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, OH.

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 severity. ¹ 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 acute event ^2-4 because early plaque development leads to expansion of the vessel wall (positive remodeling), thereby delaying luminal stenosis despite plaque accumulation. ⁵ 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 treatment.

Coronary plaque development and plaque vulnerability

Histologic and intravascular ultrasound studies have shown that coronary lesion development starts relatively early in life. ⁶ 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. ^6-8 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 ⁵ in human coronary atherosclerosis. Coronary artery wall calcification is part of the development of atherosclerosis. ⁹ 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." ¹⁰ The shoulder area at the margin of the plaque is a location of high stress, predisposed to rupture (figures 1 and 2). ^11,12 The accumulation of inflammatory cells and secretion of enzymes causes degradation of the fibrous "cap." ^7,8,10 The relation of coronary calcifications to the probability of plaque rupture is unknown, ⁹ 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

Coronary angiography

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. ¹³ 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. ^14,15 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. ^16-18 However, angiography is not as sensitive a method to evaluate calcification as intravascular ultrasound, EBCT, or fast multidetector CT. ^19-23

Computed tomography

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 mm. ^23-25 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 ²⁶ (traditional Agatston calcium score). Callister et al ²⁷ 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). ²⁸ 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. ²⁹ Because compensatory vessel enlargement (positive remodeling) allows plaque accumulation without stenosis, the correlation of calcium area with luminal dimension is only moderate. ^30,31

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. ^32-35 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 segments. ³⁶ In recent studies, MRI has been shown to quantify vessel wall area accurately, allowing assessment of arterial remodeling. ^36,37 Shinnar et al ³⁸ 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 post-mortem study.

Intravascular ultrasound

Intravascular ultrasound provides tomographic images of the vessel wall including vessel size, plaque size, and plaque morphology (figure 5). ³⁹ 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 histology. ^40-42 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. ^43-45 In particular, radiofrequency analysis has been used for the characterization of plaque structures such as the lipid pool and fibrous cap. ^44-46

Other investigational catheter-based techniques, such as IVUS-elastography, optical-coherence-tomography (OCT) have been reviewed recently. ⁴⁷ 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 vulnerability. ^48,49

Clinical applications

Coronary risk assessment in primary and secondary prevention

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. ^9,50,51 Therefore, CT can be used to predict future risk and offers the potential to follow disease progression, stabilization, and possible regression through serial imaging. ⁵² 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 ( P < 0.001). ⁵³ 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. ⁵⁴

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. ⁵⁵ 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. ⁵⁶ 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. ⁴¹ Recent studies describe an association between acute coronary syndromes and positive remodeling. ^57-59 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%) ( P = 0.001). ⁵⁷

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. ⁶⁰ 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 calcium. ⁶¹ Recent reports describe the visualization of noncalcified coronary plaque with contrast-enhanced fast multidetector CT, but the experience is limited (figure 6). ^62,63 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. ⁶⁴ 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. ^65-67 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 suitable.

Conclusion

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 treatment. AR