Left ventricular hypertrophy (LVH) is the strongest. Family History of Hypertension and Left Ventricular Mass in Youth: Possible Mediating Parameters

AJH 2001; 14:351 356 Family History of Hypertension and Left Ventricular Mass in Youth: Possible Mediating Parameters Barton B. Cook, Frank A. Treiber, George Mensah, Meenu Jindal, Harry C. Davis, and Gaston K. Kapuku Whether positive family history (FH) of essential hypertension (EH) in normotensive youth is associated with increased left ventricular mass (LVM) and hemodynamic, anthropometric, and demographic parameters previously associated with increased LVM in adults is unknown. To examine these issues, 323 healthy youth (mean age, 13.6 1.3 years), 194 with positive FH of EH (61% African Americans, 39% whites) and 129 with negative FH of EH (33% African Americans, 67% whites) were evaluated. Hemodynamics were measured at rest and during four stressors (ie, postural change, car driving simulation, video game, forehead cold). Echocardiographicderived measures of LVM were indexed separately to body surface area and height 2.7. Controlling for age and race differences (ie, 74% of African Americans v 47% of whites had positive FH), the positive FH group exhibited greater LVM/height 2.7, LVM/body surface area, higher systolic (SBP) and diastolic blood pressures (DBP), and total peripheral resistance index (TPRI) and lower cardiac index at rest (P.05 for all). The positive FH group also displayed higher peak SBP or DBP and higher TPRI increases to each stressor and came from lower socioeconomic status backgrounds (P.05 for all). Regression analyses indicated that FH of EH was not a significant determinant of LVM/height 2.7 after accounting for contributions of gender (greater in men), general adiposity, resting cardiac index and blood pressure (BP), and TPRI responsivity to video game and cold stimulation (P.05 for all). Thus, greater LVM index in positive FH of EH youth appears in part related to their greater BP and TPRI at rest and during stress. Am J Hypertens 2001;14: 351 356 2001 American Journal of Hypertension, Ltd. Key Words: Left ventricular mass, family history, adiposity, blood pressure, cardiovascular reactivity. Left ventricular hypertrophy (LVH) is the strongest independent risk factor for cardiovascular morbidity and mortality, other than advancing age. 1,2 The pathobiologic antecedents of cardiovascular disease begin in childhood, 3,4 which has prompted research into identifying early determinants of increased left ventricular mass (LVM). As in adults, studies in youth have found various aspects of body habitus (eg, height, weight, body surface area, and adiposity), as well as gender (males females) and race (African Americans whites) to be associated with increased LVM. 5 10 Various indices of hemodynamic function have also been associated with increased LVM in youth, including blood pressure (BP) at rest and in response to laboratory stressors (eg, stressful interviews, video games, dynamic exercise). 7,9 15 A family history (FH) of essential hypertension (EH) is a risk factor for future EH, 16,17 and has been associated with increased LVM in adults. 18,19 Few studies have been conducted in youth and findings have been mixed with some results indicating a positive association and others finding no relationship between FH of EH and LVM. 20 23 Furthermore, it is unclear as to what biological and sociodemographic factors that have been associated with LVM 9 15,24,25 are attributable to observed FH of EH differences in cardiac structure. The intent of the present study was threefold: 1) to examine possible differences in LVM in positive versus negative FH of EH youth, 2) to examine possible sociodemographic, anthropometric, and hemodynamic (at rest and during laboratory stressors) differences by FH of EH, and 3) to determine whether sociodemographics, anthropometrics, and hemodynamics account for FH group differences in LVM. Received April 4, 2000. Accepted August 21, 2000. From the Departments of Pediatrics (BBC, FAT, GKK) and Psychiatry (FAT), Office of Biostatistics (HCD); and the Georgia Prevention Institute (FAT, GM, MJ, HCD, GKK), Medical College of Georgia, Augusta, Georgia. This study was supported in part by National Institutes of Health Grants HL35073 and HL41781. Address correspondence and reprint request to Frank A. Treiber, PhD, Medical College of Georgia, Georgia Prevention Institute, HS1640, Augusta, GA 30912-3710; e-mail: ftreiber@mail.mcg.edu 2001 by the American Journal of Hypertension, Ltd. Downloaded from Published https://academic.oup.com/ajh/article-abstract/14/4/351/187801 by Elsevier Science Inc. 0895-7061/01/$20.00 PII S0895-7061(00)01275-9

352 FAMILY HISTORY AND LVM AJH April 2001 VOL. 14, NO. 4, PART 1 Methods Subjects The subjects were 323 youths with a mean age of 13.6 1.3 years, who are among participants in a longitudinal study of the biobehavioral antecedents of cardiovascular disease. 26,27 There were 160 African Americans (69 males), and 163 whites (81 males). Sixty percent of the subjects (n 194) had a FH of EH defined as one or both biologic parents and one or more grandparents with EH. The remaining subjects parents and majority of grandparents were negative for EH. Diagnosis of EH (ie, 140/90 mm Hg or antihypertensive medications) was verified by the individual s personal physician. All of the subjects were normotensive, apparently healthy, and free of chronic diseases based on parental reports of the child s medical history, and a brief physical examination. All procedures were evaluated and approved by the institutional review board, and parents and children provided informed consent. Laboratory Evaluation After informed consent was obtained, the subject s waist and hip circumference (in centimeters), height (in centimeters), skinfold measures (ie, triceps, subscapular, suprailiac crest), and weight (in kilograms) were measured using established protocols. 11,15 Each subject was fitted with instruments for recording BP, heart rate, and cardiac output. The Dinamap Vital Signs Monitor (model 1864SX; Critikon, Inc., Tampa, FL) was used for BP determination at rest and during stress, and the NCCOM-3 (BoMed Medical Manufacturing Ltd., Irvine, CA), a continuous thoracic bioimpedance monitor, was used to measure heart rate and cardiac output during laboratory stressors. Total peripheral resistance index (TPRI) was calculated for each stressor reading from cardiac output and mean BP. Both cardiac output and TPRI were indexed by body surface area (ie, cardiac index, TPRI). After the instrumentation was complete, the subject was placed in a supine position on an examination table for 15 min for resting hemodynamic determinations. During the final 5 min of the rest period, BP and heart rate parameters were measured simultaneously at the end of 11, 13, and 15 min. Doppler-derived estimates of resting cardiac output were obtained for the resting levels as Doppler estimates of absolute cardiac output levels are preferable over impedance-derived estimates. 28 Immediately after the baseline supine rest the postural change stressor was given. Hemodynamic parameters were measured at 1, 2, and 3 min after the subject assumed a standing position with the right arm relaxed at a 90-degree angle across the trunk. Subsequently, three laboratory stressors were presented (ie, car driving simulation, video game, and forehead cold), with the order of presentation counterbalanced using established protocols. 15,26 These three stressors were all presented with the subject in the supine position. A prestressor rest period of at least 5 min preceded each stressor until BP returned within 5 mm Hg of the baseline resting values. The video game stressor, Atari Break Out, was a 5-min challenge with the incentive of monetary reward. The car driving simulation stressor was a 5-min challenge and consisted of the subject using a virtual reality headset (Kaiser Electro-Optics Visual Immersion Monitor 500, Kaiser Aerospace and Electronics Co., Carlsbad, CA) while playing a car racing game ( Need for Speed, Pioneer Productions and Electronic Arts, Inc., Vancouver, Canada), using a Panasonic 3DO system (model FZ-1, Matsushita Electric Corporation of America, Secaucus, NJ). Hemodynamic measurements were assessed during those two stressors at minutes 1, 3, and 5 of the challenge. The forehead cold stressor was conducted by placing a plastic bag containing 6 cups of crushed ice and 1.5 cups of water (3 to 5 C) across the subject s forehead for 1 min. Hemodynamic measurements were recorded during the last 30 sec of stimulation. Echocardiographic Evaluation After completion of the above evaluation, the echocardiographic examination was conducted. The subjects were evaluated in the left lateral decubitus position. From the parasternal short axis position, M-mode determination of left ventricular posterior wall thickness, interventricular septal thickness, and left ventricular internal dimension in diastole were obtained according to the American Society of Echocardiography convention using leading edge methodology. 29 Measurements were made with a Hewlett- Packard Sonos 1500 (Andover, MA). All measurements were conducted five times and averaged on screen using the software package of Hewlett-Packard. LVM was derived using the anatomically validated formula of Devereux and Reichek. 30 The criteria of Schieken et al 31 were used to evaluate the quality of the echocardiogram. Reliability quality control checks were performed on a random sample of 20% of the subjects. Intrarater and interrater coefficients of variation for all cardiac structures assessed were less than 10%, comparable to previous studies in our laboratory 9,11,15 and to other published findings. 7,22 Data Reduction and Analyses Laboratory baseline hemodynamic data were reduced by averaging the three values obtained for each parameter. Both absolute (eg, peak response) and change score (eg, peak minus mean prestressor) responses have been associated concurrently and prospectively with LVM. 11,12,14,15 Thus, peak values and peak change scores obtained during each stressor were used as indices of stress responsivity in the analyses. To permit comparison of the findings to other pediatric studies, LVM was indexed to body surface area (in grams per meter squared) and to height 2.7 (in grams per meter 2.7 ). Because of the significant differences between the FH

AJH April 2001 VOL. 14, NO. 4, PART 1 FAMILY HISTORY AND LVM 353 groups in age (P.05) and proportion of African Americans with a positive FH of EH (74%) versus whites (47%, P.01), analyses of covariance were conducted examining FH group differences in demographics, anthropometrics, and baseline and stress hemodynamics. Type I sum of squares were used with age and racial group entered before FH group. To determine whether FH of EH was a significant independent determinant of LVM index within the context of other demographic, anthropometric, and hemodynamic correlates of LVM index, both LVM indices were used as dependent variables in separate regression analyses that did not include FH as a predictor. The all possible models regression procedure in SAS version 6.12 (Cary, NC) was used to analyze the data. Only those variables that were found to be significantly (P.05) related to the dependent variables at the zero-order level were included in the regression analyses. Furthermore, variables that were not significant within the regression models in the same direction as at the zero-order level were excluded from the regression models. Such suppressors rarely remain significant upon cross-validation. The maximum adjusted R 2 was used as the criterion for choosing the best regression model. After the best models were selected, FH was added to the model to test whether it contributed significant additional variance. Results Descriptive characteristics of the study sample by FH of EH are presented in Table 1 as unadjusted means standard deviations. Anthropometric, demographic, and resting hemodynamics are presented regardless of significance. Stress responsivity data are only presented if statistically significant. For the entire sample, resting BP and height were similar, whereas weight and body mass index were somewhat higher when compared to published norms for this age range. 32 34 Using the 95th percentile for LVH established by Daniels et al 9 in 6- to 17-year olds in which neither gender nor race differences were observed, prevalence of LVH for the entire sample was 14.2%. No significant differences were observed in LVH prevalence by race or FH of EH (P.30 for both). Males exhibited greater prevalence of LVH (20% v 9%; P.01). The covariance analyses indicated that the positive FH group had greater LVM/body surface area (P.05) and LVM/height 2.7 (P.01) than the negative FH groups. The FH groups did not differ significantly in height, weight, body surface area, body mass index nor sum of skinfolds (all P.10). The positive FH group had a significantly lower socioeconomic status, higher resting systolic blood pressure (SBP), diastolic blood pressure (DBP), and TPRI, and lower cardiac index (all P.05). Peak or TPRI reactivity change scores were significantly higher in the positive FH group to each stressor (all P.05). Peak SBP or DBP responsivity values were higher in the positive FH group to each stressor (all P.05). Table 2 presents significant correlations between the two measures of LVMI and the 1) anthropometric, 2) demographic, and 3) hemodynamic data for the entire sample. It should be noted that variables that were not significantly related to at least one of the LVM index measures were not included in Table 2. The multiple regression findings for LVM/body surface area had an R 2 0.26 (P.001) with male gender (P.001), greater height (P.001), higher supine baseline cardiac index (P.01), and FH of EH (P.05) as the best combination of predictors. The best regression model predicting LVM/height 2.7 had an R 2 0.37 and included male gender (P.001), greater adiposity (ie, body mass index; P.001), higher supine baseline cardiac index (P.001), higher video game peak SBP (P.02) and higher forehead cold TPRI change score (P.001) as predictors. Family history of EH did not significantly improve this model (P.10). Discussion Although a FH of EH has been associated with increased LVM in adults, 18,19 relatively few studies have examined this issue in youth. In the present study, irrespective of race and gender, normotensive 10- to 16-year olds with a positive FH of EH exhibited greater LVM indexed by body surface area or height 2.7. These findings corroborate and extend those of Radice et al, 20 who found that a positive FH of EH was associated with a greater LVM among a sample of 131 normotensive and borderline hypertensive adolescent males. It is also in agreement with Alli et al 21 who reported increased LVMI with positive FH of EH in a study of 86 normotensive 14- to 19-year olds. The present findings are in contrast to several smaller studies (sample sizes, 48 subjects) in which parental history of EH was not associated with increased LVM in adolescents. 22,23 Reasons for discrepancies of findings in youth studies to date may be due in part to methodologic differences including variations in sample size, age range, and the criteria of and lack of verification of family members hypertension status. A number of sociodemographic and hemodynamic parameters distinguished the positive and negative FH of EH groups. After accounting for age and race, consistent with previous findings in young adults, 17 19 a positive FH of EH was associated with higher resting SBP and DBP. The underlying hemodynamic parameter responsible for the higher pressure levels was greater total peripheral resistance index. Although not entirely consistent, a positive FH of EH has been associated with greater BP responsivity to behavioral stressors in adults. 35 Few studies have been conducted in youth but similar relationships have been observed. 36 The present findings corroborate and extend earlier studies in that increases in vasoconstrictive tone were responsible for the higher BP responses in the positive FH group to passive and active behavioral challenges. Finally, youth with positive FH of EH came from

354 FAMILY HISTORY AND LVM AJH April 2001 VOL. 14, NO. 4, PART 1 Table 1. Descriptive characteristics of sample by FH group status Positive FH Group Status Negative FH Characteristics M SD M SD Anthropometrics/demographics Age (y) 13.8 1.3 13.2 1.1 Height (cm) 161.7 9.6 159.8 9.6 Weight (kg) 57.7 5.4 54.4 16.3 Body surface area (m 2 ) 1.6 0.2 1.5 0.2 Body mass index (kg/m 2 ) 21.9 4.9 21.0 4.8 Sum of skinfolds (mm) 44.9 27.3 42.9 28.8 Hollingshead socioeconomic status* 37.6 12.7 44.1 13.1 Baseline hemodynamics SBP (mm Hg) 109.6 9.6 104.9 8.7 DBP (mm Hg) 58.5 6.4 55.7 5.5 CI (L/min/m 2 ) 3.0 0.8 3.5 0.8 TPRI (mm Hg/L/min/m 2 ) 10.7 2.3 9.9 3.1 Stress hemodynamics Postural change Peak SBP (mm Hg) 118.3 12.9 123.7 12.8 Peak CI (L/min/m 2 ) 3.2 0.9 3.6 0.9 Peak TPRI (mm Hg/L/min/m 2 )* 13.5 3.5 12.7 4.4 Virtual car driving Peak SBP (mm Hg) 124.7 13.7 117.4 12.1 Peak DBP (mm Hg) 74.7 9.8 70.8 9.8 Peak TPRI (mm Hg/L/min/m 2 )* 20.7 4.8 16.8 4.7 Change SBP (mm Hg)* 14.5 9.7 12.1 9.2 Change TPRI (mm Hg/L/min/m 2 )* 2.4 2.0 2.0 2.1 Video game Peak SBP (mm Hg)* 119.6 12.6 115.3 12.9 Peak DBP (mm Hg) 70.2 8.4 67.3 8.3 Peak TPRI (mm Hg/L/min/m 2 )* 12.8 3.2 11.7 3.6 Change TPRI (mm Hg/L/min/m 2 )* 2.1 1.8 1.7 1.6 Forehead cold Peak DBP (mm Hg) 80.8 13.2 76.0 11.4 Peak TPRI (mm Hg/L/min/m 2 ) 14.7 4.4 13.1 4.4 Change TPRI (mm Hg/L/min/m 2 ) 3.9 3.2 3.2 2.9 Echocardiographic measures LVM/BSA (g/m 2 )* 73.4 14.4 69.1 14.1 LVM/Ht 2.7 (g/m 2.7 ) 32.0 6.8 29.9 6.3 FH family history; SBP systolic blood pressure; DBP diastolic blood pressure; CI cardiac index; TPRI total peripheral resistance index; BSA body surface area; LVM left ventricular mass; Ht height. * P.05; P.01; P.001; P values adjusted for age and race, means and standard deviations unadjusted. lower socioeconomic status environments. Interestingly, lower socioeconomic status has been associated with increased prevalence of EH in adults, 37 higher resting blood pressure in youth, 38 and, most recently, increased LVM and cardiovascular responsivity to stress in youth. 39 The regression analyses revealed that LVM/body surface area was best predicted by four parameters from among those significantly associated at the univariate level. Specifically, gender (males females), height, higher resting cardiac index, and FH of EH were each independent determinants. The results for LVM/height 2.7 were similar in that gender and resting cardiac index were significant independent determinants but different in that FH of EH was not an independent predictor. In addition, a measure of general adiposity (ie, body mass index), BP responsivity to video game challenge and vasoconstrictive responsivity to cold stimulation were independent predictors of LVM/height 2.7. Collectively, these findings corroborate and extend other recent studies in youth, which found gender, adiposity, and hemodynamic function at rest and during acute stress to be independent predictors of LVM adjusted for body habitus. 5 15 In summary, these results suggest that increased LVM index in youth with FH of EH may in part be a result of underlying pathophysiologic derangements. In this context, subjects with a FH of EH have exaggerated vasoconstrictive mediated BP responses to stress and increased adiposity that over time increases vasoconstrictive tone and BP at rest. The increase in vasoconstrictive tone and BP at rest further contribute to the likelihood of development of LVH. Support for this causal pathway is inferred from other pediatric and adult findings in which FH of EH

AJH April 2001 VOL. 14, NO. 4, PART 1 FAMILY HISTORY AND LVM 355 Table 2. Significant correlations of LVM indices with anthropometric, demographic, and hemodynamic data Comparison Variable LVM/BSA LVM/ht 2.7 Anthropometrics/demographics Age 0.12* 0.02 Race (white 1; African American 2) 0.09 0.12* Gender (male 1; female 2) 0.38 0.28 Height (cm) 0.27 0.05 Weight (kg) 0.21 0.37 BMI (kg/m 2 ) 0.10 0.42 Sum of skinfolds (mm) 0.06 0.26 FH of EH ( FH 1; FH 2) 0.15 0.15 Baseline hemodynamics SBP (mm Hg) 0.30 0.26 CI (L/min/m 2 ) 0.23 0.22 Stress hemodynamics Video game CI (L/min/m 2 ) 0.25 0.29 Peak SBP (mm Hg) 0.31 0.29 Change SBP (mm Hg) 0.17 0.17 Car driving simulation Peak SBP (mm Hg) 0.25 0.22 Change DBP (mm Hg) 0.10 0.14 Change TPRI (mm Hg/L/min/m 2 ) 0.15 0.21 Forehead cold Peak SBP (mm Hg) 0.28 0.25 Peak DBP (mm Hg) 0.12* 0.13* Change SBP (mm Hg) 0.15 0.15 Change DBP (mm Hg) 0.17 0.23 Postural change Peak SBP (mm Hg) 0.29 0.25 Peak DBP (mm Hg) 0.13* 0.11* Change DBP (mm Hg) 0.10 0.12* Abbreviations as in Table 1. * P.05; P.01; P.001. has been associated with increased cardiovascular resistance to acute stress, 35 which along with adiposity, has been found to predict increases in BP levels, LVH, or EH in several prospective studies. 11,13 15,35,36 Future studies would benefit from inclusion of pubertal maturation and other parameters such as urinary sodium excretion, insulin resistance, and lean body mass, which may play roles in the development of increased LVM index and possibly serve as mediators of relationships between FH of EH and increased LVM index. References 1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561 1566. 2. Devereux R, de Simone G, Koren M, Roman M, Laragh J: Left ventricular mass as a predictor of development of hypertension. Am J Hypertens 1991;4:603 607. 3. Berenson GS, Wattigney WA, Tracy RE, Newman WP, Srinivasan SR, Webber LS, Dalferes ER Jr, Strong JP: Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study). Am J Cardiol 1992;70:851 858. 4. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA: Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults (The Bogalusa Heart Study). N Engl J Med 1998;338:1650 1656. 5. Malcolm DD, Burns TL, Mahoney LT, Lauer RM: Factors affecting left ventricular mass in childhood: the Muscatine Study. Pediatrics 1993;92:703 709. 6. Goble MM, Mosteller M, Moskowitz WB, Schieken RM: Gender differences in the determinants of left ventricular mass in childhood: the Medical College of Virginia Twin Study. Circulation 1992;85: 1661 1665. 7. Janz KF, Burns TL, Mahoney LT: Predictors of left ventricular mass and resting blood pressure in children: the Muscatine Study. Med Sci Sports Exerc 1995;27:818 825. 8. de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH: Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20:1251 1260. 9. Daniels SR, Kimball TR, Morrison JA, Khoury P, Meyer RA: Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 1995;76:699 701. 10. Urbina EM, Gidding SS, Bao W, Pickoff AS, Berdusis K, Berenson GS: Effect of body size, ponderosity, and blood pressure on left ventricular growth in children and young adults in the Bogalusa Heart Study. Circulation 1995;91:2400 2406. 11. Papavassiliou DP, Treiber FA, Strong WB, Malpass MD, Davis H: Anthropometric, demographic and cardiovascular predictors of left ventricular mass in young children. Am J Cardiol 1996;78:323 326.

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