Who gets the heart attack: noninvasive imaging markers of plaque instability
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- Narula, J. J. Nucl. Cardiol. (2009) 16: 860. doi:10.1007/s12350-009-9141-6
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Acute coronary events result from thrombotic occlusion of the coronary artery.1-5 The occlusion is secondary to rupture of an atherosclerotic plaque in up to three-fourths of subjects; plaque erosion is seen in most of the remaining subjects who have died of an acute coronary event.2 Plaque rupture is associated with traditional risk factors, whereas erosion is generally associated with smoking and is commonly observed in women or younger subjects. Upon histopathological examination, the plaques that are prone to rupture and result in an acute event are almost always large.1-5 Such plaques also demonstrate large necrotic cores that occupy a large proportion of the plaque area. These necrotic cores are often associated with intraplaque neovascularization and hemorrhage, and adventitial vasa vasorum proliferation. 6,7 The necrotic cores are covered by rather attenuated fibrous cap, which are intensely inflamed. Therefore, an imaging strategy designed to identify rupture-prone plaques would target the enormity of plaque and necrotic core volumes, positive remodeling, and plaque inflammation.4,5 The morphological characteristics of such plaques can be identified by CT angiography of coronary arteries.4,8 Magnetic resonance has been employed for morphologic characterization of carotids and can also identify intraplaque hemorrhage.9,10 Contrast-enhanced ultrasound examination has revealed plaque neovascularization and vasa vasorum proliferation.11,12 Assessment of the fibrous cap thickness needs intravascular imaging techniques such as the optical coherence tomography.13 Plaque inflammation has been successfully assessed by PET imaging using fluorodeoxyglucose (FDG).14,15 Newer molecular imaging strategies have targeted upregulation of receptors on infiltrating monocyte or cytokine production.5
Assessment of Morphologic Characteristics of Plaque Instability
CT angiography, which has been predominantly investigated for the lumen narrowing by the plaque impingement in comparison to the invasive coronary angiography, has a distinct advantage of simultaneous demonstration of the plaque and necrotic core extent and the type of segmental remodeling.8 A comparison of disrupted plaques in patients who had experienced an acute coronary syndrome (ACS) with plaques from patients undergoing coronary intervention for stable angina by CT angiography showed positive vascular remodeling (PR; external vessel wall diameter of >110% compared to a normal proximal or distal segment) and low attenuation plaque (LAP; <30 Hounsefield Units [HU]). These two features demonstrate a high accuracy for identifying culprit lesions. The interpretation of such features on CT angiographic investigation, however, is not without limitations. Suboptimal resolution does not allow precise definition of the vascular boundary, and the assessment of the extent of PR may be over or underestimated. Similarly, the LAP is based on the assessment of the HU and various imaging/technical parameters may seriously influence the soft plaque measurements. As such, various investigators have suggested different cut-off points to define soft plaques. Our comparison of IVUS and CT angiography had demonstrated that a majority of echo-lucent plaque cores could be identified by keeping the upper limit of 30 HU.16 Of interest, spotty calcification was more commonly associated with culprit lesions and large calcific plates with the stable plaques.
Although not yet ready for the primetime, I believe that when reporting a CT angiogram, we should not limit ourselves only to the extent of luminal stenosis or calcified vs. noncalcified plaques, but insist to define the vessel wall characteristics in terms of plaque magnitude and consistency. It requires a cultural change in the way we deal with the coronary disease. However, it should also be realized that heavy calcification in many subjects may preclude such as a judgment and that plaque erosions are not amenable to CT characterization. Nonetheless, the subjects harboring high-risk plaques are candidates of intense and aggressive risk factor reduction including pharmacological intervention with currently available strategies.
Adventitial Vasa Vasorum Proliferation, Intraplaque Neovascularization, and Hemorrhage
Neovascularization of the atherosclerotic plaques is closely associated with the necrotic cores. These nascent vessels are fragile and allow convenient extravasation of erythrocytes and macromolecules.7 RBC membrane is one of the richest sources of free cholesterol, and leaking RBCs or intraplaque hemorrhage contributes substantially to the necrotic core size. Greater the deposition of RBC membrane or the iron deposits in the plaque, larger is the necrotic core size. As such, culprit lesions demonstrate substantially greater density of neovascularization and RBC membrane deposits.19 The magnetic resonance images of the carotid plaques have been compared with the endarterectomy specimens obtained during surgical procedures. High T1-weighted densities and low T2* values closely correlate with the extent of intraplaque hemorrhage.9,10 It has been observed that greater the hemorrhage, larger are the plaque volumes and that the symptomatic carotid disease is almost always associated with hemorrhage.9 It is also observed that the statin administration helps reduce plaque volumes only before the plaques are complicated by hemorrhage. Although magnetic resonance imaging of coronary plaques is not yet feasible, the RBC membrane cholesterol has been shown to be higher in patients undergoing coronary interventions for an acute coronary event than the stable disease, even though these subjects may have similar circulating cholesterol levels.20
Molecular Imaging for Plaque Inflammation
Plaque inflammation is an important constituent of the plaque instability.5 The cells of monocyte-macrophage origin are seen abundantly in the fibrous caps as also around the necrotic core. These cells develop various receptors for integrins and cytokines when they interact with the injured endothelial cells and negotiate through to the subendothelial space. The macrophages in neointima develop scavenger receptors to remove modified lipoprotein cholesterol particles. Macrophages eventually succumb to necrotic and apoptotic cell death process and add to the expanding necrotic core.21 Molecular imaging has been successfully employed for targeting the receptor upregulation, macrophage metabolism, and cell death as a marker of plaque inflammation. Fluorine-18-labeled FDG and annexin A5 (AA5) have been used clinically.14,15
Since apoptosis of macrophages is commonly seen in the high-risk plaques and radiolabeled AA5 can selectively bind to apoptotic cells, annexin positivity has been proposed as a marker of instability.15 Positive Tc-99m-AA5 uptake in a patient with carotid artery disease is traced to macrophages in the endarterectomy specimen, whereas the patient with negative scan had smooth muscle-rich lesion. In experimental settings, AA5 uptake correlates closely with macrophage density and the magnitude of apoptosis in atherosclerotic plaques. Diet modification and statin treatment reduce AA5 uptake.22,23 The experimental studies have demonstrated AA5 localization in aortic lesions in rabbits22 and mice,24 as also in coronary vessels in pigs.25
It will be mandatory to develop worthy diagnostic and therapeutic strategies targeted at the prevention of plaque rupture. If identified correctly, such plaques would be treated with aggressive statin and antiplatelet therapy.28 It is possible that newer antiinflammatory agents will be developed. It is also possible that novel stents would become available such as those which are bioabsorbable and targeted at inflammation or neovascularization. Although defining the plaque characteristics by an imaging technique is within the realm of feasibility, it will be important to identify the group of high-risk asymptomatic subjects which will benefit most by an imaging procedure.