Atherosclerosis; Molecular imaging; Echocardiography; Inflammation; Therapy; Contrast; Ultrasound
Khanicheh E, Mitterhuber M, Kinslechner K, Xu LF, Lindner JR, Kaufmann BA (2012), Factors Affecting the Endothelial Retention of Targeted Microbubbles: Influence of Microbubble Shell Design and Cell Surface Projection of the Endothelial Target Molecule, in JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY
, 25(4), 460-466.
Kaufmann BA, Carr CL, Belcik T, Xie A, Kron B, Yue Q, Lindner JR (2010), Effect of Acoustic Power on In Vivo Molecular Imaging with Targeted Microbubbles: Implications for Low-Mechanical Index Real-Time Imaging, in JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY
, 23(1), 79-85.
Kaufmann BA, Carr CL, Belcik JT, Xie A, Yue Q, Chadderdon S, Caplan ES, Khangura J, Bullens S, Bunting S, Lindner JR (2010), Molecular Imaging of the Initial Inflammatory Response in Atherosclerosis Implications for Early Detection of Disease, in ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
, 30(1), 54-54.
Kaufmann BA (2009), Ultrasound molecular imaging of atherosclerosis, in CARDIOVASCULAR RESEARCH
, 83(4), 617-625.
Current methods to assess the risk of patients for cardiovascular events associated with atherosclerosis rely on well-established risk factors. However, these risk models place a large proportion of adults in western countries in an intermediate risk category, and methods for further risk assessment in this group are needed. Inflammation plays a prominent role in the initiation and progression of atherosclerosis. This inflammatory process involves the recruitment of blood monocytes into the vessel wall. The molecular mechanisms of monocyte attachment to the vascular endothelium have been shown to depend critically on the appearance of endothelial cell adhesion molecules (ECAM) on the endothelial cell surface. Two ECAMs that have been shown to be upregulated early during the pathogenesis of atherosclerosis are vascular cell adhesion molecule-1 (VCAM-1) and P-Selectin. Molecular imaging with contrast enhanced ultrasound has recently been shown to be feasible to detect the appearance of ECAMs in inflamed tissue.The overall aim of this proposal is therefore to use contrast enhanced ultrasound molecular imaging to characterize the relation between endothelial cell adhesion molecule (ECAM) expression and plaque development. These studies have been designed to test the hypothesis that abnormal expression of ECAMs can predict the future development of aggressive regional atherosclerosis, and that the response to anti-inflammatory or anti-atherogenic therapies can be assessed.The first part of this study proposal will investigate the hypothesis that longer versus shorter polyethylene glycol arms for ligand attachment to ultrasound contrast media yield better targeting efficiency. Microbubbles are composed of a gas core and a lipid shell with a protective polyethylene glycol (PEG) layer. Biotin-tipped PEG arms are also incorporated into the shell and then used to attach ligands specific for molecular targets. We hypothesize, that the use of longer versus shorter PEG arms will project ligands further away from the microbubble surface and lead to better targeting efficiency. We will test this hypothesis in (1) an in vitro flow chamber model containing vascular endothelial cells, (2) directly and visually compare the attachment efficiency of different microbubble species in vivo with intravital microscopy, and (3) use a model of mouse hindlimb ischemia-reperfusion to compare signal generation of microbubbles with a long versus a short PEG arm during noninvasive contrast enhanced ultrasound molecular imaging. Results from these studies will be used to optimize microbubbles used in the experiments described below.The second part of this study will investigate the hypothesis, that molecular imaging can detect the early expression of VCAM-1 and/or P-Selectin prior to morphologic changes in atherosclerosis, and that the spatial pattern of early VCAM-1 and/or P-Selectin expression predicts the location of subsequent plaque development. The early expression of VCAM-1 and P-Selectin will be assessed with contrast enhanced ultrasound molecular imaging in a mouse model of atherosclerotic disease. Histology and immunohistology will be used to independently assess plaque development and ECAM expression at early and late timepoints. Results from molecular imaging will be qualitatively and quantitatively compared to histology and immunohistology to assess the potential of this imaging method for early detection of vascular inflammation in atherosclerosis.The third part of this study proposal will investigate the hypothesis, that molecular imaging can assess molecular changes on endothelial cells in response to anti-inflammatory and anti-atherogenic therapies. In a mouse model of atherosclerotic disease, we will test whether contrast enhanced ultrasound molecular imaging can assess the effect of therapies with (1) the HMG-CoA inhibitor atorvastatin and (2) the NADPH oxidase inhibitor apocynin on the expression of ECAMs. The results from molecular imaging will be compared to histology and immunohistology to assess the potential of this method for the assessment of the therapeutic effect of established and emerging therapies for atherosclerosis.