In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis

Abstract

ObjectivesIntraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.MethodsVascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217–237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.Results18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02).ConclusionsIn vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.

Highly sensitive magnetic particle imaging of vulnerable atherosclerotic plaque with active myeloperoxidase-targeted nanoparticles

“…Moreover, Qiao et al 35 reported a novel osteopontin-targeted nanoprobe, which was applied in both MRI and FLI of macrophages in atherosclerosis in vivo . Jenkins et al 36 used the PET radiotracer 18F-fluciclatide to target the α v β 3 -integrin receptor, which was upregulated in angiogenesis and inflammation under atherosclerosis conditions in vivo . Due to their low positive predictive values, these imaging tracers require further evidence to confirm their role in discriminating vulnerable from stable plaques 37 .…”

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation

“…Integrin αvβ3 is expressed by activated endothelial cells, as well as macrophages. In a study of 46 patients with atherosclerosis who underwent PET imaging with the αvβ3 tracer 18 F-fluciclatide, uptake of this tracer in the aorta was higher in patients with myocardial infarction than stable angina and was correlated with measures of aortic atherosclerotic burden [57]. Other αvβ3-targeted tracers that have been evaluated for use in atherosclerosis include 18 F-Galacto-RGD and 18 F-Flotegatide [58][59][60].…”

Imaging at the inter-face of inflammation and angiogenesis by 18F-fluciclatide PET

“…The data from 46 patients presented by Jenkins et al represent the largest prospective cohort of patients with atherosclerosis imaged using an α v β 3 tracer 1. In a related study, the group previously reported that 18 F-fluciclatide could accurately identify areas of acute myocardial infarction (MI), and predict the likelihood of functional recovery in impaired, but viable, myocardium 3.…”

“…However, several key pathogenic processes known to increase the likelihood of an acute plaque event can be tracked in vivo using positron emission tomography (PET). In their Heart paper, Jenkins et al 1 examine the utility of 18 F-fluciclatide, an α v β 3 integrin-binding PET tracer, for imaging atherosclerosis. This intriguing study adds great momentum in the push to identify novel methods for imaging molecular signatures of high-risk plaques, and raises several important broader considerations for the field.…”