Towards non-invasive imaging of vulnerable atherosclerotic plaques by targeting co-stimulatory molecules.
BACKGROUND
Myocardial infarction and stroke are the life-threatening consequences after plaque rupture in coronary or carotid arteries. Positron emission tomography employing [(18)F]fluorodeoxyglucose can visualize plaque inflammation; however, the question remains whether this is specific for plaque vulnerability. The pathophysiology of vulnerable plaques suggests several molecular processes. Here, we propose the co-stimulatory molecules CD80 and CD86 as potential new targets for non-invasive imaging.


RESULTS
Human atherosclerotic segments were obtained from carotid endarterectomy and classified into stable and vulnerable plaques. We identified CD80 and CD86 with significantly higher mRNA levels in vulnerable than stable plaques. CD80+ and CD86+ cells were found in spatial proximity to CD83+ dendritic cells and CD68+ macrophages of atherosclerotic plaques. As a proof of target-expression we labeled a low molecular weight ligand, which has a high affinity for human CD80, with carbon-11 to perform in vitro autoradiography with human plaque slices. We observed 3-fold higher binding to vulnerable than stable plaques, demonstrating a first approach towards discriminating between the two plaque types. Positron emission tomography studies showed accumulation in CD80+ Raji xenografts, low radioactivity in myocardium and rapid clearance from the blood pool in mice.


CONCLUSIONS
In human carotid arteries, the co-stimulatory molecules CD80 and CD86 show significantly higher expression levels in vulnerable compared to stable plaques. With the novel CD80-specific radiotracer we are able to discriminate between stable and vulnerable atherosclerotic plaques in vitro. This is an important step towards non-invasive imaging of the life-threatening vulnerable lesions in humans.
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland. Electronic address: adrienne.mueller@pharma.ethz.ch.
Adrienne
A
Müller
Department of Nuclear Medicine, University Hospital Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Linjing
L
Mu
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Romana
R
Meletta
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Katharina
K
Beck
University Hospital Zurich, Clinic for Cardiovascular Surgery, Zurich, Switzerland.
Zoran
Z
Rancic
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Konstantin
K
Drandarov
University Hospital Zurich, Department of Nuclear Medicine, Cardiac Imaging, Zurich, Switzerland.
Philipp A
PA
Kaufmann
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Simon M
SM
Ametamey
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland; Department of Nuclear Medicine, University Hospital Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Roger
R
Schibli
Institute for Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
Nicole
N
Borel
Department of Chemistry and Applied Biosciences of ETH Zurich, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Zurich, Switzerland.
Stefanie D
SD
Krämer
D000368:Aged; D000818:Animals; D001345:Autoradiography / Q000639:trends; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016894:Endarterectomy, Carotid / Q000639:trends; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging* / Q000601:surgery; D049268:Positron-Emission Tomography / Q000639:trends*; D011859:Radiography; D016037:Single-Blind Method
D018122:B7-1 Antigen; D051940:B7-2 Antigen
Atherosclerosis; Co-stimulatory molecules; Immune system; Positron emission tomography; Vulnerable plaque