Immune Response and Coronary Atherosclerosis: Putative Cellular Markers of Plaque Development

Purpose: The need for discriminative molecular predictors of CAD presence and progression is widely acknowledged and their clinical utility in preventing CAD-associated adverse events is a matter of debate.
Methods: Plaque formation and/or growth is evaluated by CT coronary angiography, comparing two scans at 5-7 yrs interval. Blood cell transcriptome is analyzed by mRNA sequencing; monocyte subsets and phenotype are quantified by cytometry.
Results: Out of 29 CAD patients enrolled during SMARTool project, 19 showed plaque progression and/or de novo formation at scan 2, while 10 were unchanged. Clinical characteristics, risk factors and use of statins were similar. Non-obstructive CAD (20 cases) and obstructive CAD (9 cases) were equally distributed in the two groups. Biological process terms of gene ontology analysis of 14 genes reflect inflammation, apoptosis and innate immune cell differentiation. Of these, 5 genes (KCNE3, NCF4, S100A8, TLR4, TNFRSF10C) up-regulated significantly (p <0.05) in the progression group. Some monocyte markers represent the main chemokine receptors (CCR2, CCR5 and CXCR4) and adhesion molecules (CD18) involved in endothelial adhesion, transmigration and recruitment into inflammatory sites; their expression resulted up-regulated in plaque progression group and were positively correlated with TLR4 gene expression.
Conclusions: The positive correlations between chemokine receptors levels and TLR4 gene expression suggest their physio-pathological role in the cellular inflammatory process leading to plaque growth in CAD patients. Additionally, the modulation of genes controlling innate immune system activation is also associated with phenotype changes of blood monocyte subsets.

This project has received funding from the EU H2020 research and innovation programme under grant agreement No 689068.