Detection of inflamed atherosclerotic lesions with diadenosine-5',5'''-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography

Abstract. Early non-invasive imaging of atherosclerosis and in particular the detection of lesions at risk with high specificity could significantly affect cardiovascular morbidity and mortality. Conventional nuclear medicine approaches, in particular using autologous radiolabeled lipoproteins, can be related to histopathological findings; however, they fail to identify lesions at risk. Positron emission tomography (PET) tracers with much better physical properties have been examined, the most detailed information being available for F-18-deoxyglucose (FDG) and F-18-sodium fluoride (NaF). These two approaches are sensitive to different biochemical mechanisms, i.e. inflammation and microcalcification. Initial enthusiasm, in particular for F-18-FDG, has disappeared, although for F-18-NaF there is some hope, but this is not a breakthrough. No tracer is available so far that is able to identify a specific characteristic of a lesion prone to rupture. Other PET tracers in the pipeline have been examined, mainly in experimental models and only a few in patients, but they failed to contribute significantly to early lesion discovery and do not support great expectations. The key question is: Do we understand what we see? Moreover, methodological problems, a lack of standardization of imaging protocols and aspects of quantification provide a wide range for potential future improvements. While monitoring a therapeutic intervention seems to be possible for both F-18-FDG and F-18-NaF, highly specific early identification of lesions at risk by PET imaging is still far away. As of today, PET is not ready for routine clinical judgment of atherosclerotic lesions at risk to rupture. Even if all these problems can be solved, radiation exposure will still remain a concern, in particular for repeated studies.

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CXCR4-Binding Positron Emission Tomography Tracers Link Monocyte Recruitment and Endothelial Injury in Murine Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315053 ◽

2020 ◽

Author(s):

Osamu Baba ◽

Li-Hao Huang ◽

Andrew Elvington ◽

Martyna Szpakowska ◽

Deborah Sultan ◽

...

Keyword(s):

Positron Emission Tomography ◽

Chemokine Receptors ◽

Endothelial Injury ◽

Emission Tomography ◽

Atherosclerotic Lesions ◽

Inflammatory Protein ◽

Positron Emission ◽

Monocyte Recruitment ◽

Monocytes And Macrophages ◽

Cell Expression

Objective: vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer ( 64 Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe − /− mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64 Cu-DOTA-vMIP-II at Apoe −/− plaque sites was strong but declined with AAV- mApoE -induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64 Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64 Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64 Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. Conclusions: Endothelial injury status of plaques is marked by CXCR4 expression and that this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.

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