Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure

Rationale: Clonal hematopoiesis driven by mutations of DNMT3A (DNA methyltransferase 3a) is associated with increased incidence cardiovascular disease and poor prognosis patients chronic heart failure (HF) aortic stenosis. Although experimental studies suggest that clonal hematopoiesis–driver may enhance inflammation, specific signatures inflammatory cells in humans are missing. Objective: To define subsets immune mediating inflammation using single-cell RNA sequencing. Methods Results: Transcriptomic profiles peripheral blood mononuclear were analyzed n=6 HF harboring n=4 no Monocytes carrying demonstrated a significantly expression genes compared monocytes derived from without mutations. Among the upregulated prototypic IL (interleukin) IL1B (interleukin 1B), IL6, IL8 , inflammasome NLRP3 macrophage proteins CCL3 CCL4 as well resistin, which augments monocyte-endothelial adhesion. Silencing induced paracrine proinflammatory activation adhesion to endothelial cells. Furthermore, classical monocyte subset mutation carriers showed T-cell stimulating immunoglobulin superfamily members CD300LB CD83 SIGLEC12 CD2 ligand cell molecule CD58 all be involved monocyte–T-cell interactions. further characterized alpha receptor constant chain changes T helper 1, 2, 17, CD8+ effector, CD4+ memory, regulatory T-cell–specific signatures. Conclusions: This study demonstrates circulating exhibit highly inflamed transcriptome, contribute aggravation HF.