PCSK9 and coronary atherosclerosis progression beyond LDL‐cholesterol in coronary artery disease patients

BACKGROUND: This study evaluated whether plasma PCSK9 is associated with coronary plaque progression in patients with coronary artery disease (CAD) and assessed its involvement in molecular processes of atherogenesis. METHODS: Plasma PCSK9 was measured in 159 patients with stable CAD submitted to coronary computed tomography angiography (CTA) at baseline and after a follow-up of 6.5 ± 1.1 years. Plaque progression was defined as the annual increase in Total, Fibrous, Fibro-fatty, Necrotic-Core and Dense-Calcium plaque volumes (PV). Pathways linked with PCSK9 were studied by RNA-sequencing of whole blood and in vitro studies using endothelial cells (EC). RESULTS: At multivariable analysis, plasma PCSK9 was associated with an annual increase in Necrotic-Core PV (p = .022) independent of cardiovascular risk factors, molecular markers, and medications, including LDL-C and statins. At RNA-seq analysis, PCSK9 was linked to the expression of genes involved in the innate-immune response. Treating EC with PCSK9 resulted in a significant increase in ICAM-1, VCAM-1, MCP1 and IL6 mRNA expression. CONCLUSIONS: In patients with CAD, plasma PCSK9 is associated with progression of Necrotic Core-PV. The link with inflammatory pathways suggested for PCSK9 a potential role for the occurrence of prognostically adverse plaque phenotypes beyond LDL-C regulation.