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(Hypertension. 2001;37:1229.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Aortic Root Dilatation at Sinuses of Valsalva and Aortic Regurgitation in Hypertensive and Normotensive Subjects
The Hypertension Genetic Epidemiology Network Study
From the Weill Medical College of Cornell University (V.P., J.N.B., M.J.R., M.P., R.B.D.), New York, NY; University of Minnesota (D.K.A.), Minneapolis; University of Alabama at Birmingham (A.O.); Wake Forest University School of Medicine (D.W.K.), Winston-Salem, NC; University of Utah School of Medicine (P.N.K.), Salt Lake City; and Washington University Medical School (D.C.R.), St. Louis, Mo.
Correspondence to Vittorio Palmieri, MD, Division of Cardiology, Box 222, The New York Presbyterian Hospital-Weill Medical College of Cornell University, 525 East, 68th Street, New York, NY, 10021. E-mail vpalmier{at}med.cornell.edu
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Abstract |
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Abstract—The association of sinuses of Valsalva dilatation and aortic regurgitation with hypertension is disputed, and few data are available in population-based samples. We explored the relations of sinuses of Valsalva dilatation and aortic regurgitation to hypertension and additional clinical and echocardiographic data in 2096 hypertensive and 361 normotensive participants in the Hypertension Genetic Epidemiology Network study. Age and body surface area were used to predict aortic root diameter using published equations developed from a separated reference population. Aortic dilatation was defined as measured sinuses of Valsalva diameter exceeding the 97.5th percentile of the confidence interval of predicted diameter for age and body size. Aortic dilatation was present in 4.6% of the population. After adjustment for age and body surface area, mean aortic root diameter was larger in hypertensives with suboptimal blood pressure control than normotensives or hypertensives with optimal blood pressure control. In multivariate models, sinuses of Valsalva diameter was weakly positively related to diastolic blood pressure and to left ventricular mass independent of aortic regurgitation. Subjects with aortic dilatation were slightly older, were more frequently men, had higher left ventricular mass, and had lower left ventricular systolic chamber function independent of covariates. Sinuses of Valsalva dilatation was independently related to male gender, aortic valve fibrocalcification, and echocardiographic wall motion abnormalities but not to diastolic blood pressure (or history of hypertension in a separate model). The likelihood of aortic regurgitation increased with larger aortic root diameter, older age, female gender, presence of aortic valve fibrocalcification, and lower body mass index but not hypertension or diabetes. In a subsequent model, diastolic blood pressure was negatively related to aortic regurgitation independent of covariates. In a large population-based sample, sinuses of Valsalva diameter was only mildly larger in subjects with suboptimally controlled hypertension than in normotensives or well-controlled hypertensives, which did not result in differences in prevalence of aortic regurgitation among groups. Sinuses of Valsalva dilatation was associated with higher left ventricular mass and lower systolic function, which may contribute to higher cardiovascular risk in subjects with aortic root dilatation.
Key Words: aorta • heart valve diseases • hypertension, arterial • hypertrophy • echocardiography
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Introduction |
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Aortic root diameter at the sinuses of Valsalva is proportional to body size and increases with aging.1 2 3 Aortic root dilatation is a leading cause of aortic regurgitation.4 5 6 7 Aortic root dilatation at sinuses of Valsalva is diagnosed by relating actual diameter to the value predicted for a subject’s body surface area (BSA) and age.2 Results from the Framingham Heart Study suggest that blood pressure (BP) is positively related to sinuses of Valsalva diameter,1 although other studies have not found an association between sinuses of Valsalva diameter and hypertension.2 6 8 9 Little information is available on the relation between hypertension and aortic root diameter in population-based samples. Accordingly, the present study was undertaken to explore relations of arterial hypertension with dilatation at the sinuses of Valsalva and aortic regurgitation in a population-based sample controlling for common covariates.
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Methods |
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Population
The Hypertension Genetic Epidemiology Network (HyperGEN) study is part of the National Heart, Lung, and Blood Institute (NHLBI) Family Blood Pressure Program designed to assess the genetic basis of hypertension in population-based samples. Onset of hypertension by age 60 and at least 1 additional hypertensive sibling willing to participate were required to be selected. Hypertension was defined as systolic BP
140 or diastolic BP 90 mm Hg or by being
treated for hypertension. Optimal BP control was defined by BP
<140/90 mm Hg (n=1342), whereas suboptimal BP control was
defined by diastolic BP90 mm Hg (n=210). A random
sample of individuals from the same source populations was also
recruited without regard to their hypertension status. Individuals with
type I diabetes mellitus were excluded. Four of 5 field centers in
HyperGEN participated in the ancillary
echocardiographic study. Study participants were
recruited from previously defined and enumerated population-based
samples, including the Atherosclerosis Risk in
Communities study in Minneapolis and Forsyth County, North Carolina;
the Minnesota Heart Study; and the Utah Health Family Tree Study.
Selected participants from these parent studies previously participated
in the NHLBI Family Heart Study, from which a large proportion of the
hypertensive sibships was sampled for HyperGEN. Of the 2534 adult participants with demographic, anthropometric, and clinical information regarding hypertension and diabetes status who also underwent echocardiography, those whose echocardiogram that did not yield technically satisfactory left ventricular (LV) (3%) or aortic root (0.7%) measurements or had more than mild aortic stenosis were excluded. The study population comprised 2452 subjects, 2096 hypertensive and 361 normotensive subjects, representing 97% of the HyperGEN cohort.
Anthropometric Measurements, Clinical and
Laboratory Data, Medical History
Anthropometric measurements included body mass index,
BSA, percent body fat mass calculated by bioelectric impedance
according to published
methods,10 and fat-free mass
calculated as body weight - fat mass. Overweight was defined as body
mass index 27.3 or 27.8 kg/m2 in women
or men. Fasting serum glucose, lipid, lipoprotein, and
creatinine concentrations were obtained. Diabetes mellitus
was diagnosed by American Diabetes Association
criteria11 or use of
hypoglycemic medication. History of myocardial infarction and use of
antihypertensive medications were defined by participant self-reports.
Duration of hypertension was defined as years from self-reported date
of diagnosis or beginning of antihypertensive treatment or by reviewing
medical documentation.
Echocardiography
Echocardiograms were performed following methods used
in previous studies and centrally read at Cornell Medical
Center.12 13 A
standardized protocol was followed under which the parasternal acoustic
long and short-axis views were used to record on videotape 10
consecutive beats of 2-dimensional and M-mode recordings of the
aortic root and left atrium and of the LV internal diameter and wall
thicknesses at or just below the tip of the anterior mitral leaflet;
color Doppler was used to search for mitral and aortic
regurgitation. The apical window was used to record
10 cycles of 2-, 3-, 4-, and 5-chamber images and color Doppler
recordings to assess LV wall motion and identify mitral and
aortic regurgitation. Mitral anular calcification,
aortic valve fibrocalcification, and bicuspid aortic valve were
identified by visualization of the valves in long- and short-axis
2-dimensional views.
Primary Echocardiographic
Measures
Correct orientation of planes for imaging and
Doppler recordings was verified by standard
procedures.14 LV internal
dimension and septal and posterior wall thicknesses were measured at
end-diastole and end-systole by American Society of
Echocardiography
recommendations,15 averaging
up to 3 cardiac cycles. When optimal orientation of the LV M-mode could
not be obtained, correctly oriented linear dimensions were measured
from 2-dimensional imaging by the leading-edge American Society of
Echocardiography
convention.16 Wall motion
was assessed in parasternal long- and short-axis views and in apical
views, dividing the left ventricle in 5 segments at the base, 5
segments at the level of papillary muscles, and 4 segments at the
apex.17 Echocardiograms were
preliminarily read by a first reader and subsequently over-read by
highly experienced readers who were blinded to subjects’ clinical
data. The aortic annulus and sinuses of Valsalva diameters were
evaluated at end-diastole in anatomically correctly
oriented 2-dimentinal parasternal views, procedures that maximize these
dimensions.2 Annular diameter
was measured from trailing edge to leading edge at the hinging points
of the aortic cusps in parasternal 2-dimentional long-axis view, using
color flow mapping to help delineate tissue-blood interfaces when
necessary; sinuses of Valsalva diameter was measured by the
leading-edge
convention.2
Definition of Dilatation of Aortic Root at
Sinuses of Valsalva
As previously reported, BSA was used to predict
sinuses of Valsalva diameter in 20 to 40 and 40 years age-strata by
published equations.2
Dilatation at sinuses of Valsalva was diagnosed when measured diameter
exceeded the 97.5 percentile of values predicted by subject’s
BSA.2
Derived Measures of LV Structure
End-diastolic LV dimensions were used to
calculate LV mass by a formula yielding values closely related
(r=0.90) to necropsy LV
weight.18 Methods used for
LV measurements have shown excellent reliability of LV mass (intraclass
correlation coefficient=0.93) and good reliability of LV functional
measurements used in this study (intraclass correlation
coefficient=0.61 to 0.71).19
Relative wall thickness, a measure of concentricity of LV geometry, was
calculated as 2xposterior wall thickness/internal dimension.
End-diastolic and end-systolic LV volumes were
calculated by the Teichholz
method20 and validated by
comparison with invasive and Doppler reference
standards.21 22
Ejection fraction was calculated from diastolic and
systolic LV volumes.
Measures of LV Systolic
Function
The primary approach to assess myocardial contractile
efficiency was evaluation of LV systolic midwall shortening in
relation to end-systolic stress measured at the midwall at the
level of the LV minor
axis.23 24
Estimates of end-systolic stress by the described method are
closely related to values calculated by substituting central dicrotic
notch BP that was estimated using applanation tonometry for cuff BP
(r=0.95).23
Midwall shortening and midwall shortening as a percent of the value
predicted for observed end-systolic stress, termed
stress-corrected midwall shortening, were calculated using previously
reported methods.23
Stress-corrected LV chamber function was estimated by the ratio of
end-systolic stress to end-systolic
volume.25
Aortic Valve Function Assessment
Aortic stenosis was identified by detection
of moderately or severely reduced aortic cusp motion and assessment of
valve area by the continuity equation using continuous wave
recordings. Subjects with moderate or severe aortic
stenosis (valve area <0.8
cm2/m2) were
excluded. Color Doppler recordings from parasternal and
apical windows were used to evaluate aortic and mitral
regurgitation.26
Aortic regurgitation was identified on the basis of the
extent of diastolic turbulent flow (color variance signal)
in the LV outflow tract, with mild (1+) aortic
regurgitation when jets occupy <20% of aortic annular
diameter at its origin and extending less than half way to the anterior
mitral leaflet tip; 2+ regurgitation when jets fill
20% to 40% of annular diameter and extending up to the anterior
mitral leaflet tip; 3+ regurgitation when jets occupy
40% to 60% of annular diameter, extending to or slightly beyond the
anterior mitral leaflet tip; and 4+ regurgitation when
jets occupy >60% of annular diameter extending to the posterior LV
wall or more than half way to the LV apex. For jets that were oriented
perpendicular to the aortic annular plane, priority was given to jet
width criteria. Concomitant mitral regurgitation was
assessed by color Doppler regurgitant jet area and depth
criteria.26
Statistical Analyses
Data are reported as mean±SD for continuous
variables or proportions for categorical variables. For
continuous variables, differences between hypertensives and
normotensives and between participants with or without sinuses of
Valsalva dilatation were assessed by
t test for independent samples.
Fisher’s exact test was used in 2x2 cross-tables with estimation of
odds ratio (OR) and 95% confidence intervals (CI).
2 statistics were used for other
cross-tables. ANCOVA was used to assess between-group differences in
body size and composition, controlling for age and gender, and
differences in LV structure and LV systolic function,
controlling for age and BSA. Adjusted means and standard deviations are
shown in tables. Multiple regression analysis was used
to identify independent clinical and echocardiographic
correlates of sinuses of Valsalva diameter. Logistic regression
analysis was used to assess clinical and
echocardiographic correlates (as reported in figures)
of sinuses of Valsalva dilatation, or aortic
regurgitation, using enter procedure. Primary results
concerning aortic regurgitation were confirmed
controlling for an indicator for use of appetite suppressants in 33
individuals (1.4%) (results not shown). Two-tailed
P<0.05 was considered
statistically significant.
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Results |
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Characteristics of Normotensive and Hypertensive Subjects
On average, hypertensives were older (55±11 versus 53±12 years) and predominantly female (61% versus 51%) compared with normotensives (P<0.001). Adjusting for age and gender, hypertensives had higher fat-free mass (54±9 versus 52±9 kg), BSA (1.98±0.23 versus 1.94±0.22 m2), body mass index (31.9±7.0 versus 28.7±5.9 kg/m2), adipose mass (35±14 versus 30±12 kg), and BP, partially by definition, (133/75±22/14 versus 115/66±16/11 mm Hg) (all P<0.01). After adjustment for age and BSA, mean sinuses of Valsalva diameter was marginally larger in normotensive adults than hypertensive adults (34.6 versus 34.1 mm, P=0.02); a further analysis revealed that hypertensives with suboptimal BP control had larger mean sinuses of Valsalva diameter than hypertensives with optimal BP control or normotensives (35.4 versus 33.9 and 34.6 mm, respectively, both P<0.05); hypertensives with optimal BP control had smaller sinuses of Valsalva diameter than normotensives (P<0.05).
In multiple regression analysis, sinuses of Valsalva
diameter was positively related to age (ß=0.26,
P<0.001), male gender
(ß=0.38, P<0.001), BSA
(ß=0.25, P<0.001), presence
of aortic regurgitation (ß=0.26,
P<0.001), and
diastolic BP (ß=0.08,
P<0.001)
(R=0.60,
P<0.001), whereas diabetes did
not enter the model. In a subsequent model, diastolic BP
was substituted by 2 variables, one indicating normotension versus
hypertension and the other indicating subjects with suboptimal BP
control versus others: the model confirmed previous results and showed
independent positive relation of sinuses of Valsalva diameter to
suboptimal BP control
(P<0.005) but not to
hypertension (P=0.9)
(R=0.62,
P<0.001). When duration of
hypertension replaced the variable indicating suboptimal BP control
in the previous model, no independent relation of sinuses of Valsalva
diameter to hypertension or its duration (both
P0.4) was detected
(R=0.61,
P<0.001). An additional
regression analysis showed sinuses of Valsalva diameter to be
related to LV mass (ß=0.16,
P<0.001) independent of
relations to age, gender, BSA, diastolic BP, diabetes, and
aortic regurgitation
(R=0.62,
P<0.001).
Sinuses of Valsalva Dilatation and Aortic
Regurgitation: Prevalences and Correlates
The prevalence of aortic root dilatation in the whole
sample was 4.6%
(Table 1), without differences between hypertensives and
normotensives or between diabetics and nondiabetics. Sinuses of
Valsalva dilatation were associated with male gender and absence of
overweight but not smoking history.
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The prevalence of aortic regurgitation was 6.7% (Table 1) and was associated with absence of overweight, without relations to gender, hypertension, diabetes, or smoking. The prevalence of aortic regurgitation was similar in hypertensives with controlled or uncontrolled BP (6.5 versus 4.3%) (P>0.1).
Clinical and Metabolic Findings in
Subjects With or Without Sinuses of Valsalva Dilatation
Diastolic and mean BPs were higher in
subjects with dilated sinuses of Valsalva, whereas age (56±14 versus
54±11 years, P>0.1),
systolic BP, pulse pressure, and heart rate did not differ
between groups
(Table 2). Medication use and duration of hypertension did
not differ between hypertensive subjects with or without aortic
dilatation. Overall, body mass index, adipose mass, and fat-free mass
were lower in subjects with dilated sinuses of Valsalva independent of
age and gender. Glucose and creatinine levels and
prevalence of self-reported myocardial infarction were comparable
between groups. Total and HDL cholesterol were lower in
subjects with dilated sinuses of Valsalva.
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Sinuses of Valsalva Dilatation, Aortic and
Mitral Annulus Fibrocalcification, and
Regurgitation
Individuals with sinuses of Valsalva dilatation
compared with those without sinuses of Valsalva dilatation had higher
prevalence of mild (1+) (12.5 versus 3.9%) and moderate to severe
(2+) (7.1 versus 2.1%, both
P<0.001) aortic
regurgitation, whereas the prevalence of mitral
regurgitation did not differ between groups (25%
versus 19%, P>0.1). Sinuses
of Valsalva dilatation was associated with aortic valve
fibrocalcification (21.4 versus 11.3%,
P<0.001; age- and
gender-adjusted OR=1.8 and 95% CI, 1.1 to 2.9), but not mitral annular
calcification (12% versus 14%,
P>0.5) or mitral
stenosis (3 subjects, all without aortic dilatation) (all
P>0.1). Bicuspid aortic valve
(n=3) and aortic stenosis (n=6) were detected in subjects with
normal sinuses of Valsalva diameter.
LV Structure and Geometry in Subjects With or
Without Sinuses of Valsalva Dilatation
After adjustment for age and BSA, sinuses of Valsalva
dilatation was associated with larger aortic annular diameter and LV
diameter, thicker LV walls, and higher LV mass, whereas relative wall
thickness did not differ between groups
(Table 3).
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LV Systolic Function in Subjects With
or Without Sinuses of Valsalva Dilatation
Participants with dilated sinuses of Valsalva had lower
ejection fraction and midwall shortening and higher circumferential
end-systolic stress and stroke volume
(Table 3). The circumferential end-systolic
stress/end-systolic volume, afterload-corrected estimate of LV
chamber function, and stress-corrected midwall shortening, estimate of
myocardial contractility, were lower in subjects with
sinuses of Valsalva dilatation. Echocardiographically
detected segmental or global wall motion abnormalities were more than
twice as common in individuals with aortic root dilatation (OR=2.5;
95% CI, 1.5 to 4.1).
To exclude potential confounding by ischemic heart disease, LV systolic function was reanalyzed in subjects without wall motion abnormalities or self-reported myocardial infarction (n=2117; 62% women, 4.1% with sinuses of Valsalva dilatation). In this subgroup, ejection fraction and circumferential end-systolic stress/end-systolic volume were lower in subjects with dilated sinuses of Valsalva (both P<0.001), whereas circumferential end-systolic stress, midwall shortening, and stress-corrected midwall shortening showed trends parallel to those in the primary analysis.
Correlates of Sinuses of Valsalva
Dilatation
In a logistic regression analysis, sinuses of
Valsalva dilatation was associated with male gender, aortic valve
fibrocalcification, and echocardiographic LV wall
motion abnormalities (all
P<0.001) but not with
diastolic BP or other variables considered
(Figure 1).
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Correlates of Aortic
Regurgitation
As seen in
Figure 2, aortic regurgitation was directly
related to sinuses of Valsalva diameter, age, aortic valve
fibrocalcification, and female gender
(P<0.01) and negatively
related to body mass index
(P<0.01), whereas hypertension
did not enter the model. In a subsequent model that included
diastolic BP instead of the categorical variable for
hypertension, aortic regurgitation was directly related
to sinuses of Valsalva diameter, age, aortic valve fibrocalcification,
and female gender (all
P<0.001) and negatively
related to diastolic BP (OR= 0.98/mm Hg; 95% CI, 0.97 to
0.998, P<0.05) and body mass
index (P<0.005). After control
for use of appetite suppressants, aortic regurgitation
was directly related to age, aortic valve fibrocalcification, and
female gender and negatively related to body mass index
(P<0.005) but not to
diastolic BP
(P=0.08).
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Discussion |
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Hypertension and Sinuses of Valsalva Diameter and Aortic Regurgitation
Association of hypertension with aortic root dilatation is controversial.1 2 6 8 In our study in a population-based sample of hypertensives and randomly selected normotensives from the same source, hypertensives were, on average, older and had a higher body mass index and fat-free mass than normotensives. In multivariate models, neither hypertension nor duration of hypertension was significantly related to sinuses of Valsalva diameter. Diastolic BP showed a weak independent direct relation to sinuses of Valsalva diameter but not to the categorical variable indicating dilated sinuses of Valsalva. Sinuses of Valsalva diameter was strongly positively related to aortic regurgitation, which was in turn inversely related to diastolic BP. Therefore, the relation of diastolic BP to sinuses of Valsalva diameter may be mildly stronger than what we found. Moreover, most hypertensives were treated for hypertension, and those with optimal BP control had, on average, mildly smaller aortic root than normotensive subjects. Greater intra-aortic distending pressure in patients with uncontrolled hypertension was associated with larger sinuses of Valsalva, possibly related to dynamic stretch of the aorta caused by that organ’s elasticity. Although our study is cross-sectional, our findings suggest potential benefit of BP control to prevent aortic root enlargement in hypertension. However, the slightly greater sinuses of Valsalva diameter in participants with uncontrolled versus controlled hypertension did not yield more aortic regurgitation in the former group.
Aortic Root Dilatation, Aortic
Regurgitation, and LV Structure and Function
As expected, sinuses of Valsalva dilatation and aortic
regurgitation were strongly related, but hypertension
was not associated with aortic regurgitation, which is
consistent with other
studies.7 8 27 28
However, sinuses of Valsalva diameter was positively related to LV
mass, independent of covariates and aortic
regurgitation, confirming independent relation of
aortic root diameter to LV mass reported in
population29 and
clinical30 studies. The
mechanism of the association between enlargement of the sinuses of
Valsalva and LV mass independent of aortic
regurgitation is uncertain and requires further
investigation.
A new finding was that aortic root dilatation was independently associated with higher likelihood of LV wall motion abnormalities. This finding suggests a previously unrecognized association between aortic root dilatation and coronary heart disease, potentially parallel manifestations of atherosclerosis. In subjects with sinuses of Valsalva dilatation, LV enlargement without parallel increase in LV wall thickness was associated with increased end-systolic stress. Furthermore, the observed increased wall stress and LV mass necessitates increased coronary blood flow.31 However, sinuses of Valsalva dilatation was not significantly associated with self-reported myocardial infarction, suggesting that aortic dilatation may be related to clinically silent ischemic heart disease. Sinuses of Valsalva dilatation was related to lower myocardial contractility, estimated by stress-corrected LV systolic function. Further investigation is needed to verify whether the method used to calculate end-systolic stress may underestimate the "true" afterload in subjects with aortic dilatation, potentially yielding underestimation of stress-corrected LV systolic function in subjects with sinuses of Valsalva dilatation.
Aortic valve fibrocalcification has been found to be positively associated with aortic regurgitation.32 In the present report, we further demonstrate that aortic valve calcification was associated with aortic dilatation and aortic regurgitation independent of covariates including age.
Aortic Root Dilatation, Aortic
Regurgitation, and Body Composition
Adipose mass and fat-free mass were lower in subjects
with sinuses of Valsalva dilatation, independent of age and gender.
Sinuses of Valsalva diameter, age, and aortic valve fibrocalcification
were strong correlates of aortic regurgitation, and
aortic regurgitation was independently negatively
related to body mass index, confirming a recent report from the Strong
Heart Study.32 In the
Framingham Heart Study,28 a
negative relation, albeit insignificant, between the degree of aortic
regurgitation and body mass index was observed. Obesity
may negatively affect echocardiographic study quality,
potentially resulting in underestimation of aortic root diameter and
aortic regurgitation. However, only 0.7% of subjects
had nonmeasurable aortic root diameter. Prospective studies are needed
to evaluate the temporal relation of hypertension and weight change to
aortic dilatation and aortic
regurgitation.
Gender and Aortic
Regurgitation
In multivariate analyses,
aortic regurgitation was more likely in women than in
men, whereas sinuses of Valsalva dilatation was independently
associated with male gender. In the Strong Heart Study, gender was not
related to aortic regurgitation independent of age,
aortic stenosis, or mitral stenosis and higher log
urinary
albumin/creatinine.32
In the Framingham Heart
Study,28 the OR for aortic
regurgitation associated with male gender was 0.6,
adjusted for age, body mass index, and hypertension. Further
investigation is required on the relation of gender to valve
disease.
Conclusions
Uncontrolled hypertension was associated with slightly
larger sinuses of Valsalva diameter, which, however, did not result in
a greater prevalence of sinuses of Valsalva dilatation or aortic
regurgitation compared with groups with controlled BP
or normotensives. Subjects with aortic root dilatation had higher LV
mass, independent of aortic regurgitation, and lower LV
chamber systolic function, independent of overt
ischemic heart disease, which may contribute to increase the
cardiovascular risk associated with hypertension.
Sinuses of Valsalva dilatation was a strong independent correlate of
aortic regurgitation. Further investigation is needed
on the relation of aortic dilatation to ischemic heart disease,
as well as the potential benefit of antihypertensive therapy on the
prevention or reversal of aortic
dilatation.
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Acknowledgments |
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This study was supported in part by grant 5 R01 HL55673 and cooperative agreement grants 5 U10 HL54471, HL 54472, HL54473, HL54496, HL54509, and HL 54515 from the National Heart, Lung, and Blood Institute, Bethesda, Md, and grant M10RR0047-34 (GCRC) from the National Institute of Health, Bethesda, Md. We would like to thank Derek Morgan, Karen Schwander, Bill Howells, and Dawn Fishman for assistance in data management and Virginia Burns for assistance in preparation of the manuscript.
Received July 14, 2000; first decision August 21, 2000; accepted November 7, 2000.
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