Clinical Science (1999) 97, 615–624 (Printed in Great Britain)
R
E
V
I
E
W
Detection of presymptomatic atherosclerosis:
a current perspective
Mark R. ADAMS and David S. CELERMAJER
Department of Cardiology, Royal Prince Alfred Hospital, and the Heart Research Institute, Missenden Road, Camperdown,
Sydney, NSW 2050, Australia
A
B
S
T
R
A
C
T
Atherosclerosis, the pathological process underlying myocardial infarction, stroke and other
occlusive vascular disease, is the major cause of death in the Western world. The development
of techniques to accurately and reproducibly detect and measure the early changes of
atherosclerosis and/or to identify subjects at highest cardiovascular risk may aid in the
development of prevention strategies and facilitate a decrease in morbidity and mortality from
atherosclerosis. Increasing understanding of the pathophysiology of early atherosclerosis has
allowed the development of a number of potential methods for the assessment of the early stages
of atherosclerosis in humans. These include techniques for assessing early structural changes in
the coronary arteries with electron-beam computed tomography and magnetic resonance
imaging. External vascular ultrasound has also been used to image other circulations as a
surrogate marker for coronary atherosclerosis, e.g. the measurement of carotid artery intimamedia thickness. Early functional changes of atherosclerosis have also been described many years
before the development of structural changes. A number of techniques have been developed to
measure endothelial dysfunction, one of the earliest changes of atherosclerosis, including noninvasive measurement of endothelial function using external vascular ultrasound. A variety of
serum markers have also been described, and may be useful markers of atherosclerosis. We
discuss some of the more promising techniques for the detection of early, presymptomatic
atherosclerosis.
INTRODUCTION
Atherosclerosis, the pathological process underlying
myocardial infarction, stroke and other occlusive vascular
disease, is the major cause of death in the Western world
[1]. Although death rates from coronary artery disease
have declined in the United States of America and many
other industrialized countries during the last two or three
decades, cardiovascular causes of death still account for
40–50 % of deaths in these countries [2]. Importantly, if
causes of premature death (under 70 years) are examined,
coronary artery disease is by far the largest single cause of
death. In addition, since the prevalence of atherosclerosis
appears to be increasing in developing countries [1], it
may become the single largest health problem worldwide
in the near future.
Although there have been some recent improvements
in the treatment of the manifestations of atherosclerosis,
most of the improvements in mortality seem to be due to
lifestyle changes in the community, such as smoking
cessation and better eating habits, and to improvement in
risk factor management [3]. Coronary atherosclerosis is a
disease that has a long ‘ lag phase ’ between the early
phases of the disease and the development of clinical
syndromes [4]. Therefore interventions aimed at improving death rates from coronary artery disease may be
more effective if the early stages of atherosclerosis are
targeted, rather than secondary prevention and treatment
of the complications of coronary artery disease.
Macroscopic changes, such as fatty streaks and atheroma, are frequently present in the coronary arteries of
teenagers and young adults [5], with up to half of children
Key words : atherosclerosis, endothelium, nitric oxide, ultrasound.
Abbreviations : ICAM, intercellular adhesion molecule ; LDL, low-density lipoprotein.
Correspondence : Dr. David S. Celermajer (e-mail davidc!card.rpa.cs.nsw.gov.au).
# 1999 The Biochemical Society and the Medical Research Society
615
616
M. R. Adams and D. S. Celermajer
of 10–14 years of age having fatty streaks in their
coronary arteries [6]. It has been demonstrated that
endothelial dysfunction, a key early event in atherogenesis, may be present even in children as young as 6
years of age [7,8]. The endothelial dysfunction present in
childhood and teenage years relates to the presence of
traditional risk factors, including hypercholesterolaemia,
a family history of premature coronary artery disease,
hypertension and cigarette smoking. Intervention at such
an early stage, before the establishment of advanced
atherosclerotic plaques, might be expected to give the
maximum possible benefit in reducing the late complications of atherosclerosis.
Older subjects also manifest endothelial dysfunction,
as well as structural changes in the vessel wall, such as
intimal thickening and overt atherosclerotic plaques.
Both of these factors, and their interaction, are intimately
involved in the development of clinical ischaemic
syndromes [9]. Although there may be a continuum
between the early stages of functional abnormalities and
those subjects with advanced atherosclerosis, different
strategies may be required in managing these groups. In
subjects with established atherosclerosis, it may be more
important to measure the structural changes of atherosclerosis to aid in guiding more aggressive therapeutic
interventions.
The development of techniques to accurately and
reproducibly detect and measure the early changes of
atherosclerosis and\or to identify subjects at highest
cardiovascular risk would allow the evaluation of therapeutic strategies, and may allow identification of those
individual subjects likely to benefit from intervention.
Increased understanding of the pathophysiology of early
atherosclerosis has allowed the development of a number
of potential methods for the assessment of the early
stages of atherosclerosis in humans.
STRUCTURAL AND FUNCTIONAL CHANGES
IN EARLY ATHEROSCLEROSIS
The process of atherogenesis is complex, and involves
interactions between many cell types, the development of
endothelial injury, vessel wall thickening and, ultimately,
the formation of plaque [4]. In recent years there have
been many advances in the understanding of early
functional changes, and as these events generally occur
before the development of structural changes in the vessel
wall, they have been of particular interest to researchers.
Such functional changes include decreased local availability of endothelial-derived nitric oxide, enhanced
surface expression of cellular adhesion molecules,
changes in markers of inflammation, production of
cytokines, and oxidative modification of lipoproteins,
among others [10–12]. Among the many functional
# 1999 The Biochemical Society and the Medical Research Society
changes in the early stages of atherosclerosis, the measurement of endothelial nitric oxide has been of particular
interest, and a variety of both invasive and non-invasive
techniques have been developed to study this in vivo [13].
Similarly, a variety of methods have been developed for
studying some of the other functional changes, as
manifest in peripheral blood samples [13], and these will
be discussed below.
Structural alterations in the vessel wall occur at a later
stage than functional changes ; however, subtle changes,
such as increased vessel wall thickness and calcification,
may develop many years prior to the onset of symptomatic atherosclerosis. Investigators have studied the
peripheral circulation with ultrasonography, measuring
intima-media thickness and presymptomatic atherosclerotic plaque, either as a marker of disease in peripheral
circulations or as a surrogate for the coronary circulation
[14]. In addition, early changes in the coronary circulation have been documented with invasive techniques
such as coronary angiography and intravascular ultrasound, and more recently with non-invasive techniques
such as electron-beam computed tomography and
magnetic resonance imaging [15–17].
Stress testing is used by some clinicians to screen
individuals for presymptomatic coronary artery disease.
Regardless of whether electrocardiographic, echocardiographic or nuclear imaging end-points are used, the
technique relies on the presence of obstructive coronary
artery lesions. As a result, there is a high incidence of
false-positive stress tests in low-risk populations ; in
addition, considering that the majority of acute cardiac
events occur at the site of non-obstructive plaques, the
technique has a poor positive predictive value for future
clinical events in asymptomatic subjects [18,19].
In detecting presymptomatic atherosclerosis, it is
important that the technique used is reliable and reproducible. When utilized in clinical trials, it should be
accurate and reflect the clinical outcome, and when used
for screening individuals it needs to have good sensitivity
and specificity. A number of measures have proven to be
predictive of coronary artery disease in population
studies, but not when applied to individual subjects
[20,21]. In either case the test should be safe and free from
unpleasant side effects, and ideally the technique should
be non-invasive. At present no ideal test for the detection
and measurement of early atherosclerosis exists ; however, there have been many recent advances in this area,
particularly with non-invasive imaging and the study of
peripheral blood samples [13].
ARTERIAL ENDOTHELIAL FUNCTION
TESTING
Endothelial dysfunction is an early event in the development of atherosclerosis and plays a central role in
Detection of presymptomatic atherosclerosis
the pathogenesis of atherosclerosis, as well as in the
progression to clinical syndromes of ischaemia [4]. As a
result the measurement of endothelial dysfunction has
been of interest to investigators studying both the early
stages of atherogenesis and its later consequences. A
method for studying endothelial function in vivo was
first described by Ludmer et al. in 1986, involving the
assessment of the conduit vessels of the coronary
circulation [22]. This technique is invasive, requiring
cardiac catheterization, and involves the measurement of
changes in coronary artery diameter in response to intraarterial infusions of various pharmacological agents.
Although this technique has proven to be a valuable
research tool, giving many insights into coronary artery
physiology [23–27], it has the disadvantage of being
invasive. The risk of complications from cardiac instrumentation has made serial studies using this method
unattractive, and studies of truly early atherosclerosis,
which may be present in asymptomatic children and
young adults [6], practically impossible.
Some inroads have been made in the non-invasive
measurement of endothelial function in the coronary
microcirculation, as manifest by coronary flow reserve.
Using transthoracic doppler\echocardiography, it has
recently become feasible to assess flow in the left anterior
descending artery, and thus to assess coronary flow
reserve in this vascular territory [28]. Although this
technique is not suitable in all subjects and is in the early
stages of development, it may become more useful as
ultrasound technology improves. Similarly, cardiac
magnetic resonance imaging with breath-holding and
phase-contrast velocity mapping has allowed the noninvasive assessment of coronary flow reserve [29]. This
technique is also at an early stage of development, and
further investigation is required to determine its clinical
utility. Positron emission tomography also allows
measurement of myocardial blood flow, utilizing
isotopes such as "&O-labelled water [30]. This technique
has been used to demonstrate reduced coronary flow
reserve in subjects without overt coronary artery disease
but with coronary risk factors such as hypercholesterolaemia [31,32]. Its widespread use, however,
may be limited by a lack of access to such technology, its
expense, and the problem of radiation exposure.
Peripheral large vessel function
At present, invasive methods remain the only well
established means of assessing both large and small vessel
coronary endothelial function in vivo. For this reason,
measurement of endothelial function in peripheral arterial beds as a surrogate for the coronary circulation has
been assessed. In vivo measurement of endotheliumdependent dilatation in peripheral arteries using ultrasound was first described in 1992 [7]. This technique uses
high-resolution external vascular ultrasound to measure
changes in arterial diameter (in most cases in the brachial
Figure 1 Relationship between vascular risk factors and
flow-mediated dilatation (FMD)
Risk factor scores were calculated from a composite of smoking history, cholesterol
level, age, male gender and family history. Each box represents the interquartile
range, with the mean bar placed horizontally within each box. Reprinted with
permission from the American College of Cardiology [Journal of the American
College of Cardiology (1994) 24, 1468–1474].
or femoral artery) in response to reactive hyperaemia.
This hyperaemic response is induced by inflating a
pneumatic cuff distal to the imaging site to suprasystolic
pressure for approximately 4 min, resulting in transient
ischaemia distally. This results in increased flow within
the study artery ; in normal arteries, this is known to
cause an increase in the activity of endothelial nitric oxide
synthase, via the activation of shear force receptors on the
cell surface. Following this, the artery is assessed using an
endothelium-independent stimulus such as the administration of sublingual nitroglycerin, thus assessing the
vessel’s intrinsic ability to dilate. It has been shown that
this flow-mediated dilatation is dependent mainly on the
endothelial release of nitric oxide, as it can be almost
completely eliminated by the intra-arterial infusion of the
nitric oxide synthase inhibitor NG-monomethyl-L-arginine [33]. In addition, the peripheral response in the
brachial artery has been shown to correlate closely with
endothelial function measured invasively in the coronary
arteries [34], and with the severity of coronary artery
disease [35].
It has been possible using this technique to demonstrate that endothelial dysfunction is present in children as young as 6 years of age who have risk factors
for coronary artery disease, such as familial hypercholesterolaemia or passive smoking [7,8,36]. Investigators have shown that healthy adults with risk
factors such as hypercholesterolaemia, older age, cigarette
smoking, diabetes and male gender may have abnormal
endothelial function [37–40], and that these risk factors
may interact in producing impairment of endothelial
# 1999 The Biochemical Society and the Medical Research Society
617
618
M. R. Adams and D. S. Celermajer
function [38] (Figure 1). The technique is non-invasive,
well tolerated and reproducible [41], factors that have
facilitated its use as an end-point in clinical trials of
interventions aimed at improving endothelial function. A
number of clinical trials have utilized the measurement of
brachial artery flow-mediated dilatation to evaluate such
interventions in both acute and longer-term studies
[42–45]. For example, Clarkson and colleagues [43] found
that 1 month of dietary supplementation with oral Larginine in healthy hypercholesterolaemic young adults
resulted in an improvement of flow-mediated dilatation
from 1.7 % to 5.6 %. Similarly, Kugiyama et al. [44]
recently found that 1 month of supplementation with αtocopherol in older subjects produced a 3.3 % improvement in flow-mediated dilatation.
Although this technique has now been used extensively
in placebo-controlled trials and cross-sectional population studies, its utility in assessing the prognosis of
individual subjects requires further evaluation. In this
respect, it may be limited by a number of factors. The
technique is difficult to perform, being dependent on an
experienced operator. In addition, results are influenced
by a number of factors, such as vessel size and fasting
state, and there is some diurnal variation [45,46]. For
these reasons, the use of brachial artery flow-mediated
dilatation measurement cannot be recommended in
routine clinical practice, although this may change as
improved scanning methods and more data become
available.
Peripheral microcirculation
Techniques have also been developed to evaluate microvascular endothelial function in peripheral systemic
circulations. One such method is that described by
Panza et al. [47] for measuring endothelium-dependent
vasodilatation in the forearm circulation with
plethysmography, in response to intra-arterial infusions
of endothelium-dependent vasodilators. This technique
has demonstrated abnormal microvascular endothelial
function in the presence of coronary risk factors [48,49],
and has shown that these abnormalities can be acutely
reversed with certain interventions [50,51]. Although this
method is less invasive than coronary angiography, it still
requires the placement of an intra-arterial catheter. Other
less invasive techniques of measuring small vessel function have been described, e.g. measurement of laser
doppler fluximetry responses to acetylcholine and sodium nitroprusside delivered by iontophoresis [52]. It is
not known, however, whether the changes in the microvascular circulation are related to the development of
atherosclerosis in larger conduit vessels, or whether
forearm microvascular responses correlate with coronary
physiology.
Despite the important information gained from studies
of endothelial function, there are only limited data to link
endothelial dysfunction with later clinical outcomes [53].
# 1999 The Biochemical Society and the Medical Research Society
There is evidence to suggest that the degree of endothelial
dysfunction may correlate with the severity of coronary
artery disease [54] ; however, the prognostic value of
finding endothelial dysfunction in individual subjects is
unknown. Large prospective studies, with clinical outcome measures, are required to assess whether asymptomatic, healthy subjects with endothelial dysfunction are
at increased risk of later cardiac events.
MEASUREMENT OF BIOCHEMICAL,
MOLECULAR AND CELLULAR CHANGES
Although a multitude of factors have been measured in
the blood of subjects with established atherosclerosis, as
yet no blood test exists that can reliably and accurately
predict the presence and severity of atherosclerosis. Most
attention has focused on the measurement of major
serum risk factors, such as total cholesterol, low-density
lipoprotein (LDL)-cholesterol and lipoprotein (a), which
correlate with the extent of coronary artery disease with
r-values in the range 0.2–0.3 [55–57]. Serum and lipoprotein levels of antioxidant vitamins, and the level of oxidation of LDL, have been disappointing predictors of
coronary artery disease [58]. Although the susceptibility
of LDL to oxidation has been correlated with the
presence of some coronary risk factors [59], there is little
evidence to suggest that this will be a useful measure of
atherosclerosis in vivo in human subjects. Products
of lipid peroxidation, such as F2-isoprostane, have been
found in relation to risk factors such as smoking and in
the presence of coronary artery disease [60,61] ; these, as
well as novel products of lipid oxidation and lipoproteinbound oxysterols such as 7-oxocholesterol, may prove to
be useful markers of early atherosclerosis in the future
[62].
In response to various insults promoting endothelial
damage, endothelial cells and products of such cells have
been detected in peripheral blood samples. Some of these
have been investigated as potential markers of atherosclerosis. Levels of von Willebrand factor, a glycoprotein
involved in haemostasis and produced by endothelial
cells, are elevated in the setting of endothelial damage
[63]. Furthermore, levels of von Willebrand factor are
elevated in hypercholesterolaemia, and may be reduced
after lowering of cholesterol levels [64]. Tissue plasminogen activator and plasminogen activator inhibitor-1
are produced by endothelial cells, and the physiological
balance of these two factors is involved in controlling
fibrinolysis. Levels of both may be increased in response
to endothelial cell insults, such as those mediated by
hypercholesterolaemia [65]. These levels also correlate
with increased carotid intima-media thickness, as well
as with the subsequent risk of vascular events [66,67].
Adhesion molecules produced by endothelial cells may
be released into peripheral blood due to endothelial cell
Detection of presymptomatic atherosclerosis
injury. Similarly, markers of decreased fibrinolytic activity, such as elevated levels of plasminogen activator
inhibitor-1, may correlate with future cardiovascular
morbidity [68]. Increased levels of intercellular adhesion
molecule-1 (ICAM-1) and E-selectin have been documented in patients with established coronary artery
disease, as well as in asymptomatic subjects with early
structural changes [69,70]. Levels of other endothelial
products, such as thrombomodulin and endothelin-1,
may be altered due to endothelial cell damage [71,72] ;
however, the applicability of these measures in individual
subjects to predict cardiovascular events requires further
study.
Markers of inflammation, such as C-reactive protein,
serum amyloid protein A and cytokines (e.g. interleukin1β and tumour necrosis factor-α) are elevated in atherosclerosis, and particularly during acute coronary
syndromes [9,69]. Mildly elevated levels of C-reactive
protein may also be predictive of coronary events in
otherwise healthy adults [73]. Non-specific markers of
endothelial cell activation, such as soluble ICAM-1 and
vascular cell adhesion molecule-1 (VCAM-1), have been
found in subjects with atherosclerosis [74], and may
correlate with the risk of future vascular events [69].
Whether these markers of inflammation are intimately
involved in the pathophysiology of atherosclerosis, or are
a reflection of the underlying inflammatory process, is
unknown.
Monocyte adhesion to endothelial cells, with subsequent migration into the subintimal space and the
formation of foam cells, is a key early event in atherosclerosis [4]. Therefore the detection of activated monocytes may be an indicator of the early stages of atherogenesis. Markers of monocyte activation, such as the level
of monocyte integrins like CD-11b and the level of
nuclear factor-κB activation, are known to be elevated in
atherosclerosis, and also seem to be particularly raised
in acute coronary syndromes [75,76]. In addition to these
molecular markers, it may be possible to measure the
cellular behaviour of monocytes derived from peripheral
blood samples, for example by testing their adhesiveness
to endothelial cells ex vivo [76]. All of these markers,
however, may be relatively non-specific for the presence
of atherosclerosis, being abnormal either simply due to
the presence of risk factors or due to other causes of
inflammation [77,78].
ULTRASOUND MEASUREMENT OF VASCULAR
STRUCTURE
Detailed information about the structure of the coronary
artery wall can be obtained using intravascular ultrasound. Advances in intracoronary ultrasound catheters
have made it possible to measure reliably structural
changes within the coronary arteries, from the detection
of very early intimal thickening to the measurement of
plaque volume in advanced atherosclerosis [79–81].
Utilizing this technique, early presymptomatic changes
have been documented in high-risk subjects, such as
cardiac transplant recipients [79]. While the information
derived from an intravascular ultrasound examination is
potentially of great interest, its use as a research tool is
limited by the expense of the procedure, and more
importantly by its invasive nature [82]. As a result, much
interest has focused on the use of non-invasive external
vascular ultrasound to examine other vascular beds as
surrogate markers of coronary artery disease.
Measurement of vessel wall thickness is feasible in
superficial arteries, such as the carotid and femoral
arteries, using external vascular ultrasound. Carotid
artery intima-media thickness in particular has been
proposed as an early manifestation of atherosclerosis, and
its measurement has been used as an end-point in clinical
trials of disease regression [83–85]. Carotid intima-media
thickness, measured with B-mode ultrasound, correlates
well with the distance between the vessel lumen and the
periadventitia–adventitia interface [86]. This measurement can be made reliably and reproducibly in the
common carotid and bifurcation, and to a lesser extent in
the internal carotid [87]. Ultrasound has not proven to be
as useful in the reliable measurement of actual plaque size
or volume ; however, it may prove to be useful in assessing
the morphology of plaques, such as in demonstrating
intraplaque haemorrhage [88,89].
Carotid intima-media thickness has been shown to
increase with age and to correlate with atherosclerosis in
other vascular beds [90], as well as with the presence of
vascular risk factors such as older age, cigarette smoking,
increased LDL-cholesterol, hypertension and diabetes
[83,85,91]. Increased carotid intima-media thickness may
pre-date the development of symptomatic atherosclerosis
by many years, and it has been demonstrated in children
at risk of atherosclerosis as young as age 7 years [92].
Furthermore, several studies have linked increased carotid intima-media thickness with an increased risk of
subsequent cardiovascular events [83,93] (Figure 2).
These factors, as well as the simple, non-invasive and
rapid nature of carotid ultrasound, have made it an
excellent technique for serial studies of subjects in clinical
trials.
A number of investigators have therefore used such
measurements as an end-point in trials of atherosclerosis
regression [84,85]. For example, the CLAS trial demonstrated a reduction in carotid intima-media thickness of
0.05 mm over 3 years in subjects receiving cholesterollowering therapy, compared with a progression of
0.07 mm in subjects with placebo therapy [85]. Although
measurement of intima-media thickness in the carotid
artery has been useful in such clinical trials, the small
magnitude of the changes seen has limited its serial use to
trials studying large numbers of subjects. Whether carotid
# 1999 The Biochemical Society and the Medical Research Society
619
620
M. R. Adams and D. S. Celermajer
Figure 2 Incidence of myocardial infarction or stroke according to quintile of carotid artery intima-media thickness
There is an increase in the yearly incidence of stroke and myocardial infarction
with increasing quintiles of carotid intima-media thickness. CCA, common carotid
artery ; ICA, internal carotid artery ; IMT, intima-media thickness. Reprinted with
permission from N. Engl. J. Med. (1999) 340, 14–22 ; Copyright# 1999
Massachusetts Medical Society. All rights reserved.
ultrasound will prove to be a useful tool in guiding
treatment of high-risk subjects and following their
progress requires further evaluation ; however, its use as a
surrogate measure in predicting the presence of clinically
relevant coronary artery disease may be limited by a lack
of precise correlation [20].
Arterial wall thickness in other vascular beds has been
less extensively studied than in the carotid circulation ;
however, there is some evidence that femoral artery
intima-media thickness correlates with coronary
artery atherosclerosis [88], and that descending aortic
plaque, as assessed by trans-oesophageal echocardiography, may relate to the presence of coronary artery
disease [94]. A variety of other simple functional
measures have been described that have been used in
large-scale epidemiological studies as markers of presymptomatic atherosclerosis. For example, the ankle\
brachial pressure indices are often used in studies of
atherosclerosis and risk factors [95], although they are
probably more useful in the assessment of asymptomatic,
but established, disease. Also, their predictive power for
coronary artery disease makes them less useful in
individual subjects. These techniques require further
evaluation.
ELECTRON-BEAM COMPUTED
TOMOGRAPHY
Ultrafast computed tomography is a new imaging technique using electron-beam technology that allows image
acquisition at a very rapid rate. The speed of its scanning
rate makes it useful in cardiac imaging, where movement
during the cardiac and respiratory cycle has limited
conventional computed tomography [96]. Calcium
# 1999 The Biochemical Society and the Medical Research Society
makes up approximately 20 % of plaque volume, and the
association of coronary artery calcium with atherosclerotic plaque has been well known for many years
[97]. In addition, the deposition and turnover of calcium
within atherosclerotic plaques is an active process, with
cells within plaques elaborating osteocalcin and osteopontin, among other products [98]. Despite this, however, the deposition of calcium within plaques is not
uniform. Smaller plaques, which may be active, as well as
some high-grade stenoses may completely lack detectable
levels of calcium [99]. Until the development of ultrafast
computed tomography, however, accurate imaging of
this calcium in vivo was not possible. This detection
of coronary calcium seems to correlate well with
histological changes [15,100], and several studies have
documented sensitivity for detecting obstructive coronary artery disease in the range 80–100 % [98]. Although
the specificity is less impressive, some of the studies have
found a relationship between the degree of coronary
calcification and the risk of subsequent coronary events
[101].
Serial changes in coronary calcium content have been
documented in clinical trials of lipid lowering [101],
although it is not certain that these changes reflect
changes in plaque volume. Ultrafast computed tomography may prove to be a useful measure in evaluating
the progression\regression of coronary atherosclerosis.
Unfortunately, the technique has a low specificity for
clinically relevant obstructive coronary artery disease
[102], and as some plaques lack calcium altogether its
positive predictive value is not sufficient to replace
coronary angiography. In addition, coronary angiography remains relatively safe [103], allows imaging of
the complete coronary circulation, and may serve to
guide therapeutic interventions such as coronary angioplasty. Although electron-beam computed tomography
has proven useful in a variety of large epidemiological
studies, more prospective data are required to determine
its utility in clinical decision-making situations. Initial
data, however, suggest that the technique may not
accurately predict clinical events in individuals. Recently
Detrano and colleagues [21] studied 1196 high-risk
individuals and found that the presence of calcium in
coronary arteries did not accurately predict future cardiac
events. For these reasons, as well as those of cost and
radiation exposure, the technique cannot yet be recommended as a routine screening test in high-risk subjects [104]. Some of these problems may be overcome
in the future with the use of contrast enhancement and
the development of scanners with improved resolution.
MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging is a potentially useful tool
for assessing early atherosclerosis, as not only is it non-
Detection of presymptomatic atherosclerosis
invasive and safe, but it yields information on flow as well
as tissue characterization [29,105]. Magnetic resonance
imaging is used routinely in clinical practice to assess
arteries in the peripheral circulation, in particular
the cerebral arteries and the aorta [106] ; however, the
application of magnetic resonance imaging to the coronary circulation has been limited by the relatively small
size of these arteries and the rapid movements they
undergo during the cardiac and respiratory cycles.
Application of magnetic resonance imaging to the study
of the coronary circulation is particularly attractive, as it
would allow simultaneous acquisition of information on
the anatomy and ultrastructure of coronary arteries, as
well as cardiac perfusion, metabolism and function. The
use of ultrafast magnetic resonance imaging angiography
with breath holding and electrocardiographic gating still
provides only a relatively poor image of the coronary
lumen, resulting in poor sensitivity for the detection of
coronary atherosclerosis [17]. Magnetic resonance
imaging has been used effectively to measure plaque and
to visualize plaque ultrastructure in arteries ex vivo, as
well as in experimental animal studies and some human
superficial arteries in vivo [107]. These studies have
yielded important information regarding plaque architecture and behaviour under various conditions.
Although the use of magnetic resonance imaging is
limited by cost, the ability to apply this technique to the
coronary circulation would represent an exciting development in the study of presymptomatic atherosclerosis.
NUCLEAR MEDICINE
The majority of nuclear medicine techniques have proven
disappointing in the imaging of preclinical atherosclerosis, or even clinically relevant lesions. Techniques such
as the use of radiolabelled lipoproteins and immunoglobulins have been limited by poor target-to-background ratios in the coronary and carotid circulations
[108]. Peptides and monoclonal antibody fragments
directed at different components of the atherosclerotic
plaque and labelled with Technitium-99m have shown
some promise in early studies, and radiolabelled peptides
directed against the glycoprotein IIb\IIIa receptors on
activated platelets may have some use in imaging intraarterial thrombus [30].
CONCLUSIONS
Increased understanding of the pathophysiology
involved in the early stages of atherosclerosis has led to a
proliferation of methods to detect the early stages of the
disease in high-risk subjects. Techniques have been
developed to assess early functional changes, such as the
loss of endothelial nitric oxide production, and to assess
early structural changes, such as increased intima-media
thickness and coronary calcium. Although these tests
have proven useful in defining risk in large population
studies and in clinical trials, no one test currently exists
that is suitable for screening individual subjects in clinical
practice. Without a reliable test to identify high-risk
individuals, the task of targeting those who may benefit
from early intervention is difficult. At this stage novel
blood tests, ultrasound imaging of arteries and coronary
artery computed tomography appear to be the most
promising avenues for future research. The increasing incidence of atherosclerosis worldwide, and increasing
pressure on health resources, make the development of
such a screening test a vital aim of cardiovascular research
at the start of the new millennium.
REFERENCES
1 World Health Organisation (1994) World Health Statistics
Annual. World Health Organisation, Geneva
2 National Heart Foundation (1995) Heart and Stroke Facts.
National Heart Foundation of Australia, Canberra
3 Goldman, L. and Cook, E. F. (1984) The decline in
ischemic heart disease mortality rates. An analysis of the
comparative effects of medical interventions and changes in
lifestyle. Ann. Intern. Med. 101, 825–836
4 Ross, R. (1993) The pathogenesis of atherosclerosis ; a
perspective for the 1990s. Nature (London) 362, 801–809
5 Stary, H. C. (1989) Evolution and progression of
atherosclerotic lesions in coronary arteries of children and
young adults. Arteriosclerosis 9, I19–I32
6 Stary, H. C., Chandler, A. B. and Glagov, S. (1994) 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 89, 2462–2478
7 Celermajer, D. S., Sorensen, K. E., Gooch, V. M. et al.
(1992) Non-invasive detection of endothelial dysfunction
in children and adults at risk of atherosclerosis. Lancet
340, 1111–1115
8 Sorensen, K. E., Celermajer, D. S., Georgakopoulos, D.,
Hatcher, G., Betteridge, D. J. and Deanfield, J. E. (1994)
Impairment of endothelium-dependent dilation is an early
event in children with familial hypercholesterolemia and is
related to the lipoprotein(a) level. J. Clin. Invest. 93, 50–55
9 Libby, P. (1995) Molecular basis of acute coronary
syndromes. Circulation 91, 2844–2850
10 Nilsson, J. (1986) Growth factors and the pathogenesis of
atherosclerosis. Atherosclerosis 62, 185–199
11 Dinerman, J. L. and Mehta, J. L. (1990) Endothelial,
platelet and leukocyte interactions in ischemic heart
disease : insights into potential mechanisms and their
clinical relevance. J. Am. Coll. Cardiol. 16, 207–222
12 Jang, Y., Lincoff, A. M., Plow, E. F. and Topol, E. J.
(1994) Cell adhesion molecules in coronary artery disease.
J. Am. Coll. Cardiol. 24, 1591–1601
13 Celermajer, D. S. (1997) Endothelial dysfunction : does it
matter ? Is it reversible ? J. Am. Coll. Cardiol. 30, 325–333
14 Probstfield, J. L., Byington, R. P., Egan, D. A. et al. (1993)
Methodological issues facing studies of atherosclerotic
change. Circulation 87, II74–II81
15 Waller, B. F. (1989) Atherosclerotic and nonatherosclerotic coronary artery factors in acute myocardial
infarction. In Acute Myocardial Infarction (Pepine, C.,
ed.), pp. 29–104, F. A. Davis Co., Philadelphia
16 Brundage, B. H. (1995) Beyond perfusion with ultrafast
computed tomography. Am. J. Cardiol, 75, 69D–73D
17 Manning, W. J., Li, W. and Edelman, R. R. (1993) A
preliminary report comparing magnetic resonance
coronary angiography with conventional angiography.
N. Engl. J. Med. 328, 828–832
# 1999 The Biochemical Society and the Medical Research Society
621
622
M. R. Adams and D. S. Celermajer
18 Rozanski, A. and Berman, D. S. (1987) Efficacy of
cardiovascular medicine exercise studies. Semin. Nucl.
Med. 2, 104–120
19 Fishbein, M. C. and Siegel, R. J. (1996) How big are
coronary atherosclerotic plaques that rupture ? Circulation
94, 2662–2666
20 Adams, M. R., Nakagome, A., Keech, A. et al. (1995)
Carotid intima-media thickness is only weakly correlated
with the extent and severity of coronary artery disease.
Circulation 92, 2127–2134
21 Detrano, R. C., Wong, N. D., Doherty, T. M. et al. (1999)
Coronary calcium does not accurately predict near-term
future coronary events in high-risk adults. Circulation 99,
2633–2638
22 Ludmer, P. L., Selwyn, A. P., Shook, T. L. et al. (1986)
Paradoxical vasoconstriction induced by acetylcholine in
atherosclerotic coronary arteries. N. Engl. J. Med. 315,
1046–1051
23 Drexler, H. and Zeiher, A. M. (1991) Progression of
coronary endothelial dysfunction in man and its potential
clinical significance. Basic Res. Cardiol. 86, 223–232
24 Drexler, H., Zeiher, A. M., Meisner, K. and Just, H. (1991)
Correction of endothelial dysfunction in coronary
microcirculation of hypercholesterolemic patients by
L-arginine. Lancet 338, 1546–1550
25 Zeiher, A. M., Drexler, H., Wollschlager, H. and Just, H.
(1991) Modulation of coronary vasomotor tone in humans.
Progressive endothelial dysfunction with different early
stages of coronary atherosclerosis. Circulation 83,
391–401
26 Vita, J. A., Treasure, C. B., Nabel, E. G. et al. (1990)
Coronary vasomotor response to acetylcholine relates to
risk factors for coronary artery disease. Circulation 81,
491–497
27 Treasure, C. B., Klein, J. L., Weintraub, W. S. et al. (1995)
Beneficial effects of cholesterol-lowering therapy on the
coronary endothelium in patients with coronary artery
disease. N. Engl. J. Med. 332, 481–487
28 Hozumi, T., Yoshida, K., Akasaka, T. et al. (1998)
Noninvasive assessment of coronary flow velocity and
coronary flow reserve in the left anterior descending
coronary artery by doppler echocardiography. J. Am. Coll.
Cardiol. 32, 1215–1259
29 Davis, C. P., Liu, P. F., Hauser, M., Gohde, S. C., vonSchulthess, G. K. and Debatin, J. F. (1997) Coronary flow
and coronary flow reserve measurements in humans with
breath-held magnetic resonance phase contrast velocity
mapping. Magn. Reson. Med. 37, 537–544
30 Vallabhajosula, S. and Fuster, V. (1997) Atherosclerosis
imaging techniques and the evolving role of nuclear
medicine. J. Nucl. Med. 38, 1788–1796
31 Pitka$ nen, O.-P., Raitakari, O. T., Niinikoski, H. et al.
(1996) Coronary flow reserve is impaired in young men
with hypercholesterolemia. J. Am. Coll. Cardiol. 28,
1705–1711
32 Pitka$ nen, O.-P., Nuutila, P., Raitakari, O. T. et al. (1998)
Coronary flow reserve in young men with familial
combined hypercholesterolemia. Circulation 99, 1678–1684
33 Joannides, R., Haefeli, W. E., Linder, L. et al. (1995) Nitric
oxide is responsible for flow-dependent dilation of human
peripheral conduit arteries in vivo. Circulation 91,
1314–1319
34 Anderson, T. J., Uehata, A., Gerhard, M. D. et al. (1995)
Close relationship of endothelial function in the human
coronary and peripheral circulations. J. Am. Coll. Cardiol.
26, 1235–1241
35 Neunteufl, T., Katzenschlager, R., Hassan, A. et al. (1997)
Systemic endothelial dysfunction is related to the extent
and severity of coronary artery disease. Atherosclerosis
129, 111–118
36 Celermajer, D. S., Adams, M. R., Clarkson, P. et al. (1996)
Passive smoking is associated with impaired endotheliumdependent dilatation in healthy young adults. N. Engl. J.
Med. 334, 150–154
37 Lieberman, E. H., Gerhard, M. D., Uehata, A. et al. (1994)
Estrogen improves endothelium-dependent, flow-mediated
vasodilation in postmenopausal women. Ann. Intern. Med.
121, 936–941
# 1999 The Biochemical Society and the Medical Research Society
38 Celermajer, D. S., Sorensen, K. E., Bull, C., Robinson, J.
and Deanfield, J. E. (1994) Endothelium-dependent
dilation in the systemic arteries of asymptomatic subjects
relates to coronary risk factors and their interaction. J.
Am. Coll. Cardiol. 24, 1468–1474
39 Celermajer, D. S., Sorensen, K. E., Georgakopoulos, D. et
al. (1993) Cigarette smoking is associated with dose-related
and potentially reversible impairment of endotheliumdependent dilation in healthy young adults. Circulation 88,
2149–2155
40 Celermajer, D. S., Sorensen, K. E., Spiegelhalter, D. J.,
Georgakopoulos, D., Robinson, J. and Deanfield, J. E.
(1994) Aging is associated with endothelial dysfunction in
healthy men years before the age-related decline in
women. J. Am. Coll. Cardiol. 24, 471–476
41 Sorensen, K. E., Celermajer, D. S., Speigenhalter, D. J. et
al. (1995) Non-invasive measurement of endotheliumdependent arterial responses in man : accuracy and
reproducibility. Br. Heart J. 74, 247–253
42 Simons, L. A., Sullivan, D., Simons, J. and Celermajer,
D. S. (1998) Effects of atorvastatin monotherapy and
simvastatin plus cholestyramine on arterial endothelial
function in patients with severe primary
hypercholesterolemia. Atherosclerosis 137, 197–203
43 Clarkson, P., Adams, M. R., Powe, A. J. et al. (1996) Oral
L-arginine improves endothelium-dependent dilation in
hypercholesterolemic young adults. J. Clin. Invest. 97,
1989–1994
44 Kugiyama, K., Motoyama, T., Doi, H. et al. (1999)
Improvement of endothelial vasomotor dysfunction by
treatment with alpha-tocopherol in patients with high
remnant lipoprotein levels. J. Am. Coll. Cardiol. 33,
1512–1518
45 Plotnick, G. D., Corretti, M. C. and Vogel, R. A. (1997)
Effect of antioxidant vitamins on the transient impairment
of endothelium-dependent brachial artery vasoactivity
following a high fat meal. JAMA J. Am. Med. Assoc. 26,
1682–1686
46 Adams, M. R., Robinson, J., Sorensen, K. E., Deanfield,
J. E. and Celermajer, D. S. (1996) Normal ranges for
brachial artery flow-mediated dilatation : a non-invasive
ultrasound test of arterial endothelial function. J. Vasc.
Invest. 2, 146–150
47 Panza, J. A., Quyyumi, A. A., Brush, Jr., J. E. and Epstein,
S. E. (1990) Abnormal endothelium-dependent vascular
relaxation in patients with essential hypertension. N. Engl.
J. Med. 323, 22–27
48 Calver, A. C., Collier, J. G. and Vallance, P. J. T. (1992)
Inhibition and stimulation of nitric oxide synthesis in the
human forearm arterial bed of patients with insulindependent diabetes. J. Clin. Invest. 90, 2548–2554
49 Creager, M. A., Gallagher, S. H., Girerd, X. J., Coleman,
S., Dzau, V. J. and Cooke, J. P. (1990) Impaired
vasodilation of forearm resistance vessels in
hypercholesterolemic humans. J. Clin. Invest. 86, 228–234
50 Creager, M. A., Gallagher, S. J., Girerd, X. J., Coleman,
S. M., Dzau, V. J. and Cooke, J. P. (1992) L-arginine
improves endothelium-dependent vasodilation in
hypercholesterolemic humans. J. Clin. Invest. 90,
1248–1253
51 Ting, H. H., Timimi, F. K., Boles, K. S., Creager, S. J.,
Ganz, P. and Creager, M. A. (1996) Vitamin C improves
endothelium-dependent vasodilation in patients with noninsulin-dependent diabetes mellitus. J. Clin. Invest. 97,
22–28
52 Morris, S. J. and Shore, A. C. (1996) Skin blood flow
responses to the iontophoresis of acetylcholine and sodium
nitroprusside in man : possible mechanisms. J. Physiol.
(London) 496, 531–542
53 Hasdai, D., Gibbons, R. J., Holmes, Jr., D. R., Higano,
S. T. and Lerman, A. (1997) Coronary endothelial
dysfunction in humans is associated with myocardial
perfusion defects. Circulation 96, 3390–3395
54 Vogel, R. A., Vaitkevicius, P. V. and Plotnick, G. D. (1993)
Ultrasound assessment of brachial artery endotheliumdependent vasoactivity as a means for diagnosing coronary
artery disease J. Am. Coll. Cardiol. 21, 345A (abstract)
Detection of presymptomatic atherosclerosis
55 Castelli, W. P. (1984) Epidemiology of coronary heart
disease. The Framingham Study. Am. J. Med. 76 (Suppl
2A), 4–12
56 Kannel, W. B. (1989) Hypertension, blood lipids and
cigarette smoking as co-risk factors for coronary heart
disease. Ann. N. Y. Acad. Sci. 304, 128–139
57 Kuller, L., Borhani, N., Furberg, C. et al. (1994)
Prevalence of subclinical atherosclerosis and cardiovascular
risk factors in the cardiovascular health study. Am. J.
Epidemiol. 139, 1164–1179
58 Cleary, J., Mohr, D., Adams, M. R., Celermajer, D. C. and
Stocker, R. (1997) Plasma and LDL levels of major
lipophilic antioxidants are similar in patients with
advanced atherosclerosis and age-matched controls. Free
Radical Res. 26, 175–182
59 Anderson, T. J., Meredith, I. T., Charbonneau, F. et al.
(1996) Endothelium-dependent coronary vasomotion
relates to the susceptibility of LDL to oxidation in
humans. Circulation 93, 1647–1650
60 Morrow, J. D., Frei, B., Longmire, A. W. et al. (1995)
Increase in circulating products of lipid peroxidation (F2isoprostanes) in smokers. N. Engl. J. Med. 332, 1198–1203
61 Delanty, N., Reilly, M. P., Pratico, D. et al. (1997) 8-Epi
PGF2α generation during coronary repurfusion.
Circulation 95, 2492–2499
62 Deckert, V., Persegol, L., Viens, L. et al. (1997) Inhibitors
of arterial relaxation among components of human
oxidized low-density lipoproteins. Cholesterol derivatives
oxidized in position 7 are potent inhibitors of
endothelium-dependent relaxation. Circulation 95,
723–731
63 Mannucci, P. M. (1998) von Willebrand Factor. A marker
of endothelial damage ? Arterioscler. Thromb. Vasc. Biol.
18, 1359–1362
64 Blann, A. D., Davies, A., Miller, J. P. and McCollum,
C. N. (1993) Reduction in cholesterol is associated with
reduction in von Willebrand factor. Atherosclerosis 103,
299–304
65 Geppert, A., Graf, S., Beckmann, R. et al. (1998)
Concentration of endogenous tPA antigen in coronary
artery disease. Relation to thrombotic events, aspirin
treatment, hyperlipidemia, and multivessel disease.
Arterioscler. Thromb. Vasc. Biol. 18, 1634–1642
66 Ridker, P. M., Vaughan, D. E., Stampfer, M. J., Manson,
J. E. and Hennekens, C. H. (1993) Endogenous tissue-type
plasminogen activator and risk of myocardial infarction.
Lancet 341, 1165–1168
67 Salomaa, V., Stinson, V., Kark, J. D. et al. (1995)
Association of fibrinolytic parameters with early
atherosclerosis. The ARIC Study. Circulation 91, 284–290
68 Vaughan, D. E. (1998) Fibrinolytic balance, the reninangiotensin system and atherosclerotic disease. Eur. Heart
J. 19, G9–G12
69 Ridker, P. M. (1998) Inflammation, infection, and
cardiovascular risk. Circulation 97, 1671–1674
70 Hwang, S. J., Ballantyne, C. M., Sharrett, A. R. et al.
(1997) Circulating adhesion molecules VCAM-1, ICAM-1,
and E-selectin in carotid atherosclerosis and incident
coronary heart disease cases : the Atherosclerosis Risk in
Communities (ARIC) Study. Circulation 96, 4219–4225
71 Lerman, A., Holmes, D. R. J., Bell, M. R., Garratt, K. N.,
Nishimura, R. A. and Burnett, J. C. J. (1995) Endothelin in
coronary endothelial dysfunction and early atherosclerosis
in humans. Circulation 92, 2426–2431
72 Fujiwara, Y., Tagami, S. and Kawakami, Y. (1998)
Circulating thrombomodulin and hematological alterations
in type 2 diabetic patients with retinopathy. J. Atheroscler.
Thromb. 5, 21–28
73 Ridker, P. M., Glynn, R. J. and Hennekens, C. H. (1998)
C-reactive protein adds to the predictive value of total and
HDL cholesterol in determining risk of first myocardial
infarction. Circulation 97, 2007–2011
74 De Caterina, R., Basta, G., Lazzerini, G. et al. (1997)
Soluble vascular cell adhesion molecule-1 as a biohumoral
correlate of atherosclerosis. Arterioscler. Thromb. Vasc.
Biol. 17, 2646–2654
75 Ritchie, M. E. (1998) Nuclear factor-κB is selectively and
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
markedly activated in humans with unstable angina
pectoris. Circulation 98, 1707–1713
Weber, C., Erl, W. and Weber, P. C. (1995) Enhancement
of monocyte adhesion to endothelial cells by oxidatively
modified LDL is mediated by activation of CD11b.
Biochem. Biophys. Res. Commun. 206, 621–628
Kalra, V. K., Ying, Y., Deemer, K., Natarajan, R., Nadler,
J. L. and Coates, T. D. (1994) Mechanism of cigarette
smoke condensate induced adhesion of human monocytes
to cultured endothelial cells. J. Cell. Physiol. 160, 154–162
Dovgan, P. S., Edward, J. D., Zhan, X., Wilde, M. and
Agrawal, D. K. (1994) Cigarette smoking increases
monocyte adherence to cultured endothelial cell monlayer.
Biochem. Biophys. Res. Commun. 203, 929–934
St. Goar, F. G., Pinto, F. J., Alderman, E. L. et al. (1992)
Detection of coronary atherosclerosis in young adult
hearts using intravascular ultrasound. Circulation 86,
756–763
Waller, B. F., Pinkerton, C. A. and Slack, J. D. (1992)
Intravascular ultrasound : a histological study of vessels
during life. Circulation 85, 2305–2310
Nishimura, R. A., Edwards, W. D., Warnes, C. A. et al.
(1990) Intravascular ultrasound imaging : in vitro validation
and pathologic correlation. J. Am. Coll. Cardiol. 16,
145–154
Grayburn, P. A., Willard, J. E., Brickner, M. E. and
Eichhorn, E. J. (1991) In vivo thrombus formation on a
guidewire during intravascular ultrasound imaging :
evidence for inadequate heparinization. Catheter
Cardiovasc. Diagn. 23, 141–143
Salonen, R. and Salonen, J. T. (1991) Determinants of
carotid intima-media thickness : a population based study
in Eastern Finnish men. J. Int. Med. 229, 225–231
Furberg, C. D., Adams, H. P., Applegate, W. B. et al., for
the ACAPS Research Group (1994) Effect of Lovastatin
on early carotid atherosclerosis and cardiovascular events.
Circulation 90, 1679–1687
Blankenhorn, D. H., Selzer, R. H., Crawford, D. W. et al.
(1993) Beneficial effects of colestipol-niacin therapy on the
common carotid artery. Circulation 88, 20–28
Pignoli, P., Tremoli, E., Poli, A., Oreste, P. and Paoletti,
R. (1986) Intimal plus medial thickness of the arterial wall :
a direct measurement with ultrasound imaging. Circulation
74, 1399–1406
Wendelhag, I., Gustavsson, T., Suurkula, M., Berglund, G.
and Wikstrand, J. (1991) Ultrasound measurement of wall
thickness in the carotid artery : fundamental principles and
description of a computerized analysing system. Clin.
Physiol. 11, 565–577
Crouse, J. R. and Thompson, C. J. (1993) An evaluation of
methods for imaging and quantifying coronary and carotid
lumen stenosis and atherosclerosis. Circulation 87 (Suppl.
II), 17–33
Ratliff, D. A., Hames, T. K., Humphries, K. N., Birch, S.
and Chant, A. D. (1985) The reliability of Doppler
ultrasound techniques in the assessment of carotid disease.
Angiology 36, 333–340
Belcaro, G., Barsotti, A. and Nicolaides, A. N. (1991)
‘ Ultrasonic biopsy ’ – a non-invasive screening technique
to evaluate the cardiovascular risk and to follow up the
progression and the regression of arteriosclerosis. Vasa 20,
40–50
Howard, G., Sharrett, A. R., Heiss, G. et al., for the ARIC
investigators (1993) Carotid artery intimal-media thickness
distribution in general populations as evaluated by B-mode
ultrasound. Stroke 24, 1297–1304
Pauciullo, P., Iannuzzi, A., Sartorio, R. et al. (1994)
Increased intima-media thickness of the common carotid
artery in hypercholesterolemic children. Arterioscler.
Thromb. 14, 1075–1079
O’Leary, D. H., Polak, J. F., Kronmal, R. A., Manolio,
T. A., Burke, G. L. and Wolfson, S. K. (1999) Carotidartery intima and media thickness as a risk factor for
myocardial infarction and stroke in older patients.
N. Engl. J. Med. 340, 14–22
# 1999 The Biochemical Society and the Medical Research Society
623
624
M. R. Adams and D. S. Celermajer
94 Fazio, G. P., Redberg, R. F., Winslow, T. and Schiller,
N. B. (1993) Transesophageal echocardiographically
detected atherosclerotic aortic plaque is a marker for
coronary artery disease. J. Am. Coll. Cardiol. 21,
144–150
95 Fowkes, F. G., Housley, E., Riemersma, R. A. et al.
(1992) Smoking, lipids, glucose intolerance, and blood
pressure as risk factors for peripheral atherosclerosis
compared with ischemic heart disease in the Edinburgh
Artery Study. Am. J. Epidemiol. 135, 331–340
96 Bleiweis, M. S., Georgiou, D. and Brundage, B. H. (1992)
Ultrafast CT and the cardiovascular system. Int. J.
Cardiac Imaging 8, 289–302
97 Eggen, D. A., Strong, J. P. and McGill, Jr., H. C. (1965)
Coronary calcification : relationship to clinically
significant coronary lesions and race, sex, and
topographical distribution. Circulation 32, 948–955
98 Mautner, S. L., Mautner, G. C., Froehlich, J. et al. (1994)
Coronary artery disease : prediction with in vitro electron
beam CT. Radiology 192, 625–630
99 Fiorino, A. S. (1998) Electron-beam computed
tomography, coronary artery calcium, and evaluation of
patients with coronary artery disease. Ann. Intern. Med.
128, 839–847
100 Rumberger, J. A., Simons, D. B., Fitzpatrick, L. A.,
Sheedy, P. F. and Schwartz, R. S. (1995) Coronary artery
calcium area by electron-beam computed tomography
and coronary atherosclerotic plaque area : a
histopathologic correlative study. Circulation 92,
2157–2162
101 Callister, T. Q., Raggi, P., Cooil, B., Lippolis, N. J. and
Russo, D. J. (1998) Effect of HMG-CoA reductase
# 1999 The Biochemical Society and the Medical Research Society
102
103
104
105
106
107
108
inhibitors on coronary artery disease as assessed by
electron-beam computed tomography. N. Engl. J. Med.
339, 1972–1978
Achenbach, S., Moshage, W., Ropers, D., Nossen, J. and
Daniel, W. G. (1998) Value of electron-beam computed
tomography for the noninvasive detection of high-grade
coronary-artery stenoses and occlusions. N. Engl. J. Med.
339, 1964–1971
Kern, M. J. (1995) The Cardiac Catheterization
Handbook, 2nd edn., pp 1–26, Mosby-Year Book,
St. Louis, MO
Taylor, A. J. and O ’Malley, P. G. (1998) Self-referral of
patients for electron-beam computed tomography to
screen for coronary artery disease. N. Engl. J. Med. 339,
2018–2020
Masaryk, T. J., Tkach, J. and Glicklich, M. (1991) Flow,
radiofrequency pulse sequences, and gradient magnetic
fields : basic interactions and adaptations to angiographic
imaging. Top. Magn. Reson. Imaging 3, 1–11
Fuster, V. and Halperin, J. L. (1994) Aortic dissection : a
medical perspective. J. Cardiovasc. Surg. 9, 713–728
Skinner, M. P., Yuan, C., Mitsumori, L. et al. (1995)
Serial magnetic resonance imaging of experimental
atherosclerosis detects lesion fine structure, progression
and complications in vivo. Nat. Med. (N.Y.) 1, 69–73
[erratum : Nat. Med. (N.Y.) (1995) 1, 272]
Lassila, R., Badimon, J. J., Vallabhajosula, S. and
Badimon, L. (1990) Dynamic monitoring of platelet
deposition on severely damaged vessel wall in flowing
blood. Effects of different stenoses on thrombus growth.
Arteriosclerosis 10, 306–315