64Cu-DOTATATE PET/MRI for Detection of Activated Macrophages in Carotid Atherosclerotic Plaques: Studies in Patients Undergoing Endarterectomy

Sune Folke Pedersen, Benjamin Vikjær Sandholt, Sune Høgild Keller, Adam Espe Hansen, Andreas Ettrup Clemmensen, Henrik Sillesen, Liselotte Højgaard, Rasmus Sejersten Ripa, Andreas Kjær, Sune Folke Pedersen, Benjamin Vikjær Sandholt, Sune Høgild Keller, Adam Espe Hansen, Andreas Ettrup Clemmensen, Henrik Sillesen, Liselotte Højgaard, Rasmus Sejersten Ripa, Andreas Kjær

Abstract

Objective: A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [(64)Cu] [1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate ((64)Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo.

Approach and results: Ten patients underwent simultaneous PET/MRI to measure (64)Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. (64)Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo (64)Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with (64)Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model.

Conclusions: The novel PET tracer (64)Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with (64)Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that (64)Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques.

Keywords: atherosclerosis; carotid; endarterectomy; magnetic resonance imaging; positron-emission tomography.

© 2015 The Authors.

Figures

Figure 1.
Figure 1.
Multisequence MRI of the internal carotid artery at 3 different levels: first column; time-of-flight (TOF), second column; T1-weighted turbo-spin echo (T1), third column; T2-weighted turbo-spin echo (T2); and fourth column; proton density-weighted (PD). Top, Most caudal transaxial projection demonstrating A. communis (arrow). Middle, Intermediate transaxial projection demonstrating C. interna (arrowheads) and C. externa (open arrows). Bottom, Most cranial transaxial projection demonstrating C. interna (arrowheads) and C. externa (open arrows). Note the reduced blood flow on TOF in C. externa (middle) and C. interna (bottom). Plaque buildup can be seen in C. externa in T1, T2, and PD (middle) and in C. interna in T1, T2, and PD (bottom).
Figure 2.
Figure 2.
Coronal positron emission tomography (PET)/MRI of the neck region for visualization of the carotid arteries. Left, T1-weighted MR image showing atherosclerotic plaque of the left internal carotid artery marked with asterisk. Middle, Combined PET/MRI of the same projection showing [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) uptake in the plaque marked by asterisk. Right, Standalone PET image of the same projection showing 64Cu-DOTATATE distribution and left carotid artery plaque marked by asterisk.
Figure 3.
Figure 3.
[64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) positron emission tomography (PET)/MRI visualization and raw data. A, PET/MRI from 1 patient at 3 consecutive levels: (arrow) C. externa; (arrowhead) C. interna; top, most caudal transaxial projection. Left, Time-of-flight weighted MRI; middle, T1-weighted MRI; right, combined T1-weighted MRI and PET. Heterogeneous 64Cu-DOTATATE uptake is seen in plaque of the C. interna: top and bottom, clear 64Cu-DOTATATE uptake (T1-weighted MRI/PET); middle, plaque with no uptake. B, Bland Altman comparison of standardized uptake value (SUVmean) from the early PET examination compared with SUVmean from the late PET examination. Each black dot represents a 3-mm slice of the atherosclerotic plaque in the carotid artery. The red line represents the mean difference (in percent) between the 2 examinations.
Figure 4.
Figure 4.
Ex vivo combined positron emission tomography/computed tomographic visualization of a plaque recovered from the internal carotid artery demonstrating heterogeneous [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) uptake 23 hours post injection. Left, Transaxial projection of plaque exhibiting hot spots of 64Cu-DOTATATE accumulation. Middle and right, Coronal projections at 2 different levels. * indicates residual vessel lumen.
Figure 5.
Figure 5.
Case study showing histology and immunohistochemistry of an excised atherosclerotic plaque of the internal carotid artery immediately cranially to the bifurcature. Top, Hematoxylin/eosin (H/E) stain. All other rows: immunostaining, epitopes defined left of each row. Left, Negative control samples; middle, test samples; right, magnification from inserted boxes in middle panels. Scale bars provided in each panel in right lower corner. Arrowheads pointing right indicate positive immunostaining. * indicates residual arterial lumen. CD68 indicates cluster of differentiation 68; CD163, cluster of differentiation 163; CTSK, cathepsin K; IL-18, interleukin 18; and MMP9, matrix metalloproteinase-9.

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Source: PubMed

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