TY  - JOUR
AB  - BACKGROUND: The role of local alterations in endothelial functional integrity in atherosclerosis remains incompletely understood. This study used nanoparticle-enhanced optical molecular imaging to probe in vivo mechanisms involving impaired endothelial barrier function in experimental atherothrombosis. METHODS AND RESULTS: Atherosclerosis was induced in rabbits (n=31) using aortic balloon injury and high-cholesterol diet. Rabbits received ultrasmall superparamagnetic iron oxide nanoparticles (CLIO) derivatized with a near-infrared fluorophore (CyAm7) 24 hours before near-infrared fluorescence imaging. Rabbits were then either euthanized (n=9) or underwent a pharmacological triggering protocol to induce thrombosis (n=22). CLIO-CyAm7 nanoparticles accumulated in areas of atheroma (P<0.05 versus reference areas). On near-infrared fluorescence microscopy, CLIO-CyAm7 primarily deposited in the superficial intima within plaque macrophages, endothelial cells, and smooth muscle cells. Nanoparticle-positive areas further exhibited impaired endothelial barrier function as illuminated by Evans blue leakage. Deeper nanoparticle deposition occurred in areas of plaque neovascularization. In rabbits subject to pharmacological triggering, plaques that thrombosed exhibited significantly higher CLIO-CyAm7 accumulation compared with nonthrombosed plaques (P<0.05). In thrombosed plaques, nanoparticles accumulated preferentially at the plaque-thrombus interface. Intravascular 2-dimensional near-infrared fluorescence imaging detected nanoparticles in human coronary artery-sized atheroma in vivo (P<0.05 versus reference segments). CONCLUSIONS: Plaques that exhibit impaired in vivo endothelial permeability in cell-rich areas are susceptible to subsequent thrombosis. Molecular imaging of nanoparticle deposition may help to identify biologically high-risk atheroma.
AU  - Stein-Merlob, A.F.*
AU  - Hara, T.*
AU  - McCarthy, J.R.*
AU  - Mauskapf, A.*
AU  - Hamilton, J.A.*
AU  - Ntziachristos, V.
AU  - Libby, P.*
AU  - Jaffer, F.A.*
C1  - 51370
C2  - 42929
TI  - Atheroma susceptible to thrombosis exhibit impaired endothelial permeability in vivo as assessed by nanoparticle-based fluorescence molecular imaging.
JO  - Circ.-Cardiovasc. Imaging
VL  - 10
IS  - 5
PY  - 2017
SN  - 1941-9651
ER  - 

TY  - JOUR
AB  - BACKGROUND: -To prospectively evaluate an elastin-specific magnetic resonance contrast agent (ESMA) for in-vivo targeting of elastic fibers in myocardial infarction and post-infarction scar remodeling. METHODS AND RESULTS: -Myocardial infarction (MI) was induced in C57BL/6J mice (n=40) by permanent ligation of the left anterior descending coronary artery (LAD). Magnetic Resonance Imaging (MRI) was performed at 7 and 21 days post MI. The merits of gadolinium-based ESMA (Gd-ESMA) were compared to Gd-DTPA in terms of infarct-size determination, contrast-to-noise ratio (CNR) and enhancement kinetics. Specific binding in-vivo was evaluated by blocking the molecular target using non-paramagnetic Lanthanum-ESMA (La-ESMA). In-vivo imaging results were confirmed by post-mortem triphenyltetrazoliumcholride (TTC) staining, Elastica-Van-Gieson (EvG) staining and Western Blotting. Delayed enhancement MRI revealed prolonged enhancement of Gd-ESMA in the post-ischemic scar compared to Gd-DTPA. Infarct size measurements showed good agreement between Gd-ESMA and Gd-DTPA and were confirmed by ex-vivo TTC staining. Pre-injection of the blocking La-ESMA resulted in significantly lower CNR of Gd-ESMA at the infarct site (p=0.0019). While no significant differences in CNR were observed between delayed-enhancement imaging with Gd-DTPA between day 7 and 21 (1.8 ± vs 3.8, p=ns), Gd-ESMA showed markedly higher CNR on day 21 post MI (14.1 vs 4.9, p=0.0032), which correlated with increased synthesis of tropoelastin detected by Western Blot analysis and histology. Higher CNR values for Gd-ESMA further correlated with improved ejection fraction of the mice on day 21 after MI. CONCLUSIONS: -Gd-ESMA enables targeting of elastin within the infarct scar in a mouse model of myocardial infarction. The imaging properties of Gd-ESMA allow quantification of intra-scar elastin content in-vivo and thereby provides potential for non-invasive characterization of post-infarction scar remodeling.  
AU  - Wildgruber, M.*
AU  - Bielicki, I.*
AU  - Aichler, M.
AU  - Kosanke, K.*
AU  - Feuchtinger, A.
AU  - Settles, M.*
AU  - Onthank, D.C.*
AU  - Cesati, R.R.*
AU  - Robinson, S.P.*
AU  - Huber, A.M.*
AU  - Rummeny, E.J.*
AU  - Walch, A.K.
AU  - Botnar, R.M.*
C1  - 28902
C2  - 33572
CY  - Philadelphia
SP  - 321-329
TI  - Assessment of myocardial infarction and post-infarction scar remodeling with an elastin-specific magnetic resonance agent.
JO  - Circ.-Cardiovasc. Imaging
VL  - 7
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 1941-9651
ER  - 

TY  - JOUR
AB  - Background-F-18-Galacto-RGD is a positron emission tomography (PET) tracer binding to alpha(v)beta(3) integrin that is expressed by macrophages and endothelial cells in atherosclerotic lesions. Therefore, we evaluated F-18-galacto-RGD for imaging vascular inflammation by studying its uptake into atherosclerotic lesions of hypercholesterolemic mice in comparison to deoxyglucose. Methods and results-Hypercholesterolemic LDLR(-/-)ApoB(100/100) mice on a Western diet and normally fed adult C57BL/6 control mice were injected with F-18-galacto-RGD and H-3-deoxyglucose followed by imaging with a small animal PET/CT scanner. The aorta was dissected 2 hours after tracer injection for biodistribution studies, autoradiography, and histology. Biodistribution of F-18-galacto-RGD was higher in the atherosclerotic than in the normal aorta. Autoradiography demonstrated focal F-18-galacto-RGD uptake in the atherosclerotic plaques when compared with the adjacent normal vessel wall or adventitia. Plaque-to-normal vessel wall ratios were comparable to those of deoxyglucose. Although angiogenesis was not detected, F-18-galacto-RGD uptake was associated with macrophage density and deoxyglucose accumulation in the plaques. Binding to atherosclerotic lesions was efficiently blocked in competition experiments. In vivo imaging visualized F-18-galacto-RGD uptake colocalizing with calcified lesions of the aortic arch as seen in CT angiography. Conclusions- F-18-Galacto-RGD demonstrates specific uptake in atherosclerotic lesions of mouse aorta. In this model, its uptake was associated with macrophage density. F-18-Galacto-RGD is a potential tracer for noninvasive imaging of inflammation in atherosclerotic lesions.
AU  - Laitinen, I.*
AU  - Saraste, A.*
AU  - Weidl, E.*
AU  - Poethko, T.*
AU  - Weber, A.W.*
AU  - Nekolla, S.G.*
AU  - Leppänen, P.*
AU  - Yla-Herttuala, S.*
AU  - Hölzlwimmer, G.
AU  - Walch, A.K.
AU  - Esposito, I.
AU  - Wester, H.J.*
AU  - Knuuti, J.*
AU  - Schwaiger, M.*
C1  - 279
C2  - 26762
SP  - 331-338
TI  - Evaluation of ανβ₃ integrin-targeted positron emission tomography tracer ¹⁸F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice.
JO  - Circ.-Cardiovasc. Imaging
VL  - 2
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2009
SN  - 1941-9651
ER  -