Appendix 2. Description of Imaging Modalities that Have Been Evaluated in Clinical Studies to Characterize the Plaque Morphology
Traditionally, angiography is the reference standard for identifying coronary and carotid artery lesions. It provides information about the luminal diameter and enables visualization of the luminal surface to diagnose atherosclerotic disease. Angiography may show severe lesions, plaque disruption, luminal thrombosis, and calcification. Other than some calcifications, angiography does not provide information about the vessel wall or atherosclerotic plaque composition such as the vulnerable lipid-rich plaques or other histopathological features (Topol 1995). A major limitation of angiography is that diffuse atherosclerotic disease may narrow the entire lumen of the artery, and therefore underestimate the degree of local stenosis. Additionally, some outwardly displaced plaques may appear to have normal luminal diameter despite significant disease (Glagov 1987).
Catheter-based intravascular ultrasound (IVUS) is an imaging modality to detect atherosclerotic plaque distribution to characterize vessel wall and plaque morphology (Regar 2002). Coronary atheroma can be classified into categories based on plaque echogenicity: (1) highly echoreflective regions with acoustic shadows, often corresponding to calcified tissue; (2) hyperechoic areas representing fibrosis or microcalcifications; or (3) hypoechoic regions corresponding to thrombotic or lipid-rich tissue or a mixture of these elements (Nissen 2001). The main limitations of IVUS include poor resolution and inability to discriminate between fibrous and lipid-rich plaques (MacNeill 2003). Modifications of this technique using analysis of integrated backscatter and the radiofrequency envelope might improve resolution (Kawasaki 2002). IVUS elastography that combines US images with radiofrequency measurements may be able to better detect regions of increased strain prone to rupture (de Korte 2000).
Intracoronary angioscopy facilitates direct visualization of the plaque surface, color of the luminal surface, presence of thrombus, and macroscopic features of the arterial wall (Uchida 1995). The normal appearance of the vessel surface is glistening white. A white granular plaque may appear at the site of plaque rupture because of the platelet-rich thrombus. Yellow plaques correspond to the lipid-rich core and thin fibrous cap that characterize the site as vulnerable. A red, irregular surface protruding into the lumen may indicate fibrin or erythrocyte-rich thrombus (Mizuno 1991, Ueda 1996). Angioscopy visualizes the luminal surface but is insensitive to subtle differences in plaque. Therefore, the major role of angioscopy has been assessing lumen structure before and after interventions (Mizuno 1992).
Thermography is a catheter-based technique to detect heat released by activated inflammatory cells of atherosclerotic plaques. Temperature differences correlate positively with cell (macrophage) density, which may predict plaque disruption and thrombosis (Cassells 1996, Stefanadis 1999). However, there is no clear evidence that temperature differentials correlate with specific plaque vulnerability. Finally, without the structural definition obtained from high-resolution imaging techniques, the independent role of thermography is limited (Stefanadis and Toutouzas 2002).
Optical Coherence Tomography
Optical Coherence Tomography (OCT) measures the echo time delay and intensity of backscattered light due to internal microstructure in the tissue (Fujimoto 1999). OCT can provide high resolution, cross-sectional images of arterial wall. Fibrous, lipid, and calcified components of VP have been discerned by OCT (Yabushita 2002). Limitations of OCT for in vivo intravascular imaging include limited tissue penetration depth, reduction of image quality when imaging through blood or large volumes of tissue, and a relatively slow data acquisition rate (Fujimoto 1999). OCT elastography is also being evaluated by combining high-resolution imaging with radiofrequency measurements to detect foci of increased strain that are prone to plaque rupture (MacNeill 2003).
Raman spectroscopy is an intravascular optical technique that characterizes the tissue’s chemical composition. The Raman spectrum is obtained by processing the collected light scattered by tissue when illuminated with a laser. The molecular characteristics of lipid and calcium salts make Raman spectroscopy highly sensitive for plaque detection (Brennan 1997). Although, Raman spectroscopy is one-dimensional, it could be combined with other catheter-based imaging techniques, such as IVUS, to localize and quantify cholesterol and calcium salts in atherosclerotic plaques (Romer 2000).
Near Infrared Spectroscopy
Near infrared spectroscopy (NIRS) measures diffuse reflectance signals by using near infrared light as an energy source. Similar to Raman spectroscopy, NIRS also yields information about tissue chemical composition (Zhu 2000). NIRS may detect the lipid core and features of plaque vulnerability of the fibrous cap and inflammation (Moreno 2002). A limitation of this non-contact spectroscopic modality is that it is influenced by flowing blood, and its lack of structural definition restricts its independent use in VP detection (Cassis 1993).
Intravascular Magnetic Resonance Imaging
To improve the resolution of magnetic resonance imaging (MRI), an intravascular coil is inserted in the artery or the adjacent vein (Hofmann 2001). Intravascular Magnetic Resonance Imaging (IMRI) yields adequate resolution to discriminate plaque components, including lipid, collagen, thrombus, and calcium on the basis of biochemical properties (Fayad 2000). Technical limitations exist in the IMRI coil designs, requiring multiple catheter manipulations and repeated imaging. Image quality is also reduced significantly as the intravascular coil moves off axis from the external magnet field (MacNeill 2003).
Magnetic Resonance Imaging
MRI can be used as a non-invasive imaging method to assess lipid cores, fibrous caps, calcification, normal media, adventitia, as well as intraplaque hemorrhage and acute thrombosis. MRI yields images without using ionizing radiation and can be repeated sequentially over time (Toussaint 1996).
MR angiography (MRA) and high-resolution black-blood imaging of the vessel wall can be combined. MRA demonstrates the severity of stenotic lesions and their spatial distribution, while the high-resolution black-blood wall characterization technique may show plaque composition and may facilitate the risk stratification and selection of treatment (Yucel 1999). Recently MRI has been used to measure the effect of lipid-lowering therapy (statins) in asymptomatic, untreated hypercholesterolemic patients with carotid and aortic atherosclerosis (Corti 2001).
Because echogeneity of the plaque reflects its characteristics, surface ultrasound (US) can non-invasively assess plaque in the carotid vessel. Measurements of carotid wall thickness as well as qualitative and quantitative analysis of plaque can be taken. Hypoechoic heterogeneous plaque is associated with both intraplaque hemorrhage and lipids, while hyperechoic homogeneous plaque is mostly fibrous (Cohen 1997, Nissen 2001).
Ultrafast Computed Tomography
Atherosclerotic calcification is found more frequently in advanced lesions, and may occur in small amounts in early lesions (Wexler 1996). Ultrafast Computed Tomography (UFCT) allows image acquisition of plaque calcification more reliably and rapidly than conventional computed tomography (CT). Fast imaging is essential to eliminate cardiac and respiratory motion artifacts. Only electron-beam CT (EBCT) and fast-gated helical or spiral CT can measure the amount or volume of calcium (Callister 1998). However, high-risk plaques often lack calcium. While, the relation of calcification to unstable plaque remains unclear, coronary calcification as detected by EBCT seems to be an indicator of atherosclerotic burden (Moreno 2000).
Many proteins labeled with various radioisotopes have been evaluated on the basis of molecules and cells involved in atherogenesis (Vallabhajosula 1999). These include lipoproteins (native LDL and oxidized LDL), immunoglobulins against macrophages, smooth muscle cells, endothelium adhesion molecules, and antifibrin antibody fragments and peptides (which bind to glycoprotein IIb/IIIa receptors on activated platelets) (Vallabhajosula 1997, Vallabhajosula 1988, Iuliano 2000). No single radiotracer is ideally suited to image atherosclerosis and providing the prognostic and clinical indicators necessary for medical and surgical interventions (Vallabhajosula 1999).