Clinical risk scores for stroke correlate with molecular signatures of vulnerability in symptomatic carotid patients

Unstable carotid stenosis is an important cause of ischemic stroke, yet the basis of disease pathophysiology remains largely unknown. We hypothesized that integrated analyses of symptomatic carotid stenosis patients at increased stroke risk stratified by clinical scores, CAR and ABCD2, with transcriptomic and clinical data could improve identification of molecular pathways and targets for instability. We show that high CAR score reflects plaque instability processes related to intra-plaque hemorrhage, angiogenesis, inflammation, and foam cell differentiation, whereas ABCD2 associates with neutrophil-mediated immunity, foam cell differentiation, cholesterol transport, and coagulation. Repressed processes in plaques from high-risk patients were ossification, chondrocyte differentiation, SMC migration, and ECM organization. ABCB5 gene was found as the top upregulated in high-risk patient's plaques, localized to macrophages in areas with neovascularization and intra-plaque hemorrhage. The link between ABCB5 and intra-plaque hemorrhage suggests its key role for plaque instability that warrants further exploration.