VEGF-Targeted Multispectral Optoacoustic Tomography and Fluorescence Molecular Imaging in Human Carotid Atherosclerotic Plaques.

Pieter J Steinkamp,Wouter B Nagengast,Jasper Vonk,Hendrikus H Boersma,Gilles F H Diercks,Lydian A Huisman,Gert-Jan Meersma,Jan-Luuk Hillebrands,Clark J Zeebregts,Riemer H J A Slart,Gooitzen M Van Dam

doi:10.3390/diagnostics11071227

Abstract

Vulnerable atherosclerotic carotid plaques are prone to rupture, resulting in ischemic strokes. In contrast to radiological imaging techniques, molecular imaging techniques have the potential to assess plaque vulnerability by visualizing diseases-specific biomarkers. A risk factor for rupture is intra-plaque neovascularization, which is characterized by overexpression of vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW, a near-infrared tracer targeting VEGF-A, is safe and if molecular assessment of atherosclerotic carotid plaques in vivo is possible using multispectral optoacoustic tomography (MSOT). Healthy volunteers and patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were imaged with MSOT. Secondly, patients were imaged two days after intravenous administration of 4.5 bevacizumab-800CW. Ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology. In this first-in-human MSOT and fluorescence molecular imaging study, we show that administration of 4.5 mg bevacizumab-800CW appeared to be safe in five patients and accumulated in the carotid atherosclerotic plaque. Although we could visualize the carotid bifurcation area in all subjects using MSOT, bevacizumab-800CW-resolved signal could not be detected with MSOT in the patients. Future studies should evaluate tracer safety, higher doses of bevacizumab-800CW or develop dedicated contrast agents for carotid atherosclerotic plaque assessment using MSOT.

Highlights

Carotid atherosclerotic plaque rupture is a major cause of ischemic stroke, accounting for 18–25% of all stroke events [1]
No imaging method can differentiate vulnerable from non-vulnerable atherosclerotic plaques with adequate accuracy for clinical use to assess for risk stratification and patient selection prior to surgery
Our data demonstrate that microdosing 4.5 mg bevacizumab-800CW is safe in a vulnerable patient population undergoing carotid endarterectomy (CEA)

Summary

Introduction

Carotid atherosclerotic plaque rupture is a major cause of ischemic stroke, accounting for 18–25% of all stroke events [1]. Carotid endarterectomy (CEA) is recommended if the degree of extracranial internal carotid artery (ICA) stenosis is >70% in symptomatic patients to prevent a second ischemic stroke event or death [2]. Some ischemic strokes do not correlate with stenosis severity but with plaque rupture [3]. Identification of these ‘vulnerable plaques’ by obtaining information on plaque composition could be a valuable tool to select symptomatic and eventually asymptomatic patients with increased risk for ischemic stroke that would benefit from a CEA [1] There is strong evidence that vulnerable plaques show increased levels of inflammation, characterized by a thin fibrous cap, a necrotic core and increased macrophage infiltration [4,5]. Successful imaging of VEGF-A to identify vulnerable, unstable plaques has been shown through positron emission tomography [6,7]

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