Abstract 441: Spatially Resolved Metabolites In Stable And Vulnerable Human Atherosclerotic Plaques Identified By Mass Spectrometry Imaging

Abstract

There is a growing interest in elucidating the mechanisms that govern atherosclerotic plaque instability, which has so far highlighted the role of dysregulations in lipid, carbohydrate, and amino acid metabolism. However, where these impairments occur in a plaque has yet to be revealed. This is critically important because lipid deposition, cell composition, and matrix stiffness are heterogeneous throughout human atheromas, particularly in regions of the fibrous cap and near the necrotic core. Furthermore, lesional cells are constantly bombarded with various intrinsic and extrinsic metabolic insults that influence cell phenotype. Mass spectrometry imaging (MSI) is a powerful technology for the visualization of the spatial localization and relative abundance of hundreds to thousands of analytes in thin tissue sections without the need for a priori knowledge of analytes present in the tissue. Imaging is performed using matrix-assisted laser desorption/ionization (MALDI) to interrogate small areas from a tissue surface after the addition of a chemical matrix to the section which serves to extract, co-crystallize, and ionize molecules from the sample. In the present study, we performed MSI of late-stage, stable and vulnerable human atherosclerotic plaques using MALDI-MSI to visualize the distribution of metabolites in the fibrous cap and necrotic core. This platform was able to identify 856 metabolites assigned with chemical formulas. We were then able to confidently annotate 189 metabolites using a data filtering system whereby we queried detected and quantified metabolites from the Human Metabolome Database (HMDB). Coupled with RNAseq examining human stable and unstable atheromas, we identified differences in pathways related to nitric oxide metabolism, collagen catabolism, arginine metabolism, tryptophan metabolism, lipid metabolism, and reactive oxygen species. This work represents the first study to begin defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this work will be a valuable resource for the scientific community and will ultimately open new avenues of research in cardiovascular disease.