The mechanisms through which obesity and stress. Relationship of Body Composition to Stress-Induced Pressure Natriuresis in Youth

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1 AJH 2004; 17: Relationship of Body Composition to Stress-Induced Pressure Natriuresis in Youth Martha E. Wilson, Gregory A. Harshfield, Luis Ortiz, Coral Hanevold, Gaston Kapuka, Lynne MacKey, Delores Gillis, Lesley Edmonds, and Conner Evans Background: The contribution of stress to obesityrelated cardiovascular disease is uncertain. The purpose of this study was to examine the influence of body composition on stress-induced pressure natriuresis. Methods: Dual energy x-ray absorptiometry was performed in 127 African American and white youths to assess lean body mass (LBM), fat mass (FM), and total percentage of body fat (%BF). The stress protocol was comprised of a 2-h baseline period, 1-h video game competition stressor, and 2-h recovery period. Blood and urine samples were collected hourly and blood pressure (BP) was obtained at 15-min intervals. Results: Both BP and urinary sodium excretion (U Na V) increased from baseline to stress and returned to prestress levels after stress (P.001 for each). The BP levels and changes were positively correlated with LBM. In contrast, levels and changes in sodium excretion U Na V were inversely correlated with FM and The mechanisms through which obesity and stress contribute to the development of essential hypertension (HTN) and blood pressure (BP) related target organ damage remain unclear. We hypothesize that an impaired natriuretic response to stress contributes to this process by increasing the cardiovascular load experienced by the individual in response to stress. Our previous studies support this hypothesis, demonstrating both body mass index (BMI) 1 and total percentage of body fat (%BF) 2 are associated with impaired stress-induced pressure natriuresis (SIPN). We define impaired SIPN as an increase in BP without an appropriate compensatory increase in urinary sodium excretion (U Na V) to contribute to the return of BP to prestress levels. 3,4 %BM. Multiple regression analyses that included ethnicity, sex, angiotensin II (Ang II), and measures of body composition in the models indicated the following: a) LBM was the best predictor of stress systolic BP and independently contributed with ethnicity to stress diastolic BP; b) ethnicity was the only independent predictor of the stress-related change in systolic and diastolic BP; c) LBM was the only independent predictor of the change in BP from stress to recovery for both systolic and diastolic BP; and d) total percent body fat accounted for 11.2% of the variance of stress U Na V, with Ang II contributing an additional 6.1%. Conclusions: Based on the results of this study, ethnicity and body composition are related to stress-induced pressure natriuresis. Am J Hypertens 2004;17: American Journal of Hypertension, Ltd. Key Words: Lean body mass, blood pressure, stress, race, pressure natriuresis. Studies by our group and others suggest there are ethnicity-related differences in SIPN, with a blunted natriuretic response to the stress-induced increase in BP in African Americans. 3,5 We also observed genderrelated differences in SIPN, 1 with similar levels of natriuresis in boys and girls despite higher levels of BP in boys. From a mechanistic perspective, the reninangiotensin-aldosterone system is the only physiologic system that has been related to impaired SIPN to date. 1,6 The purpose of this study was to examine the relative contribution of ethnicity, sex, and body composition to SIPN. Specifically, we examined the correlations of lean body mass (LBM), fat mass (FM), and %BF with BP and U Na V throughout a 5-h protocol that included a 2-h base- Received December 18, First decision May 24, Accepted May 29, From the Georgia Prevention Institute and the Department of Pediatrics (MEW, GAH, LO, CH, GK, LM, DG, LE, CE) and the Department of Physiology (GAH), Medical College of Georgia, Augusta, Georgia. This study was supported by grants HL and HL from the National Institutes of Health and HL from the National Heart, Lung, and Blood Institute. Address correspondence and reprint requests to Dr. Gregory A. Harshfield, Medical College of Georgia, MCG Annex H.S. 1640, Augusta, GA ; Gharshfi@mail.mcg.edu 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc /04/$30.00 doi: /j.amjhyper

2 1024 BODY COMPOSITION AND PRESSURE NATRIURESIS AJH November 2004 VOL. 17, NO. 11 Table 1. Subject characteristics and casual measurements (n 127) line period, a 1-h stress period (competitive video games for monetary reward), and a 2-h recovery period. Multiple linear regression models were then run which included measures of body composition, ethnicity, and sex in the models. Angiotensin II (Ang II) was also included in the models for U Na V. Methods Subjects The protocol was approved by the Human Assurance Committee of the Medical College of Georgia. Written informed parental consent and subject assent were obtained before testing. The subject characteristics are provided in Table 1. Protocol Variable Boys (N 63) Casual BP was obtained during a screening appointment and was the average of three measurements obtained in the seated position using a mercury manometer. Dual energy x-ray absorptiometry (Hologic QDR-1000, Bedford, MA) was performed before testing to determine LBM, FM, and %BF as previously described. 7 Our testing protocol has been described in detail. 1,4 Briefly, the subjects were placed on a controlled sodium diet of mg/day for 3 days before testing. Overnight urine samples were collected for each night to assess dietary compliance. On day 4 the subjects performed the stress protocol. The protocol consisted of a 2-h baseline period, a 1-h stress period consisting of competitive video games for monetary reward (Snowboard; Sony, Foster City, CA), and a 2-h recovery period. Urine samples were collected hourly and BP was obtained at 15-min intervals using the Dinamap compact monitor (Dinamap, Tampa, FL). The subjects were required to drink 200 ml of water every hour to ensure that they remained hydrated and were able to provide adequate urine samples. Girls (N 64) Total (N 127) Age (y) Height (cm)* Weight (kg)* Casual SBP (mm Hg)* Casual DBP (mm Hg) Lean body mass (kg)* Fat mass (kg) Total percent body fat (%) Angiotensin II (pg/ml) DBP diastolic blood pressure; SBP systolic blood pressure. * Boys girls, P.007; girls boys, P.001. Electrolytes Electrolytes were analyzed by the ion selective electrode technique using a NOVA 16 Analyzer (NOVA Biomedical, Waltham, MA). Angiotensin II Angiotensin II was evaluated by radioimmunoassay (RIA). Plasma was extracted with high performance liquid chromatography grade methanol on phenylsilylsilica extraction columns. The sample was reconstituted in Tris buffer. Angiotensin II was measured by RIA with a kit (Buhlmann) distributed by ALPCO (Windham, NH). The minimal detectable level of the assays was 2 pg/ml for Ang II. The intra-assay coefficient of variation was 10% for Ang II, and the interassay coefficient of variation was 20.7%. Statistical Analysis Statistical analysis was performed with SPSS 11.5 (SPSS Inc., Chicago, IL). A repeated-measures analysis of variance with the Bonferroni adjustment for multiple comparisons was performed for BP and U Na V to determine significant effects across the testing conditions. Pearson correlation coefficients were then performed to determine the relationships between body composition, BP, and U Na V. This was followed by a series of stepwise multiple linear regressions. The models included ethnicity, sex, LBM, FM, and %BF. Ang II was included in the models for U Na V. Separate models were run for the level of BP and U Na V during stress, the changes in BP and U Na V from baseline to stress, and the changes in BP and U Na V from stress to recovery. Results Subject Characteristics The subject characteristics are provided in Table 1. The sample was composed of 96 individuals of African American and 31 of white ethnicity, including a similar number

3 AJH November 2004 VOL. 17, NO. 11 BODY COMPOSITION AND PRESSURE NATRIURESIS 1025 FIG. 1. Systolic blood pressure (a) and sodium excretion (b) throughout the protocol. of boys and girls who were of similar age. The boys were taller, weighed more, and had greater casual systolic BP (SBP) and LBM. In contrast, the girls had greater FM, %BF, and AngII. Stress-Induced Pressure Natriuresis The effect of condition was significant for SBP (P.0001). The stress-induced increase and poststress-related decrease in SBP were significant (Fig. 1a). Similar results were observed for DBP, with a significant effect of condition (P.0001). Diastolic BP increased from baseline to stress (60 7to65 7mmHg;P.0001) and decreased to 62 7mmHg(P.0001) after stress. Finally, the effect of condition was significant for U Na V(P.0001). Sodium excretion increased from baseline to stress and decreased to recovery (Fig. 1b). Body Composition and BP Correlations between the various indices of body composition and the BP are presented in Table 2. Lean body mass was correlated positively with the levels and changes of both SBP and diastolic BP (DBP) throughout the protocol, reaching statistical significance in all cases except the change in DBP from baseline to stress. A similar pattern was observed for the partial correlations between LBM adjusted for FM and BP. Fat mass was not correlated with any of the BP measurements. Percentage of body fat was inversely correlated with stress SBP and the change in SBP from baseline to stress. Lean body mass was the only significant predictor in the multiple regression model for stress SBP, accounting for 23.5% of the variance, with greater LBM associated with higher BP. Two factors contributed to the model for DBP during stress. Ethnicity accounted for 14.0% of the variance, with higher DBP in African Americans (mean 67 6 v 61 6, P.0001). Lean body mass contributed an additional 5.6% to the model. Ethnicity was the only significant factor in the model for change in SBP from baseline to stress, accounting for 4.1% of the variance. In addition, ethnicity was the only significant factor in the model for the change in DBP, accounting for 4.5% of the variance. Lean body mass was the only significant factor to enter the model for the change in SBP from stress to recovery, accounting for 4.5% of the variance. Lean body mass was also the only factor to enter the model for the change in DBP from stress to recovery accounting for 10.8% of the variance. Body Composition and Sodium Excretion There was a small but significant correlation between LBM and U Na V during stress, which remained significant Table 2. Correlation coefficients between body composition and blood pressure throughout the protocol Variable LBM Adjusted* FM %BF Stress SBP Stress DBP Stress SBP Stress DBP Recovery SBP Recovery DBP BF total percent body fat; DBP diastolic blood pressure; FM fat mass; LBM lean body mass; Recovery stress recovery 1; SBP systolic blood pressure; Stress stress baseline 2. * Partial correlations with LBM adjusted for FM; P.01; P.05.

4 1026 BODY COMPOSITION AND PRESSURE NATRIURESIS AJH November 2004 VOL. 17, NO. 11 Table 3. Correlation coefficients between body composition and sodium excretion throughout the protocol Variable LBM Adjusted* FM %BF Ang II Stress U Na V Stress U Na V Recovery U Na V U Na V urinary sodium excretion; other abbreviations as in Table 2. * Partial correlations with LBM adjusted for FM; P.05; P.01. after adjustment for FM. Both FM and %BF were inversely correlated with U Na V during stress and the changes before and after stress (Table 3). Two variables entered the multiple regression model for U Na V during stress. Total percent body fat was the first factor accounting for 11.2% of the variance. This was followed by Ang II, which accounted for an additional 6.1%. The %BF was the only factor in the model for the change in U Na V from baseline to stress accounting for 4.6% of the variance. Two variables entered the model for the change in U Na V from stress to recovery. The first factor was %BF, which accounted for 8.6% of the variance, followed by Ang II, which accounted for an additional 4%. Discussion The major finding of this study is that body composition is related to the pressure natriuresis response to mental stress. Specifically, greater LBM was associated with higher BP during stress. In contrast, greater body fat was associated with a slower natriuretic response to stress as well as slower natriuresis during stress, which is in part related to Ang II. These results expand our previous findings regarding the relationship between body size and SIPN using the same protocol. In one study 2 we reported an association between %BF and SIPN in 84 African American youths. Specifically, obese subjects ( 25% body fat) compared with lean subjects (12% to 20% body fat) had a similar BP response. However, the obese group had a significantly smaller stress-induced increase in U Na V, indicating impaired SIPN. In addition, there was a tendency for a larger number of obese individuals to retain rather than to excrete sodium during stress as compared with the lean group. A second study 1 examined the relationship of body mass index (BMI) to sex differences in SIPN in 292 youths. Blood pressure was higher for boys during stress but U Na V did not differ, indicating impaired SIPN in the boys. For boys, BMI was correlated positively with stress BP and negatively with stress U Na V, suggesting that it contributed to both the higher level of BP and the lower level of U Na V. These results are consistent with previous studies in humans and several animal models of obesity which demonstrated that obesity-related HTN is characterized by a shift in the pressure natriuresis curve, that is, impaired pressure natriuresis (for reviews see 8 10 ). Studies demonstrating salt sensitivity in obesity provide further evidence of obesity related impaired pressure natriuresis. One study is particularly relevant to the current study because it was performed in adolescents. Rocchini et al 11 demonstrated that the pressure natriuresis slope was positive indicating salt sensitivity and shifted to a higher level of BP for obese compared with nonobese subjects on a high sodium but not a low sodium diet. However, a minimal weight loss normalized the pressure natriuresis relationship. Lean body mass was the strongest predictor of the BP response to stress, accounting for almost one quarter of the variance. These results are consistent with the relatively few studies that examined the influence of LBM on casual BP in children and adolescents. Daniels et al 12 performed a study in 201 adolescent individuals aged 6 to 17 years in which LBM and FM were determined by dual energy x-ray absorptiometry, as in the present study. The sample included approximately equal numbers of normotensive African American and white subjects. They observed a positive association between LBM and BP. In a multiple regression analysis, LBM was the sole significant determinant of BP accounting for 36% of the variance. Brandon and Fillingin 13 found that BP levels were related to LBM in children aged 9 to 12 years. Wilks et al 14 reported a positive association between LBM and BP in Jamaican children. Most recently, Julius et al 15 reported data on 231 adolescents and 944 adults from the Tecumseh Blood Pressure study. For the adolescents LBM was highly correlated with SBP (r 0.52; P.001). This relationship was also observed in the adult study population and was not related to sex. Another study by Daniels et al 12 concludes that LBM and FM are independently related to the hemodynamic parameters that determine BP, and that LBM is a more important determinant than FM in children and adolescents. Our results extend this association to the dynamic regulation of BP by examining the pressure natriuresis relationship in response to stress. Ethnicity also contributed to the model for BP during stress, with higher levels for African Americans. These results are consistent with an extensive literature demonstrating greater BP responses to mental stress in African Americans (see Treiber et al 16 for a recent review). In addition, these results are consistent with previous studies by our group 3,4 and others 17 that demonstrated that African American individuals are characterized by impaired

5 AJH November 2004 VOL. 17, NO. 11 BODY COMPOSITION AND PRESSURE NATRIURESIS 1027 SIPN. Our initial study 3 examined changes in pressure natriuresis over a series of stressors in subjects with a confirmed family history of HTN. African American compared with white subjects had a greater stress-induced increase in BP coupled with a higher level throughout the stressor. However, this was associated with a smaller change in U Na V, suggesting impaired SIPN in these individuals. Our second study 4 was performed on a cohort of African American youths using the same protocol as the current study. We observed that a significant percentage of the youths (approximately 32%) decreased U Na V during stress. This pattern of response was associated with a volume-mediated increase in BP as compared with the resistance-mediated increase for those who showed the expected natriuresis during stress. More importantly, BP remained at a higher level in these individuals after stress. As such, they were exposed to a greater cardiovascular load for the same level of stress. We believe that the positive relationship between LBM and SIPN suggests that LBM facilitates the pressure natriuretic response to stress. In contrast, the inverse relationship between %BF and natriuresis suggests that greater fat impairs this response. This conclusion is consistent with the well established positive association between fitness (as reflected by greater LBM) and cardiovascular disease (CVD) coupled with the negative association between obesity and CVD (for recent reviews see ). Our conclusions appear to be contradictory to the reactivity literature that has provided evidence showing that exaggerated BP responses to stress are a marker for, or mechanism in, the development of HTN and CVD However, we do not believe that our results are contradictory to this literature. We observed a stress-induced increase in BP of approximately 5% averaged across an extended (1-h) period of stress. As such, the changes are physiologically appropriate to meet the primarily psychological but also physical demands of the stressor. This contrasts with reactivity studies that report acute increases of 10% or greater in high risk populations This probably exceeds the physiologic demands for increased blood flow necessary to cope with the stressor and may lead to the early development of HTN. Our results regarding the relationship between LBM and SIPN are consistent with studies using ambulatory BP monitoring These studies indicate that it is the inability to regulate BP to an adequate extent that puts an individual at risk, perhaps more so than an exaggerated BP response to acute stress. This is best illustrated by the numerous disorders characterized by the inability of individuals to lower their BP from daytime to nighttime, 28 a pattern referred to as nondipping. In each disorder, the impaired regulation of one or more BP systems prevents the normal nocturnal decline in BP, thus increasing the cardiovascular load that an individual s system is exposed to over time. We and others have demonstrated a similar pattern in African American individuals 29,30 and have related this pattern to the early development of HTN and BP related target organ damage in this population. 29,30 References 1. Harshfield GA, Wilson ME, McLeod K, Hanevold C, Kapuku GK, Mackey L, Gillis D, Edmonds L: Adiposity is related to gender differences in impaired stress-induced pressure natriuresis. Hypertension 2003;42: Barbeau P, Litaker MS, Harshfield GA: Impaired pressure natriuresis in obese youths. Obes Res 2003;11: Harshfield GA, Treiber FA, Davis H, Kapuku GK: Impaired stressinduced pressure natriuresis is related to left ventricle structure in blacks. 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