Haematopoietic loss of KDM6A impairs cardiac recovery in heart failure via epigenetic reprogramming of myeloid cells (Bulk RNA-SEQ Mouse)
Clonal haematopoiesis (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. Here, we perform multi-omics profiling and functional characterisation of mouse models and patient-derived data to show that haematopoietic KDM6A loss impairs cardiac recovery after myocardial infarction. KDM6A deficiency increases myeloid-cell recruitment to the injured heart and reprogrammes monocytes, macrophages and neutrophils towards inflammatory, migratory and glycolytic states. Patients with heart failure and KDM6A-driven CH show similar pro-inflammatory monocyte signatures. KDM6A-silenced macrophages promote cardiomyocyte hypertrophy and cardiac fibroblast activation. Importantly, IL-1ß blockade post-MI rescued the adverse cardiac phenotype of haematopoietic KDM6A loss. These findings identify KDM6A-driven CH as a driver of immune dysregulation and IL-1ß signalling as a potential therapeutic target in in CH-associated heart failure.
Clonal haematopoiesis (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. Here, we perform multi-omics profiling and functional characterisation of mouse models and patient-derived data to show that haematopoietic KDM6A loss impairs cardiac recovery after myocardial infarction. KDM6A deficiency increases myeloid-cell recruitment to the injured heart and reprogrammes monocytes, macrophages and neutrophils towards inflammatory, migratory and glycolytic states. Patients with heart failure and KDM6A-driven CH show similar pro-inflammatory monocyte signatures. KDM6A-silenced macrophages promote cardiomyocyte hypertrophy and cardiac fibroblast activation. Importantly, IL-1ß blockade post-MI rescued the adverse cardiac phenotype of haematopoietic KDM6A loss. These findings identify KDM6A-driven CH as a driver of immune dysregulation and IL-1ß signalling as a potential therapeutic target in in CH-associated heart failure.