Relations of Left Ventricular Mass to Fat-Free and Adipose Body Mass. The Strong Heart Study

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1 Relations of Left Ventricular Mass to Fat-Free and Adipose Body Mass The Strong Heart Study Jonathan N. Bella, MD; Richard B. Devereux, MD; Mary J. Roman, MD; Michael J. O Grady, BA; Thomas K. Welty, MD, MPH; Elisa T. Lee, PhD; Richard R. Fabsitz, MA; Barbara V. Howard, PhD; for the Strong Heart Study Investigators Background It is unclear whether increased left ventricular (LV) mass in overweight individuals is related to their adiposity or to greater fat-free mass (FFM). Methods and Results We compared echocardiographic LV mass to FFM and adipose body mass by bioelectric impedance and to anthropometric measurements in 3107 American Indian participants in the Strong Heart Study. In men and women, the relations of LV mass and FFM (r 0.37 and 0.38, P 0.001) were closer (P 0.05 to 0.001) than they were with adipose mass, waist/hip ratio, body mass index, systolic blood pressure, height, or height 2.7. Regression analyses showed that in men LV mass had the strongest independent relation with FFM, followed by systolic blood pressure and age (all P 0.001); in women, LV mass was related to FFM more strongly than it was to systolic blood pressure, age (all P 0.001), and diabetes (P 0.012). Adipose mass had no independent relation to LV mass. When waist/hip ratio or body mass index were substituted for adipose mass, LV mass was independently related to FFM (P 0.001) and body mass index (P 0.02) but not to waist/hip ratio in men and was independently related to FFM and waist/hip ratio (both P 0.001) but not to body mass index in women. Using 97.5 percentile gender-specific partitions for LV mass/ffm in reference individuals, we found that LV hypertrophy occurred in 20.8% of Strong Heart Study participants with hypertension, overweight, or diabetes compared with 10.5% and 16.7% by LV mass indexed for body surface area or height 2.7. Conclusions LV mass is more strongly related to FFM than to adipose mass, waist/hip ratio, body mass index, or height-based surrogates for lean body weight; LV mass/ffm criteria may increase sensitivity to detect LV hypertrophy. (Circulation. 1998;98: ) Key Words: obesity echocardiography hypertension hypertrophy Left ventricular (LV) hypertrophy has been shown to be an independent risk factor for cardiovascular morbidity and mortality. 1 5 However, despite numerous studies, the best method for relating LV mass to body size to identify LV hypertrophy remains uncertain. 6 9 It has been shown that traditional indexations of LV mass for body surface area or body height, which assume first power relations between LV mass and these measures of body size, may underestimate or overestimate, respectively, the degree of hypertrophy in obese adults. 10 Accordingly, it has been demonstrated that an index of LV mass based on height adjusted to the appropriate allometric power (height 2.7 ) identified more clearly the occurrence of LV hypertrophy than LV mass/body surface area in obese adults. 11 However, it has been suggested that fat-free body mass (FFM) would be the optimal parameter for normalization of LV mass instead of the height-based indices often used as surrogates for lean body weight. With the advent of bioelectric impedance analysis (BIA) and dualenergy x-ray absorption technique (DEXA), more accurate measurement of FFM and adiposity in population studies is now possible BIA has been used to assess body composition indirectly and it has been shown to yield more precise measurements of adiposity than body mass index. 14 In this study, we compared the relations of echocardiographic LV mass and FFM, adipose mass calculated by BIA, waist/hip ratio, body mass index, height, and height 2.7 in participants in Phase II of the Strong Heart Study (SHS). Methods The SHS is an epidemiological survey of cardiovascular risk factors and prevalent and incident cardiovascular disease in American Received April 30, 1998; revision received July 24, 1998; accepted August 13, From the Department of Medicine, The New York Hospital-Cornell Medical Center, New York; the Aberdeen Area of the Indian Health Service, Rapid City, SD (T.K.W.); the University of Oklahoma School of Public Health Services, Oklahoma City (E.T.L.); the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (R.R.F.); and the Medlantic Research Institute, Washington, DC (B.V.H.). The views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service. Correspondence to Richard B. Devereux, MD, Division of Cardiology, Box 222, The New York Hospital-Cornell Medical Center, New York, NY rbdevere@mail.med.cornell.edu 1998 American Heart Associaqtion, Inc. Circulation is available at

2 Bella et al December 8, Indians. As previously described, the population includes adult members of the following tribes: (1) the Pima/Maricopa and Pima/ Papago (Tohon O odham) communities living on the Gila River and Salt River and the Akchin Indian communities in Arizona; (2) the Seven Tribes of Southwestern Oklahoma (Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita); and (3) the Oglala and Cheyenne River Sioux in South Dakota and the Spirit Lake community in the Fort Totten area of North Dakota. Tribal members aged 45 to 74 years were recruited from defined sampling frames (overall participation rate 61%) for the Phase I examination between July 1989 and January A total of 3637 SHS cohort members (89% of those alive) attended the Phase II SHS examination from August 1993 to December The examination included medical history, ECG, measurement of brachial and ankle blood pressure, fasting glucose, glycosylated hemoglobin, insulin, lipid and lipoprotein levels, and a 2-hour, 75-g glucose tolerance test. Anthropometric measurements were done including body mass index and waist/hip ratio. 15 Fat-free mass (FFM) and adipose body mass were estimated by the use of an RJL impedance meter (model B14101; RJL Equipment Co) and equations based on total body water validated in the American Indian population: 15,19 20 Watermales (L) { log [height (cm)] log [resistance( )] log [weight(kg)]} e Water females (L) { log [height (cm)] log [resistance( )] log [weight(kg)]} e Fat-free mass (FFM) water (L)/0.732 Adipose Body Mass Weight FFM Phase II SHS participants were classified as hypertensive if resting blood pressure exceeded 140 mm Hg systolic or 90 mm Hg diastolic or if participants were on antihypertensive medications Individuals were considered diabetic, according to World Health Organization criteria, if they had a fasting plasma glucose level 140 mg/dl or a glucose level 200 mg/dl 2 hours after 75-g glucose load, or if they were taking insulin or oral hypoglycemic medications. 21 Impaired glucose tolerance was defined as a fasting glucose level 140 mg/dl and a 2-hour glucose level 140 and 200 mg/dl. On the basis of the second National Health and Nutrition Examination Survey (NHANES II) criteria, overweight was defined as body mass index of 27.8 to 31.0 for men and 27.3 to 32.2 for women, and obesity was defined as body mass index of 31.1 for men and 32.3 for women. 22 Echocardiographic Methods As previously described, studies were performed with Acuson 128 (Acuson, Inc) phased-array echocardiograph with M-mode, 2-dimensional, and pulsed, continuous, and color-flow Doppler capabilities. Examinations were performed with the head of the examining table elevated 30 in a partial decubitus position. The parasternal acoustic window was used to record at least 10 consecutive beats of 2-dimensional and M-mode recordings of the LV internal diameter and wall thicknesses at or just below the tips of the anterior mitral valve leaflets in both the long- and short-axis views. Additional M-mode, 2-dimensional, and Doppler recordings made on these subjects have been previously described elsewhere The protocol was designed to be completed in 30 minutes so that participants would not be excessively burdened, and recordings were made entirely on videotape. Echocardiographic Measurements Correct orientation of planes for imaging and Doppler recordings was verified by the use of previously described procedures. 25 Measurements were made with a computerized review station (Digisonics, Inc) equipped with a digitizing tablet and monitor screen overlay for calibration and performance of each needed measurement. LV internal dimension and interventricular septal and posterior wall thicknesses were measured at end-diastole and endsystole according to the recommendations of the American Society of Echocardiography 26 on up to 3 cycles. When optimal orientation of the LV could not be obtained, correctly oriented 2-dimensional linear dimensions were made by the leading-edge convention according to the recommendations of the American Society of Echocardiography. 27 As previously reported, 28 there was a close correlation (r 0.967, mean difference 0.49 g, SD g) between LV mass measurements by these 2 methods in 196 adults studied in our laboratory. Calculation of Derived Variables End-diastolic LV dimensions were used to calculate LV mass by an anatomically validated formula. 29 Relative wall thickness was defined as the following ratio: 2 end-diastolic posterior wall thickness/end-diastolic LV internal dimension. 25 LV mass was considered as an unadjusted variable and also after normalization to body height 2.7, where 2.7 is the power of the allometric or growth relation between LV mass and body height. 10 For consistency, LV mass was also normalized for body surface area, calculated according to the Dubois formula. 30 The primary height-based criterion used to examine the prevalence of LV hypertrophy was a prognostically validated LV mass/height 2.7 partition value of 51 g/m 2.7 in both genders. 31 Gender-specific partition values for LV mass/height 2.7 are 50 g/m 2.7 for men and 47 g/m 2.7 for women. These represent the upper limits of the normal gender-specific 95% CIs of a previously described reference population. 31 In addition, LV mass/body surface area partition values of 117 g/m 2 in men and 104 g/m 2 in women were also used as the upper limit of gender-specific normal 95% CIs. 10,31 Upper 95% CIs for LV mass/ffm were derived in a reference group comprising 281 SHS participants (147 men and 134 women) who had normal body weight, normal fasting blood sugar and glucose tolerance, and normal blood pressure on no antihypertensive medications. The prevalence of LV hypertrophy by different criteria was assessed in a high-risk group encompassing 2826 participants who were overweight, diabetic or with impaired glucose tolerance, or hypertensive or taking antihypertensive medications. Data Handling and Statistical Analyses Data are presented as mean SD for continuous variables and proportions for categorical variables. Data management and analysis were performed with Crunch 4 software (Crunch, Inc) and SPSS 7 (SPSS). Because of the known impact of gender on LV mass, analyses were performed separately in men and women. Correlation coefficients were calculated to determine which independent variables had significant univariate associations with LV mass. Multiple linear regression analysis with assessment of collinearity diagnostics was used to determine the independence of correlates of LV mass. Partial correlation coefficients were used to estimate the proportion of variance of LV mass explained by each independent variable. The strength of correlations of different variables to the same reference standard was compared by use of Fisher s z statistic. Two-tailed P 0.05 indicated statistical significance. Results Echocardiograms were obtained in 3585 participants in the SHS Phase II. Of these, 3107 (86%) had technically satisfactory LV echocardiograms and complete data for other evaluated characteristics necessary for inclusion in the study. More than half of the cohort were women (Table 1). The mean ages for men and women were identical and ranged from 48 to 81 and from 46 to 80 years, respectively. All measures of body and body adiposity were higher in women; in addition, FFM was higher in men.

3 2540 Left Ventricular Mass and Body Composition TABLE 1. Subject Characteristics Variable Men (n 1155) Women (n 1952) P Age, y NS Height, cm Weight, kg Body surface area, m Body mass index, kg/m FFM, kg Adipose mass, kg Percent adipose mass Waist/hip ratio Correlates of Left Ventricular Mass The correlation coefficients between measures of LV size and age, blood pressure, and body size in men and women are presented in Table 2. In univariate analyses, LV mass correlated better with FFM than with adipose mass, body mass index, the waist/hip ratio, systolic blood pressure, height, or height 2.7 in both men and women. Age was only marginally related to LV mass in women. In both genders, FFM, adipose mass, body mass index, the waist/hip ratio, height, and height 2.7 were associated more with LV chamber size than wall thicknesses, whereas this was not consistently true for diabetes (Table 3 and 4). Multivariate Analyses Regression analyses to determine the closeness and independence of association of independent variables with LV mass are summarized in Tables 5 and 6 for men and women, respectively. Gender-specific regression analyses showed that LV mass had the strongest independent positive correlation with FFM followed by systolic blood pressure and age. Diabetes had an independent relation with LV mass in women but not in men. Neither adipose mass nor height 2.7 independently added information to multivariate models. Measures of Obesity and LV Mass Alternative regression analyses were performed in a model with LV mass as the dependent variable and age, systolic TABLE 2. Univariate Correlates of Left Ventricular Mass in Men and Women Variable Men (n 1155) Women (n 1952) r P r P FFM Adipose mass 0.24* * Waist/hip ratio 0.16* * Body mass index 0.33* * Body weight 0.35* * Systolic blood pressure 0.26* * Height 0.11* * Height * * Age 0.04* * *P 0.05 versus gender-specific correlations between left ventricular mass and FFM using Fisher s z statistic. TABLE 3. Univariate Correlates of Independent Variables and Left Ventricular Dimensions and Mass in Men Variable IVSd LVIDd PWTd LV Mass RWT FFM * Adipose mass Waist/hip ratio 0.07* Body mass index Body weight Systolic blood pressure Diabetes Height 0.07* Height * 0.15 Age IVSd indicates end-diastolic interventricular septal thickness; LVIDd, end-diastolic left ventricular internal dimension; PWTd, end-diastolic posterior wall thickness; and RWT, relative wall thickness. *P 0.05; P 0.01; P blood pressure, and height 2.7 as independent variables and with each of the other measures of body size being substituted for each other. Among men, the measure of body size most associated with LV mass was FFM ( 0.408), followed by body weight ( 0.383), body surface area ( 0.355), body mass index ( 0.342), adipose mass ( 0.253), and the waist/hip ratio ( 0.145) (all P 0.001). Likewise, among women, LV mass was most closely associated with FFM ( 0.405), followed by body surface area ( 0.366), body weight ( 0.360), body mass index ( 0.298), adipose mass ( 0.278), and the waist/hip ratio ( 0.138) (all P 0.001). Results With Alternative Measures of Obesity When the waist/hip ratio was substituted for adipose mass in the model in Table 5, LV mass in men was strongly related to higher FFM ( 0.389), followed by higher systolic blood pressure ( 0.174) and older age ( 0.122) (all P 0.001) but not to the waist/hip ratio or the other variables in Table 5. TABLE 4. Univariate Correlates of Independent Variables and Left Ventricular Dimensions and Mass in Women Variable IVSd LVIDd PWTd LV Mass RWT FFM Adipose mass Waist/hip ratio Body mass index Body weight * Systolic blood pressure Diabetes Height Height Age * n Abbreviations as in Table 3. *P 0.05; P 0.01; P

4 Bella et al December 8, TABLE 5. Multivariate Correlates of Left Ventricular Mass in Men and Women Men (n 1155) Women (n 1952) Variable B SE P B SE P FFM Systolic blood pressure Age Diabetes Adipose mass Height Constant B indicates regression coefficient; SE, standard error of the regression coefficient. Among women, LV mass was most strongly related to greater FFM ( 0.388), followed by higher systolic pressure ( 0.238), waist/hip ratio ( 0.066) (all P 0.001), and age ( 0.08, P 0.001) but not to the other variables in Table 5. Body mass index was then substituted for adipose mass as the indirect measure of obesity. Because collinearity diagnostics revealed that body mass index and height 2.7 were highly collinear, height 2.7 was deleted from the multivariate model. The resultant model demonstrated LV mass in men was strongly related to FFM ( 0.327), followed by systolic blood pressure ( 0.167), age ( 0.117) (all P 0.001), and body mass index ( 0.109, P 0.02), but not to diabetes. Among women, LV mass was independently associated with FFM ( 0.381) followed by systolic blood pressure ( 0.236), age ( 0.119) (all P 0.001), and diabetes ( 0.06, P 0.01) but not body mass index. TABLE 6. Criteria Prevalence Rates of Left Ventricular Hypertrophy Reference Group (n 281), % High-Risk Group (n 2772), % Unified criteria LV Mass/FFM 4.10 g/kg LV Mass/height g/m LV Mass/BSA 125 g/m Gender-specific criteria LV Mass/FFM, g/kg Men 3.6 Women 4.4 LV Mass/height 2.7, g/m Men 50 Women 47 LV Mass/BSA, g/m * Men 117 Women 104 LV Mass/height, g/m Men 126 Women 105 BSA indicates body surface area. *P by McNemar test vs gender-specific LV Mass/FFM criteria. P Regression Analyses With Cardiac Variables A final linear regression analysis was performed; the dependent variable was LV mass as a continuous variable. and the independent cardiac (Doppler stroke volume and stresscorrected midwall shortening) and clinical (age, gender, height, and FFM) variables were the same as in a previous report from the SHS 23 except that FFM was substituted for body mass index. This analysis yielded a minimally higher multiple R than previously published (R 0.72 versus R 0.71, P NS) and showed that LV mass is independently related to afterload-independent midwall shortening ( 0.447), followed by higher stroke volume ( 0.405), FFM ( 0.353), systolic blood pressure ( 0.228), female gender ( 0.089) (all P 0.001), and older age ( 0.039, P 0.007). Height was not an independent correlate of LV mass. Except for the latter finding, the results confirm the previous report that indicated that LV mass was independently related to afterload-corrected midwall shortening, stroke volume, systolic blood pressure, body mass index, height, and male gender. Prevalence of Left Ventricular Hypertrophy Using a 97.5 percentile partition value of 4.10 g/kg for LV mass/ffm in the reference population, we found that LV hypertrophy occurred in 2.7% of the reference population and 9.6% of the high-risk population. Gender-specific partition values of 3.63 g/kg and 4.86 g/kg for men and women, respectively, showed an 8-fold higher prevalence of LV hypertrophy in high-risk individuals than in the reference group. Using a prognostically validated partition value of 51 g/m 2.7 for LV mass/height 2.7, we found that 2.3% of the reference population and 16.7% of the high-risk population had LV hypertrophy. Table 6 summarizes the prevalence rates of LV hypertrophy in both populations, and includes additional criteria for LV mass/body surface area and LV mass/height. Discussion The present study demonstrates that FFM calculated by BIA is a stronger correlate of LV mass in both women and men than adipose mass, the waist/hip ratio, height, or height 2.7 in a population-based sample of middle-aged to elderly adults. In both women and men, LV mass was independently associated with FFM, followed by higher systolic pressure and older

5 2542 Left Ventricular Mass and Body Composition age, whereas in women diabetes was also independently associated with increased LV mass. Adipose mass was not independently associated with LV mass in either gender. These findings demonstrate that although obesity is a strong clinical predictor of LV mass, FFM rather than adipose mass is the main variable determining the level of LV mass. When other measures of ponderosity, including the waist/hip ratio and body mass index, were entered into the multivariate analyses, FFM remained the strongest correlate of increased LV mass. These results document a strong relation between FFM and LV mass in an age range in which the latter variable has been shown to be a strong predictor of cardiovascular events. 2 5 Precedent for our findings is provided by previous results in younger individuals. Daniels et al 35 assessed the relation of echocardiographic LV mass to lean body mass and fat mass determined by DEXA in 201 white or African-American children and adolescents 6 to 17 years old. In multivariate analysis, they found that only lean body mass, fat mass, and systolic pressure were independent correlates of LV mass. Lean body mass explained 75% of the variance of LV mass, whereas fat mass and systolic blood pressure explained only 1.5% and 0.5% of the variance, respectively. They concluded that lean body mass was the most important determinant of LV mass in children. 35 Our regression analyses confirm that among adult American Indians, LV mass is more strongly independently associated with FFM than with other measures of body size. It has been previously reported that a major proportion of the differences among adults in LV mass follows differences in nonadipose body size, including greater physiological LV hypertrophy in men than in women that parallels gender differences in height to its allometric power and fat-free mass However, compared with the study of Daniels et al, 35 the association between FFM and LV mass is weaker among adults than in children and adolescents. This does not necessarily imply a weaker biological association but, rather, may reflect the progressive accrual among middle-age adults of conditions such as hypertension and diabetes that cause significant target organ damage and thereby decrease the relation between body size and heart size The age-related loss of a portion of original body height and fluctuations in body weight during adulthood may make measurements of body size and body adiposity less representative of those responsible for heart size than they were during maturation. 39,41 In addition, the greater ease of echocardiography performance in young individuals and their lack of obesity or acquired lung disease may have reduced measurement variability in Daniels population. The parallelism between FFM and LV mass appears to have 2 explanations. First, FFM generates nearly all the metabolic activity of the body and governs total oxygen demand, which in turn determines the required cardiac output and, for a given heart rate, the stroke volume. It has been shown by several investigators that LV mass correlates with stroke volume more closely than blood pressure. 40,42 45 Our regression analyses, which showed a modest reduction of the association between stroke volume and LV mass when FFM was substituted for body mass index in a previously published model, 23 suggest that part of the linkage between FFM and LV mass may be due to this hemodynamic connection. Alternatively, genetic and hormonal influences that affect skeletal mass and organ mass may also directly affect the heart and may thereby contribute to the association between FFM and LV mass. It has been demonstrated that height-based indexations of LV mass, which identify both blood pressure and obesityassociated increases in LV mass, maintain and may enhance prediction of cardiac risk by LV mass measurements. de Simone et al 31 reported that future cardiovascular events were best predicted in patients with uncomplicated hypertension by the use of partition values for LV mass/height 2.7 to define LV hypertrophy. However, another report by Liao et al 46 suggested that the predictive value of different indices of LV mass was roughly equivalent in a predominantly African- American patient population. The SHS will provide an unusual opportunity to examine whether indexation of LV mass for fat-free body mass enhances prediction of cardiovascular events because this cohort has high prevalence of both obesity and cardiovascular events. 47 Numerous methods have been used to measure body adiposity Hydrodensitometry is considered the most rigorous reference standard for measuring lean body mass. However this is a cumbersome and technically involved method, limiting its application in large clinical or epidemiologic populations. BIA offers a safe, portable and noninvasive alternative way of measuring body composition BIA has been validated to be as accurate as hydrodensitometry in measuring total body fat and FFM. 53 Likewise, BIA has been shown to be reliable for repeated measurements and for interobserver and intraobserver comparisons with standardized measurement techniques. 54 When compared with the traditional noninvasive methods, ie, skinfold-thickness measurements and body mass index, BIA had a significantly lower variability of estimates. 55 A recent study from Framingham demonstrated that BIA is sufficiently precise and accurate to offer valid body-composition measurements compared with DEXA as the reference technique. 13 Prediction equations have been validated and cross-validated in children, youths, adults, and the elderly in primarily white populations and, to a limited extent, in American Indian, African-American, and Asian populations ,56 58 After defining 97.5 percentile gender-specific partition values for LV mass/ffm of 3.63 g/kg for men and 4.86 for women in the reference population of apparently normal adults, LV hypertrophy was detected in 20.4% of individuals with conditions associated with increased LV mass. This represents an 8-fold increase in prevalence of LV hypertrophy from the reference population. In contrast, prognostically validated gender-specific partition values for LV mass/ height 2.7 and for LV mass/body surface area showed only 6-fold and 5-fold increases in prevalence of LV hypertrophy in the high-risk individuals (ie, those who were overweight or had diabetes or impaired glucose tolerance or had hypertension). The increased proportion of high-risk individuals identified as having LV hypertrophy by LV mass/ffm criteria is particularly noteworthy because FFM increases with obesity. However, further studies need to be performed

6 Bella et al December 8, to evaluate the relation of the LV mass/ffm ratio to pathophysiologic variables and to assess its usefulness as a predictor of cardiovascular events. In addition to the study of Daniels et al 35 discussed above, several other investigators have identified FFM as an independent correlate of LV mass. In the Muscatine Study, 124 children aged 7.9 to 12 years were evaluated to determine predictors of LV mass and resting blood pressure. 59 In boys, 72% of the variability in LV mass was explained by FFM, sum of skinfolds, and peak systolic blood pressure, whereas in girls FFM and peak systolic blood pressure explained 69% of the variability of LV mass. In a study of 100 elderly Swedish men, 40 investigators found that LV mass and stroke volume had significant correlations with FFM. Likewise, in a smaller study of German athletes, Urhausen et al 60 showed that LV wall thickness, LV end-diastolic diameter, and LV mass correlated significantly with FFM. These findings in other populations of white and, to a lesser extent, African- American individuals across a wide range of ages make it likely that the results of the present study performed with American Indian participants in the SHS will be applicable to other populations. Conclusions This study demonstrates that LV mass is more strongly related to FFM than to adipose mass, the waist/hip ratio, body mass index, or the height-based indices commonly used as surrogates for lean body weight to normalize the level of LV mass for body size. LV mass/ffm criteria also appear to increase sensitivity for detection of LV hypertrophy. Further studies are needed to validate the indexation of LV mass for FFM by the additional, but most important, test of demonstrating its utility as a predictor of prognosis. Acknowledgments This work was supported by cooperative agreements U01-HL41642, U01-HL41652, U01-HL41654, and M10RR (GCRC) from the National Institutes of Health, Bethesda, Md. 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