Nanoparticle-Enhanced Near Infrared Fluorescence Imaging of Atheroma Detects Thrombosis-Prone Plaques Prior to Rupture

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Nanoparticle-Enhanced Near Infrared Fluorescence Imaging of Atheroma Detects Thrombosis-Prone Plaques Prior to Rupture

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Title: Nanoparticle-Enhanced Near Infrared Fluorescence Imaging of Atheroma Detects Thrombosis-Prone Plaques Prior to Rupture
Author: Stein-Merlob, Ashley F. ORCID  0000-0001-6261-6431
Citation: Stein-Merlob, Ashley F. 2015. Nanoparticle-Enhanced Near Infrared Fluorescence Imaging of Atheroma Detects Thrombosis-Prone Plaques Prior to Rupture. Doctoral dissertation, Harvard Medical School.
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Abstract: Introduction: Acute coronary syndromes - including unstable angina, acute myocardial infarction and sudden death - are primarily due to sudden luminal thrombosis from disruption of an atherosclerotic plaque. It has been established that inflammation plays an important role in atherogenesis and the destabilization of plaques. However, the role of inflammation in catalyzing plaque rupture is incompletely understood. Here, we experimentally investigated the in vivo spatial distribution of a novel atheroma cell targeted near-infrared fluorescence (NIRF) imaging agent, CLIO-CyAm7, prior to triggered plaque rupture, using intravascular molecular imaging. We hypothesized that CLIO-CyAm7 would illuminate macrophages on in vivo intravascular NIRF imaging and preferentially localize to atheroma that develop plaque thrombosis under triggering conditions.

Methods: Atherosclerosis was induced in rabbits (n=28) using a 12-week hyperlipidemic diet with alternating 1% high cholesterol and normal chow with concomitant aortic balloon injury at 2 weeks. Rabbits were injected with 2.5mg/kg of CLIO-CyAm7 24 hours prior to in vivo imaging. In vivo NIRF and intravascular ultrasound (IVUS) imaging were used to assess baseline structural and inflammation characteristics of atheroma. Control rabbits (n=6) were sacrificed prior to triggering. Pharmacological triggering was performed using Russell’s Viper Venom (0.15mg/kg IP) and histamine (0.02mg/kg IV) injections twice over 48-hours. IVUS imaging was repeated prior to sacrifice to identify luminal thrombi in vivo. NIRF imaging was quantified using target-to-background ratio (TBR), the ratio between an area of atheroma compared to normal, uninjured aorta. A subset of rabbits (n=7) was injected with Evans Blue (6mL 0.5% IV) 30 minutes prior to sacrifice to identify permeability of the endothelium. After sacrifice, ex vivo imaging, fluorescence microscopy (FM), RAM-11 immunofluorescence (IF) of macrophages, alpha-smooth muscle actin IF for smooth muscle cells, CD31 IF for endothelial cells, and Carstairs’ staining for fibrin and collagen, were performed systematically along the length of the aorta at 1.5cm increments. Data is presented as mean±SD.

Results: On microscopy, CLIO-CyAm7 localized primarily at the intimal-luminal border of atheroma, with some penetration into the media and adventitia. There was significantly higher CLIO-CyAm7 accumulation in areas of atheroma compared to control segments of the aorta (1.73±1.9% vs. 0.13±0.28%, p<0.0001). On IF, CLIO-CyAm7 signal correlated with subsets of macrophages, endothelial cells and smooth muscle cells in atheroma with minimal CLIO-CyAm7 evident in normal arteries. Evans blue showed increased endothelial permeability in regions of increased subendothelial CLIO-CyAm7 accumulation. CD31+ endothelial cells in the neovessels at the intima-media border indicated delivery of CLIO-CyAm7 via vaso vasorum. In vivo, CLIO-CyAm7+ plaques were detectable via intravascular NIRF imaging. Areas of atherosclerosis, determined by IVUS, showed significantly higher NIRF peak TBR than normal segments of the aorta (2.86±1.82 vs. 1.55±0.65, p=0.001). In vivo IVUS imaging and Carstairs’ staining for fibrin identified plaque thrombosis in 10 of 15 rabbits undergoing the triggered protocol (67%). Notably, plaques with luminal thrombosis showed significantly higher CLIO- CyAm7 accumulation compared to undisrupted atheroma (2.1±1.7% vs. 1.5±1.9%, p=0.0446), indicating that atheroma cell phagocytic capacity may underlie plaque rupture.

Conclusion: CLIO-CyAm7 is a novel NIRF molecular imaging agent that identifies a subset of phagocytically active cells that are increased in atheroma prone to plaque thrombosis. Intravascular 2D NIRF imaging provides a promising future translational tool for high-resolution imaging of biologically high-risk plaques.
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:15821600
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