme strata. The sample of children (N = 272) was free of secondary hypertensives and was tested by a restricted glucose tolerance test. As a parameter of cellular glucose kinetics, a "peripheral insulin resistance" was defined as one-hour glucose (mg/dl) X one-hour insulin (microU/ml). For white boys, this product showed an increase from 2745 in the low blood pressure strata to 6615 in the high blood pressure strata. To assess the relationship between blood pressure measured during the reexamination and fasting plasma glucose level, we classified the children according to their peripheral insulin resistance in a low, medium, and high group. After controlling for body weight, only white children in the high blood pressure strata with high insulin resistance had a positive association between fasting plasma glucose and systolic blood pressure. The relationship may be initiated by inappropriate intravascular water retention influencing the blood pressure in children with high peripheral insulin resistance and susceptible to hypertension.

The association of heart-related mortality with tissue cadmium and lead in a study of autopsies performed on persons who resided in a soft-water, leached-soil area of North Carolina was examined. Liver cadmium concentrations and aortic lead level were indices of these elements. Both cadmium and lead levels had statistically significant correlations with cause of death (heart-related disease vs. non-heart-related disease, excluding cancer). Although cause of death was significantly associated with age, the association with cadmium and lead persisted after statistical adjustment for the effect of age. The combined effects of cadmium and lead provided sufficient information in an additive model to predict cause of death correctly for 80% of the cases, with age contributing insignificantly. These findings indicate the intimate relation of these two trace metals with increased risk of heart-related mortality, even in light of known conventional causes of such deaths.

Eighty per cent of all identified children 2 1/2-5 1/2 years old in a total geographic community in Bogalusa, Louisiana, were examined for cardiovascular disease risk factor variables, including blood pressure (BP), anthropometric measurements, and blood lipids. Blood pressure was measured by three instrument types, each with three readings, according to a rigid, randomized design. Results from the three instruments were compared, and potential biases for each instrument are listed. All observations on the children were analyzed by multiple regression with BP as the dependent variable. After controlling for the mood of the child, the authors found that some index of body size was positively related to BP, whereas age, race, and serum lipids were not consistently related. The regressions of blood pressure on height as well as on log weight fit straight lines. These results conform with the findings for the 5- to 14-year-olds in this community. The basal or fundamental reference blood pressure is likely to rise gradually from birth to the age of incipient adult stature, and to be linearly related to height and to log weight. Changes observed over time are needed to relate BP levels in childhood to the early natural history of essential hypertension.

Blood pressure, height, weight, maturation, triceps skinfold thickness, serum lipids, and hemoglobin were measured as risk factors for coronary artery disease in 3,524 children (93% of the eligible population) in Bogalusa, Louisiana. Nine blood pressures were taken on each child by trained observers with mercury sphygmomanometers (Baumanometer) and Physiometrics automatic recorders in a rigid randomized design in a relaxed atmosphere with other children present. The pressures observed were low compared to reported data. Black children had significantly higher blood pressures than white children. This difference, starting before age 10, was largest in the children in the upper five percent of the pressure ranks. Stepwise multiple regression analysis revealed that this racial differnce was significant when measured by an automatic recorder. Body size, expressed by height and by weight/height3 index, was a strong determinant of blood pressure level. Other positive determinants were blood hemoglobin and external maturation.

Cancer mortality is high among white men residing in southern Louisiana parishes (counties). In an effort to elucidate this phenomenon, we studied three environmental correlates of cancer-namely, smoking, residence in urban communities, and residence in the wetlands. Multiple regression analysis was applied to cancer mortalities adjusted for age and urban residency, and specific for race, sex, amount of standing water area in the parish, and cancer site. Cancer sites were grouped according to their correlation with smoking: strong, moderate, and no correlation. For men, the smoking-related cancer mortality not only showed an association with residence in wetlands but also was higher in the Louisiana wetlands than in the remainder of the United States.

The onset of essential hypertension early in life is indicated by the high tracking of blood pressure during adolescence; intervention in adults with mild hypertension has been found successful. How, then, can high blood pressure levels in children be modified to prevent early hypertensive cardiovascular disease in adulthood? In an entire biracial town (population 9000) we surveyed 1604 (89%) of all children aged 8--18 years for blood pressure and reexamined those in the upper decile of mean blood pressure (for each race, sex, and height) on three additional occasions. On each examination nine blood pressures were taken by trained observers. All children consistently in the top decile were randomly allocated into either a treatment (n = 50) or comparison (n = 50) group. These two groups and an additional midrange blood pressure comparison group (n = 50) were followed regularly using school facilities including community and school programs. Treatment consisted of 1) dietary guidance; 2) modifications of school lunches and snacks with healthy substitutes; 3) parental involvement; 4) a low dose diuretic and beta-antagonist given by usual standards. All study groups were monitored for blood pressure in a blind manner. In 6 months of observation, blood pressure in the treatment group remained 5 and 3 mm Hg (systolic and diastolic) less than controls (p less than 0.001 and p less than 0.01). An orchestrated community-wide attack on early-stage hypertension is feasible and seems to offer exciting potential for prevention of early hypertensive disease.

A special in-depth substudy was conducted on 388 children from a total biracial (black-white) population, who were stratified on levels of serum beta- and pre-beta-lipoprotein cholesterol to explore factors associated with lipoprotein levels in childhood. Biochemical parameters on venous blood samples were obtained both on fasting subjects and after an abbreviated glucose tolerance test, along with selected anthropometric measures like height, weight, and skinfolds. Biochemical and anthropometric relationships were minimal for children with elevated beta-lipoprotein cholesterol and low pre-beta-lipoprotein cholesterol. On the other hand, children with higher levels of pre-beta-lipoprotein cholesterol, with or without elevated beta-lipoprotein cholesterol, showed associations with fatness and slightly higher levels of glucose and insulin, with other biochemical parameters considered within normal levels. These differences noted among free-living children with different levels of serum lipoproteins provide clues to mechanisms involved in the early natural history of coronary artery disease.

Body height and body mass as determinants of basal blood pressure in children--The Bogalusa Heart Study. Am J Epidemiol 106:101-108, 1977. Risk factor variables for coronary artery disease were measured in a total biracial community study of 3524 children, ages 5-14 years. Anthropometric variables, serum lipids, and blood pressure (BP) were measured in a rigid randomized design. Blood pressure data were obtained with an automatic recording instrument that avoids excessive pressure readings in obese children by the use of an over-sized arm cuff bladder with a built-in infrasonic transducer. By reducing the anxiety of the child and by taking multiple readings, pressures were obtained that approached published basal levels. A multiple regression analysis showed that all measured variables could account for 39% of the systolic BP variation. Major determinants were based on weight (W) and height (H). The BP levels, when related to H and to a weight-height index (W/H3), suggest a strong influence of H and an additional influence of W/H3 on BP, both consistent and proportionate over the entire ranges of H and W/H3. The total spectrum of observed correlates of BP, resulting from the multiple regression analysis, suggests that the BP measured under basallike conditions increases as the child grows and is proportional to lean body mass and total body mass. Practical criteria for evaluating abnormal blood pressure levels in children should be based on normative values derived from body weight and body height rather than from age.

During the past 10 years, much clinical information has been obtained on cardiovascular (C-V) risk factors in pediatric populations. Impetus to study C-V risk in children for adult heart diseases evolved naturally from adult population studies, i.e., Framingham, Tecumseh, Evans County and others. The major medical advance was made in documenting clinical parameters that predict morbid C-V events. It became apparent that similar clinical parameters could be observed in children. Equally important to the clinical observations has been recognition that atherosclerotic lesions are already present in early life. ZEEK (1), HOLMAN et al. (2) noted atherosclerotic lesions developed early, even in infancy. Findings of coronary artery lesions in soldiers necropsied in the Korean War (3), and later in Vietnam (4), were impressive. The nature of coronary artery lesions, occurring early and gradually increasing during a subclinical phase, is now well recognized. As an outgrowth to this history, it became important as part of an epidemiology program, to study the early natural history of coronary artery disease in children (5) and to correlate anatomic changes along with clinical C-V risk factors.

Geographical differences in cardiovascular mortality within the United States have not yet been adequately explained. Age-adjusted rates of mortality due to arteriosclerotic heart disease in the white residents of 99 of the 100 largest cities in the United States were compared with the hardness of the finished drinking water of the municipal supplies and with the altitude of residence above sea level. This mortality showed a higher negative correlation with the latter variable than with the former for white residents. These findings are coherent with results from other epidemiological studies showing decreased cardiovascular disease mortality at high altitude. Animal experiments and pathological observations in the literature make it likely that hypoxia causes an increase of collateral circulation in the coronary arteries. However, alternative explanations of the presently observed relationship have not been excluded by our study.

Publisher Summary The question of how changes in behavior can modify the process of atherosclerosis and hypertension during adolescence is practical and important. However, no uniform answers exist to that question. There is an abundance of studies with animals relating nutritional and psychological states to cardiovascular risk factors, but there is a serious question about how applicable those models are for prescribing intervention in the atherosclerotic/hypertensive process. The atherosclerotic/hypertensive process has apparently evolved so recently that even within the human species, blacks and whites have different mechanisms for the development of this process. Inter- and intra-species differences in non-human primates limit the applicability of these studies to cardiovascular disease in man. Further, the limitation of hospital-based studies to symptomatic individuals in later and complicated stages of the process is well known. There is a great need for an epidemiologic approach to cardiovascular disease in man. This chapter discusses nutritional and other behavior associated with increased risk of coronary artery disease and also considers the following four risk factors — obesity, high blood pressure, blood lipids, and blood insulin-glucose.

The relationship between body fat indexes, lipid and lipoprotein levels, and blood pressure was studied in 2230 children, each examined during 1973, 1976, and 1978. The children were grouped with the use of seven percentile (P) intervals of triceps skinfold thickness that were specific for race, sex, and age; cardiovascular risk factor variables were assessed over time. Of the 238 children initially in the lowest P group (less than 15P), 44% remained there, and 65% had skinfold thicknesses below 30P on the three occasions. Of the 352 children in the highest P group (greater than or equal to 85P), who were considered to be very obese, 39% remained at this level while 69% remained at 70P or greater. Of the 366 considered to be obese (greater than or equal to 70, less than 85%P), 38% remained at or above 70P. At baseline, children in the seven groups differed in weight, ponderosity (wt/ht3), systolic and diastolic blood pressures, serum triglyceride levels, and pre-beta- and beta-lipoprotein cholesterol levels. Pairwise comparison of data from children in each of the six other groups with those from children in the middle range (greater than or equal to 40, less than 60P) showed that the obese and very obese children had significantly higher systolic blood pressures (p less than .05), while only those in the highest P group had significantly greater diastolic blood pressures (p less than .05). These differences increased and diverged over time. Those in the obese and very obese groups showed a striking drop over time in alpha-lipoprotein cholesterol levels and increases in pre-beta-lipoprotein cholesterol levels and systolic blood pressure. Triglyceride levels decreased over time for the lowest and middle range groups but remained at higher levels in obese and very obese children. There was a strong tendency for tracking (remaining in the same P group over time) in lean, obese, and very obese children. Those who tracked showed definite differences in risk factor variables at the baseline level and over time when compared with the middle range group. Since consistent obesity in early life enhances cardiovascular risk, the measurement over time of skinfold thickness in children is a useful method to detect the potential for adult cardiovascular disease.

• There is evidence that atherosclerosis, coronary artery disease, and essential hypertension begin early in life. The Bogalusa (La) Heart Study has examined cardiovascular risk factors and their determinants during the pediatric age span in a total community study. Reliable measurements were obtained and then analyzed to identify "tracking" of risk factors over time and clusters or aggregations of various risk factors at high levels. Serum lipoprotein levels, obesity, BP, and plasma insulin levels were all correlated after a glucose load, implying causal interrelationships. Although such relationships are only partly elucidated, the associations potentially enhance premature atherosclerosis. Certain kinds of behavior, for example cigarette smoking and type A behavior, may also contribute to early coronary artery disease. Our observations suggest that practicing physicians should assess risk factors in children and encourage changes in life-style to combat the high incidence of coronary artery disease and essential hypertension in the United States. (Am J Dis Child1982;136:855-862)

There is a growing realization that essential hypertension in the adult is a disease which likely has its onset in childhood [1,2]. At present, however, little is known about pediatric essential hypertension and the early natural history of this disease. Comprehension of the evolution of primary hypertension from youth until the disease state becomes recognizable in adulthood is important to our goal of trying to prevent this major cardiovascular problem. In the United States, hypertension is the second most common cardiovascular disease, and its importance is compounded by its role in accelerating coronary artery disease. Further, hypertension is a more severe disease with a greater morbidity and mortality in the black population of this country than in whites. Evidence indicates familial aggregation of hypertension; therefore, occurrence in parents might signal a tendency toward hypertension in children of affected families and, when combined with observations at a young age, may provide an indication of future hypertensive disease.

Essential hypertension, a highly prevalent and devastating disease, likely begins in childhood, and presumably might respond at this stage to general preventive measures. The problems encountered in the recording of reproducible blood pressure levels are largely of a quantitative nature, and involve instrument validity, observer (examiner) training, and the interaction between the child and the physician's office environment. The problems of early diagnosis of hypertension are related to the lack of long-term observations of children. Population percentiles of normal blood pressure values could aid in the early diagnosis of hypertension. For this purpose the method of blood pressure measurement in the physician's office has to be strictly comparable to methods employed in accumulating the percentile or reference observations. Repeated measurements under basal-like conditions are advised, and the weight or height of the child is more important for standardization than is age.

Since atherosclerosis and essential hypertension are believed to begin asymptomatically in early life, much interest has recently been shown in the study of risk factor variables in children. Extensive information is now available on cardiovascular (CV) disease risk factor variables of children in a general population, somewhat comparable to information from similar studies of adults (Monograph 1978). Additional research is now providing longitudinal observations following time-course changes of CV risk factor variables (Voors et al. 1979b, Frerichs et al. 1979) and determining how levels during the pediatric years may relate to adulthood, when the risk of coronary heart disease or essential hypertension can be judged by morbid events. Although there is a lack of understanding of the clinical significance and aftermath of disease in children, such as it occurs in adults, there are certain advantages to studying children. Heretofore, most of the epidemiologic studies described adult disease during a time when biologic changes of risk factors are less obvious. For example, in adults, stature, body weight, and serum total cholesterol change relatively little when compared to the dramatic changes that occur in the developing infant or child (Berenson et al. in press). These temporal changes in children occur during life periods when clues to mechanisms responsible for different levels of risk factor variables are available. The observation of race and sex contrasts enhances the potential usefulness of a pediatric study.

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to-0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P