Blood Pressure Control in Juveniles - Longitudinal Study

BACKGROUND:

Blood pressure increases with age, and over time, reaches proportions consistent with clinically defined hypertension in some individuals. The age-dependent increase in blood pressure starts in mid-childhood and accelerates during puberty and in the post-pubertal period. Thus, mechanisms for the development of hypertension are likely present at an early age. The National Heart, Lung, and Blood Institute sponsored the 'Workshop on Juvenile Hypertension' in May 1983. The Workshop conclusions were that although a great deal had been accomplished in the past decade, research in juvenile hypertension had slowed and little effort was evident in some important areas of the field. They noted especially the paucity of effort in research relating to mechanisms of blood pressure regulation and elevation, to clinical management of the hypertensive state, and to identification of the prehypertensive state. Based on the recommendations of the Workshop, this study was initiated in response to a Request for Applications on 'Juvenile Hypertension and the Prehypertensive State' released by the NHLBI in October 1984.

DESIGN NARRATIVE:

Production of aldosterone and norepinephrine is examined in a mixed-longitudinal study design in white and Black boys and girls beginning at ages 6 to 12 and extending to age 17. Levels of these pressor systems are determined in the basal state from measurements made in urine samples collected overnight. To enhance the likelihood that school children would comply with the multiple observations required for this longitudinal study, measurements are deliberately restricted to non-invasive ones. Specifically, aldosterone and norepinephrine excretion measured in sleep urine are obtained at six month intervals in addition to blood pressure, heart rate, weight, height, and skin-fold thickness. Family history of hypertension and parental blood pressures are used as covariates in analysis of data in children. A second part of the study concerns the observation that blood pressure increases at a faster rate during adrenarche, a period of increasing adrenal androgen production, and during puberty. Androgen production during periods of adrenal and gonadal maturation may contribute to the increase in blood pressure. The relationship of androgen to blood pressure is examined by distinguishing blood pressure responses to androgen production from effects of androgens on physical growth, thus exploring the concept that androgens interact directly with pressor systems to raise blood pressure. Androgen production during the adrenarche is determined by measurement of dehydroepiandrosterone-sulfate excretion, and during puberty by measurement of luteinizing hormone excretion in sleep urine samples. Studies continue on the relationship between aldosterone excretion rate, dietary potassium intake, and blood pressure. A cross-over study is conducted to examine the effect of potassium supplementation on aldosterone production. Segregation analysis of the 'low-aldosterone'phenotype is performed on family members of children with low-aldosterone.

The study was renewed in 1996 to continue the longitudinal study of children (a biracial population, ages 6-16 years) for whom influences of hormones on blood pressure are being examined. Twice yearly the children have had blood pressure and anthropometrics measured, and overnight urine samples collected for measurement of aldosterone, adrenal androgens (AA), luteinizing hormone (LH), sodium, potassium, and creatinine. Rates of growth and the changes in blood pressure with age have been well characterized for this population. From the original observations, several differences were observed between racial groups; specifically, Black children were found to consume less potassium, produce about 40 percent less aldosterone and have higher blood pressures than white children. It was observed that children with positive families histories of hypertension were more likely to have lower aldosterone-excretion rates.

As part of the proposed continuation of longitudinal studies, the hypothesis is tested that children with low-aldosterone levels are predisposed to higher blood pressures. Although Black children had lower potassium intakes, cross-sectional data indicated that only part of the racial difference in aldosterone production was secondary to a lower intake of potassium (potassium is a known stimulus of aldosterone production). Subjects with known low-aldosterone production (Blacks and whites) have diets supplemented with potassium to test the hypothesis that Blacks with low-aldosterone production have a reduced responsiveness to potassium when compared to white children with low-aldosterone. Families of children with potassium-resistant low-aldosterone production are screened for evidence of low-aldosterone production, and segregation analyses is performed to establish the mode of inheritance of the 'low-aldosterone' phenotype. In cross-sectional studies, AA-excretion rates were positively related to blood pressure in subjects greater than or equal to 10 years of age, suggesting an important role for the adrenarche in determining blood pressure levels in young people. In future longitudinal studies the role of AA as well as gonadal hormones will be studied as more children reach adolescence (the current mean age of the cohort is 12.7 yr). In addition, to better distinguish the individual influences of adrenarche, gonadarche, and increases in body size on blood pressure, a series of patients where these phenomenon are dissociated will be studied.

The study was renewed in FY 2002 to identify new mechanisms for hypertension using a strategy which identifies the sodium transporters in kidney that account for why blacks retain more sodium than whites. Three sites along the nephron will be studied based on compelling evidence that they are linked to the increased sodium-retention in blacks.