Molecular Imaging of Macrophage Cell Death for the Assessment of Plaque Vulnerability

Abstract

Abstract-The ability to identify atherosclerotic plaques that are prone to rupture, also called vulnerable plaques, may provide a major step forward in the recognition of patients that have a high risk of developing acute myocardial infarction. A therosclerotic disease remains killer number one in both developed and developing nations. It afflicts women and men alike. Because of the epidemic proportions of obesity and aging of the population, it is expected that the impact of atherosclerotic disease will remain high in the new century as well. The first signs of the impact of the escalating proportions of obesity may have influenced recent event rates in the United States, wherein the decline in the incidence of acute myocardial infarction in men has come to a halt, and in women the numbers have started to escalate.The main challenge for clinicians is to identify individuals who have a high likelihood of developing myocardial infarction. Clinical risk profiling algorithms, such as the Framingham and the Procam risk scores, have proven to be useful tools for the identification of individuals with a high risk to develop acute myocardial infarction in the next 10 years. Typically, the clinical risk scoring profiles categorize individuals in low risk (less than 5% 10-year risk), intermediate risk (5% to 20%), and high risk (20% or more) to develop acute myocardial infarction. 1 However, clinical risk profiling does not provide a clear answer about the time frame when events may occur in the next 10 years. We may also need to find ways to improve the area under the ROC curve to enhance predictive value. Recent studies have shown that the addition of novel serum biomarkers to clinical risk profiling had limited beneficial effect, and that novel strategies need to be developed to improve the predictive value of diagnostic algorithms. 2 One way to obtain better predictive values and more precise information is the use of imaging technology for identification of plaques that are vulnerable to rupture. 3 Traditional imaging methods have provided excellent information about the location and the extent of luminal narrowing of atherosclerotic lesions. 4 Clinical research studies have demonstrated that the occurrence of acute myocardial infarction is related to plaque characteristics. In at least 70% to 80% of cases, acute myocardial infarction is attributable to rupture of a vulnerable plaque, resulting in local thrombus formation and acute disruption in the coronary blood supply in the affected area. 5 These studies have shown that vulnerable plaques are characterized by a large necrotic core, a thin fibrous cap, and by the presence of macrophages. 6 Cell death of inflammatory cells by the process of apoptosis has recently been proposed to contribute to plaque vulnerability. Apoptosis has been linked to thinning of the fibrous cap, the development of the necrotic core, and positive vessel remodeling. 7 Identification of apoptosis in atherosclerotic lesions may help identify vulnerable atherosclerotic plaques in patients. Be...

The Vascular Biology of Atherosclerosis and Imaging Targets

“…Cells undergoing apoptosis exteriorize phosphatidylserine, a target for molecular imaging of dying cells and potentially for reporting on the biology associated with cell death in atheromata. Annexin V binds to phosphatidylserine, providing a ligand for imaging cell death (42,43).…”

Localization of Deoxyglucose and Annexin A5 in Experimental Atheroma Correlates with Macrophage Infiltration but not Lipid Deposition in the Lesion

“…Although these techniques provide anatomic information such as location, lesion thickness, lipid content and lumen incursion, they do not provide functional information. The metabolic rate of inflammatory cells in the lesion and induction of apoptosis are two indicators of lesion vulnerability that are likely to identify more advanced lesions vulnerable to rupture [7][8][9][10]. 2-Deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG), a marker of metabolic activity, and [ 99m Tc]annexin A5, a marker of apoptosis, have been advocated as imaging agents to detect metabolically active atheroma and monitor treatment efficacy [11][12][13][14][15].…”

Imaging Cell Death

“…Despite being a monomer in solution, AnxV forms trimer-based lattices on the surface of apoptotic cells, inducing strong cooperative phosphatidylserine-binding and driving cellular internalization. However, despite the early promise of 99m Tc-AnxV probes for detecting apoptosis in cardiovascular disorders (6) and for monitoring treatment response in head and neck cancer (1), AnxV has shown suboptimal biodistribution profiles, characterized by slow clearance and nonspecific binding to abdominal tissues (7). A second generation of site-specific mutants of AnxV has been proposed (8), yet the same problems persist, namely suboptimal pharmacokinetics and low specificity (9).…”