W164 - Inflammatory Chromatin Accessibility in Monocytes of Patients Undergoing Elective Coronary Angiography with Severe versus Minimal Coronary Disease

Abstract Text:

Background:
Experimental data suggest epigenetic changes prime monocytes and macrophages in cardiovascular disease (CVD), making them predisposed to hyper-inflammation even absent higher inflammatory gene expression. We hypothesized blood monocytes of stable outpatients with severe coronary artery disease (CAD) have more open chromatin at major inflammatory gene loci than those with none to minimal CAD with similar cardiometabolic risk factors.

Method:
We first performed single-cell ribonucleic acid and assay for transposase-accessible chromatin sequencing (scRNA-seq/scATAC-seq) on peripheral blood mononuclear cells, then bulk RNA-seq and ATAC-seq on sorted monocytes (N= 32). Primary analyses compared gene expression and chromatin accessibility at pre-specified inflammatory gene loci for those with severe multivessel CAD versus none to minimal CAD.

Results:
scRNA-seq/scATAC-seq analyses of severe CAD cases vs. CAD-free controls revealed monocyte-specific increased chromatin accessibility at IL1B in absence of higher IL1B expression for cases vs controls. Bulk RNA- and ATAC-seq in the larger cohort confirmed more accessible chromatin (p < 0.05 for all) for cases vs. controls around key inflammatory genes including IFNG, IL1B, IL10, and CCL2, in absence of higher expression of these genes. Additionally, mitochondrial oxidative phosphorylation genes NDUFB7, NDUFAF8, NDUFB, as well as several gene sets involved in oxidative stress (NCF1, CYBA, HMOX1) and angiogenesis/hypoxia response (VHL and HIF1a), are significantly repressed in cases compared to controls.

Conclusion:
Stable outpatients with severe CAD exhibit increased chromatin accessibility around key inflammatory gene loci in circulating monocytes in absence of overtly higher expression of these genes, suggesting an inflammatory imprint.