Molecular Imaging and Atherosclerotic Plaques

Jacques Ohayon, PhD and Roderic I. Pettigrew, MD, PhD

Laboratory TIMC-IMAG/DyCTiM, UJF, CNRS UMR 5525, In3S
Faculty of Medicine  of Grenoble - 38706 La Tronche Cedex, France

High Affinity avb3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits - Mol Imaging Biol., 12(1):2-8, 2010 - A new synthetic integrin αvβ3 targeted optical probe (ITOP) showing 20 times higher binding affinity for αvβ3 receptor compared to the commercially available cyclic peptide c[RGDfv] has been demonstrated to target cancer cells, in vivo.  Since integrin αvβ3 is known to be overexpressed in atherosclerosis, the present study was designed to investigate the possibility of detecting early plaque by using this high affinity ITOP. Five Watanabe heritable hyperlipidemic rabbits as a model of atherosclerosis and 2 New Zealand White rabbits as controls were studied. Rabbits were dissected and parts of the ascending and descending aortas were snap frozen, cut into 7-8µm frozen sections and mounted on slides. For detecting the presence of αvβ3 on the frozen aortic tissue, slides were incubated 1hr with the ITOP (αvβ3 selective antagonist labeled with fluorescein isothiocyanate), and the fluorescent signal was assessed under a microscope using ultraviolet light source (Nikon E1000). Sites of plaque accumulation in different regions of the ascending and descending aortas were efficiently labeled, corresponding to the same sites labeled with an anti-αvβ3 antibody.  The signal was found principally in the adventitia and proximal intima of the vessel, but also in the media of the wall where there was some disruption.  Moreover, there was a close correlation between the level of labeling with the ITOP and the degree of adventitial thickness. This high affinity synthetic ITOP can be used for the detection of the αvβ3 integrin which is associated with early atherosclerotic plaque development. Thus, this new probe could provide molecular imaging of a potential biomarker of the level of plaque inflammation, as its signal correlates with the adventitial thickening. (Doctoral research of Julie Héroux, Ph.D. Std)



Fig. 1: Intensity of fluorescence staining in Watanabe rabbit descending aorta sections (A, B, C) correlated with adventitia thickness and plaque histology (D, E, F).  In images (100X magnifications) of aorta sections with relatively small adventitia (mild thickening) (D, E), the level of staining and the intensity of the αvβ3 targeted probe signal is relatively mild (A, B).  In a similar direct correlation, for the aorta sections with large adventitia (marked thickening) (F), the signal from the αvβ3 targeted probe is marked (C).  There was also an apparent inverse correlation between the intensity of labeling and the organization within the plaque.  Staining is very intense when the media appears disrupted (C) and less intense when the media is well delineated (A, B).  FITC, fluorescein isothiocyanate; Ad, adventitia; M, media; NI, neointima.

Selected Publications

  Ohayon J, Mesnier N, Broisat A, Toczek J, Riou L, Tracqui P. Elucidating atherosclertic vulnerable plaque rupture by modeling cross substitution of ApoE-/- mouse and human plaque component stiffnesses. Biomechanics and Modeling in Mechanobiology. (in press), 2011.


•  Ohayon J, Gharib AM, Garcia A, Heroux J, Yazdani SK, Malvè M, Tracqui P, Martinez MA, Doblare M, Finet G, Pettigrew RI. Is arterial wall-strain stiffening and additional process responsible for atherosclerosis in coronary bifurcations? in vivo Study Based on Dynamic CT and MRI. Am J Physiol Heart Circ Physiol. 301(3):H1097-106, 2011.


 Broisat A, Toczek J, Mesnier N, Tracqui P, Ghezzi C, Ohayon J, Riou L. Assessing the low levels of mechanical stress in aortic atherosclerosis lesions from ApoE-/-mouse . Arterioscler Thromb Vasc Biol. 31(5):1007-10, 2011.


 Tracqui P, Broisat A, Toczek J, Mesnier N, Ohayon J, Riou L. Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy . Journal of structural Biology 174(1):115-23, 2011.


  Heroux J, Gharib AM, Danthi NS, Cecchini S, Ohayon J, Pettigrew RI. High Affinity avb3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits. Mol Imaging Biol., 12(1):2-8, 2010.


•  Soloperto G, Keenan NG, Sheppard MN, Ohayon J, Wood N, Pennell DJ, Mohiaddin RH, Xu XY. A combined imaging, computational and histological analysis of a ruptured carotid plaque. Artery Research, 4(2):59-65, 2010.


  Le Floc'h S, Cloutier G, Finet G, Tracqui P, Pettigrew RI, Ohayon J. On the potential of a new IVUS elasticity modulus imaging approach for detecting vulnerable atherosclerotic coronary plaques: in vitro vessel phantom study. Phys. Med. Biol., 55:5701-5721, 2010.


  Finet G., Huo Y, Riouffol G, Ohayon J, Guerin P, Kassab GS.  Structure-function relation in the coronary artery tree: from fluid dynamics to arterial bifurcations. EuroIntervention, 6:J10-J15, 2010.


  Le Floc'h S, Ohayon J, Tracqui P, Finet G, Gharib AM, Maurice R, Cloutier G, Pettigrew RI. Vulnerable Atherosclerotic Plaque Elasticity Reconstruction Based on a Segmentation-Driven Optimization Procedure Using Strain Measurements: Theoretical Framework. IEEE Trans Med Imaging, 28(7):1126-37, 2009.


•  Kotys MS, Herzka DA, Vonken EJ, Ohayon J, Heroux J, Gharib AM, Stuber M, Pettigrew RI. Profile order and time-dependent artifacts in contrast-enhanced coronary MR angiography at 3T: origin and prevention. Magn Reson Med., 62(2):292-9, 2009.


  Eskandari H, Salcudean SE, Rohling R, Ohayon J. Viscoelastic characterization of soft tissue from dynamic finite element models. Physics in Medicine and Biology, 53(22):6569-90, 2008.


•  Ohayon J, Finet G, Gharib AM, Herzka DA, Tracqui P, Heroux J, Rioufol G, Kotys MS, Elagha A, Pettigrew RI. Necrotic core thickness asnd positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture. Am J Physiol Heart Circ Physiol., 295(2):H717-27, 2008.


•  Ohayon J, Dubreuil O, Tracqui P, Le Floc'h S, Rioufol G, Chalabreysse L, Thivolet F, Pettigrew RI, Finet G. Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture. Am J Physiol Heart Circ Physiol., 293(3):H1987-96, 2007.


•  Boudou T., Ohayon J., Arntz Y., Finet G., Picart C., Tracqui P. An extended modeling of the micropipette aspiration experiment for the characterization of the Young’s modulus and Poisson’s ratio of adherent thin biological samples: Numerical and experimental studies. Journal of Biomechanics, 39:1677-85, 2006.


•  Boudou T., Ohayon J., Picart C., Tracqui P. Characterization of the Young’s modulus and Poisson’s ratio of polyacrylamide gels using micropipette aspiration technique. Biorheology, 43(6): 721-8, 2006.