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Papers In Press, published online ahead of print May 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800460-JLR200

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Journal of Lipid Research, Vol. 50, 787-797, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

A robust rabbit model of human atherosclerosis and atherothrombosis

Alkystis Phinikaridou^*, Kevin J. Hallock, Ye Qiao^* and James A. Hamilton^1,*,

^* Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA
Department of Biomedical Engineering, Boston University, Boston, MA

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables and three figures.

This work was supported by National Institutes of Health Grant P50 HL-083801 (J.A.H.) and partially funded by the Wallace H. Coulter Translational Partnership Award.

Published, JLR Papers in Press, January 12, 2009.

¹ To whom all correspondence should be addressed. e-mail: jhamilt{at}bu.edu

Disruption and thrombosis of atherosclerotic plaques cause most acute cardiovascular events, but their systematic study has been hampered by the lack of suitable animal models. To assess the value of a modified rabbit model of atherothrombosis, we performed detailed histology of rabbit aortic plaques. Atherosclerosis was induced with a high cholesterol diet fed 2 weeks prior to and 6 weeks after balloon injury of the aorta, followed by 4 weeks of normal diet. We found six out of eight types of plaques cataloged by the American Heart Association in the rabbit aorta. Vulnerable plaques were defined as those with attached platelet and fibrin-rich thrombi after pharmacological triggering with Russell's viper venom and histamine. Ruptured plaques had, as also described for human plaques: i) marked medial and adventitial changes, including neovascularization and inflammation; ii) cholesterol monohydrate crystals and liquid crystalline cholesterol esters in the intima and the fibrous cap; and iii) inflamed, thin fibrous caps. Increased cholesterol monohydrate area, internal elastic lamina area, positive remodeling, fibrous cap inflammation, adventitia breakdown, and inflammation were independent predictors of plaque disruption. Our findings reveal novel insights into plaque vulnerability and could guide the design of noninvasive imaging approaches for detecting and treating high-risk plaques.

Supplementary key words thrombosis • lipids • vulnerable plaques

Abbreviations: AHA, American Heart Association; CE, cholesteryl ester; CholM, cholesterol monohydrate crystals; CNZW, Constantinides New Zealand white; CSN, cross-sectional narrowing; IEL, internal elastic lamina; LA, lipid area; MRI, magnetic resonance imaging; OR, odds ratio; PA, plaque area; RR, remodeling ratio; SMC, smooth muscle cell

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