The author reviews the clinical presentation and radiologic findings of the disorders comprising chronic diffuse infiltrative lung disease, specifically addressing the use of high-resolution CT imaging. The identification of specific patterns and distribution of disease radiologists in formulating and narrowing a potaentially broad differential diagnosis, guiding potential sites for lung biopsy,and following the response to various therapies.
Dr. Schoenhagen is a Fellow in Cardiovascular Medicine; Dr.
Halliburton is an Imaging Scientist in the Section of
Cardiovascular Imaging, Division of Radiology; Dr. White is a
Professor of Radiology and Medicine and Director of the
Cardiovascular Imaging Center in the Department of Radiology;
Dr. Vince is Assistant Staff in the Department of Biomedical
Engineering; Dr. Nissen is Vice-Chairman of Cardiology; and Dr.
Tuzcu is a Professor of Medicine and the Director of the IVUS
Core Laboratory at The Cleveland Clinic Foundation, Cleveland,
Plaque accumulation in coronary arteries eventually leads to the
obstruction of blood flow and angiographic stenosis. Several
angiographic studies have shown the prognostic value of stenosis
However, it has become clear that dynamic changes of coronary
plaques residing in the vessel wall precede luminal stenosis and,
therefore, better reflect the development of coronary artery
disease. In fact, most plaques that eventually cause acute coronary
syndromes (vulnerable plaques) are not severely stenotic before the
because early plaque development leads to expansion of the vessel
wall (positive remodeling), thereby delaying luminal stenosis
despite plaque accumulation.
More recently, investigators have focused on the composition of
coronary plaques as an important factor in the development of acute
coronary events. The first evidence that morphologic
characteristics of the vessel wall have prognostic value came from
angiography, demonstrating that the extent of coronary
calcification is correlated to plaque burden and predicts the
likelihood of coronary events. The prognostic value of coronary
calcifications has been further defined with electron-beam computed
tomography (EBCT) and more recently with fast multidetector CT.
Other methods, particularly intravascular ultrasound (IVUS) and
magnetic resonance imaging (MRI), attempt to characterize the
morphology of individual lesions to assess plaque vulnerability.
There is accumulating evidence that plaque characterization can be
used in clinical practice. The overall plaque burden and morphology
has prognostic value and can influence preventive treatment plans;
serial observation of plaque burden allows recognition of disease
progression or regression. In addition, the pre-interventional
morphology of individual lesions affects outcome after coronary
interventions and could be used to guide the interventional
Coronary plaque development and plaque
Histologic and intravascular ultrasound studies have shown that
coronary lesion development starts relatively early in life.
Macrophages accumulate at future plaque sites and, by incorporating
cholesterol, become "foam cells." In advanced lesions, further cell
accumulation leads to the formation of a lipid-rich core, which is
separated from the lumen by a fibrous cap.
Atheroma size is not well reflected by luminal stenosis because
outward-directed growth of the plaque initially maintains lumen
size despite increasing plaque burden. This compensatory vessel
enlargement in response to plaque growth is termed positive
arterial remodeling and was first described by Glagov et al
in human coronary atherosclerosis. Coronary artery wall
calcification is part of the development of atherosclerosis.
Absent in the normal vessel wall, coronary artery calcification
occurs in small amounts in early lesions and is found more
frequently in advanced lesions.
The size of the lipid pool within the atherosclerotic plaque and
the thickness of the overlying fibrous "cap" are important
characteristics predicting the stability of advanced plaques.
Vulnerable plaques are characterized by a large lipid pool with a
thin fibrous "cap."
The shoulder area at the margin of the plaque is a location of high
stress, predisposed to rupture (figures 1 and 2).
The accumulation of inflammatory cells and secretion of enzymes
causes degradation of the fibrous "cap."
The relation of coronary calcifications to the probability of
plaque rupture is unknown,
and plaques vulnerable to fissure or erosion are frequently present
in the absence of lesion calcification. The pathophysiological and
clinical significance of lesions is related to plaque size and
morphology, which in turn determine plaque stability. Chronic
lesions with severe obstruction reduce blood flow and cause stable
angina pectoris. However, most acute coronary syndromes are caused
by sudden changes of mildly stenotic, vulnerable plaques. The
initiating event is rupture or erosion of the fibrous cap, followed
by luminal thrombus formation.
Diagnostic methods to characterize lesions
Imaging techniques visualizing coronary plaque morphology in
vivo may allow identification of vulnerable lesions before rupture.
A coronary angiogram shows the geometry of the vessel lumen, but
not the vessel wall and plaque.
However, it provides limited information about the surface of the
plaque (smooth, irregular) and calcifications of the vessel wall.
Several studies described that a majority of culprit lesions in
patients with unstable angina had a characteristic angiographic
appearance. These lesions have been termed Ambrose type II lesions.
However, these characteristics describe plaques that have already
ruptured, rather than those at risk to rupture.
The extent of fluoroscopic calcifications is a marker of the
overall disease burden and, therefore, has prognostic value.
However, angiography is not as sensitive a method to evaluate
calcification as intravascular ultrasound, EBCT, or fast
Computed tomography is very sensitive in detecting and
quantitating coronary artery calcifications and can survey the
entire coronary tree noninvasively. Epicardial coronary arteries
are visualized easily by CT because the lower CT density of
periarterial fat markedly contrasts to blood in the coronary
arteries, and mural calcifications are identified because of their
high CT density.
Electron-beam computer tomography allows the acquisition of
serial transaxial images with a thickness of 3 to 6 mm and a
temporal resolution of 100 ms. Thirty to 40 adjacent axial scans
are obtained during 1 to 2 breath-holding periods. The short time
window for acquiring each image virtually eliminates motion-related
artifacts caused by cardiac and respiratory movements. Conventional
CT, using fast multidetector technology, has been validated as an
alternative technique to EBCT for coronary calcium detection and
quantitation. Several recent reports describe the visualization of
coronary calcifications with multidetector CT scanners, capable of
acquiring 4 slices simultaneously and covering the entire heart in
a single breath-hold with a slice thickness between 1.25 and 2.5
Figure 3 shows a calcium scoring image obtained with fast
multidetector CT. Calcium is clearly displayed in the left anterior
descending coronary artery.
For the purposes of coronary calcium evaluation, CT examinations
are performed without contrast agent administration and, therefore,
display only calcified components of plaque. Usually, tissue
densities >= 130 Hounsfield units are set as the attenuation
level corresponding to calcified plaque. A calcium scoring system
has been devised based on the maximum x-ray attenuation
coefficient, or CT number measured in Hounsfield units, and the
area of calcium deposits
(traditional Agatston calcium score). Callister et al
evaluated an alternative method of determining the calcium score by
quantifying the actual volume of plaque analogous to that possible
in prior histological studies (total calcium volume score, CVS).
Both calcium scoring algorithms can be applied to either EBCT or
fast multidetector CT images and provide a measure of total
coronary plaque burden. The prognostic value of this information
has been examined in several studies.
Because compensatory vessel enlargement (positive remodeling)
allows plaque accumulation without stenosis, the correlation of
calcium area with luminal dimension is only moderate.
Magnetic resonance imaging
Magnetic resonance imaging is a noninvasive two- or
three-dimensional imaging technique that differentiates tissue
structures on the basis of their proton magnetic properties. A wide
range of image contrast can be obtained with different pulse
sequences. Using clinical MRI scanners with customized software,
these techniques are used to study atherosclerotic lesion
morphology in animal models and human vessels.
The extent of atherosclerotic plaque burden has been defined with
high-resolution MRI in human popliteal arteries, demonstrating
significant plaque burden in angiographically "normal" vessel
In recent studies, MRI has been shown to quantify vessel wall area
accurately, allowing assessment of arterial remodeling.
Shinnar et al
describes the diagnostic accuracy of MRI for plaque
characterization but also underlines the significant technical
improvements in resolution and gating that are needed before this
technique can be applied to the examination of coronary arteries in
clinical settings. Figure 4 shows a three-dimensional T1-weighted
gradient-echo MRI image from a human coronary artery segment from a
Intravascular ultrasound provides tomographic images of the
vessel wall including vessel size, plaque size, and plaque
morphology (figure 5).
During cardiac catheterization, a miniature ultrasound catheter is
placed beyond the target lesion site. The ultrasound catheter is
then withdrawn during continuous imaging, resulting in a series of
cross-sections. The vessel wall of each cross-section can be
described by its signal characteristics on a continuum from
echodense (bright echo signal) to echolucent (faint echo signal).
The measurement of lumen area, intima-media area, and external
elastic membrane (EEM) area allows assessment of arterial
remodeling and plaque burden. Several IVUS studies have
demonstrated the reliability of ultrasound imaging in predicting
the composition of the atherosclerotic plaque when compared with
Lipid-laden lesions appeared as hypoechoic, "soft" areas and
fibrous or calcified tissues were recognized as bright echoes. In
lipid-laden lesions with prominent overlying fibrous caps, a more
reflective structure separating the soft echoes from the lumen was
identified on the corresponding images.
Advances in data analysis of the intravascular ultrasound
information may allow a more detailed description of vessel wall
and plaque morphology.
In particular, radiofrequency analysis has been used for the
characterization of plaque structures such as the lipid pool and
Other investigational catheter-based techniques, such as
IVUS-elastography, optical-coherence-tomography (OCT) have been
An indirect approach to plaque characterization is the development
of serum markers reflecting characteristics of coronary lesions. In
particular, markers of inflammation like C-reactive protein (CRP)
and high-sensitivity CRP may reflect lesion development and plaque
Coronary risk assessment in primary and secondary
Total atherosclerotic plaque burden and its progression or
regression reflects disease severity and activity. Quantification
of coronary calcium with EBCT calcium scores has been shown to
reflect the total atherosclerotic plaque burden.
Therefore, CT can be used to predict future risk and offers the
potential to follow disease progression, stabilization, and
possible regression through serial imaging.
In a serial study, the CVS was determined in 149 patients before
and after 1 year of treatment with either HMG-CoA reductase
inhibitors or diet alone. The average increase of the CVS during
the follow-up period in the statin-treated and diet group was 5% ±
28% and 52% ± 36%, respectively (
However, according to a current AHA/ACC consensus statement, the
incremental value of calcium scores over "traditional" multivariate
risk-assessment models has not yet been established. These
guidelines, therefore, do not recommend CT screening of coronary
calcification for asymptomatic individuals, but conclude that it is
justified in selected patient groups with intermediate risk.
Serial studies have evaluated IVUS assessment of plaque burden.
A small study examined the effect of 3-year treatment with
pravastatin or diet in mildly diseased coronary arteries.
During follow-up, plaque area increased by 41% in the control group
but decreased by 7% in the treatment group. External elastic
membrane area increased by 9% in the control group but did not
change in the treatment group. Lumen area decreased by 9% in the
control group but increased by 10% in the treatment group. The
overall plaque burden demonstrated by IVUS or CT may direct
preventive treatment plans. Theoretically, the progression or
regression of plaque burden in serial studies may be used to assess
the effectiveness of these treatments.
Assessment of plaque vulnerability
An important goal of plaque characterization is to correlate
plaque structure to the subsequent risk of rupture leading to acute
coronary syndromes. Currently, a reliable identification of these
vulnerable plaques in not yet possible.
However, using IVUS, several groups have found differences between
stable and vulnerable coronary plaques. Plaque echolucency has been
associated with the clinical presentation of unstable angina.
Recent studies describe an association between acute coronary
syndromes and positive remodeling.
Our group has studied 85 patients with unstable and 46 patients
with stable coronary syndromes using IVUS. Positive remodeling was
significantly more frequent in unstable than in stable lesions
(51.8% vs. 19.6%), while negative remodeling was more frequent in
stable lesions (56.5% vs. 31.8%) (
A recent, prospective, serial IVUS study found that mildly
stenotic lesions exhibiting positive remodeling and echolucent
plaques at baseline more frequently caused acute coronary syndromes
during follow-up than did echodense lesions with negative
remodeling at baseline.
The evidence for the ability of CT to identify vulnerable plaques
remains limited. While a higher calcium-score may predict an
overall greater number of vulnerable plaques, coronary
calcifications of individual lesions are not a marker for
vulnerability and several studies found vulnerable plaques without
Recent reports describe the visualization of noncalcified coronary
plaque with contrast-enhanced fast multidetector CT, but the
experience is limited (figure 6).
Plaque morphology has been studied with MRI in animal models and
human peripheral arteries. The clinical role of MRI in the
assessment of vulnerable lesions is not yet known.
Role in interventional cardiology
Interventional catheter-based techniques can be used to evaluate
the morphology of individual lesions before coronary interventions
are performed. This baseline morphology predicts the response of
the lesion to the intervention. The depth and circumferential
extent of calcifications affect lesion expansion during balloon
angioplasty, and dissections frequently occur at the junction
between soft tissue and calcium.
In recent IVUS studies, positive remodeling was associated with
higher target-lesion revascularization rate after nonstent
interventions. This effect was not seen in stented lesions.
Therefore, not only the degree of luminal stenosis, but also the
composition of the atherosclerotic plaque may determine the
decision of which interventional strategy would be most
Plaque characterization describes imaging methods assessing
morphologic characteristics of coronary plaques. Catheter-based
imaging techniques provide characterization of individual lesions
in the catheterization laboratory. Noninvasive imaging techniques
evaluate characteristics of the entire coronary tree.
There is accumulating evidence that plaque characterization can
be used in several ways in clinical practice. The overall plaque
burden and plaque morphology has prognostic value and could
influence preventive treatment plans. Serial observation of plaque
burden allows the recognition of disease progression or regression
and can be used to assess the effect of treatment. The
pre-interventional morphology of individual lesions affects outcome
after coronary interventions and can guide interventional