Molecular Imaging of Cardiovascular Diseases - Projects

Although morphologies of human arteriosclerosis are well defined by imaging such as MRI or CT, which are applicable to delineate the atheroplaques in LDLr-/- and ApoE-/- mouse models (Figure 5), morphological information alone usually does not identify vulnerable plaques, which will rupture leading to ischemia insults to the brain (stroke) or heart (heart attack). Mounting evidence from basic research over the past decade reveals that inflammation and endothelial dysfunction are the central processes in all stages of atherosclerosis, levels of the inflammatory mediators (cells such macrophages, or enzymes such as matrix metalloproteinases) accumulated in the plaque would be a way to estimate its vulnerability. Based on our previous experience in modifying low density lipoprotein (LDL) to map the LDLr on the liver (Figure 4), we are developing a lipoprotein nanoparticle that targets one of the inflammatory components of the atheroplaque.

The long term goal of the project is to develop imaging probes specific to vulnerable atheroplaques, better understanding of which evolves with the advances in basic research.

Figure 4

Plaques

Figure 4. Figure 4 Labeling LDL particles for imaging LDLr.

Upper panel: structure of PTIR267, which contains a GdDTPA moiety for MR imaging and a fluorophore for fluorescent confocal microscopy. It also contains a 16-carbon alkyl chain for intercalative labeling of LDL particles.

Lower panel (a-d): T1-weighted images of LDLr -/- mouse liver before (a) and 4 hours after injection (b) of labeled LDL. T1 maps of normal liver before (c) and 16 hours after injection (d) of PTIR267-labeled LDL. The intensity of each pixel represents its T1 value as indicated by the gray scale bar, which presents the T1 value in milliseconds.

Figure 5

Plaques

Figure 5. Arteriolosclerosis in LDLr-/- mouse detected by in vivo (A-B) and ex vivo (C) MR imaging. Diagram of lipoprotein-iron oxide (IO) nonoparticles (D) and Prussian blue staining of artery segments after injection ofnanoparticles (E). AA= ascending aorta, DA= descending aorta.