Abstract P3068: Hematopoietic Loss Of Y-chromosome In Circulating Monocytes Derived From Heart Failure Patients Associates With Cardiac Fibrotic Signaling

Abstract

Background: Hematopoietic mosaic loss of Y chromosome (LOY) correlates with age and associates with increased cardiovascular disease incidence. Moreover, new murine studies propose that LOY could promote cardiac fibrosis by stimulating cardiac infiltration and activation of circulating macrophages. Yet, specific profiles of hematopoietic LOY cells in patients with heart failure (HF) are missing. Methods and Results: To decipher the genetic profile of human circulating immune cells and assess the effects of LOY, we performed single-cell RNA-sequencing (scRNA-seq) with immune cells of 10 male patients having chronic ischemic HF (mean age 67.3 years, ejection fraction 34.4%). We bioinformatically sorted immune cells by presence or absence of Y-chromosome-associated genes. Relative distribution of LOY was assessed, with monocytes having the greatest absolute count of LOY cells with no significant change in distribution among cell types. Given the abundance of monocytic LOY cells, we examined LOY monocytic cells transcriptional profiles (29810 Y-carrier monocytes, 2205 LOY monocytes) in an unbiased manner. Using a patient-specific, paired analysis, LOY monocytes showed significantly diminished expression of TGF-ß inhibiting genes (SMAD7, TGIF2) in LOY cells versus Y-carrier cells. Opposingly, from 193 upregulated genes, LOY cells showed elevated markers associated with monocyte/macrophage-mediated tissue damage and pro-fibrotic cardiac remodelling (S100A8, CLEC4D, TLR2). Gene ontology terms derived from upregulated genes in LOY cells further supported a mechanistic link to cardiac fibrosis by calling terms associated with TLR signaling, which are known to enhance cardiac fibrosis. Conclusion: This is the first study to study the genetic signature of LOY monocytes in HF patients. Our results considerably extend very recent experimental results in mice that LOY sensitizes macrophages to enhanced signaling associated with cardiac fibrosis. Reduced TGF-ß inhibitory molecule expression and enhanced TLR signaling may contribute to the aggravation of heart failure by LOY in patients with HF.