© 1998 American Heart Association, Inc.
Original Contributions |
Relation of a Postmortem Renal Index of Hypertension to Atherosclerosis and Coronary Artery Size in Young Men and Women
From the University of Texas Health Science Center at San Antonio (H.C.M., C.A.M.); Louisiana State University Medical Center, New Orleans (R.E.T., M.C.O., J.P.S.); the Southwest Foundation for Biomedical Research, San Antonio, Tex (H.C.M.); The Cleveland Clinic Foundation, Cleveland, Ohio (J.F.C.); and Ohio State University, Columbus (E.E.H.).
Correspondence to Henry C. McGill, Jr, MD, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail jstron{at}lsumc.edu
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Abstract—In a cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth, we measured atherosclerosis of the aorta and right coronary artery (RCA) in 2403 black and white men and women 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories. We measured the diameter of the opened, flattened, and fixed RCA and the diameter, intimal thickness, intimal cross-sectional area, medial thickness, and medial cross-sectional area of the pressure-perfused, fixed left anterior descending (LAD) coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure during life, we classified the cases as normotensive (mean arterial pressure <110 mm Hg) or hypertensive (mean arterial pressure
110 mm Hg).
The prevalence of hypertension by age, sex, and race corresponded
closely with that measured in a survey of the living population.
Hypertension had little or no effect on fatty streaks. Hypertension was
associated with more extensive raised lesions in the abdominal aortas
and RCAs of blacks >20 years of age and in the RCAs of whites >25
years of age. At all ages, women had less extensive raised lesions in
the RCAs than did men, but the effect of hypertension on raised lesions
was similar to that in men. Adjustment for serum lipoprotein
cholesterol levels and smoking in a subset of cases yielded
results similar to those obtained without adjustment. Hypertension was
associated with larger diameters of the RCA and LAD coronary artery and
with larger cross-sectional intimal and medial areas of the LAD
coronary artery. Hypertension augments atherosclerosis
in both men and women primarily by accelerating the conversion of fatty
streaks to raised lesions beginning in the third decade of life, and
the effect of hypertension increases with age.
Key Words: coronary arteries • aorta • atherosclerosis • arterial structure • hypertension
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We have known for a long time that hypertension is associated with the severity of atherosclerosis1 and risk of CHD2 in middle-aged and older adults. Recent angiographic studies, also performed on adults, have shown that hypertension is associated with impaired reactivity of the coronary arteries3 independently of atherosclerosis. Children, adolescents, and young adults demonstrate a wide range of blood pressures,4 5 but it was not known whether elevated blood pressure affected the structure of the coronary arteries or the progression of atherosclerosis in youth.
We addressed these issues in a study of atherosclerosis
among young people, 15 through 34 years of age, in the Pathobiological
Determinants of Atherosclerosis in Youth (PDAY)
study.6 7 Investigators participating in this
multicenter project collected 
3000 sets of coronary
arteries and aortas from young men and women who had died of external
causes (accidents, homicides, and suicides) and had been autopsied in
forensic laboratories. We measured atherosclerotic lesions in these
arteries and measured risk factors in blood and tissue, including blood
pressure estimated from the thickness of the intima of small renal
arteries. Analysis of data from 1164 men showed that
hypertension was associated with more extensive raised lesions, but not
fatty streaks, in both the aorta and RCA.8 The
current report is based on about twice the number of cases, includes
young women as well as men, and extends the observations to the
dimensions of the coronary artery and the coronary
artery wall.
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Study Design
Fifteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and submit them to central laboratories for analysis. A statistical coordinating center received all data pertaining to each case from the collection centers and central laboratories.
Subjects
Study subjects were persons 15 through 34 years of age who had
died of external causes (accidents, homicides, and suicides) within 72
hours after injury and were autopsied within 48 hours after death in 1
of the cooperating medical examiners' laboratories. Age and race were
obtained from the death certificate. Persons of race other than black
or white and those with congenital heart disease, Down syndrome, AIDS,
or hepatitis were excluded. From a total of 3210 cases collected
between June 1, 1987, and August 31, 1994, we excluded 334 cases
because they did not meet the study criteria. Of the 2876 accepted
cases, kidney samples were available for 2833 cases, of which 2145 were
men and 688 were women. All available cases were used to estimate the
prevalence of hypertension. Because we previously reported large
effects of elevated glycohemoglobin on
atherosclerosis,9 we eliminated
107 cases with glycohemoglobin 8% and 323 cases with missing
glycohemoglobin. These exclusions resulted in 2403 cases, of which 1824
were men and 579 were women, for analyses of hypertension,
atherosclerosis, RCA size, and heart weight.
Cases for which serum samples were available were identified for histomorphometry of the LAD coronary artery. After exclusion of specimens with significant branch artifacts or sections that were torn, 1062 cases, of which 798 were men and 264 were women, were available. The Institutional Review Board of each participating center approved the use of tissue, blood, and data from the human subjects in this study.
Dissecting and Preserving Arteries
The forensic pathologist and his assistants removed the aorta
along with other organs. The PDAY team dissected the aorta from a point
2 cm proximal to the ligamentum arteriosum to a point 2 cm distal from
the aortic bifurcation. Branching arteries were severed close to the
aortic wall, and adventitial fat was removed by sharp dissection. The
PDAY team opened the aorta along a line on the dorsal surface midway
between the orifices of the intercostal and lumbar arteries, rinsed the
intimal surface with Hanks' modified balanced salt solution, and
flattened it with the adventitial surface downward. The PDAY team then
split the aorta longitudinally along a line on the ventral surface that
bisected the celiac, superior mesenteric, and inferior
mesenteric ostia; prepared the right half for histochemical and
chemical analyses; and placed the left half on a piece of
cardboard with the adventitia downward. This left half was covered with
absorbent cotton and fixed in 10% neutral buffered formalin in a flat
pan for 48 hours.
The PDAY team opened the RCA from its origin to the point where it turned downward along the posterior interventricular sulcus with the use of blunt-point microdissecting scissors, dissected it from the heart, removed the epicardial fat, and fixed it in the same manner as the aorta. The left main and LAD coronary arteries were fixed by perfusion with 10% neutral buffered formalin under 100 mm Hg pressure.
The collection centers placed each half aorta and RCA in a plastic bag and shipped accumulated tissues to a central laboratory each week. The central laboratory stained the arteries with Sudan IV10 and packaged each artery with its identification number in a transparent plastic bag with a slight excess of 10% neutral buffered formalin.
The collection centers wrapped the left main and LAD coronary arteries in absorbent cotton sufficient to splint but not compress the arteries, suspended them in a screw-top tube with 1% formalin, and shipped them to a central laboratory each week. The central laboratory removed a 5-mm-long segment of the LAD coronary artery just distal to the origin of the circumflex artery, embedded it in paraffin, and sectioned it at 6 µm. Sections were stained with the Gomori's trichrome stain. An adjacent proximal block of the fixed LAD coronary artery was sectioned at 20 µm in the frozen state and stained with ORO, counterstained with Lillie's hematoxylin, and mounted in glycerol jelly.
Height
The length of the cadaver, from the vertex of the cranium to the
base of the heel, was measured in units commonly used by the local
medical examiner or coroner. The measuring instrument was laid parallel
to the body, which was in a supine position and with the
inferior extremities extended. Measurements were
recorded to the nearest centimeter or one-half inch.
Heart Weight and LV Thickness
The prosector weighed the heart to the nearest gram after
removing blood clots and the extraneous proximal aorta and
pulmonary vessels. The PDAY team measured the thickness of the
LV to the nearest millimeter at its obtuse margin halfway between the
mitral valve and apex and also measured the thickness of the right
ventricle at the conus, 1 cm from the pulmonary valve.
Grading Arteries
Pathologists, blinded to demographic, clinical, or pathological
observations and collection site, evaluated the RCAs and left halves of
the aortas. They visually estimated the extent of intimal surface
involved with fatty streaks, fibrous plaques, complicated lesions, and
calcified lesions by procedures developed in the International
Atherosclerosis Project.10 A
fatty streak was a flat or slightly elevated intimal lesion stained by
Sudan IV and without other underlying changes. A fibrous plaque was a
firm, elevated, intimal lesion, sometimes partially or completely
covered by sudanophilic deposits. A complicated lesion was a plaque
with hemorrhage, thrombosis, or ulceration. A calcified lesion
was an area in which calcium was detectable, either visually or by
palpation, and without overlying hemorrhage, ulceration, or
thrombus. The sum of the percentages of surface involved with fibrous
plaques, complicated lesions, and calcified lesions by gross visual
grading was designated "raised lesions." Most of the raised lesions
were fibrous plaques.7 Consensus grading of
lesions was the mean of independent gradings by 3 pathologists.
Intraobserver variability was assessed by repeated independent gradings
of coded specimens randomly interspersed among new specimens. Agreement
among observers was reported previously.7
Morphometry of Coronary Arteries
The morphometry laboratory scanned 35-mm color transparencies of
each Sudan IV–stained RCA at a resolution of 512x256 pixels by 8-bit
gray scale through a green filter, stored the image on a DEC MicroVAX
II computer, and displayed it on a Gould Vicom IP9527 image processing
system. The operator manually identified fiducial points, consisting of
pairs of points 1 cm apart along the outer edges of the opened and
flattened vessel. Using these points, we measured the width of the
opened and flattened RCA in the digitized images at 1-cm intervals,
beginning 1 cm from the proximal end. Because there were a number of
irregular cuts at the origin of the RCA and because many arteries were
not >5 cm long, we used only the measurements at 2, 3, and 4 cm from
the proximal end. Assuming that the artery was circular in cross
section, we computed the approximate diameter from the width
measurements. The mean diameter decreased 8% over this 2-cm interval.
Because analysis of the diameter at 2, 3, and 4 cm yielded
similar results concerning the effects of hypertension, we present
the results of the mean diameter over this entire interval.
The morphometry laboratory scanned the trichrome- and ORO-stained sections of the LAD coronary artery at a resolution of 1024x1024 pixels by 24-bit full color with the use of an Eikonix 78/99 digital scanner and stored and displayed the image on the same system used for the gross images of the RCA. On each image, the operator manually identified the luminal border, the IEL, and the EEL. If the IEL or EEL was broken, the operator drew a smooth curve between the visible ends. The operator then measured the length of the EEL; the cross-sectional areas of the intima and media; and the minimum, maximum, and mean thicknesses of the intima and media. Because some sections of the artery wall were flattened transversely during histological processing, we assumed that the EEL was a circle and calculated the LAD coronary artery diameter and total artery cross-sectional area from the length of the EEL. We computed the cross-sectional area of the lumen by subtracting the measured intimal and medial areas from the calculated arterial cross-sectional area.
Dissecting, Preserving, and Processing Kidney Tissue
The PDAY technicians stripped the kidneys of the capsule and
perirenal fat and bisected them. One section that included the cortex
and medulla from each kidney was fixed in 10% neutral buffered
formalin and shipped to the central laboratory. At the central
laboratory, blocks perpendicular to the capsular surface were embedded
in Paraplast, sectioned at 6 µm, and stained with periodic
acid–Schiff–Alcian blue. The 2 sections represented 2 to
4 cm2 of cross-sectional area of the renal
cortex.
Classification of Hypertension Status
We measured arterial changes associated with
hypertension in histological sections of kidney by a
method developed by Tracy et al.11 The grader
used a microscope equipped with 10x and 40x objective lenses and an
eyepiece ruler marked in units corresponding to 10 µm under the
10x objective lens. The grader measured the outer diameter, from 1
outer media to the other, of the least axis of the elliptical profile
of all arterial profiles with outer diameters of 80 to
300 µm. The grader then measured the thickness of the intima,
also along the least axis, under the 40x lens. The measurement was
made in the better presented of the 2 opposite walls; if both
were equally well presented, a mean of the 2 was used. One
observer measured an average of 36.8 arteries per case (range, 6 to
69). We grouped the measurements into those derived from arteries with
outer diameters of 80 through 149 µm (arteries remote from the
heart) and those derived from arteries with outer diameters of 150
through 300 µm (arteries more proximal to the heart). We
calculated a renal measure of hypertension by dividing the mean
thickness of the intima by the mean outer diameter of the artery
separately for the measurements made on the smaller (remote) arteries
and the measurements made on the larger (proximal) arteries.
We classified each case as normotensive or hypertensive by an algorithm that predicts MAP from the renal measure of hypertension and age.12 (A typographic error in the published equation was corrected by changing the sign for 1 coefficient from positive to negative.) Because young women have lower blood pressures than do young men with similar renal measure of hypertension values, a small adjustment was added to the MAP of women to apply the algorithm to them. The adjusted value was obtained by comparing average blood pressures of young men and women as measured in living populations.13
The normotensive category included cases with a predicted MAP
<110 mm Hg; hypertensive, those with a predicted MAP 110
mm Hg. These cutpoints were selected on the basis of analysis
of lengthy lifetime records of blood pressure measurements in
persons whose kidneys were examined after autopsy. The cutpoints were
similar, but not identical, to MAPs computed from systolic and
diastolic pressures that have been used as cutpoints in
epidemiological surveys. For example, a frequently used definition of
borderline hypertension as a systolic blood pressure between
140 and 160 mm Hg and a diastolic blood pressure
between 90 and 95 mm Hg yields a lower limit for computed MAP
(sum of the systolic plus twice the diastolic
divided by 3) of 107 mm Hg; in contrast, a definition of
hypertension as a systolic blood pressure >160 mm Hg and
a diastolic blood pressure >95 mm Hg yields a limit
for computed MAP of 117 mm Hg. Agreement within and among
observers was reported previously.8
We analyzed the relation of hypertension classification to atherosclerotic lesions by using renal measure of hypertension values derived from proximal and remote arteries separately. The results were similar; therefore, we present only the results based on measurements of the smaller remote arteries.
Statistical Methods
We analyzed by ANOVA14 the
associations of hypertension, sex, race, and 5-year age group with
percent intimal surface area involved with lesions, heart weight, heart
weight-height ratio, ventricle thicknesses, RCA diameter, and LAD
measurements (diameter, cross-sectional area, intimal cross-sectional
area and thickness, medial cross-sectional area and thickness, total
wall cross-sectional area and thickness, ORO-positive area, and percent
of intimal area that was ORO-positive). The linear model included the
main effects of hypertension, sex, race, and 5-year age group and all
2-factor interactions. We applied a logit
transformation15 to the proportion of surface
area involved with lesions and to the proportion of intimal area that
was ORO-positive. A small constant (0.001) was added to avoid the
logarithm of zero. We applied a logarithmic transformation to the heart
weight, heart weight-height ratio, ventricle thickness, and LAD
coronary artery measurements. The prevalence of cases classified as
hypertensive was analyzed using logistic
regression.16
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Prevalence of Hypertension
Table 1
shows the prevalence of
hypertension by sex, race, and 5-year age groups. Hypertension was more
frequent in men than women (P=0.0001) and was more frequent
in blacks than whites (P=0.0002). Prevalence changed with
age (P=0.0304). There was no interaction between sex and
race, sex and age, or race and age in their effects on the prevalence
of hypertension.
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Figure 1 compares the prevalence of
hypertension in PDAY cases with the prevalence observed in the 1976 to
1980 National Health and Nutrition Survey (NHANES
II)17 by sex, race, and age. The PDAY and NHANES
II prevalence rates were significantly different in 2 of the groups
(black men 18 to 24, P=0.0125; white men 25 to 34,
P=0.0267), but the discrepancies were in opposite
directions.
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; white men 25 to 34, 
;
white women 18 to 24, 
; white women 25 to 34, 
; black men 18 to
24, 
; black men 25 to 34, 
; black women, 18 to 24, 
; and black
women 25 to 34, 
.
The prevalence of hypertension in cases with missing glycohemoglobin
was not significantly different from the prevalence in cases with
normal glycohemoglobin. The prevalence of hypertension was higher in
cases with elevated (8%) glycohemoglobin than in cases with normal
glycohemoglobin (hypertension prevalence with elevated glycohemoglobin,
23.4%; with normal glycohemoglobin, 15.3%; P=0.0660), but
the differences in prevalence did not vary significantly with sex,
race, or age. In all subsequent analyses, we excluded cases
with elevated or missing glycohemoglobin values.
Effects of Hypertension on Atherosclerosis
Thoracic Aorta
Hypertension did not affect the extent of fatty streaks, nor were
there interactions of hypertension with sex, race, or age. Hypertension
was associated with more extensive raised lesions
(P=0.0239). The effect of hypertension on raised lesions was
greater in women than men (interaction of sex and hypertension,
P=0.0592) and was greater in blacks than whites (interaction
of race and hypertension, P=0.0013). The effect of
hypertension increased with age (interaction of age and hypertension,
P=0.0009; results not shown).
Abdominal Aorta
Hypertensive women had less extensive fatty streaks than did
normotensive women, whereas hypertensive men had similar involvement
(interaction of hypertension and sex, P=0.0608; Figure 2).
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, SE.
Black hypertensives had more extensive raised lesions than did black
normotensives, whereas there was little effect of hypertension in
whites (interaction of race and hypertension, P=0.0006;
Figure 3). The effect of hypertension on
raised lesions increased with age (interaction of age and hypertension,
P=0.0051).
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RCA
Hypertension did not affect fatty streaks in men, but hypertensive
women had less extensive fatty streaks than did normotensive women
(Figure 4) (interaction of hypertension
and sex, P=0.0749). There were no interactions of
hypertension with race or age.
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Hypertension increased the extent of raised lesions
(P=0.0253), and the effect increased with age (interaction
of age and hypertension, P=0.0012; Figure 5). There was no interaction of
hypertension with sex (P=0.3266). The effect of hypertension
was slightly, but not significantly, greater in blacks than whites
(interaction of race and hypertension, P=0.1240). Raised
lesions in both normotensive and hypertensive women lagged 5 years
behind those in normotensive and hypertensive men, respectively.
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We examined a subset of cases in which serum lipoprotein cholesterol and thiocyanate (an indicator of smoking) levels were measured.18 Adjustment for VLDL+LDL and HDL cholesterol levels and smoking status yielded similar results for the effects of hypertension (results not shown).
Hypertension Effect on Heart Weight and Ventricular
Thickness
Figure 6 shows the heart weight by
age, sex, race, and hypertension. There was an interaction of age and
hypertension (P=0.0012). In the 15- to 19-year age group,
hypertensive individuals had lower heart weights than did normotensive
individuals (P=0.0015). In contrast, hypertensive
individuals >age 20 had higher heart weights than did normotensive
individuals (P=0.0312). Similar relationships resulted when
the heart weight-height ratio was compared; among persons 15 to 19
years, hypertensives had lower ratios than did normotensives; in
contrast, among persons 20 years and above, hypertensives had higher
ratios (results not shown). Hypertension did not affect the thickness
of the right ventricle or LV (results not shown).
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Hypertension Effect on Coronary Artery Diameter
Hypertension was associated with a greater mean diameter (measured
on the opened and flattened artery) of the RCA (P=0.0128;
Figure 7). The effect was similar in
women and men (interaction of sex and hypertension,
P=0.1276), in blacks and whites (interaction of race and
hypertension, P=0.7697), and in all age groups (interaction
of age and hypertension, P=0.3267).
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Hypertension was also associated with a greater mean diameter (computed
from the length of the EEL measured in the cross-section of the
perfused, fixed specimen) of the LAD coronary artery
(P=0.0005; Figure 8). The
effect of hypertension was greater among women than among men
(interaction of sex and hypertension, P=0.0193) but was
similar in blacks and whites (interaction of race and hypertension,
P=0.7339) and in all age groups (interaction of age and
hypertension, P=0.5353).
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Hypertension Effect on Area and Thickness of LAD
Coronary Artery Intima
Hypertension was associated with a slightly larger intimal area of
the LAD coronary artery (P=0.0810; Figure 9), and the effect was similar in both
races and both sexes. There was no effect of hypertension on mean,
maximum, or minimum intimal thickness (results not shown).
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Hypertension Effect on Area and Thickness of LAD
Coronary Artery Media
Hypertension was associated with a larger cross-sectional medial
area of the LAD coronary artery (P=0.0105; Figure 10) but not with any difference in
mean, maximum, or minimum medial thickness (results not shown).
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Hypertension Effect on LAD Coronary Artery Total
Wall Area
The cross-sectional total wall area was larger in hypertensive men
and women than in normotensive men and women at all ages
(P=0.0367; results not shown). The effect of hypertension on
total wall area represents the combined effect of hypertension
on the intimal area (Figure 9
) plus its effect on the medial area
(Figure 10). Hypertension did not affect the mean, minimum, or maximum
wall thickness (results not shown).
Hypertension Effect on Lumen Area
Hypertension was associated with a larger lumen area of the LAD
coronary artery (Figure 11) in
women but not in men (interaction of sex and hypertension,
P=0.0019).
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Hypertension did not affect the ratio of intimal area to potential
arterial lumen (area enclosed within the IEL, ie,
"stenosis"; P=0.7004, results not shown); but
there was a trend, not statistically significant (interaction of sex
and hypertension, P=0.1056), for the ratio to be greater in
hypertensive men than in normotensive men, whereas the reverse was true
in women. This trend was consistent with the greater effect of
hypertension on the LAD coronary artery diameter in women than
in men (Figures 7 and 8).
Hypertension Effect on ORO-Stained Intimal Area
Hypertension was associated with a larger cross-sectional intimal
area stained with ORO (P=0.0795) in both sexes and both
races (results not shown). When expressed as a percent of intimal area
stained with ORO, the effect of hypertension was not significant
(P=0.1630).
Relation of LAD Variables to RCA Gross Lesions
All measures of intimal involvement in cross sections of the LAD
coronary artery were positively correlated with the percentage
of surface involved with fatty streaks and raised lesions in the RCA.
The correlations were stronger with raised lesions (Table 2).
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Summary of Results
Between the ages of 15 and 19 years, hypertension, as indicated by the intimal thickness of small renal arteries, does not affect raised lesions of the abdominal aorta or the RCA. Between ages 20 and 34 years, hypertension is associated with more extensive raised lesions in the abdominal aorta of blacks and with raised lesions of the RCA in both blacks and whites. The effect of hypertension increases with age. Hypertension affects raised lesions similarly in women and men.
Hypertension is associated with a larger diameter of the RCA and LAD coronary artery and with greater intimal and medial cross-sectional areas of the LAD coronary artery between the ages of 15 and 34 years. The greater cross-sectional areas of the intima and media are due to the larger diameter of the artery and not to a greater thickness of either the intima or media.
Validity of Hypertension Assessment
Despite the differences in populations, time at which observations
were made, and methods of assessing hypertension, the prevalence rates
reported by NHANES II17 are remarkably similar to
those reported here. The greater heart weight and greater
coronary artery diameter in cases classified as hypertensive
also support the validity of this method of assessing hypertension.
Hypertension and Atherosclerosis
Results from these 1824 men and 579 women confirm and extend the
previous results based on data for 1164 men8 and
are consistent with findings from the limited number of cases
examined in the Bogalusa Heart Study, in which blood pressure was
measured before death.19 20 The effect of
hypertension on atherosclerosis is principally to
accelerate the formation of raised lesions rather than fatty streaks.
The excess of raised lesions begins to appear at 25 years of age
(Figures 3 and 5). Furthermore, the multiplicative effect of
hypertension on raised lesions (ie, the ratio of the extent of raised
lesions in hypertensive persons to the extent in normotensive persons)
increases with age (significant interaction of age and hypertension).
By the beginning of the fourth decade, hypertensive subjects have
approximately double the extent of raised lesions in their
coronary arteries as do normotensive subjects.
These results do not provide information about physiological mechanisms by which hypertension produces this effect, but they indicate that the search for mechanisms should focus on those involved in the progression of fatty streaks to raised lesions.
Interaction of Hypertension With Sex
The lesser extent of fatty streaks in the abdominal aortas and
RCAs of hypertensive women compared with that in normotensive women
(Figures 2 and 4) may be accounted for by the greater extent of raised
lesions in hypertensive women in the 30- to 34-year age group (Figures 3 and 5), but raised lesions do not explain the differences in fatty
streaks in younger age groups. Although the excess of fatty streaks in
normotensive women was statistically significant in both arteries
(interaction of hypertension and sex, P=0.0608 for abdominal
aorta; P=0.0749 for RCA), the number of young hypertensive
women was small (Table 1), and we do not believe that this unexpected
result should be considered conclusive.
The multiplicative effect (see above) of hypertension on raised lesions
in the abdominal aorta and RCA is similar in women and men (Figures 3 and 5; interaction of sex and hypertension was not significant). In the
abdominal aorta, the extent of raised lesions is similar in men and
women. In the RCA by age 30 to 34 years, hypertensive women have about
the same extent of raised lesions as do normotensive men and about half
the extent of raised lesions as do hypertensive men. Thus, the
protection from advanced atherosclerosis enjoyed by
women does not attenuate the effect of hypertension. The effects of
hypertension on raised lesions in young men and women parallel closely
the effects of hypertension on CHD events among middle-aged and elderly
men and women.21 22 23 CHD events in adult men were
about twice as high in hypertensive as in normotensive men and about
twice as high in hypertensive as in normotensive women; events in
hypertensive men and in normotensive men were each about twice as high
as those in hypertensive women and in normotensive women,
respectively.
Interaction of Hypertension With Race
The higher frequency of hypertension in blacks than in whites is
well established17 and is again demonstrated in
these cases (Table 1). The multiplicative effect of hypertension on
raised lesions in the RCA of blacks is similar to that in whites
(Figure 5; interaction of race and hypertension is not significant),
but the multiplicative effect of hypertension on raised lesions of the
abdominal aorta is much greater in blacks, both men and women, than in
whites (Figure 3; interaction of race and hypertension,
P=0.0006). Smoking selectively affects raised lesions of the
abdominal aorta, but the prevalence of smoking in these cases is lower
in blacks than in whites,18 a difference that
would produce the opposite effect. We examined the effects of
hypertension in PDAY cases for which smoking status was ascertained and
found that hypertension had the same effect on abdominal aortic raised
lesions in smokers and nonsmokers.
Categories 441 to 448 ("Other diseases of arteries, arterioles, and capillaries") of the US Mortality Statistics include aortic aneurysm and peripheral arterial disease. Mortality rates for these categories in 199024 were higher in white men and women than in black men and women. An extensive literature search disclosed no more detailed data comparing the incidence, prevalence, or mortality related to atherosclerosis of the abdominal aorta among blacks and whites. This topic deserves further exploration.
Validity of Coronary Artery Size Measurements in
Postmortem Arteries
Dodge et al25 measured the diameters of
coronary arteries free of atherosclerotic lesions from
angiograms in 60 men and 10 women (mean age, 45 years), all of whom
were normotensive. In men, the lumen of the proximal LAD
coronary artery measured 3.6 or 3.8 mm in diameter,
depending on whether the right or left artery was dominant. Our
measurement of the lumen diameter of the pressure-perfused and fixed
LAD coronary artery (computed from the cross-sectional area of
the lumen, assuming it was circular) of normotensive 30- to 34-year-old
men was 3.0 (SE, 0.05) mm. It was not feasible to assess right or
left dominance.
The proximal segments of RCAs of men25 measured 2.8 or 3.9 mm in diameter, depending on right or left dominance. Our measurement of the diameter of the RCA (computed from the width of the opened, flattened, and fixed artery, assuming it was circular) of normotensive 30- to 34-year-old men was 2.4 (SE, 0.03) mm.
The arteries of normotensive women measured in angiograms were 9% smaller than those of men.25 In PDAY cases, the diameter of the LAD coronary arteries of women averaged 13.6% less, and the diameter of the RCAs of women averaged 15.8% less, than those of men.
In 16 middle-aged men and women with no risk factors for CHD and no
coronary atherosclerosis, the mean diameter of
the proximal LAD coronary artery measured by intravascular
ultrasound was 4.2 mm and of the midportion of the LAD
coronary artery, 3.5 mm.26 The
measures were 10% less during diastole than during
systole.
Because arteries are likely to collapse after death and because fixation causes tissues to shrink, possibly more in the unperfused RCAs than in the pressure-perfused LAD coronary arteries, these measures of postmortem-fixed tissues are smaller than corresponding measures during life. However, they probably reflect accurately the differences in coronary artery dimensions during life. Furthermore, our oldest age group was younger than the subjects studied during life.
Hypertension and Coronary Artery Size
Echocardiographic studies of the carotid artery
have shown that its diameter is increased in
hypertension.27 28 29 Three comparisons of
coronary artery reactivity in hypertensive subjects with that
in normotensive subjects showed a trend for coronary artery
diameter in hypertensives to be greater in the basal state, but the
numbers of subjects in each study were not large enough for the trend
to be statistically significant.3 30 31
The coronary arteries of hypertensive subjects showed loss of coronary vasodilator reserve, even when myocardial mass was not increased32 ; loss of flow-dependent dilatation30 ; either impaired vasodilator response to acetylcholine33 34 35 or vasoconstriction in response to acetylcholine3 36 ; and depressed bioavailability of NO.37
The current findings show that hypertension is associated with a larger
RCA (Figure 7), a larger LAD coronary artery (Figure 8), a
larger LAD intimal cross-sectional area (Figure 9), and a larger LAD
medial cross-sectional area (Figure 10). The lumen is not enlarged in
hypertensive men but is enlarged in hypertensive women (Figure 11;
interaction of sex and hypertension, P=0.0019). These
effects of hypertension on coronary artery size are
consistent with many other observations from humans and
experimental animals showing that hypertension alters the structure and
composition of large elastic and muscular
arteries38 and also increases
arterial stiffness.39
Coronary artery distention is consistent with the
increased arterial stiffening observed with hypertension. A
10-mm Hg difference in blood pressure was also associated with
increased stiffness of the carotid arteries of 13-year-old
children.40 Results reported here show that
enlargement of the coronary artery begins at least by 15 to 19
years of age (Figures 7 through 10), and possibly earlier, before
cardiac hypertrophy occurs (Figure 6) and before there is
an effect of hypertension on raised lesions (Figure 5).
Limitations of this Study
The selection of cases entered into this study was influenced by
policies of the medical examiner or coroner, local laws, and other
circumstances that influenced which deaths were autopsied and which
could be used for research. Societal factors and individual
characteristics that influence vulnerability to homicide, suicide, and
accidents also affected inclusion in this study. Previous
analyses of these cases have shown consistent
associations of atherosclerosis with risk factors
across cause of death categories.18 Therefore,
despite the potentially biased sample, we conclude that the effects of
hypertension on arterial structure and atherosclerotic
lesions represent those that exist in the living population of
young persons.
Implications for Clinical and Public Health Medicine
Hypertension begins to affect coronary artery structure
during the teenage years, nearly a decade before hypertension begins to
affect the advanced lesions of atherosclerosis. These
changes indicate that the altered reactivity of coronary
arteries demonstrated in older hypertensive persons probably is also
present in young persons. Although we doubt that anyone would
recommend antihypertensive drug therapy for moderately elevated blood
pressure in teenagers or young adults, these results strengthen the
case for control of elevated blood pressure in youth by hygienic
measures (weight control, physical activity, and salt restriction) as a
long-range strategy for preventing irreversible coronary artery
changes, retarding the progression of atherosclerosis,
and deferring the onset of clinically manifest CHD.
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Selected Abbreviations and Acronyms |
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
the PDAY Research Group
The investigators cooperating in the multicenter study, The Pathobiological Determinants of Atherosclerosis in Youth" and the grants supporting their activities are listed below.
Program Director
Jack P. Strong, MD, 1996 to present; Robert W. Wissler,
PhD, MD, 1985 to 1996.
Steering Committee
J. Fredrick Cornhill, DPhil; Henry C. McGill, Jr, MD; C.
Alex McMahan, PhD; Gray T. Malcom, PhD; Margaret C. Oalmann, DrPH; Jack
P. Strong, MD; and Robert W. Wissler, PhD, MD.
Participating Centers, Principal Investigators, Coinvestigators,
and Supporting Grants from the National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Md
University of Alabama, Birmingham
Department of Medicine: Steffen Gay, MD (HL-33733);
Department of Biochemistry: Edward J. Miller, PhD (HL-33728).
Albany Medical College, Albany, NY
Assad Daoud, MD, and Adriene S. Frank, PhD (HL-33765).
Baylor College of Medicine, Houston, Tex
Louis C. Smith, PhD (HL-33750).
University of Chicago, Chicago, Ill
Robert W. Wissler, PhD, MD; Dragoslava Vesselinovitch, DVM,
MS; Akio Komatsu, MD, PhD; Yoshiaki Kusumi, MD; Toshinori Oinuma, MD;
Alyna Chien, MA; Alexis Demopoulos, MD; Gertrud Friedman, BA; R.
Timothy Bridenstine, MS; Robert J. Stein, MD; Robert H. Kirschner, MD;
Manuela Bekermeier, ASCP; Blanche Berger, ASCP; and Laura Hiltscher,
ASCP (HL-33740, HL-45715).
University of Illinois, Chicago
Abel L. Robertson, Jr, MD, PhD; Robert J. Stein, MD; Edmund
R. Donoghue, MD; Robert J. Buschmann, MD; and Yoshihisa Katsura, MD
(HL-33758).
Louisiana State University Medical Center, New Orleans
Jack P. Strong, MD; Gray T. Malcom, PhD; William P. Newman
III, MD; Margaret C. Oalmann, DrPH; Richard E. Tracy, MD, PhD;
Sulochana Y. Bhandaru, MD, MPH; Cynthia S. Zsembik, BS; DeAnne G.
Gibbs, BS; and Dana A. Troxclair, MS (HL-33746, HL-45720).
University of Maryland, Baltimore
Wolfgang Mergner, MD, PhD; Catherine Cole, PhD; and J.
Smialek, MD (HL-33752, HL-45693).
Medical College of Georgia, Augusta
A. Bleakley Chandler, MD; Raghunatha N. Rao, MD; D. Greer
Falls, MD; Ross G. Gerrity, PhD; Benjamin O. Spurlock, BA; Kalish B.
Sharma, MD; and Joel S. Sexton, MD (HL-33772).
University of Nebraska Medical Center, Omaha
Bruce M. McManus, MD, PhD, and Jerry W. Jones, MD
(HL-33778).
Ohio State University, Columbus
J. Fredrick Cornhill, DPhil; William R. Adrion, MD; Patrick
M. Fardel, MD; Brian Gara, MS; Edward Herderick, BS; and Larry R. Tate,
MD (HL-33760, HL-45694).
Southwest Foundation for Biomedical Research, San Antonio, Tex
James E. Hixson, PhD (HL-39913).
University of Texas Health Science Center at San Antonio
C. Alex McMahan, PhD; Henry C. McGill, Jr, MD; Yolan
Marinez, MA; and Thomas J. Prihoda, PhD (HL-33749, HL-45719).
Vanderbilt University, Nashville, Tenn
Renu Virmani, MD; James B. Atkinson, MD, PhD; and Charles
W. Harlan, MD (HL-33770, HL-45718).
West Virginia University Health Sciences Center, Morgantown
Singanallur N. Jagannathan, PhD, and James Frost, MD
(HL-33748).
|
Footnotes |
|---|
Reprint requests to Jack P. Strong, MD, Louisiana State University Medical Center, 1901 Perdido St, New Orleans, LA 70112-1393.
Received December 4, 1997; accepted January 28, 1998.
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