© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effects of Coronary Heart Disease Risk Factors on Atherosclerosis of Selected Regions of the Aorta and Right Coronary Artery
From the University of Texas Health Science Center at San Antonio (H.C.M., C.A.M.); the Southwest Foundation for Biomedical Research (H.C.M.), San Antonio; Ohio State University (E.E.H.), Columbus; and the Louisiana State University Medical Center (R.E.T., G.T.M., A.W.Z., J.P.S.), New Orleans.
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
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—We examined topographic distributions of atherosclerosis and their relation to risk factors for adult coronary heart disease in right coronary arteries and abdominal aortas of more than 2000 autopsied persons 15 through 34 years of age. We digitized images of Sudan IV–stained fatty streaks and of manually outlined raised lesions and computed the percent surface area involved by each lesion in each of 6 regions of each artery. In abdominal aortas of 15- to 24-year-old persons, fatty streaks involve an elongated oval area on the dorsolateral intimal surface and another oval area in the middle third of the ventral surface. Raised lesions in 25- to 34-year-old persons involve an oval area in the distal third of the dorsolateral intimal surface. In other areas of the abdominal aortas of older persons, fatty streaks occur but raised lesions are rare. In the right coronary arteries of 15- to 24-year-old persons, fatty streaks are most frequent on the myocardial aspect of the first 2 cm. Raised lesions follow a similar pattern in 25- to 34-year-old persons. High non-HDL cholesterol and low HDL cholesterol concentrations are associated with more extensive fatty streaks and raised lesions in all regions of both arteries. Smoking is associated with more extensive fatty streaks and raised lesions of the abdominal aorta, particularly in the dorsolateral region of the distal third of the abdominal aorta. Hypertension is not associated with fatty streaks in whites or blacks but is associated with more extensive raised lesions in blacks. Risk factor effects on arterial regions that are vulnerable to lesions are
25% greater than risk factor
effects assessed over entire arterial segments. These risk
factor effects on vulnerable sites emphasize the need for risk factor
control during adolescence and young adulthood to prevent or delay the
progression of atherosclerosis.
Key Words: atherosclerosis • aorta • coronary artery • topography • risk factors
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Atherosclerosis follows a distinctive topographical distribution in the intimal surface of each affected artery. Hypotheses explaining the localization of atherosclerotic lesions include hemodynamic stresses related to arterial geometry1 2 3 4 ; anatomic, cellular, or biochemical variations in the arterial wall, particularly in endothelium5 ; smooth muscle cell mutations leading to monoclonal proliferation6 ; and infectious agents.7
Most of the established major risk factors for coronary heart disease are associated with the extent of both fatty streaks and raised lesions in the large muscular and elastic arteries of adults8 and also in arteries of adolescents and young adults.9 10 11 The magnitude of the effect of each risk factor varies among the arterial beds: for example, hypertension selectively augments atherosclerosis of the cerebral arteries,8 whereas smoking selectively augments atherosclerosis of the abdominal aorta and the iliac and femoral arteries.12 Although the prevailing opinion is that raised lesions (fibrous plaques and the other advanced lesions of atherosclerosis) arise from fatty streaks,13 dissimilarities in their topographical distributions are cited as evidence against that relationship.14 For example, fatty streaks are prevalent in the thoracic aortas of children and adolescents, but raised lesions rarely appear in the thoracic aortas of adults.15 These observations, together with the identification of lesion-prone and lesion-resistant intimal areas within each artery,16 suggest that the risk factors may affect regions selectively within an artery as well as between different arteries.
The multicenter cooperative study Pathobiological Determinants of
Atherosclerosis in Youth (PDAY)17
collected arteries and risk factor measurements from 3000 young
persons. The age range of these persons, 15 through 34 years, spans the
period during which fatty streaks are well established and raised
lesions begin to appear. We previously have shown associations of the
serum lipoprotein cholesterol concentrations, smoking, and
hypertension with atherosclerosis in the abdominal
aorta and right coronary artery (RCA) in these young
persons.9 10 11 In this report, we examine the associations
of the risk factors with atherosclerosis measured by
computerized image analysis in regions of the abdominal aorta
and the RCA.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Design
Fifteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and data and to 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,
inclusive, who died of external causes (accidents, homicides, 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. We collected 3210 cases
from June 1, 1987, to August 31, 1994. Of these, 334 did not meet the
study criteria. Of the 2876 accepted cases, we used 4 subsets in the
analyses to be reported here (Table 1
). Multiple subsets enabled us to
match the case selection criteria used in previous PDAY reports of risk
factor effects on atherosclerosis in an entire
arterial segment. Subjects with elevated glycohemoglobin
(
8%) indicative of diabetes or impaired glucose tolerance were
excluded in these analyses. Fifty-two percent of the PDAY cases
were black, and 76% were men.
|
The Institutional Review Board of each participating center approved the use of tissue, blood, and data from the human subjects in this study.
Dissection and Preservation of Arteries
The aorta was dissected from a point 2 cm proximal to the
ligamentum arteriosum to a point 2 cm distal to the iliac bifurcation.
The aorta was opened along a line on the dorsal surface midway between
the orifices of the intercostal and lumbar arteries, the intimal
surface was rinsed with Hanks’ modified balanced salt solution (HBS),
and the vessel was flattened with the adventitial surface downward. The
aorta was then split longitudinally along a line on the ventral surface
that bisected the celiac, superior mesenteric, and inferior
mesenteric ostia; the right half was prepared for chemical
analyses; the left half was placed on cardboard with the
adventitia downward. The left half was covered with absorbent cotton
and fixed in 10% neutral buffered formalin for 48 hours.
The RCA was opened along the epicardial surface from its origin to the point at which it turned downward along the posterior interventricular sulcus with blunt-point microdissecting scissors. It was then dissected from the heart, the epicardial fat was removed, the intimal surface was rinsed with HBS, and the RCA was fixed in the same manner as the aorta. The left coronary artery and its branches were prepared for other studies.
Each aorta and RCA was placed in a plastic bag with 10% formalin at the collection center, and accumulated tissues were shipped to the central laboratory each month. The central laboratory stained the arteries with Sudan IV and packaged each artery with its identification number in a transparent plastic bag with a slight excess of 10% formalin.18
Grading Atherosclerosis by Pathologists
Three pathologists independently estimated the percentage of the
intimal surface area involved with fatty streaks and raised lesions in
the left half of the aorta and in the entire RCA. The consensus lesion
grade was the average of the grades of 3 pathologists. A fatty streak
was an intimal area stained by Sudan IV without other underlying
changes. A raised lesion was a firm, elevated intimal lesion, sometimes
partially or completely covered by sudanophilic deposits. Raised
lesions rarely included an area of hemorrhage, thrombosis,
ulceration, or calcification.
Grading Atherosclerosis by Computerized Image
Analysis
To assess the extent of fatty streaks, the morphometry
laboratory scanned 35-mm color transparencies of each Sudan IV–stained
RCA and each aorta 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 by use of
anatomic landmarks in the aorta and pairs of points 1 cm apart along
the outer edges of the RCA. An algorithm converted each image into a
standard template of the artery.
When any 1 of 3 pathologists classified an artery (either the abdominal aorta or the RCA) as positive for raised lesions, the artery was photographed and a black-and-white print was prepared. A designated pathologist, while examining the artery, outlined with a black pen on the photograph the intimal area he believed to be occupied by a raised lesion. A second designated pathologist examined the same artery and photograph; if he agreed with the marking, it was left unchanged. If he disagreed, he outlined his assessment of the raised lesions, and a third pathologist resolved the difference. Thus, the area designated as raised lesion was confirmed visually by 2 pathologists. The morphometry laboratory scanned the final marked print and converted the image into the same standard template as that used for fatty streaks.
An algorithm computed the fraction of pixels in the image of each
artery (or each defined region of the artery) involved by Sudan IV
staining (fatty streaks) or by pathologists’ identification of raised
lesions. The fraction of involved pixels was taken to represent
the percent of intimal surface involved by each type of lesion. The
prevalence of lesions at each pixel location was also displayed in maps
by banded isopleths. Regional measurements of the abdominal aorta were
computed only for cases with a complete abdominal aorta, and regional
measurements of the RCA were computed only for cases with an RCA of 6
cm.
Agreement Between Pathologists’ Consensus and Results From
Image Analyses
We compared the extent of involved surface area derived from the
consensus of 3 pathologists with the involved surface area computed by
image analysis. Intraclass correlation coefficients describing
the agreement were 0.90 for abdominal aortic fatty streaks, 0.93 for
abdominal aortic raised lesions, 0.79 for RCA fatty streaks, and 0.94
for RCA raised lesions.
Definition of Regions
By examining color prints of composite images of arteries with
fatty streaks and of composite images of the same arteries with raised
lesions, we identified regions that corresponded to the distribution
patterns of lesions. Figure 1 shows the
outline of the left half of the abdominal aorta divided into 6 regions
by 2 lines along the long axis and 3 lines perpendicular to the long
axis. A narrow strip at the dorsal edge was excluded to avoid the
orifices of the lumbar arteries. In preliminary studies, we ascertained
that the left and right halves of the abdominal aorta were approximate
mirror images of one another. Figure 2
shows the RCA divided into 6 regions at 1-cm intervals, beginning at
the origin.
|
|
Blood
Blood collected at autopsy from the aorta, heart, or vena cava
was centrifuged. Frozen serum and cells were shipped to the
central laboratory for analysis.
Lipoprotein Cholesterol
We measured total serum cholesterol and HDL
cholesterol (HDL-C) after precipitation of other
lipoproteins with heparin MnCl2 by the
cholesterol oxidase method.19 The coefficient
of variation for blind duplicate analyses of serum
cholesterol was 1.3%; for HDL-C, it was 5.2%. The
non-HDL-C concentration was obtained by subtraction.
Triglyceride concentrations in these postmortem serum
samples could not be interpreted because we could not ascertain the
prandial status, and therefore, LDL was not calculated. Several studies
have demonstrated that postmortem levels of serum
cholesterol and lipoproteins are
representative of premortem levels.20 21
However, because emergency medical teams often administer large
quantities of intravenous fluids to some individuals
immediately before death from violent causes, we excluded all serum
values from the statistical analysis when serum
cholesterol was <2.59 mmol/L (100 mg/dL).
In the statistical analyses for effects of lipoprotein cholesterol concentrations on atherosclerosis, we used the definitions of upper and lower thirds of non-HDL-C and of HDL-C established in the 1443 cases previously reported.11 Low non-HDL-C was <2.79 mmol/L (108 mg/dL); high was >3.88 mmol/L (150 mg/dL). Low HDL-C was <1.11 mmol/L (43 mg/dL); high was >1.55 mmol/L (60 mg/dL).
Thiocyanate
We measured color produced by the thiocyanate–ferric nitrate
complex after treatment of trichloroacetic acid filtrates of serum with
ferric nitrate.22 The coefficient of variation for blind
duplicate analyses was 5.5%. A smoker was defined as having a
serum thiocyanate level 90 µmol/L. Forty-five percent of PDAY
cases were classified as smokers.
Glycohemoglobin
We measured glycohemoglobin by affinity column
chromatography.23 Values 8% were
defined as elevated.24 An elevated glycohemoglobin
concentration 8% corresponds to an average blood glucose
concentration of 8.3 mmol/L (150 mg/dL) for the previous 2 or
3 months.
Estimation of Blood Pressure
We measured the thickness of the intima of small renal arteries
in histological sections of kidney. Using a method
developed by Tracy et al,25 we classified each case as
normotensive or hypertensive by an algorithm that predicted mean
arterial pressure (MAP) from the renal measurements and
age. Details of the application of this method to PDAY specimens were
described in previous publications.10 26
The normotensive category included cases with a predicted MAP
<110 mm Hg; those with predicted MAP 110 mm Hg were
classified as hypertensive. The prevalence of hypertension was 12%
among whites and 18% among blacks. The prevalence of hypertension by
race, sex, and age determined in PDAY cases by this method corresponded
well with prevalence reported from a survey of a living
population.10
Statistical Methods
We analyzed the associations of sex, race, 5-year age
group, third of non-HDL-C, third of HDL-C, smoking status, and
hypertension status with the percentage of arterial intimal
surface involved with lesions in the defined regions of the abdominal
aorta and RCA by use of multivariate
ANOVA.27 The linear model included main effects and
2-factor interactions. We applied a logit transformation to the
proportion of surface area involved with lesions to better satisfy the
assumptions underlying the statistical analysis.28
A small constant was added to avoid the logarithm of zero.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Race Effects on Atherosclerosis by Region
Blacks have more extensive fatty streaks than whites in regions 1 and 2 of the abdominal aorta (P<0.0038) and in regions 3 through 6 of the RCA (P<0.0037) (results not shown). In regions 1 and 2 of the RCA, white and black men have similar involvement with fatty streaks, whereas black women have more extensive involvement than white women (interaction of sex and race, P<0.0184) (results not shown). Subsequent results regarding risk factor effects, except for those associated with hypertension, are adjusted for race.
Abdominal Aorta: Distribution of Fatty Streaks and Raised Lesions
by Region, Age, and Sex
Figure 1
shows, by 5-year age groups and sex, maps of the
prevalence of fatty streaks (left) and of raised lesions (right) in the
abdominal aorta. Superimposed on the maps are outlines of the 6
regions. In younger persons (15 to 24 years of age), fatty streaks are
concentrated in an elongated oval area on the dorsolateral intimal
surface of the abdominal aorta, filling regions 1, 3, and 5, and in
another elongated oval area on the ventrolateral intimal surface
filling region 4. The prevalence of fatty streaks is less in region 5
in the 30- to 34-year age group than in the 25- to 29-year age group
because this area becomes heavily involved with raised lesions. Raised
lesions (right) appear to an appreciable degree in the 20- to 24-year
age group in region 5, and in older persons, they remain concentrated
in region 5 and extend into adjacent regions 3, 4, and 6.
The extent of fatty streaks changes with age in all regions (P=0.0001). In all regions except regions 2 and 6, the extent of fatty streaks either declines or remains unchanged in the older groups, reflecting the replacement of fatty streaks by raised lesions. The extent of raised lesions increases with age in all regions (P=0.0001). Region 5 has the most extensive raised lesions (P=0.0001); regions 3, 4, and 6 are similar in extent of raised lesions, and regions 1 and 2 have little involvement with raised lesions.
In the abdominal aorta, women have more extensive fatty streaks in all regions except region 2 (P=0.0001). Men and women have similar involvement with raised lesions in all regions, although older women have more extensive raised lesions than men in regions 1 and 4 (interaction of sex and age, P<0.0369).
RCA: Distribution of Fatty Streaks and Raised Lesions by Region,
Age, and Sex
Figure 2 shows maps of the prevalence of fatty streaks
(left) and of raised lesions (right) in the RCA by 5-year age group and
sex. Superimposed on the maps are outlines of the 6 regions. Fatty
streaks (left) in younger persons (15 to 24 years of age) form a
pattern with an area of high prevalence near the origin (regions 1 and
2), another area of high prevalence at the midpoint (region 4), and a
third area of high prevalence distal to region 6. These areas of more
frequent involvement by fatty streaks are on the myocardial aspect of
the arterial circumference. Raised lesions (right), which
follow a pattern of involvement similar to that of fatty streaks, begin
in the 20- to 24-year age group and become more extensive in succeeding
age groups.
The extent of fatty streaks and raised lesions increases with age in all regions (P=0.0001). Men have more extensive fatty streaks in regions 3, 4, and 6 (P<0.0251) as well as in region 5, where the difference is less pronounced (P=0.0693). Men have more raised lesions than women in regions 1 through 4 (P<0.0062).
Non-HDL-C Effects by Region
In the abdominal aorta (results not shown), the extent of fatty
streaks is positively associated with third of non-HDL-C in all regions
except regions 3, 4, and 6 in the 15- to 24-year age groups
(P<0.0487) and in all regions in the 25- to 34-year age
groups (P<0.0192). The extent of raised lesions is
positively associated with third of non-HDL-C in regions 3, 5, and 6 in
the 25- to 34-year age groups (P<0.0139).
In the RCA, the extent of fatty streaks is positively associated with
third of non-HDL-C (Figure 3; for
clarity, the results for the middle third are not shown) in all regions
in the 25- to 34-year age groups (P<0.0254). The extent of
raised lesions is positively associated with third of non-HDL-C in
regions 1, 2, 3, and 6 in the 25- to 34-year age groups
(P<0.0273), whereas regions 4 and 5 show a smaller increase
(P<0.0565). The effects of non-HDL-C by region follow the
same pattern in men and women (no interaction of sex and
non-HDL-C).
|
) or upper (•)
third of non-HDL-C, adjusted for race, HDL-C, and smoking status.
Vertical bars represent SE.
HDL-C Effects by Region
In the abdominal aorta (results not shown), the extent of fatty
streaks is negatively associated with third of HDL-C in all regions
after age 25 years (P<0.0269) and in all regions except
regions 4 and 5 in the 20- to 24-year age group (P<0.0435),
with the decrease in region 5 being slightly smaller
(P=0.0561). The extent of raised lesions is negatively
associated with third of HDL-C in regions 2, 4, and 6 in the 25- to 29-
and 30- to 34-year age groups (P<0.0367) and in region 3 in
the 25- to 29-year age group (P=0.0686) and the 30- to
34-year age group (P=0.0460).
In the RCA, the extent of fatty streaks is negatively associated with
third of HDL-C (Figure 4; for clarity,
the results for the middle third are not shown) in all regions after
age 25 years (P<0.0203); in regions 1, 3, and 5 in the 20-
to 24-year age group (P<0.0245); and to a lesser extent in
region 2 (P=0.0575). The extent of raised lesions is
negatively associated with third of HDL-C in regions 2, 3, and 4 in the
25- to 34-year age group (P<0.0629). The effects of HDL-C
by region follow the same pattern in men and women (no interaction of
sex and HDL-C).
|
Smoking Effects by Region
In the abdominal aorta (Figure 5),
the extent of fatty streaks is greater in smokers than nonsmokers in
all regions except region 5 (P<0.0442) and is greater in
smokers to a lesser degree in region 5 (P=0.0882). Smokers
have more extensive involvement with raised lesions than nonsmokers in
all regions after age 25 years (P<0.0001) and in all
regions in the 20- to 24-year age group (P<0.0282), except
region 2, for which the effect of smoking is less
(P=0.0651). The effects of smoking by region follow the same
pattern in men and women (no interaction of sex and smoking).
|
There are no statistically significant effects of smoking on either fatty streaks or raised lesions in any regions of the RCA (results not shown).
Hypertension Effects by Region
In regions 1, 4, 5, and 6 of the abdominal aorta, the extent of
fatty streaks in hypertensive women is less than that in normotensive
women (P<0.0338) (results not shown). This difference is
probably due to the replacement of fatty streaks by raised lesions in
the lesion-susceptible areas. In the 20- to 24-year age group,
hypertensive blacks have a slightly greater extent of raised lesions
than normotensive blacks in regions 5 and 6 (P<0.0066). In
the 25- to 29- and 30- to 34-year age groups, hypertensive blacks have
more extensive raised lesions than normotensive blacks in all regions
(P<0.0570). The effects of hypertension are similar in men
and women (no interaction of sex and hypertension).
In the RCA, the extent of fatty streaks is not associated with hypertension (results not shown). In the 25- to 29- and 30- to 34-year age groups, hypertensive blacks have more extensive raised lesions than normotensive blacks in all regions (P<0.0200). Hypertensive whites also have more extensive raised lesions than normotensive whites, but the difference is not statistically significant. The effect of hypertension on raised lesions is similar in men and women except in regions 1 and 4, where the effect of hypertension is smaller in women than in men (interaction of sex and hypertension, P<0.0322).
Effects of Risk Level Based on Combinations of Risk
Factors
We identified cases in subset 4 (Table 1) as "high
risk" on the basis of their having the highest third of non-HDL-C,
lowest third of HDL-C, smoking, and hypertension; and as contrasting
"low risk" on the basis of their having the lowest third of
non-HDL-C, highest third of HDL-C, not smoking, and normotension. These
risk groups define the extremes of risk profiles on the basis of the 4
mutable risk factor variables included in this analysis.
The extents of involvement with lesions in the low- and high-risk
groups are shown in Figure 6. For
abdominal aortic fatty streaks, within 5-year age groups, the
differences in extent of involvement between high- and low-risk groups
are statistically similar in all regions, except that the differences
are less in region 6 for 15- to 19-year-old subjects and region 2 for
25- to 29- and 30- to 34-year-old subjects. For abdominal aortic raised
lesions, the differences between the low- and high-risk groups are
similar for regions 1 and 2 and for regions 3, 4, and 6. After age 25
years, the differences between the low- and high-risk groups are
greatest for region 5, intermediate for regions 3, 4, and 6, and least
for regions 1 and 2 (P<0.0007).
|
For RCA fatty streaks, within 5-year age groups, the differences between the low- and high-risk groups are similar in all regions. For RCA raised lesions, the differences between the low- and high-risk groups are similar in regions 1, 2, 3, and 4 and in regions 5 and 6. The differences between the low- and high-risk groups become apparent after age 25 years (P<0.0066). In the 25- to 29- and 30- to 34-year age groups, the differences are greater in regions 1, 2, 3, and 4 than in regions 5 and 6 (P<0.0445).
Relation of Lesion Extent in Selected Regions and Lesion Extent in
an Entire Artery
The correlation coefficients within 5-year age groups between
extent of involvement with fatty streaks in the individual regions and
extent of involvement with fatty streaks in the entire
arterial segment are >0.66 (P<0.0001) for the
abdominal aorta and >0.78 (P<0.0001) for the RCA. In the
25- to 29- and 30- to 34-year age groups, the correlation coefficients
between extent of raised lesions in the individual regions and the
extent of raised lesions in the entire artery are >0.44
(P<0.0001) for the abdominal aorta and >0.69
(P<0.0001) for the RCA. In the 25- to 29- and 30- to
34-year age groups, the correlation coefficients between extent of
raised lesions in region 5 of the abdominal aorta and the entire
abdominal aorta are >0.83 (P<0.0001). In the 25- to 29-
and 30- to 34-year age groups, the correlation coefficients between
extent of raised lesions in region 2 of the RCA and the entire RCA are
>0.89 (P<0.0001).
Table 2 shows the extent of involvement
with raised lesions, in both lesion-prone regions and the entire
arterial segment, in the low- and high-risk 30- to 34-year
age groups. The extent of involvement in each lesion-prone region and
in each entire artery is lower in the low-risk group than in the
high-risk group. However, the extent of involvement in a lesion-prone
region (expressed as a percentage) may be substantially greater than in
an entire arterial segment, as illustrated in the RCA, for
which the percentage of surface involved in region 2 is about double
the percentage of surface involved in the entire RCA. The estimates of
risk factor effects on atherosclerosis, that is, the
ratio of extent of involvement in high-risk individuals to that in
low-risk individuals, are 25% greater in lesion-prone regions than
the estimates of risk factor effects on atherosclerosis
in entire arterial segments.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Summary of Results
Fatty streaks develop in a characteristic pattern in the abdominal aortas of 15- to 24-year-old persons, but only fatty streaks in an area on the dorsolateral intimal surface of the distal half are replaced by raised lesions in 25- to 34-year old persons. Fatty streaks in the proximal half of the abdominal aorta, like those in the thoracic aorta, rarely are converted to raised lesions during young adulthood. Fatty streaks develop in a characteristic pattern in the RCA of younger persons, and the distribution of raised lesions follows the same pattern. Elevated non-HDL-C and low HDL-C augment both fatty streaks and raised lesions in both arteries, but smoking augments fatty streaks and raised lesions only in the lower half of the aorta. Hypertension augments only raised lesions in both arteries.
Comparison With Previous Results
These results in the RCA are consistent with the lesion
prevalence for 1-cm segments of the RCA reported in 1968 by Montenegro
and Eggen.29 They also reported similar patterns of lesion
prevalence for the left anterior descending and circumflex
coronary arteries. Our results for the abdominal aorta also are
consistent with many anecdotal observations on the distribution
of fatty streaks and raised lesions in that artery.
Implications for Relationship of Raised Lesions to Fatty
Streaks
Raised lesions do not appear to any appreciable extent in segments
of the abdominal aorta or RCA that are not likely to have been involved
by fatty streaks at younger ages. These observations are
consistent with the presumed progression of fatty streak to
fibrous plaque and other more advanced lesions under certain conditions
(presence of the risk factors) and in certain locations (the
lesion-prone areas).
Additional evidence supporting the progression from fatty streaks to raised lesions is derived from chemical, physical chemical, histological, and electron microscopic studies.30 31 32 33 34 35 36 These results show a continuous process of transition from the simple fatty streak to the typical fibrous plaque and to complicated lesions. Until noninvasive methods are sufficiently sensitive to measure fatty streaks and early raised lesions in young persons, these gross, microscopic, and chemical observations provide the best evidence supporting the precursor-product relationship of fatty streaks and raised lesions that we can obtain.
Fatty streaks in some well-defined intimal areas, such as regions 1 and 2 of the abdominal aorta, almost never progress to raised lesions, whereas fatty streaks in other regions, such as region 5, are likely to progress to raised lesions. This difference in propensity of fatty streaks to progress to raised lesions provides an opportunity to compare the anatomic and physiological characteristics of these areas that might be associated with their divergent tendencies.
Most studies of the effects of flow-related variables have focused on the left coronary artery, which is geometrically more complex than the RCA, because the left coronary artery branches into the circumflex and left anterior descending arteries.37 Furthermore, the proximal portion of the left anterior descending coronary artery is well known to be the most frequent site of advanced and occlusive lesions in the coronary system. However, the results from the RCA presented here show that lesions follow a consistent pattern of localization in a coronary artery with less complex geometry. Whether nonlipid intimal thickening precedes the appearance of the fatty streak in the RCA as it does in the left anterior descending coronary artery is not known, because intimal thickening of the RCA has not been extensively mapped.
Differential Effects of Risk Factors
An atherogenic lipoprotein profile affects both types of lesions
to about the same degree in both arteries. Plausible cellular and
molecular mechanisms that are now available account for intimal lipid
deposition and a subsequent chronic inflammatory and reparative
reaction in the presence of elevated plasma LDL concentrations. These
mechanisms involve oxidized LDL, the macrophage and its
scavenger receptors, and inflammatory mediators.38
Variations in intimal macrophages, endothelial
transport and modification of LDL, oxidants and antioxidants, and many
other processes provide possible proximate causes for localization of
lesions.
In contrast, smoking selectively affects atherosclerosis in the abdominal aorta at a younger age than in the coronary arteries. This observation is consistent with the well-known predisposition of smokers to peripheral arterial disease.39 However, because we have little knowledge about the mechanism by which smoking affects atherosclerosis, no physiological explanation of this selective effect is available.
Hypertension accelerates the formation of raised lesions where fatty streaks occur but is not associated with the appearance of raised lesions at sites where fatty streaks typically do not occur in younger persons. This observation suggests that hypertension accelerates the transformation of fatty streaks to raised lesions. As with smoking, the mechanism of the effect of hypertension is not known.
Regional Measurements Compared With Total Artery
Measurements
The extent of involvement with fatty streaks and the extent of
involvement with raised lesions after age 25 years in the entire
abdominal aorta and in the entire RCA were associated with the extent
of involvement in the lesion-prone regions. These results indicate that
much of the information concerning the grossly detectable lesions is
contained in the measurement of the extent of involvement for an entire
artery. These findings validate the conclusions from studies of
atherosclerosis conducted over the last 40 years that
were based on measurements of entire arteries.
Estimates of risk factor effects based on measurement of
atherosclerosis in the most vulnerable regions are
25% greater than estimates of risk factor effects on
atherosclerosis in entire arterial
segments. The extent of involvement in an entire arterial
segment may be substantially lower than in a selected small region, as
illustrated by the high-risk group with 5.24% intimal surface area
involved with raised lesions in region 2 of the RCA compared with
2.72% for the entire RCA. Because only a small part of an artery needs
to be involved to cause clinical disease, some of these young adults
probably are closer to the clinical disease threshold than we might
anticipate on the basis of the results for an entire artery.
Limitations of Study
Because there is within-subject biological variation in the risk
factor variables measured in serum, the single measurement
available for each subject in this study reflects the long-term average
less precisely than multiple measurements that are possible in living
subjects. Hemodilution or hemoconcentration, either of which occurs in
some subjects, introduces additional variation. These sources of
additional variation are expected to reduce the observed association of
the risk factors measured in serum with atherosclerotic lesions.
Therefore, the associations reported here probably are underestimates
of the true associations. We have found no reason why these postmortem
measurements of risk factors should result in spurious overestimation
of the relation of risk factors to atherosclerotic lesions.
Implications for Future Studies of Atherosclerosis
The propensity to develop atherosclerosis varies
widely by region within the abdominal aorta and the RCA. Some regions
are resistant to atherosclerosis, whereas
others are lesion-prone. The topographic distributions of fatty streaks
and raised lesions are similar in the RCA, with the first 2 cm of the
artery being the most frequently involved. In contrast, in the
abdominal aorta, a region on the dorsolateral intimal surface of the
middle third (region 3) is prone to develop fatty streaks during the
15- to 24-year age span that do not become raised lesions, but a more
distal region on the dorsolateral intimal surface (region 5) is prone
to develop fatty streaks that are replaced by raised lesions later in
life. These differences in the propensity of fatty streaks to become
raised lesions among portions of the abdominal aorta should be taken
into account in studies of the pathogenesis of
atherosclerosis based on aortic tissues.
Implications for Prevention
The observations reported here showing that risk factor effects
are greater in vulnerable regions of the coronary arteries and
aorta reinforce the previously reported effects of risk factors on
atherosclerosis in young persons. Although some fatty
streaks (particularly those in the thoracic aorta and upper half of the
abdominal aorta) do not progress, even in the presence of the risk
factors, others are susceptible to progression to clinically
significant lesions in the presence of 1 of the established risk
factors for adult coronary heart disease. At least as early as
15 years of age, and probably earlier, control of dyslipoproteinemia,
blood pressure, and smoking should be implemented to retard the
progression of atherosclerosis at vulnerable sites in
the coronary arteries and aorta.
|
Acknowledgments |
|---|
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; Robert W. Wissler, PhD, MD.
Participating Centers, Principal Investigators and Coinvestigators, and Supporting Grants from the National Heart, Lung, and Blood Institute and Other Sources
University of Alabama, Birmingham: Department of Medicine: Steffen Gay, MD (HL-33733) and Department of Biochemistry: Edward J. Miller, PhD (HL-33728).
Albany Medical College, Albany, NY: Assad Daoud, MD; 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; Laura Hiltscher, ASCP (HL-33740; HL-45715).
The University of Illinois, Chicago, Ill: Abel L. Robertson, Jr, MD, PhD; Robert J. Stein, MD; Edmund R. Donoghue, MD; Robert J. Buschmann, MD; 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; Dana A. Troxclair, MS (HL-33746, HL-45720).
University of Maryland, Baltimore: Wolfgang Mergner, MD, PhD; Catherine Cole, PhD; 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; Joel S. Sexton, MD (HL-33772).
University of Nebraska Medical Center, Omaha: Bruce M. McManus, MD, PhD; Jerry W. Jones, MD (HL-33778).
The Ohio State University, Columbus: J. Fredrick Cornhill, DPhil; William R. Adrion, MD; Patrick M. Fardel, MD; Brian Gara, MS; Edward Herderick, BS; Larry R. Tate, MD (HL-33760, HL-45694).
Southwest Foundation for Biomedical Research, San Antonio, Tex: James E. Hixson, PhD (HL-39913); Henry C. McGill, Jr, MD (gift from Peter and Beth Dahlberg).
The University of Texas Health Science Center at San Antonio, San Antonio, Tex: C. Alex McMahan, PhD; Henry C. McGill, Jr, MD; Yolan Marinez, MA; Thomas J. Prihoda, PhD (HL-33749, HL-45719).
Vanderbilt University, Nashville, Tenn: Renu Virmani, MD; James B. Atkinson, MD, PhD; Charles W. Harlan, MD (HL-33770, HL-45718).
West Virginia University Health Sciences Center, Morgantown: Singanallur N. Jagannathan, PhD; James Frost, MD (HL-33748).
|
Footnotes |
|---|
Reprint requests to Jack P. Strong, MD, Department of Pathology, Louisiana State University Medical Center, 1901 Perdido St, New Orleans, LA 70112-1393.
Received July 9, 1999; accepted October 11, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Fry DL. Acute vascular endothelial
changes associated with increased blood velocity gradients. Circ
Res. 1968;22:165–197.
[Abstract/Free Full Text] -
Friedman MH. A biologically plausible model of
thickening of arterial intima under shear.
Arteriosclerosis. 1989;9:511–522.
[Abstract/Free Full Text] - Nerem RM. Vascular fluid mechanics, the arterial wall, and atherosclerosis. J Biomed Eng. 1992;114:274–282.
- Giddens DP, Zarins CK, Glagov S. The role of fluid mechanics in the localization and detection of atherosclerosis. J Biomed Eng. 1993;115:588–594.
-
Ross R. Atherosclerosis: a problem of
the biology of arterial wall cells and their interactions
with blood components. Arteriosclerosis. 1981;1:293–311.
[Free Full Text] -
Benditt EP, Benditt JM. Evidence for a monoclonal
origin of human atherosclerotic plaques. Proc Natl Acad Sci
U S A. 1973;70:1753–1756.
[Abstract/Free Full Text] -
Benditt EP, Barrett T, McDougall JK. Viruses in the
etiology of atherosclerosis. Proc Natl Acad Sci
U S A. 1983;80:6386–6389.
[Abstract/Free Full Text] -
Solberg LA, Strong JP. Risk factors and
atherosclerotic lesions: a review of autopsy studies.
Arteriosclerosis. 1983;3:187–198.
[Abstract/Free Full Text] -
McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC,
Strong JP, Pathobiological Determinants of
Atherosclerosis in Youth (PDAY) Research Group.
Relation of glycohemoglobin and adiposity to
atherosclerosis in youth. Arterioscler Thromb
Vasc Biol. 1995;15:431–440.
[Abstract/Free Full Text] -
McGill HC Jr, McMahan CA, Tracy RE, Oalmann MC,
Cornhill JF, Herderick EE, Strong JP, for the Pathobiological
Determinants of Atherosclerosis in Youth (PDAY)
Research Group. Relation of a postmortem renal index of hypertension to
atherosclerosis and coronary artery size in
young men and women. Arterioscler Thromb Vasc Biol. 1998;18:1108–1118.
[Abstract/Free Full Text] -
McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong
JP, for the PDAY Research Group. Effects of serum lipoproteins and
smoking on atherosclerosis in young men and women.
Arterioscler Thromb Vasc Biol. 1997;17:95–106.
[Abstract/Free Full Text] - Strong JP, Richards ML. Cigarette smoking and atherosclerosis in autopsied men. Atherosclerosis. 1976;23:451–476.[Medline] [Order article via Infotrieve]
-
Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W
Jr, Rosenfeld ME, Schaffer SA, Schartz CJ, Wagner WD, Wissler RW. A
definition of initial, fatty streak, and intermediate lesions of
atherosclerosis: a report from the Committee on
Vascular Lesions of the Council on
Arteriosclerosis, American Heart Association.
Circulation. 1994;89:2462–2478.
[Abstract/Free Full Text] - Stehbens WE. The epidemiological relationship of hypercholesterolemia, hypertension, diabetes mellitus and obesity to coronary heart disease and atherogenesis. J Clin Epidemiol. 1990;43:733–741.[Medline] [Order article via Infotrieve]
- Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest. 1968;18:509–526.[Medline] [Order article via Infotrieve]
- Cornhill JF, Herderick EE, Vince DG, PDAY Research Group. The clinical morphology of human atherosclerotic lesions: lessons from the PDAY Study. Wien Klin Wochenschr. 1995;107:540–543.[Medline] [Order article via Infotrieve]
- Wissler RW. U S A Multicenter Study of the pathobiology of atherosclerosis in youth. Ann N Y Acad Sci. 1991;623:26–39.[Medline] [Order article via Infotrieve]
- Guzman MA, McMahan CA, McGill HC Jr, Strong JP, Tejada C, Restrepo C, Eggen DA, Robertson WB, Solberg LA. Selected methodologic aspects of the International Atherosclerosis Project. Lab Invest. 1968;18:479–497.[Medline] [Order article via Infotrieve]
- Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470–475.[Abstract]
- Glanville JN. Post-mortem serum cholesterol levels. BMJ. 1960;2:1852–1853.
- Hornick CA, Baker HN, Malcom GT, Newman WP, Roheim PS, Strong JP. Lipoproteins and apolipoproteins in postmortem serum. Mod Pathol. 1988;1:480–484.[Medline] [Order article via Infotrieve]
- Bowler RG. The determination of thiocyanate in blood serum. Biochem J. 1944;38:385–388.
-
Klenk DC, Hermanson GT, Krohn RI, Fujimoto EK, Mallia
AK, Smith PK, England JD, Wiedemeyer H-M, Little RR, Goldstein DE.
Determination of glycosylated hemoglobin by affinity
chromatography: comparison with
colorimetric and ion-exchange methods, and effects of
common interferences. Clin Chem. 1982;28:2088–2094.
[Abstract/Free Full Text] - Santiago JV. Lessons from the Diabetes Control and Complications Trial. Diabetes. 1993;42:1549–1554.[Medline] [Order article via Infotrieve]
- Tracy RE, Berenson G, Wattigney W, Barrett TJ. The evolution of benign arterionephrosclerosis from age 6 to 70 years. Am J Pathol. 1990;136:429–439.[Abstract]
-
McGill HC Jr, Strong JP, Tracy RE, McMahan CA, Oalmann
MC, Pathobiological Determinants of Atherosclerosis in
Youth (PDAY) Research Group. Relation of a postmortem renal index of
hypertension to atherosclerosis in youth.
Arterioscler Thromb Vasc Biol. 1995;15:2222–2228.
[Abstract/Free Full Text] - Morrison DF. Multivariate Statistical Methods. New York, NY: McGraw-Hill; 1967.
- Carroll RJ, Ruppert D. Transformation and Weighting in Regression. New York, NY: Chapman and Hall; 1988.
- Montenegro MR, Eggen DA. Topography of atherosclerosis in the coronary arteries. Lab Invest. 1968;18:586–593.[Medline] [Order article via Infotrieve]
- Hata Y, Hower J, Insull W Jr. Cholesteryl ester-rich inclusions from human aortic fatty streak and fibrous plaque lesions of atherosclerosis, I: crystalline properties; size and internal structure. Am J Pathol. 1974;75:423–456.[Medline] [Order article via Infotrieve]
- Katz SS, Shipley GG, Small DM. Physical chemistry of the lipids of human atherosclerotic lesions: demonstration of a lesion intermediate between fatty streaks and advanced plaques. J Clin Invest. 1976;58:200–211.
- Bocan TMA, Guyton JR. Human aortic fibrolipid lesions: progenitor lesions for fibrous plaques, exhibiting early formation of the cholesterol- rich core. Am J Pathol. 1985;120:193–206.[Abstract]
- Bocan TMA, Schifani TA, Guyton JR. Ultrastructure of the human aortic fibrolipid lesion: formation of the atherosclerotic lipid-rich core. Am J Pathol. 1986;123:413–424.[Abstract]
- Guyton JR, Klemp KF. Transitional features in human atherosclerosis: intimal thickening, cholesterol clefts, and cell loss in human aortic fatty streaks. Am J Pathol. 1993;143:1444–1457.[Abstract]
-
Guyton JR, Klemp KF. Development of the atherosclerotic
core region: chemical and ultrastructural analysis of
microdissected atherosclerotic lesions from human aorta.
Arterioscler Thromb. 1994;14:1305–1314.
[Abstract/Free Full Text] - Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 1989;9(suppl 1):I-19–I-32.
- Friedman MH, Brinkman AM, Qin JJ, Seed WA. Relation between coronary artery geometry and the distribution of early sudanophilic lesions. Atherosclerosis. 1993;98:193–199.[Medline] [Order article via Infotrieve]
-
Steinberg D. Low density lipoprotein oxidation and its
pathobiological significance. J Biol Chem. 1997;272:20963–20966.
[Free Full Text] -
Auerbach O, Garfinkel L.
Atherosclerosis and aneurysm of aorta in
relation to smoking habits and age. Chest. 1980;78:805–809.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  H. C. McGill Jr, C. A. McMahan, and S. S. Gidding Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study Circulation, March 4, 2008; 117(9): 1216 - 1227. [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Skilton Intrauterine Risk Factors for Precocious Atherosclerosis Pediatrics, March 1, 2008; 121(3): 570 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rogacheva, T. Laatikainen, K. Tossavainen, T. Vlasoff, V. Panteleev, and E. Vartiainen Changes in cardiovascular risk factors among adolescents from 1995 to 2004 in the Republic of Karelia, Russia Eur J Public Health, June 1, 2007; 17(3): 257 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakashima, H. Fujii, S. Sumiyoshi, T. N. Wight, and K. Sueishi Early Human Atherosclerosis: Accumulation of Lipid and Proteoglycans in Intimal Thickenings Followed by Macrophage Infiltration Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1159 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Volanen, M. J. Jarvisalo, R. Vainionpaa, M. Arffman, K. Kallio, S. Angle, T. Ronnemaa, J. Viikari, J. Marniemi, O. T. Raitakari, et al. Increased Aortic Intima-Media Thickness in 11-Year-Old Healthy Children With Persistent Chlamydia pneumoniae Seropositivity Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Zieske, R. P. Tracy, C. A. McMahan, E. E. Herderick, S. Homma, G. T. Malcom, H. C. McGill Jr, J. P. Strong, and for the Pathobiological Determinants of Atheroscle Elevated Serum C-Reactive Protein Levels and Advanced Atherosclerosis in Youth Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1237 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Jacobs and R. H. Eckel Evaluating and Managing Cardiovascular Disease in Women: Understanding a Woman's Heart Circulation, February 1, 2005; 111(4): 383 - 384. [Full Text] [PDF]
|
|
|
|
|
|
S. M. Mone, M. W. Gillman, T. L. Miller, E. H. Herman, and S. E. Lipshultz Effects of Environmental Exposures on the Cardiovascular System: Prenatal Period Through Adolescence Pediatrics, April 1, 2004; 113(4/S1): 1058 - 1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. VanderLaan, C. A. Reardon, and G. S. Getz Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 12 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. T. Raitakari, M. Juonala, M. Kahonen, L. Taittonen, T. Laitinen, N. Maki-Torkko, M. J. Jarvisalo, M. Uhari, E. Jokinen, T. Ronnemaa, et al. Cardiovascular Risk Factors in Childhood and Carotid Artery Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study JAMA, November 5, 2003; 290(17): 2277 - 2283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. Massing, K. A. Foley, C. A. Sueta, M. Chowdhury, D. P. Biggs, C. M. Alexander, and R. J. Simpson Jr. Trends in Lipid Management Among Patients With Coronary Artery Disease: Has diabetes received the attention it deserves? Diabetes Care, April 1, 2003; 26(4): 991 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|