Chronic ischemic heart failure in humans is associated with changes in expression of antigen processing HLA types and activation of T-cells

Abstract

Abstract Background Sustained pathological inflammation is a hallmark of chronic ischemic heart failure (HF). The short term response to myocardial ischemia has found a protective phenotype for T regulatory cells, yet the extent and consequence of prolonged T-cell activation in chronic ischemic heart failure is unclear. Methods and results Single cell RNA sequencing of circulating immune cells (n=181,712 cells) from healthy (n=8) and heart failure donors (n=8) revealed a relative increase in the proportion of activated T cells in heart failure patients relative to healthy controls. T cell activation molecules of the HLA-DR series genes on antigen presenting cells were found to be strongly associated with heart failure patients in the sequencing data, with decreases in antigen processing genes (HLA-DM series) in heart failure patients. Validation via flow cytometry in 27 healthy controls and 43 heart failure patients showed relative decreases of greater than 30% for HLA-DM to HLA-DRB molecule ratios in HF patients (p=0.0082), suggesting an aberrant antigen presentation to T cells linked to autoimmunity in heart failure patients. Additionally, costimulatory molecules such as ICAM-1 (p=0.004) and activation markers like TREM-1 (p=0.04) were elevated in circulating monocytes cells, which may potentiate T cell activation. Correspondingly, a significant and striking decrease in CD4+ and CD8+ naïve T cells along with increases in combined effector memory and TEMRA cells could be evidenced in heart failure patients. Levels of the T-cell homing marker CCR5 were elevated in patients with heart failure. To gain additional insights into potential functional consequences in the heart, supernatants from 3h LPS stimulated immune cells (peripheral blood mononuclear cells or T cells) were applied to various vascular cell types (endothelial cells, pericytes) and with cardiac organoids for 48h. Apoptosis was increased more than 3 fold following incubation with media derived from peripheral blood cells of HF patients, suggesting that immune cells from heart failure patients can directly and indirectly impair cardiovascular cells. Conclusion Heart failure is marked by sustained increases in relative proportions of effector T cell and TEMRA populations and homing markers suggesting these cells may undergo extravasation to tissues and deteriorate inflamed myocardium - hastening heart failure progression, worsening prognosis. Further research is required to assess how these cells may migrate to myocardial tissues and what interventions could be useful for blocking myocardial damage. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK, DGK, SFB