Atherosclerosis
leading to coronary heart disease is complex in origin. Involved in the
pathogenesis of atherosclerosis are hemodynamic, thrombotic, and
carbohydrate–lipid metabolic variables, along with intrinsic
characteristics of the arterial wall.
1
These physiologic and biochemical factors underlie the clinical events
that may eventually occur. Environmental factors such as smoking or a
sedentary lifestyle also contribute to this process. The progression of
atherosclerotic disease and the increasing severity of atherosclerosis
relate not only to the presence and extent of cardiovascular risk
factors but also to the persistence of risk factors over time.
2,3
Sudden death may occur in a young person with only a single lesion
complicated by a coronary thrombus, without extensive vessel disease.
Consequently, the extent of vascular lesions may not be directly related
to the occurrence of clinical events, such as myocardial infarction.
Morbidity due to coronary artery disease, however, is generally related
to the extent of vascular lesions.
4 In this regard, clinical risk factors are considered to be useful in predicting the severity of atherosclerosis.
5
Epidemiologic
studies have established that multiple risk factors increase the
probability of cardiovascular events, since cardiovascular risk factors
tend to reinforce each other in their influence on morbidity and
mortality.
6
Although a specific risk factor influences the risk that a person will
have cardiovascular disease, risk factors tend to aggregate and usually
appear in combination. Furthermore, since clustering of risk factors is
evident in childhood and persists into young adulthood,
7-10 the presence of multiple risk factors could indicate the acceleration of atherosclerosis in young people.
Coronary
arteriography has contributed considerably to elucidating the relation
of the severity of coronary artery disease to cardiovascular risk
factors. Unfortunately, assessing the extent of atherosclerotic coronary
lesions by this invasive method in asymptomatic young people is not
practical, and its value is limited as compared with that of actual
anatomical observations.
11
Autopsy data from epidemiologic studies have shown a relation between
coronary artery disease and cardiovascular risk factors; for example,
high serum total cholesterol concentrations and cigarette smoking are
important contributors to the development of coronary atherosclerosis.
6
Autopsy studies from the Bogalusa Heart Study have demonstrated a
strong association of specific antemortem risk factors with vascular
lesions in children and young adults.
12,13
These observations have been extended by the findings in a larger,
multicenter postmortem study, Pathobiological Determinants of
Atherosclerosis in Youth.
14-17
Multiple risk-factor data collected ante mortem in the Bogalusa Heart
Study can be applied further to autopsy data. In this study we examined
the influence of multiple risk factors on the extent of atherosclerosis
in the aorta and coronary arteries in young people.
Methods
Study Population
The
Bogalusa Heart Study is a long-term epidemiologic study of
cardiovascular risk factors from birth through the age of 38 years in a
biracial population (65 percent white and 35 percent black).
18,19
Seven cross-sectional surveys, each including more than 3500 children,
have been carried out since 1973. Since 1978, five follow-up surveys
have been conducted among young adults who participated in previous
cross-sectional surveys as children. Participation rates ranged from
approximately 80 percent for school-age children to approximately 60
percent for the adult cohort. To date, data have been collected on
approximately 14,000 people.
For the autopsy studies, a local
information system was established in 1978 to obtain the family's or
coroner's consent to conduct an autopsy after the death of a young
person. For practical and logistic reasons, an autopsy was conducted on
any resident of Washington Parish in Bogalusa, Louisiana, or adjacent
parishes who died between the ages of 2 and 39 years. Not all the young
people who died in this area had been eligible for the Bogalusa Heart
Study's survey of cardiovascular risk factors, which was restricted to
ward 4 of Washington Parish. Most deaths were due to accidents or
homicide; only about 10 percent were due to renal, neoplastic, or
infectious diseases or suicide. Autopsies were conducted in local
funeral homes or in hospitals in adjacent communities, and selected
tissues (including the heart and coronary arteries, aorta, and kidneys)
were brought to the Department of Pathology at Louisiana State
University Medical Center in New Orleans for study.
As of January
1996, specimens had been collected at autopsy from 86 white males, 52
black males, 36 white females, and 30 black females, representing more
than 60 percent of all known eligible deaths. The mean (±SD) age at
death ranged from 20.4±6.6 years among white females to 21.8±6.8 years
among black males. Of the 204 persons examined at autopsy, 93 had
previously been surveyed as part of the Bogalusa Heart Study and
therefore had provided data on antemortem risk factors. Among these 93
persons, the mean age at death was 19.6±5.7 years for the 41 white
males, 20.4±6.2 years for the 19 white females, 21.7±5.2 years for the
23 black males, and 22.4±6.0 years for the 10 black females.
Characterization of Cardiovascular Risk Factors
Essentially
the same protocols were used in all surveys. The methods used to
measure each risk factor have been described in detail previously.
19
Height was measured to the nearest 0.1 cm and weight to the nearest 0.1
kg. Body-mass index (the weight in kilograms divided by the square of
the height in meters) was used as a measure of obesity.
Blood
pressure was measured in the right arm, with the subject in a relaxed,
sitting position. The average of six measurements (three taken by each
of two examiners) with a mercury sphygmomanometer was used in all
analyses. The fourth Korotkoff phase was considered the diastolic blood
pressure. Cigarette-smoking status, which was assessed by a
questionnaire beginning at the age of eight and continuing through
adulthood, was measured in terms of the number of cigarettes smoked per
week.
20
Serum total cholesterol, triglycerides, and high-density lipoprotein
(HDL) and low-density lipoprotein (LDL) cholesterol were measured by
standardized procedures,
21 which met the performance requirements of the lipid-standardization program of the Centers for Disease Control and Prevention.
Evaluation of Atherosclerotic Lesions
At
autopsy, the aorta and coronary arteries were opened longitudinally and
stained with Sudan IV to localize lipid deposition. The extent of the
intimal surface that was covered with fatty streaks and raised fibrous
plaques in the vessels was graded visually according to procedures
developed in the International Atherosclerosis Project
22;
these procedures are currently used by the Department of Pathology at
Louisiana State University Medical Center. The pathologists grading the
lesions were unaware of the subjects' risk-factor data. Briefly, the
grader first estimated the percentage of the total intimal surface area
involved with any atherosclerotic lesion and then estimated the
percentage distribution of fatty streaks, fibrous plaques, complicated
lesions (those with evidence of hemorrhage, ulceration, necrosis, or
thrombosis, with or without calcification), and calcified lesions within
this lesion-covered area. The recorded percentages of individual types
of lesions within the lesion-covered area were converted to percentages
of the total intimal surface area by multiplying each estimate by the
fraction of intimal surface area covered with atherosclerotic lesions.
Three
pathologists evaluated the vessels independently; the extent of
atherosclerosis was expressed as the mean of the three values assigned
by these pathologists for the percentage of the intimal surface covered
by lesions. The prevalence of atherosclerotic lesions was defined as the
percentage of persons studied who had at least minimal sudanophilic
intimal deposits.
Statistical Analysis
We
used z scores (standardized values) specific for the study period,
race, sex, and age to eliminate the effects of age, race, sex, and
potential variations in laboratory measurements on the antemortem
risk-factor variables. For the 65 persons whose risk-factor status was
assessed more than once, we used the average of the adjusted levels.
Risk factors were defined as values above the 75th percentile (specific
for study period, race, age, and sex) for the group as a whole.
Antemortem values for very-low-density lipoprotein cholesterol and
triglyceride values in nonfasting subjects were not included in the
analyses.
Spearman correlation analysis was used to examine the
association between the extent of fatty-streak or fibrous-plaque lesions
in the aorta and coronary arteries and age at death and the z scores of
individual risk-factor variables. A multivariate technique, referred to
as canonical correlation analysis, was then used to examine the
association between the two sets of variables — that is, the antemortem
risk-factor variables and the extent of fatty-streak and fibrous-plaque
lesions in the aorta and coronary arteries. The prevalence of
atherosclerosis in various age groups was evaluated with a chi-square
test. The influence of cigarette smoking on the extent of
atherosclerosis and the effect of multiple risk factors on the extent of
atherosclerosis were evaluated with analysis of covariance after the
extent of lesions was adjusted for race, sex, and age at death; subjects
with no risk factors were compared with those with one, two, and three
or four risk factors. All statistical tests were two-sided. SAS software
was used for all analyses.
23
Results
Prevalence, Extent, and Interrelations of Lesions
Essentially
all persons in the age groups we studied had fatty streaks in the
aorta. In contrast, the prevalence of fatty streaks in the coronary
arteries increased with age from approximately 50 percent at 2 to 15
years of age to 85 percent at 21 to 39 years (P=0.01). The prevalence of
raised fibrous-plaque lesions in the aorta and coronary arteries is
shown in
Figure 1Figure 1
The Prevalence of Fibrous-Plaque Lesions in the Aorta and Coronary Arteries in 204 Children and Young Adults, According to Age..
In the aorta, there was a trend toward increasing prevalence with age
(P=0.001), especially after the age of 15 years; prevalence increased to
60 percent by the age of 26 to 39 years. In the coronary vessels, this
age-related trend was even more consistent (P=0.001), with the
prevalence increasing from 8 percent at 2 to 15 years to 69 percent at
26 to 39 years.
For each type of lesion, there was a trend toward
involvement of an increasing percentage of the intimal surface with
increasing age. In the aorta, the mean (±SD) percentage of the surface
involved with fatty streaks increased from 13.8±15.5 percent at 2 to 15
years of age to 28.8±15.3 percent at 26 to 39 years (P<0.001), and
the percentage involved with fibrous plaques increased from 0.2±0.5
percent to 4.0±7.4 percent, respectively (P<0.001). In the coronary
arteries, the percentage of the surface involved with fatty streaks
increased from 0.5±0.7 percent to 7.1±8.2 percent (P<0.001), and the
percentage involved with fibrous plaques increased from 0.2±0.9 percent
to 6.9±11.4 percent (P<0.001).
With respect to the
interrelation of types of lesions in the aorta and coronary arteries,
the correlation of the extent of fatty streaks and fibrous plaques in
the aorta with the extent of lesions of the same type in the coronary
arteries was only moderate (r=0.36 to 0.37, P=0.001). Furthermore, the
correlation between the extent of fatty streaks and that of fibrous
plaques was much greater in the coronary arteries (r=0.60, P<0.001)
than in the aorta (r= 0.23, P=0.03).
Relation of Lesions to Specific Risk Factors
Correlations between the extent of lesions and specific antemortem risk factors are shown in
Table 1Table 1
Correlation between the Extent of Lesions in the Aorta and Coronary Arteries and Antemortem Risk-Factor Variables..
The extent of atherosclerotic lesions correlated positively and
significantly with body-mass index, systolic blood pressure (except in
the case of fibrous plaques in the aorta), diastolic blood pressure
(this was true only for fibrous plaques in the coronary arteries), serum
total cholesterol concentrations (except for fibrous plaques in the
aorta and coronary artery), serum LDL cholesterol concentrations (except
for fibrous plaques in the aorta), and serum triglyceride
concentrations (except for fatty streaks in the aorta). Furthermore,
canonical correlation analysis showed that the extent of fatty-streak
and fibrous-plaque lesions in the aorta and coronary vessels as a group
were associated moderately strongly with body-mass index (r=0.48),
systolic blood pressure (r=0.55), serum triglyceride concentrations (r=
0.50), and LDL cholesterol concentrations (r=0.43) and associated weakly
with diastolic blood pressure (r=0.22) and HDL cholesterol
concentrations (r= –0.16). On the other hand, antemortem risk-factor
variables as a group were most strongly associated with the extent of
fatty streaks in the coronary arteries (r=0.55), followed by the extent
of fibrous plaques in the coronary arteries (r=0.52), fibrous plaques in
the aorta (r=0.40), and fatty streaks in the aorta (r=0.38). Overall,
the highest canonical correlation between antemortem risk-factor
variables and the extent of lesions in the aorta and coronary arteries
was 0.70 (P<0.001).
The influence of cigarette smoking on the prevalence and extent of aortic and coronary-artery lesions is shown in
Figure 2Figure 2
The
Influence of Cigarette Smoking on the Prevalence (Top Panels) and
Extent (Bottom Panels) of Atherosclerosis in the Aorta and Coronary
Arteries in Children and Young Adults.. The prevalence of
lesions in these vessels was similar in the 15 smokers and the 34
nonsmokers (for the remaining subjects, smoking status was unknown). The
mean (±SE) percentage of the intimal surface involved with
fibrous-plaque lesions in the aorta was higher in smokers than in
nonsmokers (1.22±0.62 percent vs. 0.12±0.07 percent, P=0.02), as was the
percentage involved in fatty-streak lesions in the coronary vessels
(8.27±3.43 percent vs. 2.89±0.83 percent, P=0.04).
Relation of Lesions to Multiple Risk Factors
The
mean percentage of the intimal surface covered by lesions in patients
with different numbers of risk factors (0, 1, 2, and 3 or 4) is shown in
Figure 3Figure 3
The
Effect of Multiple Risk Factors on the Extent of Atherosclerosis in the
Aorta and Coronary Arteries in Children and Young Adults..
The risk factors we evaluated included body-mass index, systolic blood
pressure, serum triglyceride concentration, and serum LDL cholesterol
concentration. In subjects with 0, 1, 2, and 3 or 4 risk factors, 19.1
percent, 30.3 percent, 37.9 percent, and 35.0 percent, respectively, of
the intimal surface area was involved with fatty streaks in the aorta (P
for trend=0.01). In the coronary arteries, 1.3 percent, 2.5 percent,
7.9 percent, and 11.0 percent, respectively, of the intimal surface was
involved with fatty streaks (P for trend=0.01), and 0.6 percent, 0.7
percent, 2.4 percent, and 7.2 percent was involved with collagenous
fibrous plaques (P for trend=0.003). The extent of fatty-streak lesions
in the coronary arteries was 8.5 times as great in persons with three or
four risk factors as in those with none (P=0.03), and the extent of
fibrous-plaque lesions in the coronary arteries was 12 times as great
(P=0.006).
Discussion
Observations
from autopsy studies by the Bogalusa Heart Study and the multicenter
Pathobiological Determinants of Atherosclerosis in Youth study clearly
documented a strong relation between coronary atherosclerosis and
cardiovascular risk factors in young people.
12-17
Our observation that specific antemortem risk factors such as
elevations in body-mass index, systolic blood pressure, serum LDL
cholesterol concentration, and serum triglyceride concentration and
cigarette smoking are significantly related to the extent of
atherosclerotic lesions in young people is in agreement with the
findings in those studies. Furthermore, the prevalence and extent of
lesions in the coronary arteries, especially fibrous-plaque lesions that
encroach on the lumen, increased with age in the young people we
studied. Previous studies of the natural history of atherosclerosis
indicated that in populations with high rates of premature coronary
artery disease, advanced lesions begin to appear with greater frequency
during childhood and young adulthood.
24
Although there has been some question about the clinical significance
of fatty streaks in the aorta, which some suggest are evanescent, their
presence in association with fibrous plaques in coronary vessels is
considered to indicate that atherosclerosis is progressive and severe.
25
In the current study, the correlation between the extent of fatty
streaks and that of fibrous plaques was much greater in the coronary
arteries than in the aorta. Also, the proportion of collagenous fibrous
plaques in relation to fatty streaks was greater in the coronary vessels
than in the aorta.
We found that the extent of atherosclerotic
lesions in the coronary vessels increased markedly in young people with
multiple risk factors. This finding supports the concept that multiple
risk factors have a synergistic effect on morbidity and mortality from
coronary heart disease in middle age and later, as has been demonstrated
by epidemiologic studies such as the Framingham Study.
26
We could not examine the effect of multiple risk factors on the extent
of atherosclerosis separately according to race and sex because of the
small numbers of persons in each group within our sample.
The
multiple risk factors we evaluated included high values for body-mass
index, systolic blood pressure, and LDL cholesterol and triglycerides in
serum. Cardiovascular risk factors such as dyslipidemia, hypertension,
hyperinsulinemia or insulin resistance, and obesity often coexist in
both children and young adults.
9,10 Since the clustering of these conditions — termed syndrome X,
27 the deadly quartet,
28 or insulin-resistance syndrome
29
— is seen so frequently, a common pathophysiologic mechanism involving
insulin resistance has been suggested. Although we did not measure
plasma insulin and glucose concentrations as indicators of
carbohydrate–lipid metabolism, it is reasonable to suggest that these
variables may be part of the cluster of risk factors in the study
population, as we have shown previously.
9,10,30
In this regard, the effects of elevated glycosylated hemoglobin
concentrations and of obesity on atherosclerosis are evident throughout
the group of 15-to-34-year-old subjects in the Pathobiological
Determinants of Atherosclerosis in Youth study.
16
Our
observation that the extent of fatty-streak lesions in the coronary
vessels of children and young adults was higher in cigarette smokers
than in nonsmokers is in agreement with the findings of the
Pathobiological Determinants of Atherosclerosis in Youth study.
14,17
Therefore, it is to be expected that cigarette smoking by young people
who have multiple other risk factors will adversely influence the extent
of coronary atherosclerosis.
The effects of multiple risk
factors on coronary atherosclerosis give further justification for the
evaluation of cardiovascular risk in young people and provide a
rationale for both prevention and intervention. It may be important to
focus on multiple cardiovascular risk factors early in life, rather than
on a specific risk factor, such as hypercholesterolemia. Interventions
related to modifiable risk factors, such as the prevention of smoking,
weight control, and encouragement of physical exercise and a prudent
diet, if undertaken early in life, may retard the development of
atherosclerosis.
Supported
by grants from the National Heart, Lung, and Blood Institute (HL-38844)
and the National Institute of Child Health and Human Development
(HD-32194).
We are indebted to the many people who collaborated
with the Bogalusa Heart Study for their cooperation, to Bettye Seal for
her work as community coordinator, and to the children and young adults
of Bogalusa, Louisiana, without whom this study would not have been
possible.
Source Information
From
the Tulane Center for Cardiovascular Health, Tulane School of Public
Health and Tropical Medicine (G.S.B., S.R.S., W.B., W.A.W.); and the
Department of Pathology, Louisiana State University Medical Center
(W.P.N., R.E.T.) — both in New Orleans.
Address reprint requests
to Dr. Berenson at the Tulane Center for Cardiovascular Health, Tulane
School of Public Health and Tropical Medicine, 1501 Canal St., 14th Fl.,
New Orleans, LA 70112-2824.
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