Abstract
AIMS: Age-associated clonal haematopoiesis of indeterminate potential (CHIP) has been linked to increased incidence and worse prognosis of chronic heart failure (CHF). CHIP arises from somatic mutations in haematopoietic stem and progenitor cells. Mosaic loss of Y chromosome (LOY), the most common somatic mutation in male blood cells, increases with age, drives clonal expansion of myeloid cells, and has been experimentally associated with cardiac fibrosis and heart failure in mice. However, its prognostic value and interplay with CHIP in CHF patients remain unclear. METHODS AND RESULTS: We analysed 781 male CHF patients across the full spectrum of left ventricular ejection fraction to assess the prevalence and prognostic relevance of LOY and the two most common CHIP-driver mutations, DNMT3A and TET2. Both LOY and CHIP mutations increased with age and co-occurred in 27.1% of men >70 years. LOY independently predicted all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF). The co-occurrence of LOY and DNMT3A/TET2 mutations further increased mortality among CHIP carriers. This detrimental prognostic effect of LOY was confirmed in a validation cohort of HFrEF patients. Single-cell RNA sequencing of peripheral blood mononuclear cells from HFrEF patients with ischaemic heart failure revealed elevated pro-fibrotic signalling in LOY monocytes, characterized by increased inflammatory and remodelling markers (S100A8, TLR2, CLEC4D) and decreased expression of transforming growth factor-β inhibitors (SMAD7, TGIF2). In patients with both LOY and DNMT3A mutations, monocytes showed enhanced pro-inflammatory gene expression, including alarmins (S100A8, HMGB2) and interferon-related genes (IFNGR1, TRIM56, CD84). CONCLUSIONS: Somatic mutations in blood cells-particularly LOY-are associated with increased mortality in male CHF patients, with LOY emerging as an independent prognostic marker.