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Contrast enhanced ultrasound molecular imaging of vascular inflammation in atherosclerosis: development of methods for early detection of cardiovascular risk and assessment of the effect of targeted therapies

English title Contrast enhanced ultrasound molecular imaging of vascular inflammation in atherosclerosis: development of methods for early detection of cardiovascular risk and assessment of the effect of targeted therapies
Applicant Kaufmann Beat
Number 123819
Funding scheme Ambizione
Research institution Klinik für Kardiologie Bereich Medizin Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.04.2009 - 31.03.2012
Approved amount 701'438.00
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Keywords (7)

Atherosclerosis; Molecular imaging; Echocardiography; Inflammation; Therapy; Contrast; Ultrasound

Lay Summary (English)

Lead
Lay summary
Atherosclerosis is the cause of myocardial infarction ("heart attack"), stroke and many other diseases. Atherosclerosis progresses silently for decades before causing symptoms. Inflammation has been identified to play a crucial role both in the very early and also the later stages of atherosclerosis. This inflammation involves the recruitment of white blood cells from the blood stream into the vessel wall. The recruitment of these inflammatory cells is tightly regulated by adhesion molecules. Adhesion molecules are proteins that appear on the inner cell lining of blood vessels in response to inflammatory stimuli (elevated cholesterol levels for example). These adhesion molecules allow white blood cells to attach to the vessel cell lining and then emigrate to the vessel wall. Appearance of these adhesion molecules has been shown to precede the formation of atherosclerotic lesions in blood vessels. Thus, imaging of the appearance of these adhesion molecules in blood vessels could allow early detection of atherosclerosis and could be used clinically to guide preventive therapy. Contrast enhanced ultrasound molecular imaging uses tiny microbubbles that can be detected with ultrasound after they have been injected into a living organism. These microbubbles can be directed to attach to specific targets in the body by attaching antibodies on their surface. In the present research proposal, this method will be used to assess, whether detection of the expression of adhesion molecules is possible before the development of advanced atherosclerotic lesions in a mouse model of atherosclerosis. We will also assess, whether this method offers the capability to assess the effect of anti-inflammatory therapies on the expression of adhesion molecules.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Factors Affecting the Endothelial Retention of Targeted Microbubbles: Influence of Microbubble Shell Design and Cell Surface Projection of the Endothelial Target Molecule
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.
Effect of Acoustic Power on In Vivo Molecular Imaging with Targeted Microbubbles: Implications for Low-Mechanical Index Real-Time Imaging
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.
Molecular Imaging of the Initial Inflammatory Response in Atherosclerosis Implications for Early Detection of Disease
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.
Ultrasound molecular imaging of atherosclerosis
Kaufmann BA (2009), Ultrasound molecular imaging of atherosclerosis, in CARDIOVASCULAR RESEARCH, 83(4), 617-625.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Euroecho 14.12.2011 Budapest
Schweizerische Gesellschaft für Kardiologie 10.06.2011 Basel


Awards

Title Year
Finalist, Young Investigators Award, Euroecho 2011 2011

Associated projects

Number Title Start Funding scheme
128782 R'equip grant for Visual Sonics Vevo 770 high resolution small animal ultrasound system 01.12.2009 R'EQUIP
169905 Non-invasive ultrasound molecular imaging of atherosclerosis: development of clinically translatable tracers for targeting of Vascular Cell Adhesion Molecule 1 01.04.2017 Project funding (Div. I-III)
149718 Non-invasive ultrasound molecular imaging of myocarditis and autoimmune myocardial inflammation 01.04.2014 Project funding (Div. I-III)
108514 Atherosclerosis and angiogenesis: targeted imaging of cell adhesion molecules promoting inflammation in atherosclerosis and integrins in angiogenesis with contrast enhanced ultrasound 01.07.2005 Fellowships for prospective researchers
141603 Contrast enhanced ultrasound molecular imaging of vascular inflammation in atherosclerosis: development of methods for early detection of cardiovascular risk and assessment of the effect of targeted therapies 01.04.2012 Ambizione

Abstract

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.
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