Hematopoietic loss of KDM6A impairs cardiac recovery in heart failure via epigenetic reprogramming of myeloid cells

Abstract Clonal hematopoiesis (CH), the expansion of blood cell clones carrying acquired mutations, is an independent risk factor for cardiovascular disease. Although mutations in DNMT3A and TET2 are well studied, the cardiovascular consequences of KDM6A mutations remain unclear. KDM6A is an X-linked histone demethylase that is commonly mutated in patients with heart failure (HF). Here we performed multiomics profiling and functional characterization of mouse models and patient-derived data to show that hematopoietic KDM6A loss impairs cardiac recovery after myocardial infarction (MI). KDM6A deficiency increases myeloid cell recruitment to the injured heart and reprograms monocytes, macrophages and neutrophils toward inflammatory, migratory and glycolytic states. Patients with HF and KDM6A-driven CH show similar pro-inflammatory monocyte signatures. KDM6A-silenced macrophages promote cardiomyocyte hypertrophy and cardiac fibroblast activation. Notably, IL-1β blockade after MI rescued the adverse cardiac phenotype of hematopoietic KDM6A loss. These findings identify KDM6A-driven CH as a driver of immune dysregulation and IL-1β signaling as a potential therapeutic target in CH-associated HF.