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(Circulation. 2001;103:2705.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults
Evidence From Intravascular Ultrasound
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{at}ccf.org
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Abstract |
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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 
0.5 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 50 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.
Key Words: atherosclerosis • ultrasonics • plaque • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although patients with coronary artery disease typically become symptomatic after age 40 years, necropsy studies have demonstrated that atherosclerotic changes in the vessel wall begin early in life.1 2 3 4 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 10 11 12 Comparative studies have documented a close correlation between ultrasound measurements 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 investigation 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 atherosclerotic disease process.
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Methods |
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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.
IVUS Examination
The method of IVUS imaging has been reported
previously in detail.7 After
coronary angiography, patients received anticoagulation with
heparin, and 100 to 200 µg nitroglycerin IC was
administered. A 30-MHz, 3.5F monorail ultrasound catheter (Boston
Scientific) was advanced over an angioplasty guidewire to a distal
location in the coronary artery, and the position of the
transducer was documented by angiography. Ultrasound images were
displayed with a dedicated scanner
(Hewlett-Packard Corp) and recorded on S-VHS
tape during a slow, distal-to-proximal manual pullback. During
pullbacks, voice annotation and frequent angiography were used to
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
digitized full-motion IVUS sequences (30 frames per second) at a
640x480 pixel matrix with 24 bits per pixel. Images were considered
suitable for analysis if they were free of ultrasound
artifacts, such as extreme catheter angulation or nonuniform rotational
distortion. 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 characteristics and severity:
Atherosclerotic
lesion: Any site with an intimal thickness 0.5
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 areax100
Angiographic Analysis
Coronary angiography was performed by
standard techniques. Angiograms 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.
Statistical Analysis
Normally distributed data were reported as mean±SD,
and categorical variables were expressed as number and percentage
of the cohort.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 donor characteristics are listed in the Table
.
In the 262 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.
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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.
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Prevalence of
Atherosclerosis
Of 262 individuals, 136 (51.9%) had 1
atherosclerotic site (intimal thickness >0.5 mm)
(Figure 2). In these 136 subjects, 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 1 site
with intimal thickness exceeding the 0.3-mm or 0.5-mm thresholds used
for the definition of atherosclerosis
(Figure 4). Strikingly, when the more stringent definition of
>0.5 mm was used, even the 12- to 19-year-old age group showed
atherosclerosis in 17% of subjects. By age 40 years,
>70% of individuals showed 1 coronary site with an intimal
thickness >0.5 mm. With a less conservative threshold of 0.3
mm, 21% of teenagers and 91% of individuals >40 years old had 1
atherosclerotic lesion.
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Intimal Thickness and Stenosis
Severity
From each of the 1477 CASS segments, the sites
with the largest value for intimal thickness, whether normal or
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).
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Angiographic Findings
Coronary arteriography was completely normal in
241 patients (92%). In 21 patients (8%), an angiographic luminal
irregularity was identified by the blinded observers. These were
typically subtle findings with an average percent diameter 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 1 site by ultrasound was observed in 33 patients
(12.6%).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 individuals 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. Necropsy studies dating back to 1948 describe coronary atherosclerosis in a young population, but none have provided quantitative measures of disease severity.1 2 3 4 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 thickness, 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 investigation assessed atherosclerosis in vivo and quantified lesions 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 dependency 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 thickness 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
atherosclerosis. Previous ultrasound studies have
established that intimal thickness detected within 8 weeks of
transplantation represents 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 1 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 1 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
characteristics 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 thickness 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 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 24 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 detection 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 observed 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 atherosclerosis 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 imaging 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.17A 17B 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 population 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 described 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 strong correlation between the conventional risk factors and coronary atherosclerosis was documented.29 30 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.
Received December 11, 2000; revision received March 14, 2001; accepted March 15, 2001.
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K. Winkler, B. R. Winkelmann, H. Scharnagl, M. M. Hoffmann, A. B. Grawitz, M. Nauck, B. O. Bohm, and W. Marz Platelet-Activating Factor Acetylhydrolase Activity Indicates Angiographic Coronary Artery Disease Independently of Systemic Inflammation and Other Risk Factors: The Ludwigshafen Risk and Cardiovascular Health Study Circulation, March 1, 2005; 111(8): 980 - 987. [Abstract] [Full Text] [PDF]
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H. J. Eisen Adverse outcomes from the use of older donor hearts in cardiac transplant recipients: The pros and cons of expanded donor criteria J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1562 - 1564. [Full Text] [PDF]
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S. E. Nissen Pathobiology, not angiography, should guide managementin acute coronary syndrome/non-ST-segment elevation myocardial infarction: The non-interventionist's perspective J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 103S - 112S. [Abstract] [Full Text] [PDF]
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M. H. Yamani, E. M. Tuzcu, R. C. Starling, N. B. Ratliff, Y. Yu, D. G. Vince, K. Powell, D. Cook, P. McCarthy, and J. B. Young Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor ({alpha}v{beta}3), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy Circulation, April 23, 2002; 105(16): 1955 - 1961. [Abstract] [Full Text] [PDF]
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