Abstract 13067: Chronic Ischemic Heart Failure Defines Immune Cell Activation Signatures From ScRNA-seq and Flow Cytometry With Implications for Cardiac Resident Cells

Abstract

Adverse remodelling and sustained inflammation are key features of chronic ischemic Heart Failure (HF) with reduced ejection fraction. The importance and role of monocytes and T cells in early stages after myocardial infarction are known, however their role in progression of chronic HF remains elusive. Single cell RNA sequencing of peripheral immune cells from healthy and HF donors was performed to gain insights into these altered immune profiles, revealing an increase of activated T cells in HF together with an enrichment of antigen presenting molecules (incl. HLA-DRB5) and co-stimulatory molecules (ICAM-1) on antigen presenting cells. Validation via flow cytometry in 55 young healthy controls and 110 HF patients confirmed elevated HLA-DRB5 levels in HF derived monocytes, which was positively correlated with both ICAM-1 and TREM-1 (p=0.0001 for both), indicating T cell activation induction. Accordingly, significant increases in activated CD4+ and CD8+ T cells (p=0.0001 for both) were observed in HF. Also, increasing relative TCR clonality from T cell receptor (TCR) sequencing of HF patients and age matched controls suggests that circulating T cells expanded. Examination of potential downstream effects of the enhanced immune cell activation was done by measuring the serum of HF patients, showing increases in sICAM-1, IL-6 and TNFRI levels (1.75x-, 5.30x-, 2.63x-fold respectively). This secretome of HF patients was applied to endothelial cells to study direct effects, revealing increased adhesion capacity to co-cultured monocytes. Additionally, these HF secretome-exposed endothelial cells had decreased levels of the checkpoint inhibitor PD-L1 which is known to block autoimmune activity by T cells. Taken together, these data suggest HF is associated with enhanced monocyte and T cell activation as well as T cell clonal expansion. These processes may disturb resolution of inflammation in the cardiac tissue and lead to adverse remodelling and cardiac damage. More data are needed to assess the specific role of chronic monocyte and T cell activation in the progression of heart failure.