High Prevalence of Coronary Atherosclerosis in

Asymptomatic Teenagers and Young Adults

Evidence From Intravascular Ultrasound
E. Murat Tuzcu, MD; Samir R. Kapadia, MD; Eralp Tutar, MD; Khaled M. Ziada, MD;
Robert E. Hobbs, MD; Patrick M. McCarthy, MD; James B. Young, MD; Steven E. Nissen, MD

Background—Most of our knowledge about atherosclerosis at young ages is derived from necropsy studies, which have
inherent limitations. Detailed, in vivo data on atherosclerosis in young individuals are limited. Intravascular
ultrasonography provides a unique opportunity for in vivo characterization of early atherosclerosis in a clinically
relevant context.
Methods and Results—Intravascular ultrasound was performed in 262 heart transplant recipients 30.9⫾13.2 days after
transplantation to investigate coronary arteries in young asymptomatic subjects. The donor population consisted of 146
men and 116 women (mean age of 33.4⫾13.2 years). Extensive imaging of all possible (including distal) coronary
segments was performed. Sites with the greatest and least intimal thickness in each CASS segment were measured in
multiple coronary arteries. Sites with intimal thickness ⱖ0.5 mm were defined as atherosclerotic. A total of 2014 sites
within 1477 segments in 574 coronary arteries (2.2 arteries per person) were analyzed. An atherosclerotic lesion was
present in 136 patients, or 51.9%. The prevalence of atherosclerosis varied from 17% in individuals ⬍20 years old to
85% in subjects ⱖ50 years old. In subjects with atherosclerosis, intimal thickness and area stenosis averaged
1.08⫾0.48 mm and 32.7⫾15.9%, respectively. For all age groups, the average intimal thickness was greater in men than
women, although the prevalence of atherosclerosis was similar (52% in men and 51.7% in women).
Conclusions—This study demonstrates that coronary atherosclerosis begins at a young age and that lesions are present in
1 of 6 teenagers. These findings suggest the need for intensive efforts at coronary disease prevention in young adults.
(Circulation. 2001;103:2705-2710.)
Key Words: atherosclerosis 䡲 ultrasonics 䡲 plaque 䡲 coronary disease

A lthough patients with coronary artery disease typically

become symptomatic after age 40 years, necropsy stud-
ies have demonstrated that atherosclerotic changes in the
vessel wall begin early in life.1–5 Characterization of coronary
disease through postmortem examination of young subjects
has important limitations, however, particularly the presence
of nonphysiological conditions (arteries not pressure-
distended) and fixation artifacts.6 Few in vivo data have
documented the extent and severity of atherosclerosis in
young, healthy subjects.7,8
Miniaturization of high-frequency transducers has allowed
the development of intravascular ultrasound (IVUS), a unique
imaging modality that permits direct examination of the
vessel wall in living humans.9 –12 Comparative studies have
documented a close correlation between ultrasound measure-
ments of atherosclerosis performed in vitro and histological
measurements performed in pressure-distended arteries.8,13,14
We sought to determine the prevalence of atherosclerosis
in subjects with no clinical or angiographic evidence of
significant coronary disease. The population for this investi-
gation consisted of patients who had recently undergone
cardiac transplantation. We used IVUS to determine the
presence, extent, and distribution of atherosclerosis in the
donor coronary arteries within weeks of transplantation.
Because most donors are relatively young, this approach
provided the opportunity to characterize the early atheroscle-
rotic disease process.
Methods
Patient Population
Between December 1992 and May 1999, IVUS examination was
performed in 262 heart transplant recipients 30.9⫾13.2 days after
transplantation. The donor population consisted of 116 women
(44%) and 146 men (56%) with a mean age of 33.4⫾13.2 years.
None of the patients had known coronary artery disease because
potential donors were screened for heart disease before proceeding
with transplantation. The hospital’s Institutional Review Board
approved the study protocol. All participants provided informed
consent.

Received December 11, 2000; revision received March 14, 2001; accepted March 15, 2001.
From the Departments of Cardiology (E.M.T., S.R.K., E.T., K.M.Z., R.E.H., J.B.Y., S.E.N.) and Cardiothoracic Surgery (P.M.M.), The Cleveland
Clinic Foundation, Cleveland, Ohio.
Correspondence to E. Murat Tuzcu, MD, Cleveland Clinic Foundation, F25 9500, Euclid Ave, Cleveland, OH 44195. E-mail tuzcue@ccf.org
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

2705
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2706 Circulation June 5, 2001

IVUS Examination Characteristics of Donor Population

The method of IVUS imaging has been reported previously in
Characteristic
detail.7 After coronary angiography, patients received anticoagula-
tion with heparin, and 100 to 200 ␮g nitroglycerin IC was adminis- Age, y 33.4⫾13.2
tered. A 30-MHz, 3.5F monorail ultrasound catheter (Boston Scien- Male sex, n (%) 146 (56)
tific) was advanced over an angioplasty guidewire to a distal location
in the coronary artery, and the position of the transducer was Hypertension, n (%) 39/260 (15)
documented by angiography. Ultrasound images were displayed with Smoking, n (%) 126/164 (77)
a dedicated scanner (Hewlett-Packard Corp) and recorded on S-VHS White race, n (%) 227 (86.6)
tape during a slow, distal-to-proximal manual pullback. During
pullbacks, voice annotation and frequent angiography were used to Body mass index, kg/m2 25.2⫾5.9
document the location of imaging sites of interest.

Offline IVUS Analysis
Images were reviewed on a video monitor in the IVUS core
laboratory. Using an image-processing computer, a technician digi-
tized full-motion IVUS sequences (30 frames per second) at a
640⫻480 pixel matrix with 24 bits per pixel. Images were consid-
ered suitable for analysis if they were free of ultrasound artifacts,
such as extreme catheter angulation or nonuniform rotational distor-
tion. For each segment, defined according to Coronary Artery
Surgery Study (CASS) classification, the operator selected 2 sites,
one with the least intimal thickness and another with the greatest
intimal thickness.15
Although single frames were selected for analysis, the operator
examined the full-motion sequence to facilitate optimal border
delineation. The lumen and external elastic membrane (EEM)
borders of the selected frames were manually traced to yield
measurements of maximum intimal thickness, minimum intimal
thickness, and both luminal and EEM cross-sectional areas.
The following definitions were used to describe lesion character-
istics and severity:
Atherosclerotic lesion: Any site with an intimal thickness
ⱖ0.5 mm.
Normal site: Within any CASS segment, the site with the least
intimal thickness among the sites without atherosclerosis.
Eccentric lesion: A lesion was classified as eccentric if the
maximum intimal thickness was more than twice the value for the
minimum intimal thickness.
Calcified lesion: A lesion containing an echogenic structure that
blocked penetration of ultrasound, thereby producing acoustic
shadowing.
Percent area stenosis: EEM area⫺lumen area/EEM area⫻100
Angiographic Analysis
Coronary angiography was performed by standard techniques. An-
giograms were reviewed on a screen at a fixed distance with a rear
projection system (Tagarno 35 Ax) and classified as normal or
abnormal by experienced angiographers blinded to the donor clinical
data and ultrasound findings. For each vessel, the CASS segment
classification system was used to identify the most distal site imaged
by ultrasound. In abnormal angiograms, stenosis severity at sites
showing any luminal narrowing or abnormality was measured with a
digital caliper system (Sandhill Scientific, Inc). For each identifiable
lesion, the operator determined vessel diameter at the stenosis site
and at an adjacent angiographically normal reference site to quantify
percent diameter stenosis.
subjects, 574 major epicardial coronary arteries other than the
left main trunk were imaged (2.2 arteries per patient). The left
anterior descending coronary artery (LAD) was visualized in
238 patients (90% of the cohort), the left circumflex (LCx) in
180 (69%), and the right coronary artery (RCA) in 156 (56%).
All 3 arteries were imaged in 97 patients (37% of subjects), 2
arteries in 118 (45%), and only 1 vessel in 47 (18%). From
these arteries, ultrasound images were analyzed for a total of
2014 sites within 1477 CASS segments.
Intimal Thickness at the Normal Sites
Figure 1 shows the frequency distribution of the normal site
with least intimal thickness in each patient for different age
cohorts. If the donor was ⬍40 years of age, the smallest
intimal thickness in each patient was always ⬍0.3 mm. Even
when the donor age was ⬎40 years, the normal intimal
thickness was always ⬍0.5 mm. Therefore, in the present
study, we used the threshold of 0.5 mm to define the presence
of an atherosclerotic lesion and to determine the prevalence
of atherosclerosis. We also present the data according to the
less stringent criterion of 0.3 mm.
Prevalence of Atherosclerosis
Of 262 individuals, 136 (51.9%) had ⱖ1 atherosclerotic site
(intimal thickness ⬎0.5 mm) (Figure 2). In these 136 sub-
jects, the intimal thickness at the lesion was 1.08⫾0.48 mm,
and percent stenosis averaged 32.7⫾15.9%. Figure 3 shows
the frequency distribution of greatest intimal thickness in
each patient for different age groups, demonstrating that
intimal thickness increases progressively with advancing age.
In all age groups, a portion of the cohort had ⱖ1 site with
intimal thickness exceeding the 0.3-mm or 0.5-mm thresholds
used for the definition of atherosclerosis (Figure 4). Strik-

Statistical Analysis
Normally distributed data were reported as mean⫾SD, and categor-
ical variables were expressed as number and percentage of the
cohort.

Results
Patient Population and Extent of Imaging
All donors in the study were free of known heart disease, the
mean age was 33⫾13.2 years, and 56% were male. Other Figure 1. Frequency distribution of least intimal thickness in
donor characteristics are listed in the Table. In the 262 each patient for all age cohorts.

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 Tuzcu et al
ingly, when the more stringent definition of ⬎0.5 mm was
used, even the 12- to 19-year-old age group showed athero-
sclerosis in 17% of subjects. By age 40 years, ⬎70% of
individuals showed ⱖ1 coronary site with an intimal thick-
ness ⬎0.5 mm. With a less conservative threshold of 0.3 mm,
21% of teenagers and 91% of individuals ⬎40 years old had
ⱖ1 atherosclerotic lesion.
Intimal Thickness and Stenosis Severity
From each of the 1477 CASS segments, the sites with the
largest value for intimal thickness, whether normal or
Figure 3. Frequency distribution of greatest intimal thickness in
each patient for all age cohorts.
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Atherosclerosis in Teens and Young Adults 2707
Figure 2. A, Example of atherosclerosis
in LAD of 17-year-old man. Eccentric
intimal thickening representing early ath-
erosclerosis is evident. Note normal
intima opposite diseased arc. Right,
Magnified view of same lesion. B, Evi-
dence of advanced atherosclerosis in
32-year-old woman.
diseased, were selected. The intimal thickness and percent
area stenosis at these sites were 0.35⫾0.34 mm and
12.4⫾11.8%, respectively. The distribution of these values
by age group is shown in Figure 5. The intimal thickness
and percent area stenosis at these sites correlated with
donor age (r⫽0.55, P⬍0.001 and r⫽0.56, P⬍0.001,
respectively).
Figure 4. Prevalence of coronary atherosclerosis by age with
0.5- and 0.3-mm thresholds for defining atherosclerotic lesions.
2708 Circulation June 5, 2001
Figure 5. Intimal thickness and area stenosis at sites with great-
est intimal thickness in all 1477 segments.
Angiographic Findings
Coronary arteriography was completely normal in 241 pa-
tients (92%). In 21 patients (8%), an angiographic luminal
irregularity was identified by the blinded observers. These
were typically subtle findings with an average percent diam-
eter narrowing of 23%. None of the donors ⬍30 years of age
had angiographic evidence of atherosclerosis; all 21 donors
with an angiographic disease were ⬎30 years old.
Lesions in Patients With 3-Vessel Imaging
To assess the distribution patterns of atherosclerosis in the
young, lesions were investigated separately in the subgroup
of 97 patients (1026 sites) in whom ultrasound imaging was
performed in all 3 epicardial coronaries. The mean age of
these patients was 32.4⫾13.2 years, and 58% were male
(similar to entire cohort). A lesion was present in the LAD in
41 patients (42%), the RCA in 38 (39%), and the LCx in 26
(27%). The proportion of segments with a lesion was
19⫾25% for the LAD, 12⫾23% for the LCx, and 18⫾26%
for the RCA.
Distribution and Composition of Lesions
Atherosclerotic lesions were identified in proximal segments
more frequently (59%) than mid and distal segments, and the
vast majority of lesions were eccentric (91%). The most
diseased site involved a coronary bifurcation in 43% of
patients. Calcification at ⱖ1 site by ultrasound was observed
in 33 patients (12.6%).
Discussion
Atherosclerotic coronary disease is the leading cause of death
and a major source of morbidity in developed countries,
resulting in nearly 1 million deaths and $100 billion in annual
costs in the United States alone.16 Necropsy studies have
demonstrated that atherosclerosis begins at a very early stage
in life. The present study provides unequivocal in vivo
evidence of atherosclerosis in young asymptomatic individ-
uals with no evidence of clinical coronary artery disease
(Figure 3). This study is unique because it provides detailed,
clinically relevant, quantitative, in vivo information on early
atherosclerosis from an asymptomatic young population.
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Necropsy studies dating back to 1948 describe coronary
atherosclerosis in a young population, but none have provided
quantitative measures of disease severity.1–5 In Korean and
Vietnam war victims, the degree of obstruction was judged by
gross inspection and microscopic examination performed
without pressure fixation. Stary, in an elegant study,17a
performed light and electron microscopy on pressure-fixed
segments of the proximal LAD and LCx in 565 subjects ⬍29
years old. The focus of this careful investigation, however,
was lesion morphology, not measurement of plaque thick-
ness, area stenosis, or lesion distribution. In the Pathological
Determinants of Atherosclerosis in Youth (PDAY) study, the
RCA was the only vessel examined.4 In the Korean War
study, as well as the Bogalusa and PDAY studies, dissection
of coronary arteries was longitudinal, not cross-
sectional.1,3,17b In contrast to these studies, the present inves-
tigation assessed atherosclerosis in vivo and quantified le-
sions with methods used in clinical practice.
Limited data are available to describe the range of normal
intimal thickness in humans. Using vessels that were not
pressure-fixed, a necropsy study showed an age-related de-
pendency of intimal thickness, averaging 0.21 mm for ages
21 to 25 years, increasing slightly to 0.25 mm for ages 36 to
40 years.18 Other small studies report normal intimal thick-
ness ranging from 0.1 to 0.35 mm and medial thickness from
0.15 to 0.25 mm.7,12,19
In the present study, we thought it particularly important to
rigorously define the threshold for presence of atherosclero-
sis. Previous ultrasound studies have established that intimal
thickness detected within 8 weeks of transplantation repre-
sents preexisting coronary atherosclerosis in the donor.7,20,21
Furthermore, there was no difference in the prevalence and
severity of intimal thickness in hearts that were examined 2 to
4 or 6 to 8 weeks after transplantation. Because all of the 262
subjects showed ⱖ1 site with an intimal thickness ⬍0.5 mm,
we felt justified in using this threshold as a conservative
definition of atherosclerosis. Because all patients ⬍40 years
of age showed ⱖ1 site with intimal thickness ⬍0.3 mm, this
latter value may actually represent a less stringent but more
reasonable definition for atherosclerosis. It is important to
recognize, however, that intimal thickness is a continuous
variable and that defining atherosclerosis as a categorical
variable has limitations. Furthermore, intimal thickness does
not necessarily indicate atherosclerosis. Morphological char-
acteristics of intimal thickening observed in this study helped
to identify the atherosclerotic origin of these findings. The
majority of the areas with intimal thickening were eccentric,
located proximally, adjacent to bifurcations.
Ultrasound techniques for quantification of intimal thick-
ness measure different boundaries than classic necropsy
studies. An ultrasound reflection occurs at a tissue interface
whenever there is an abrupt change in acoustic impedance.
Normally, 2 strong acoustic interfaces are visualized by
ultrasound: the leading edge of the intima (at the interface
between the blood-filled lumen and the endothelium) and the
outer border of the media (at the junction of the media and the
EEM). Accordingly, ultrasound techniques measure intimal
thickness from the intimal leading edge to the EEM, thus
including the media. This practice is used routinely in all
 Tuzcu et al
other ultrasound techniques, such as carotid or peripheral
vascular imaging, for quantification of atherosclerosis.22
Few lesions were detected by angiography, the traditional
“definitive” method for in vivo evaluation of the vascular
lumen. Angiograms were abnormal in only 8% of the full
cohort of 262 patients. No angiogram was abnormal in any
patient ⬍30 years old, yet 28% of these subjects had
ultrasound evidence of atherosclerosis. Angiography provides
excellent resolution but does not depict the vessel wall.7,23–25
Because compensatory remodeling is evident in many early
lesions, the lumen is usually preserved in the early phase of
the disease.26 Accordingly, angiography is insensitive for
early detection and estimation of lesion severity. The greater
sensitivity of IVUS is a result of its ability to provide
tomographic images of the vessel wall, which permits detec-
tion of disease before the onset of luminal narrowing.8,9,11,13,14
The present study represents a thorough interrogation of
the epicardial coronary arteries, including distal coronary
segments. No statistically significant differences were ob-
served in distribution of lesions within the different coronary
arteries, although there was a trend toward higher prevalence
in the LAD and the lower prevalence within the LCx, with
intermediate probability for the RCA. We were also able to
confirm the finding of previous necropsy studies that most
early lesions occur in proximal segments.27,28 Early disease is
highly eccentric (91% of lesions), with a strong predilection
for involvement at bifurcation sites (nearly half of lesions).
These findings suggest that flow patterns in the coronary
arteries may be particularly important in the genesis of the
early lesion.
Our findings regarding the high prevalence of atheroscle-
rosis in young people are consistent with those of most other
studies, including 2 small IVUS investigations. Examining
only the proximal LAD, St Goar et al8 reported a 24%
prevalence in 40 patients but no atherosclerosis in donors
⬍25 years old. We previously reported on multivessel imag-
ing in 50 patients with a prevalence rate of 56%.7 Gross
inspection of coronaries of the American soldiers killed in the
Korean and Vietnam wars demonstrated atherosclerosis in
77% and 45% of autopsies, respectively.12 In the Bogalusa
Heart Study, the prevalence in children ⬍15 years old was
8%, reaching 69% in adults between 26 and 40 years old.17
With a conservative definition of disease and imaging in vivo,
the prevalence rates in our study were similar, showing
unequivocal evidence of atherosclerosis in 28% of subjects
⬍30 years old and 17% of individuals ⬍20 years old. It is
possible that incidence of atherosclerosis in the young pop-
ulation is even higher because many potential donors were
rejected during pretransplant screening on the basis of clinical
or angiographic evidence of coronary artery disease. It is
important to recognize that coronary atherosclerosis de-
scribed in these studies represent early phases of a continuous
process. Some of those with atherosclerosis later develop
clinical coronary artery disease, frequently as a result of a
complication, such as plaque rupture.
In this study, the risk factor information was incomplete.
Thus, the impact of the risk factors other than age on the
development of atherosclerosis could not be adequately
assessed. In the PDAY and Bogalusa studies, however, the
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Atherosclerosis in Teens and Young Adults 2709
strong correlation between the conventional risk factors and
coronary atherosclerosis was documented.29 –31 It remains
unproven whether early intervention to curtail atherosclerosis
in this young population can limit the development of
symptomatic disease. The compelling in vivo data from this
study, however, along with previously published necropsy
data, emphasize the need to focus societal strategies to limit
death and disability from coronary heart disease on the young
population.
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 High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults:
Evidence From Intravascular Ultrasound
E. Murat Tuzcu, Samir R. Kapadia, Eralp Tutar, Khaled M. Ziada, Robert E. Hobbs, Patrick M.
McCarthy, James B. Young and Steven E. Nissen

Circulation. 2001;103:2705-2710
doi: 10.1161/01.CIR.103.22.2705
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