From the Division of Cardiology, The New York Hospital–Cornell
Medical Center, New York, NY (G. de S., R.B.D., M.J.R.); the Department of
Clinical and Experimental Medicine, Federico II University Hospital, Naples,
Italy (G. de S., G.F.M., F.C.); and Children's Hospital Medical Center,
Division of Cardiology, Department of Pediatrics, University of Cincinnati
(Ohio) (T.R.K., S.R.D.).
Correspondence to Dr Giovanni de Simone, Department of Clinical and Experimental Medicine, Federico II University Hospital, via S. Pansini 5, 80131 Naples, Italy. E-mail simogi{at}unina.it
Procedures
Body weight and height were measured on the day of
echocardiographic evaluation. Definition of normal
weight was based on gender-specific body mass index partition values
from the 1985 NIH Consensus Conference7 for
adults. For children and adolescents older than 3 to 12 years of age,
the age-based method reported by Himes and Dietz8
was used to define normal weight. Children younger than 3 years old
were considered normal weight.
Echocardiography
Measurements of interventricular septal thickness,
posterior wall thickness, and LV dimensions were taken at or just below
the mitral valve tips, by the leading edge–to–leading edge method,
according to the American Society of
Echocardiography
recommendations.13 Interobserver and
intraobserver variability for echocardiographic
measurements from the laboratories involved in the present study
has been previously reported.12 14 15 Short- and
long-term test-retest analyses on various M-mode primary or
derived measurements have also been reported from all three
laboratories.15 16
LV mass was calculated by adjusted ASE-method17
and was normalized for height2.7, as previously
reported.1 2 LV end-diastolic and
end-systolic volumes were calculated with the Teichholz'
correction of the cube formula.18 19 Stroke
volume by this method has been recently shown to parallel closely
Doppler-derived stroke volume with a mean difference of 2 mL/beat
in a large population sample.20 Blood pressure
was recorded at the end of echocardiographic
examination, with arm-cuff sphygmomanometer with cuffs of appropriate
size for children and infants. Stroke work (SW) was estimated as
systolic blood pressure times stroke volume and was converted
in gram-meters (g-m) by multiplying by 0.0144. Substitution of
mean (m) for systolic
(s) arterial pressure yielded values
for stroke work that were lower (by a mean of 26±5%) but closely
correlated (r=.99, P<.0001) with those derived
by systolic arterial pressure
(SWm=0.14+0.74SWs±4);
similarly, use of awake systolic blood pressure gave stroke
work values that were closely correlated with those obtained by resting
systolic pressure (r=.95, P<.0001).
Stroke work index was calculated as systolic blood pressure
times stroke index (stroke work/body surface area).
Statistical Analysis
Data are expressed as mean±1 SD. The 95% confidence interval is also
reported for variables derived from
echocardiographic measurements. The
Weight estimation was used to determine the extent of impact of
increasing age on the precision of prediction of LV mass from body
size. With this procedure, data points were weighted by the reciprocal
of age to a power determined by a best-fitting iteration in which the
program evaluated the log-likelihood function for all powers within a
given grid (-2 to 2) to select the power correspondent to the largest
log-likelihood.21
Stepwise multiple regression analysis was used to study the
hemodynamic and demographic predictors of LV mass, with
F to enter and F to remove set to P<.05 and to
P<.10, respectively. Gender was treated as a dummy
variable, by assigning 1 to male subjects and 2 to female subjects.
Unstandardized ß coefficients (slope) with relative standard error,
standardized ß coefficients and the value of constant±SE are
reported for each model. Statistical significance was set at a
two-tailed value of P
Effect of Age on Relation Between LV Mass and Body Size
A weight estimation of LV mass was therefore implemented by using age
(ie, a physiologically possible source of
heteroscedasticity as shown by Fig 1
Interaction Between Body Size, Cardiac Workload, and LV
Mass
Stroke work increased with age by 4.44 g-m/beat per year in infants,
children, and adolescents (P<.0001) and by 0.30 g-m/beat
per year in adults (P<.02) (Fig 3
In the entire study population, LV mass was closely related to
systolic blood pressure (r=.56,
P<.0001), stroke volume (r=.85,
P<.0001), and stroke work (Fig 4
Table 2
In the whole study population, the variance of LV mass associated with
independent variables increased from the 69% observed for the
univariate relation with height2 to
82% in a multiple regression model including sex (slope=-5.71±1.57,
ß=-0.06, P<.0001) and stroke work (slope=0.65±0.03, ß
=0.52, P<.0001) in addition to
height2 (slope=17.05±0.97, ß=0.42,
P<.0001; constant=-10.85±3.65, multiple R=
.90, SEE=21 g, P<.0001). When systolic blood
pressure and stroke volume were added to the regression model, the
result did not change: partial r values were .004 for
systolic blood pressure and -.03 for stroke volume (both
P=NS). Similar results were obtained in a subset of 133
adults who also had Doppler stroke volume measurements: neither
resting systolic pressure nor stroke volume (both
P>.06) added to the significant association
(P<.0001) between LV mass and stroke work by the formula
used in this study. Weighting for age slightly increased the magnitude
of variance of LV mass associated with independent variables (86%)
compared with the unweighted model (82%), indicating that most of the
association between age and LV mass in this model appeared to be
mediated by age-related increases in stroke work and by the effect of
male gender after puberty. In this analysis, 18% of variance
of LV mass was not mathematically attributed to demographic or
hemodynamic factors.
Regression analysis was also repeated in separate groups
of children and adolescents, and adults. In children and
adolescents, height2 was the main determinant
of LV mass (slope=17.8±0.98, ß=0.63, P<.0001),
with minor but significant independent contributions of
stroke work (slope =0.36±0.04, ß=0.30, P<.0001) and sex
(slope=-3.88±1.55, ß=-0.07, P<.01; constant=1.58±3.47
g; multiple R=.87, SEE=14.7 g, P<.0001). In
contrast, during adulthood, the level of LV mass was most strongly
associated with stroke work (slope=0.64±0.04, ß=0.56,
P<.0001) and sex (slope= -18.1±3.23, ß=-0.24,
P<.0001) and less strongly with
height2 (slope=6.63±2.48, ß=0.12,
P<.001; constant= 55.37±13.82 g; multiple
R=.78, SEE=23.2 g, P<.0001).
The increasing error of prediction of LV mass by a measure of body size
(height2 in this study) with increasing body
size (and age) may be due to (1) increasing methodological error with
the increasing magnitude of LV mass; (2) unrelated and undetectable
biological phenomena; or (3) changes in biological variables other
than body size occurring with increasing age. In the present study
this third hypothesis has been tested. It was made evident by a
weighting procedure that the role of age as a source of
heteroscedasticity of residuals of LV mass was associated with a real
biological phenomenon that could help to explain the progressively
increasing scatter of residuals. Increase in stroke work with age was
primarily due to rising mean levels and interindividual variability of
arterial pressure in adults and to increasing levels of
scatter of both blood pressure and stroke volume in children and
adolescents.
Previous studies from this and other
laboratories24 25 have shown that volume load is
an even more important determinant of increase in LV mass than blood
pressure, even when the latter is measured by ambulatory
monitoring.26 Of note, the statistically
independent association of higher Doppler-derived stroke volume
with LV mass26 27 has been presumed to be
mediated by stimulation of LV growth by an increase in
end-diastolic LV wall stress.28 The
evidence that LV concentric remodeling is associated with very high
peripheral resistance and low stroke
volume29 suggests that the interaction between
the two hemodynamic components (volume and pressure) is
crucial for increasing LV mass. Accordingly, stroke work
represents an approximate measure of this interaction. Stroke
work rises quickly after birth and on average reaches a maximum level
at the time of complete body maturation, when both stroke volume and
blood pressure are stabilized. During adulthood, aging is only weakly
associated with further increase in stroke work in normotensive
individuals. As expected from the above considerations, the relation of
LV mass with stroke work was strong and, in
multivariate analysis, completely excluded
arterial pressure and stroke volume from the regression
model.
The close linear relation with a near-zero intercept between stroke
work and LV mass confirms the appropriateness of normalizing stroke
work for the first power of LV mass, a ratio used in the past as an
index of LV performance.30 Application of
this procedure in our population study allowed us to clarify that
stroke work per unit of LV mass was higher in females than in males, a
difference that attained statistical significance during adulthood.
Therefore, for comparable LV mass, adult women develop more cardiac
work at rest than men, suggesting better resting LV
performance, consistent with previous findings from
these and other laboratories.31 32 33
In regression analysis a substantial part of the variance
of LV mass was associated with body size
(height2.7) and stroke work, both variables
positively correlated with increasing age during body growth and male
gender, a factor whose effect on LV mass is especially prominent after
puberty.23 The 18% of variance of LV mass that
remained statistically unexplained could be due to both intrinsic error
of measurements, and, perhaps mainly, undetectable (in this study)
genetic or environmental influences. The extent of technical error can
be suggested to be at least 9%, which is the difference between the
variance of LV mass that is expected to be explained by the weighting
procedure (91%) and that actually explained in
multivariate model including body size, gender, and
cardiac load (82%).
Age-Related Changes of Correlates of LV Mass
During adulthood, when there is little further increase in weight, the
influence of changes in body size is minimal in this normal-weight
normotensive population, whereas the variability of stroke work becomes
the overwhelming correlate of LV mass. As expected, the effect of male
gender on the variability of LV mass becomes more important after
puberty.
Limitations
Stroke volume does not completely determine the LV filling volume that
contributes to LV end-diastolic stress because of the
variable volume remaining after the previous systole and the
potential impact of valvular regurgitation.
However, the exclusion of individuals with valvular
regurgitation eliminates one source of confounding in
the present study. Furthermore, a supplemental regression
analysis showed that Doppler stroke volume remained a
highly significant (P<.0001) correlate of LV mass in New
York subjects after end-systolic volume was taken into
account.
Finally, LV mass represents a relatively stable geometric
adaptation to cardiac workload that varies over time. A measurement of
cardiac workload at rest at a single point in time cannot completely
reflect chronic LV load. However, the relatively modest paired
difference between awake ambulatory and resting systolic blood
pressures in the subset of patients studied in New York suggests that
the potential imprecision of a single point measurement may be balanced
by the size of the study population.
Conclusions
Received September 29, 1997;
first decision October 21, 1997;
accepted December 15, 1997.
2.
de Simone G, Devereux RB, Daniels SR, Koren MJ,
Alderman MH, Laragh JH. Effect of growth on variability of left
ventricular mass: assessment of allometric signals in
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3.
de Simone G, Devereux RB, Daniels SR, Mureddu GF,
Roman MJ, Kimball TR, Greco R, Witt S, Contaldo F. Stroke volume and
cardiac output in normotensive children and adults: assessment of
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function by the midwall fractional shortening/end-systolic
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afterload and contractility in pediatric patients with
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Kimball TR, Daniels SR, Meyer RA, Hannon DW, Tian J,
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20.
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PS, Mureddu GF, Roman MJ, Howard BV. Estimation of left
ventricular chamber and stroke volume by limited M-mode
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24.
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© 1998 American Heart Association, Inc.
Scientific Contributions
Interaction Between Body Size and Cardiac Workload
Influence on Left Ventricular Mass During Body Growth and Adulthood
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—The development of
the left ventricle parallels body growth. During infancy, the relation
between body size and left ventricular (LV) mass is very
close. With advancing age, variability of LV mass in relation to body
size markedly increases. To test the hypothesis that the age-related
increase in variability of LV mass is due to the progressive impact of
hemodynamic stimuli on LV growth, quantitative M-mode
echocardiograms were obtained in 766 normal-weight, normotensive
individuals over a range of ages from 1 day to 85 years (330 female
subjects, 373 subjects younger than 18 years). LV mass was linearly
related to height2
(r2=.69). Prediction of values of LV
mass by body size was more accurate at birth and progressively less
precise with increasing age. Stroke work (stroke volume times
systolic pressure) was closely related to LV mass
(r2=.74). The explained variance of
LV mass increased from 69% in the univariate regression
with height2 to 82% in a multivariate
model including height2.7, stroke work, and gender. In
children and adolescents (younger than 18 years), height2
was the main determinant of LV mass, whereas during adulthood stroke
work and gender were more important predictors of LV mass than
height2.7. Thus (1) the influence of body growth on
development of LV mass decreases after early infancy because of both
the variability of hemodynamic load and the increasing
effect of gender; (2) after adolescence, during adulthood, in
normotensive, normal-weight individuals, the impact of
hemodynamic load and male gender on LV mass is greater
than the one of body size; and (3) an appreciable proportion of
variability of LV mass remains unexplained with the studied models.
This might be due to genotypic variations and/or measurement
error.
Key Words: age • hemodynamics • gender • ventricular function, left • hypertrophy, left ventricular
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Body growth
influences cardiac development. The close relation between body size
and left ventricular (LV) mass1
during childhood and adolescence is the hallmark of this influence.
However, in infancy virtually the entire variability of LV mass is
explained by body size, whereas with increasing age the ability of body
size to precisely predict LV mass decreases. In fact, the difference
between the value of observed LV mass and that predicted from body size
increases with increasing age (heteroscedastic distribution of
residuals).2 This phenomenon might be explained
by the progressive hemodynamic load that faces the left
ventricle right after birth as the fundamental stimulus for LV muscular
development. There is little information on the interaction between
change in body size and in cardiac workload induced by body growth in
relation to development of LV mass in large normal populations across a
wide age span. Accordingly, this study has been designed to investigate
the relation between the age-related increase in LV mass and the
age-related change in cardiac workload by taking into account the
influence of body size during body growth and adulthood in a large
study population of normotensive, normal-weight individuals.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Seven hundred sixty-six normal-weight, normotensive individuals,
1 day to 85 years old, were studied in three centers: 212 men and 138
women from a cohort of employed adults evaluated at the New York
Hospital–Cornell Medical Center; 139 boys and 127 girls as part of a
population-based epidemiological study at the Children's Hospital,
University of Cincinnati; and 69 boys, 42 girls, 16 men, and 23 women
as part of population-based studies at Federico II University of
Naples, Italy. Among the 766 subjects, 393 were older than 17 years,
and 330 were female (166 children to adolescents and 164 adults).
Detailed information on this cohort has been previously
reported.3 4
Informed consent was obtained from all adult volunteers and from
parents or guardians of children under protocols approved by the
Institutional Review Boards for Research in Human Subjects. Blood
pressure was measured with mercury sphygmomanometers and cuffs of
appropriate size. In adults, blood pressure below 140/90 mm Hg
(three readings in at least two clinical examinations) was considered
normal. In American children 1 year of age or older, normal blood
pressure was defined according to criteria presented by Rosner
et al,5 based on 95th percentile of a gender- and
height-specific normal distribution. Children under 1 year of age were
assumed to have normal blood pressure when systolic and
diastolic blood pressures were lower than 101/55
mm Hg, the 95th percentile of blood pressure values in 1-year-old boys
at the 25th percentile of height.5 In Italian
children, who have been reported to have higher average blood pressure
than children of the same age from other European countries, normal
blood pressure was established by the Blood Pressure Tables of the
Italian Society of Pediatrics for Italian
children.6 In a subset of 223 of the New York
subjects who also underwent 24-hour blood pressure monitoring, the
resting systolic pressure used for this study was at least as
closely correlated with LV mass as was the awake ambulatory
systolic pressure (r=.41 and .39, respectively, both
P<.0001; P=NS for difference between the two
correlation coefficients). Mean awake systolic blood pressure
was modestly higher than resting systolic blood pressure, by
5.9±9.0 mm Hg (P<.001 by paired t
test).
Two-dimensionally targeted M-mode echocardiograms were performed
by expert sonographers as previously
described9 10 11 with the subjects in a partial
left decubitus position and in held expiration, when possible, with
commercially available echocardiographs. M-mode
tracings were recorded on strip-chart paper at 50 mm/s. In New
York, echocardiograms were performed by a single experienced
sonographer and read by an experienced investigator (R.B.D., M.J.R., or
G. de S.). In Naples, echocardiograms were performed by a single
experienced sonographer and double-read by two experienced
investigators (G.F.M. and G. de S.).11 In
Cincinnati, echocardiograms were performed by two experienced
sonographers and double-read by two experienced investigators (T.R.K.
and S.R.D.)12; in these centers the two readers'
measurements were averaged.
Because Italian children had blood pressure values slightly
higher than same-age Americans, analyses have been adjusted for
"center effect" by use of the following procedure: primary
echocardiographic measurements
(end-diastolic and end-systolic LV internal
dimension and wall thickness), blood pressure, and heart rate were
related as dependent variables to a dichotomous variable
representing the center in age-matched groups of
subjects.3 4 Thus Italian children were combined
with Cincinnati children in the same range of age (6 to 11 years) and
Italian adults were combined with New York adults in the same range of
age (20 to 69 years) and dependent variables were related to the
dummy variable indicating the center (1 or 2). The variables
considered in this preliminary analysis were therefore adjusted
by the linear coefficient of regression (b). Thus
the adjusted variable (adjV) was
adjV=V-b(x-µ), where V was the observed value
of the dependent variable, x was the dummy variable
representing the Center, and µ was the average value of
the variable representing the centers. 
2 statistic was used for categorical
variables. Student's t test was used for simple
comparisons of continuous variables. Least squares linear
regression was used to assess univariate relations.
Distribution of residuals of the relation of LV mass to
height2 in relation to age was assessed by
least squares linear regression of their absolute value versus age. 
.05.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Table 1
shows demographic
characteristics in children-adolescents and in adults. Table 1 also
shows that males exhibited higher values of LV mass (as both absolute
values and normalized for height2.7), stroke
volume, stroke index, stroke work, and stroke work index than females
(.05<P<.0001) in both age strata, with greater differences
during adulthood.
View this table:
[in a new window]
Table 1. Demographics, LV Mass, and
Hemodynamic Parameters in Normal
Individuals
LV mass was related to all measures of body size, linearly
to body weight (y=1.8*x) and by allometric
signals to body surface area
(y=53*x1.5) and body height (Fig 1;
y=27*x2.8; all
P<.0001). For consistency with our initial
study in a nonoverlapping subject population,1
height2 was used as the main measure of body
size linearly related to LV mass. Similar to the findings in the
previous study-population, residuals of the relation between LV mass
and height2 increased their dispersion with
increasing age during infancy, childhood, and early adolescence
(heteroscedastic distribution, Fig 2),
whereas the dispersion was more homogeneous across the age
span during adulthood (homoscedastic distribution, Fig 2).
View larger version (19K):
[in a new window]
Figure 1. Relation between left ventricular (LV)
mass and height in 373 children and adolescents ( 
) and 393 adults
(
): The allometric signal regulating this relation is 2.8
(r=.834), similar to 2.73 (r=.833,
SEE=26.7 g, in the present study-population) previously reported in
Reference 1.
View larger version (21K):
[in a new window]
Figure 2. Relation between age (horizontal axes) and
unstandardized residuals of regression between left
ventricular (LV) mass and height2 (vertical
axes) in 373 children and adolescents (top) and 393 adults (bottom).
The dispersion of residuals increases with age in children and
adolescents (heteroscedastic distribution), whereas it is stable in
adults (homoscedastic distribution). 
) as a weight variable. With
this procedure, explained variance of LV mass rose to 91%
(R2=.91, SEE=6.2 g, P<.0001).
The effects on the relation between LV mass and body height of
variables other than body size, able to influence development of LV
mass, were therefore examined.
Cardiac workload was measured as stroke work. The relations of the
two components of stroke work to age were determined. Systolic
blood pressure increased by 0.33 mm Hg per year in the age
stratum formed by infants, children, and adolescents (n=373,
r=.13, P<.0001) and, similarly, by 0.33
mm Hg per year in the wider age range of the adult population (n=393,
r=.40, P<.0001). In contrast, stroke volume
increased markedly between birth and 17 years (2.7 mL/beat per year,
r=.64, P<.0001), whereas it was stable during
adulthood (r=-.02, P=NS). ).
View larger version (25K):
[in a new window]
Figure 3. Relation between age (horizontal axis) and stroke
work in 373 children and adolescents ( , continuous line) and 393
adults (, dotted line)., r=.86,
P<.0001). Increase in LV mass with increasing stroke work
was similar in children and adults (0.87 and 0.82 g/g-m per beat,
respectively), as well as in boys and girls (0.96 and 0.74 g/g-m per
beat) and men and women (0.70 and 0.63 g/g-m per beat).
View larger version (24K):
[in a new window]
Figure 4. Relation between stroke work (horizontal axis) and
left ventricular (LV) mass (vertical axis in 373 children
and adolescents ( ) and 393 adults (). The regression line is
obtained in the whole study-population (n=766). shows that among infants,
children, and adolescents, the ratios of stroke work to LV mass was not
statistically different in males and females, whereas the values were
lower by a mean of 8% in adult men than in women
(P<.0001). This result remained statistically significant
even after taking into account body surface area.
View this table:
[in a new window]
Table 2. Ratio of Stroke Work to LV Mass in Normotensive,
Normal-Weight Individuals
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Studies of comparative physiology have shown that the
fundamental determinant of dimensions, and often functions, of organs
is body size, in mammals as well as in other
animals.22 The weight of the human left ventricle
follows this rule and has been shown to strictly depend on body size,
especially during body growth.1 2 23 The positive
influence of body size, however, progressively decreases during body
growth until the maturation of the body is completed. This phenomenon
is clearly shown by the heteroscedastic distribution of residuals of
the relation between LV mass and body height2.7,
plotted with age, as reported in a previous
study-population2 and confirmed in the
present nonoverlapping population that extends our previous
observations to the neonatal period. The present study also
confirms our previous observations that, in contrast, the distribution
of residuals of the LV mass–body height relation in adults is
homogeneous (homoscedastic).
After birth, a rapid and progressive increase in cardiac
workload occurs because of both a mild increase in blood pressure and a
more marked and progressive increase in stroke volume. Therefore, the
two basic hemodynamic stimuli for development of LV
mass, volume, and pressure, begin to progressively affect the initially
tight correlation between body and cardiac size during growth and
maturation. In our study population stroke work, as a simple summary
measure of LV workload increases markedly during childhood and
adolescence and adds substantially to the variance of LV mass. However,
in the younger age group body growth remains the main determinant of LV
mass. Until puberty, male gender has a minor though statistically
significant impact.
The cuff systolic blood pressure has been used in this
study as a surrogate for mean LV systolic pressure to calculate
stroke work. Mean LV systolic pressure is lower than the peak
pressure measured at the arm, and this difference increases with
increasing arterial stiffness. In addition, stroke volume
measured by M-mode echocardiogram may be affected by imprecision of
measurements. However, in an epidemiological study, M-mode stroke
volume was as closely related to Doppler stroke volume (mean
difference=1.6±5.0 mL/beat)34 as closely as
the latter has been to invasive stroke volume determination in
validation studies.
This study demonstrated that the influence of body growth on the
level of LV mass decreases after early infancy because of both the
variability of hemodynamic load and the increasing
effect of gender. After adolescence, in normotensive, normal-weight
individuals, the impacts of hemodynamic load and male
gender on LV mass are greater than that of body size. A regression
model including a measure of body size, a measure of cardiac workload,
and gender can explain up to 82% of the variability of LV mass in a
population ranging in age from early infancy to late adulthood. The
reported regression equation derived from normal subjects can provide a
tool for estimating the adequacy of LV hypertrophic response in a
number of diseases affecting cardiac loading conditions.
Acknowledgments
This study was supported in part by grants HL-18323,
HL-30605, HL-47540, and HL-34698 from the National Heart, Lung, and
Blood Institute, Bethesda, Md; grant MURST-158/1994 and 1995 of
Ministry of University and Research, Italy; and a grant from Federico
II University of Naples for supporting international
cooperation.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
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 of the impact of overweight. J Am
Coll Cardiol. 1992;20:1251–1260.[Abstract]20 years of age. Am J Cardiol. 1991;68:1383–1387.[Medline]
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