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European Heart Journal Supplements (2002) 4 (Supplement F), F47–F53
Understanding the pathophysiology of the arterial
wall: which method should we choose?
Electron beam computed tomography
R. Erbel1, T. Budde2, G. Kerkhoff2, S. Möhlenkamp1 and A. Schmermund1
1Department
of Cardiology, University Essen, and 2Department of Internal Medicine and Cardiology,
Alfried Krupp Hospital, Essen, Germany
Coronary imaging techniques may be direct or indirect.
Indirect methods permit visualization of the coronary artery
lumen but not the diseased coronary artery vessel wall. In the
early stages of coronary arteriosclerosis, vessel size enlargement compensates for up to 50% stenosis from plaque
formation. Indirect methods are therefore unable to visualize
early signs of coronary arteriosclerosis. Direct techniques are
those that permit visualization of non-calcified and calcified
plaque deposits within the coronary artery vessel wall. Electron
beam computed tomography (EBCT) is currently the standard
technique for assessing calcified lesions. It allows direct
visualization of the coronary arteries in a non-invasive manner.
Coronary calcium within a plaque is accurately detected and
quantified by EBCT. This modality therefore holds promise as
a method for studying the natural history of coronary artery
disease, irrespective of symptomatic status. Studies have shown
that the presence of calcification almost invariably indicates the
presence of coronary artery disease, and that the absence of
calcification can almost rule out significant coronary artery
disease. Moreover, a close correlation exists between the
degree of calcification and severity of coronary artery disease.
EBCT may also be used in young patients with risk factors in
order to detect disease in pre-clinical stage, and to provide new
information on the natural history of coronary artery disease.
(Eur Heart J Supplements 2002; 4 (Suppl F): F47–F53)
© 2002 The European Society of Cardiology
Introduction
therefore important, in particular because the degree of
calcification has been shown to correlate with plaque
load[3–5] and provides a means of verifying the presence of
coronary arteriosclerosis.
Coronary imaging techniques can be either indirect or
direct. Indirect techniques permit visualization of the artery
lumen but not the diseased artery wall, and include selective
coronary angiography, magnetic resonance angiography,
contrast-enhanced electron beam tomography angiography
and synchrotron radiation angiography[6]. Direct techniques
permit visualization of both non-calcified and calcified
plaque deposits within the vessel wall. Fluoroscopy and,
more recently, digital fluoroscopy have been used to detect
coronary calcification[7,8]. However, it is virtually
impossible to localize and quantify calcification using
fluoroscopy. Therefore, other techniques have been
developed that also allow non-invasive diagnosis of
coronary arteriosclerosis, including electron beam computed
tomography (EBCT). This modality is now the technique of
choice for assessing calcified lesions, and has become the
The development of arteriosclerosis is divided into five
stages (Stary lesion types I–V), according to the recommendations of the American Heart Association[1]. Lesions of
types I and II are regarded as normal degenerative disease.
Type III is an intermediate stage, which is characterized by
increasing numbers of lipid droplets that coalesce to form a
lipid core, leading to the formation of a type IV lesion – an
atheroma. If the plaque contains collagen, then the lesion is
classified as type V (fibroatheroma)[1]. Calcification does not
necessarily indicate advanced disease because it may be
detected in type III lesions, first intra-cellularly and then
extra-cellularly[2]. Detection of coronary calcification is
Correspondence: Raimund Erbel,MD, FESC, FACC, FAHA,
University Professor of Medicine/Cardiology, European Cardiologist,
Department of Cardiology, Division of Internal Medicine, University
Essen, Hufelandstr. 55, D-45122 Essen, Germany.
1520-765X/02/0F0047 + 07 $35.00/0
Key Words: Arteriosclerosis, atherosclerosis, calcification,
coronary artery disease, electron beam computed tomography,
non-invasive imaging.
© 2002 The European Society of Cardiology
F48
R. Erbel et al.
ECG
Echocardiography
Noninvasive
methods
Scintigraphy
PET
EBCT, cardiac CT
Invasive
methods
0%
Intracoronary ultrasound
Coronary angiography
20%
45%
60%
70%
90%
Remodeling
Figure 1 Overview of the diagnosis of coronary atherosclerosis. Current non-invasive techniques are focused on
detecting myocardial ischaemia that occurs as a consequence of flow-obstructing coronary stenoses. Therefore, nonstenotic coronary atherosclerotic lesions are not detected. In contrast, electron beam computed tomography (EBCT),
or other CT methods with sufficiently rapid image acquisition, visualize coronary plaque formation directly.
Accordingly, non-stenotic plaques can be identified. Whereas coronary angiography (the standard method for invasive
diagnosis) is best suited to analyzing highly stenotic lesions, intra-vascular ultrasound (IVUS) allows visualization of
calcified and non-calcified coronary plaques of all degrees of stenosis. However, because of its invasive nature and the
associated costs, the use of IVUS is limited to a small subgroup of patients. PET=positron emission tomography.
‘gold standard’ of non-invasive direct coronary imaging
techniques (Fig. 1)[6].
Technique of electron beam
computed tomography
EBCT uses an electron sweep of stationary tungsten target
rings in order to generate X-ray images that can accurately
detect small amounts of calcium[9]. The EBCT scanner can
be operated in various scanning modes, using up to four
target rings. For coronary artery imaging, the ‘single-slice
mode’, which employs only one target ring, gives optimal
spatial resolution[6].
The EBCT examination is performed using a C100, C150
or C300 scanner (GE Imatron, South San Francisco,
California, U.S.A.), with contiguous, non-overlapping
3-mm slices, and an acquisition time of 100 ms. Patients are
supine and, after localization of the main pulmonary artery,
36–40 slices in the craniocaudal direction through the apex
of the heart are obtained, with ECG triggering at 80% of the
R–R interval. The presence of coronary calcium is evaluated
at each level. The threshold for calcific lesions is usually set
at a CT density of 130 Hounsfield units (HU), in an area of
at least 0·52 mm2 (two pixels, 512 × 512 pixel matrix and a
26-cm field of view). This threshold has been shown to
provide sufficient differentiation from surrounding tissue
and blood, and has been widely accepted as signifying
calcification[10,11]. The total examination time is 3–4 min. In
addition, 5–10 min are needed for evaluation, quantification
of calcification and generation of a report; ideal
presumption for a screening technique.
Eur Heart J Supplements, Vol. 4 (Suppl F) September 2002
Detection of coronary calcification
EBCT permits non-invasive visualization of coronary artery
calcification[10–17]. In the different scan fields, all lesions
exceeding 130 HU (representing coronary calcification with
the image intensities similar to bone structures) are imaged
(Figs 2–4). Figure 4 is a typical example, showing
calcification not only in the proximal coronary arteries but
also in the distal parts of the left and right coronary arteries.
Distribution of calcification
All lesions exceeding 130 HU are regarded as calcified
lesions and the distribution of calcification in the left and
right coronary arteries can therefore be analyzed (Figs 3 and
4). The distribution of calcification is semi-quantitatively
described, in accordance with the 16-segment model of the
American Heart Association[18]. The referring physician
must be aware of the vessel segments involved, in order to
correlate coronary calcification with wall motion, or
location of myocardial infarction[5,11,19].
Quantification of calcification
Traditionally, the scoring algorithm introduced by Agatston
et al.[10] has been used to quantify coronary calcium. The
calcium score is defined as the product of the area of
coronary artery calcium (at least two contiguous pixels,
with a CT density ≥130 HU) and a factor (rated 1–4) that is
Electron beam computed tomography
Figure 2 Quantification of calcification by electron
beam computed tomography (EBCT). Quantification of
coronary calcification according to the Agatston score of
a calcification in segment 6 of the left anterior descending coronary artery. The area of pixels with Hounsfield
units exceeding 130 are summed up and multiplied by
the maximum computed tomographic number (MCTN),
according to a given score. In this example the number
is 3 based on 313 HU and the area 8 mm2, giving a score
of 24. AO=aorta; C=calcification.
dictated by the maximum CT density within that lesion
(1 = 130–200 HU; 2 = 201–300 HU; 3 = 301–400 HU;
4 = >400 HU). In the example shown in Fig. 2 the area is
8 mm2 and the density is 313 HU, giving a calcium grade of
3; the Agatston score is therefore 24. Calcification can be
analyzed for separate coronary segments, such as those
classified by the American Heart Association, and summed
F49
Figure 3 (A) Electron beam computed tomography
(EBCT) and (B) angiography of a healthy patient with
normal coronary arteries. Coronary calcification is
absent in the left main and in segment 6/7 of the left
anterior descending coronary artery. Ao=aorta;
LAD=left anterior descending; RVOT=right ventricular
outflow tract.
for each artery to yield a total score[5]. As in the example
shown in Fig. 2, calcification is typically found in segment
6 of the left anterior descending coronary artery. Figure 4
shows a lesion with an Agatston score greater than 2000.
Accuracy of electron beam
computed tomography
In order to evaluate its accuracy, EBCT has been compared
with intra-coronary ultrasound, which is able to visualize
not only calcified but also non-calcified plaques at high
resolution (100–150 µm)[5,11]. It has been demonstrated that
even single spots of calcification detected by intra-coronary
Figure 4 (A) Electron beam computed tomography (EBCT) and (B) angiography of a patient with coronary artery
disease. Shown are EBCT images in four slices of a patient with severe coronary calcification, confirmed by
coronary angiography with main stem stenosis, and severe disease in left circumflex and right coronary arteries. In
the different slices, the highlighted areas are those in which the pixels exceed 130 Hounsfield units. AO=aorta;
RVOT=right ventricular outflow tract.
Eur Heart J Supplements, Vol. 4 (Suppl F) September 2002
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R. Erbel et al.
ultrasound can also be visualized using EBCT. These
findings are particularly significant because the comparison
was conducted in individuals with no or minimal luminal
narrowing. EBCT is therefore a highly accurate method for
detecting coronary calcification non-invasively. Moreover,
EBCT shows a strong relationship between the number of
coronary segments with plaque formation and the number
of calcified coronary segments, confirming in vivo the high
correlation found at autopsy between plaque load and
amount of calcification[3,4].
EBCT has been compared with coronary angiography in
many studies[19–23]. Those comparisons were unable to
evaluate the accuracy of EBCT because coronary angiography only visualizes the lumen of coronary arteries
whereas EBCT visualizes the arterial wall. However, new
developments in EBCT and particularly multislice computed
tomography (MSCT) have shown that, when contrast is
injected in order to discriminate the arterial wall from the
coronary lumen, not only calcified but also non-calcified
lesions can be visualized[24].
Prevalence of coronary calcium
Pathological studies, conducted in soldiers and individuals
who have died from causes other than cardiac disease (such
as car accidents), have demonstrated the presence of
advanced stages of coronary plaque formation (Stary
lesions types IV/V). More than 15% of young adults have
advanced coronary lesions (atheroma and fibroatheroma)[2]
that can be detected by fluoroscopy[25].
Janowitz et al.[26] demonstrated that the prevalence of
calcification as visualized by EBCT is similar to that seen in
pathological studies. Calcified plaques have been detected
in 20% of patients aged 30–39 years, in 40% of those aged
40–49 years, in 50–60% of those aged 50–59 years, and in
70–80% of those aged 60–69 years[23]. In the Muscatine
study[8], conducted in people aged 29–37 years, coronary
calcification was detected in 31% of men and 10% of
women. The Coronary Artery Risk Development in Young
Adults (CARDIA) study[27], which analyzed persons aged
28–40 years, detected coronary calcification in 17% of men
and 9% of women. Those studies demonstrate that coronary
calcification is not only present in the advanced stages of
the disease but can also be detected quite early in a high
proportion of young adults in the general population.
Risk factors for coronary calcification
Risk factors for development of coronary arteriosclerosis are
well known and have been classified according to cardiovascular risk in the Framingham study[28]. The following risk
factors for coronary calcification were identified by
multivariate regression analysis[5,14]: age, fibrinogen, the
total cholesterol/high-density lipoprotein cholesterol ratio,
hypertension, male sex and positive familial history. Lowdensity lipoprotein (LDL)-cholesterol, diabetes and current
Eur Heart J Supplements, Vol. 4 (Suppl F) September 2002
smoking were positively correlated with frequency of
calcified and non-calcified plaques[5].
Topography of coronary calcification
In order to elucidate the natural history of coronary
calcification, EBCT was used to investigate the distribution
and prevalence of calcification in various coronary
segments of young persons with or without coronary
luminal narrowing[29]. Calcification was first observed in
segment 6 of the left anterior descending coronary artery –
a finding consistent with pathological anatomy reports that
coronary arteriosclerosis is first found in the proximal 2 cm
of the left anterior descending coronary artery[30]. Later,
calcification is also found in the middle and proximal right
coronary arteries, as well as in the proximal left circumflex
coronary artery. In more advanced stages, the middle part of
the left anterior descending and the left main arteries are
involved. Only in the most advanced stages of the disease is
calcification also found in distal segments of the left
anterior descending and left circumflex arteries. The
distribution in the right coronary artery is more even[29].
Coronary calcification in acute
coronary syndromes
Because coronary calcification is found in the early stages of
the disease, it is not surprising that it is found in a high
percentage of people suffering sudden cardiac death[31–34]. In
a study of 50 cases of sudden death due to coronary
thrombosis, plaque rupture was found in 28 out of 50
individuals and plaque erosion in 22 out of 50 individuals[31];
69% of the ruptured plaques and 23% of the eroded plaques
were calcified. In another study, the plaques responsible for
sudden cardiac death in 108 individuals (mean age 50 years)
were classified as ‘stable’ (n = 20), ‘erosion’ (n = 33), ‘acute
rupture’ (n = 37), or ‘healed rupture’ (n = 18), and it was
found that 80% of ruptured plaques were calcified[34].
Similarly, in a study of 79 adults (mean age 49 ± 11 years,
71% male) who suffered sudden cardiac death, those with
stable (n = 27) or ruptured (n = 30) plaques showed
significantly more coronary calcification than did those with
eroded plaques (n = 22)[32]. Recently, in a study of 28
individuals under 50 years old who suffered sudden cardiac
death, Schmermund et al.[33] reported that calcification was
present either at or close to the site of plaque rupture in a high
percentage of cases. This indicates a close association
between coronary calcification and plaque rupture. The
presence of calcium appears to influence the mechanics of
the arterial wall, increasing wall and shear stresses, and
thereby increasing the likelihood of plaque rupture.
Prognostic value of coronary
calcification determination
In six studies, coronary calcification (as determined using
EBCT) and mortality were analyzed in order to calculate the
Electron beam computed tomography
relative risk ratio[35–40]. In one follow-up study 288 patients
who had undergone EBCT scanning at the same time as
coronary angiography were contacted after a mean of
6·9 years[35]. It was found that there was a significant
relative risk ratio (1·88; P < 0·05) associated with the extent
of coronary calcification at baseline and the incidence of
future hard cardiac events (cardiac death and non-fatal
myocardial infarction). In a multicentre prospective study,
491 patients (mostly symptomatic, with suspected coronary
artery disease) underwent both EBCT and coronary
angiography[36]. The data showed that patients who suffered
a coronary event had calcification scores of 100 or greater,
whereas those who did not have an event had calcification
scores below 100.
In a study of over 1000 asymptomatic individuals
(baseline age 53 years, 71% men), over an average followup of 3·6 years, it was found that a baseline coronary
calcification score of 160 or greater was associated with an
odds ratio of 15·8 for all coronary events and of 22·2 for
cardiac death or non-fatal myocardial infarction[38]. In a
study of 172 patients with a first acute myocardial infarction
(mean age 53 ± 8 years), 165 patients (96%) showed
coronary calcification by EBCT, and in 87% of the 172
patients the degree of calcification was greater than
expected for their age and sex[39].
The prognostic value of EBCT-determined coronary
calcification was confirmed in a recent prospective study of
221 patients (mean age 53 ± 9 years, 54% men)[40]. Patients
underwent EBCT scanning, in addition to usual care, on
admission to the emergency department of a large tertiary
care hospital for chest pain syndromes. When calcification
was present, the relative risk ratio for coronary events was
found to be 28 within an average follow-up time of
4·2 years.
Implementation of detection and
grading of coronary calcification
According to the Prevention Conference V proceedings,
individuals may be classified as having low, intermediate, or
high risk for cardiovascular events[41]. High risk is defined
as a 20% chance of suffering a cardiovascular event within
10 years. Risk factors are subdivided into causal risk factors
(hypertension, hypercholesterolaemia, diabetes and
smoking) and conditional risk factors (lipoprotein[a], high
triglyceride levels and elevated fibrinogen). If carotid
stenosis, coronary artery disease, aortic aneurysm, or
peripheral vascular disease is present, then the individual is
considered to be at high risk. Also at high risk are those
individuals with more than two causal risk factors or more
than four conditional risk factors. Individuals with two
causal risk factors or three to four conditional risk factors
are considered to be at intermediate risk.
The Prevention Conference V participants considered the
role of several measures of subclinical disease in order to
determine whether individuals at intermediate risk should
be reclassified as high risk. Currently, an intima–media
thickness greater than 1 mm, an ankle brachial index below
F51
0·9, or an elevated level of C-reactive protein are the criteria
used to redefine such individuals. It is anticipated that
EBCT will provide an additional method of risk assessment.
The advantage of EBCT is that it measures a direct sign of
coronary arteriosclerosis (coronary calcification) rather than
an indirect sign, such as intima–media thickness or
peripheral artery disease.
Progression of coronary calcification
In order to demonstrate spontaneous progression of coronary
artery disease, EBCT was used to visualize changes in
calcification over time in 102 asymptomatic persons[29].
Over a mean period of 18 months, the area of calcification as
well as the Agatston score were measured, because it has
been suggested that the former provides the most
reproducible results for serial EBCT studies[42]. Calcification
was analyzed in the 12 major coronary segments, as
classified by the American Heart Association. The median
relative annual progression in the total area of calcification
and in total Agatston score were 27% and 32%, respectively.
In the near future, it is likely that, because of lower interobserver variability, the calcium volume score will be used
to calculate total coronary calcium load. Thus far, all
prognostic long-term studies have used the Agatston score.
Other studies have also analyzed the progression of
coronary calcification over time. Maher et al.[43] measured
the change in coronary calcification in 88 individuals over a
3·5-year period, and showed an average increase of 24% per
year in calcification score. Möhlenkamp et al.[44] observed
an increase of the Agatston score in non-obstructive
coronary artery disease of 8 ± 2 and in obstructive coronary
artery disease of 46 ± 9 per year[44]. Janowitz et al.[26]
reported an increase of the Agatston score in unknown
coronary artery disease of 20 ± 8 and in obstructive
coronary artery disease of 159 ± 10. The data indicate a
linear relationship between increases in Agatstons score and
scores measured at the first EBCT study time. The
progression mainly occurred in areas where most calcium
was already detected.
Measurement of coronary calcification
to study the treatment of
arteriosclerosis
The detection of coronary calcification, and its quantification by EBCT, is an ideal pharmacodynamic method for
studying the effects of treatment on arteriosclerosis. It has
recently been shown that statins influence the development
of coronary calcification[45]. A retrospective study was
conducted in 149 patients (age range 32–75 years, 61%
men) with no history of coronary artery disease, who were
referred for EBCT screening. All patients underwent
screening at baseline and at a follow-up assessment
12–15 months later. Calcium volume was calculated as an
estimate of plaque burden. Statin treatment was started at
Eur Heart J Supplements, Vol. 4 (Suppl F) September 2002
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R. Erbel et al.
the discretion of the referring physician, and serial
measurements of LDL-cholesterol were correlated with
change in calcium volume over time. The 44 (30%) patients
who did not receive treatment had an average LDLcholesterol level of 120 mg . dl – 1 or greater at follow-up,
and a significant increase (52%) in calcium volume. Of the
105 (75%) patients who received statin treatment, a net
reduction (–7%) in calcium volume was observed only in
those patients (n = 65) whose LDL-cholesterol levels at
follow-up were below 120 mg . dl – 1; the treated patients
whose LDL-cholesterol levels were 120 mg/dl or greater at
follow-up (n = 40) had a significant increase (25%) in mean
calcium volume, although the increase was smaller than that
in the untreated group. In addition, Achenbach et al.[46]
recently reported a reduction in coronary calcification
progression with cerivastatin therapy. Whereas a first
follow-up study showed an increase in calcium volume
score of 28%, it was reduced by cerivastatin to 9%.
In order to study the effect of lipid-lowering therapy on
coronary calcification in more detail, several studies have
been initiated. The Beyond Endorsed Lipid Lowering with
EBT Scanning (BELLES) study was designed to compare
aggressive lipid-lowering therapy using atorvastatin with a
more moderate regimen using pravastatin, in postmenopausal women with hypercholesterolaemia[47]. In the
EBCT Assessment of Coronary Calcification in High Risk
Patients with Minimal or Moderate Coronary Arteriosclerosis (EBEAT), patients received intensified lipidlowering therapy with low and high doses of atorvastatin.
The Treat-to-Target study uses a new phosphate-binding
drug in haemodialysis patients.
Future developments
In the future, studies of coronary calcification will not only
utilize EBCT but also MSCT[48]. In addition to allowing
visualization of calcified plaques, MSCT is showing
promise for the visualization of non-calcified plaques when
contrast material is used in addition to native scanning[49,50].
Similar results have been obtained with EBCT, allowing the
concurrent visualization of coronary calcification and
luminal narrowing.
Conclusion
The detection of coronary calcification in asymptomatic
persons allows us to step beyond secondary prevention and
to identify the high-risk patient for primary prevention.
Prevention will therefore not be based on risk factor
assessment alone but also on direct visualization of
coronary arteriosclerosis, allowing treatment to be targeted
only at those who require it, reducing cost and risk. EBCT
is an ideal technique for assessment of risk and it can be
used in emergency units. It may be expected that this
technique will be included in future coronary heart disease
guidelines, in order to classify patients at intermediate risk
Eur Heart J Supplements, Vol. 4 (Suppl F) September 2002
more accurately. EBCT is already in use as a new tool in
pharmacodynamic studies of arteriosclerosis.
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