Age-associated clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased incidence and worse prognosis of chronic heart failure. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPC). Mosaic loss of the Y chromosome (LOY), the most common somatic mutation in blood cells of men, also correlates with clonal expansion of myeloid cells, increases with age and was experimentally shown to lead to diffuse cardiac fibrosis and subsequent heart failure in mice. However, the prognostic significance of LOY as well as its potential interaction with CHIP in patients with chronic heart failure is unknown. We investigated the prevalence and prognostic significance of the extent of LOY and the two most common CHIP-driver mutations DNMT3A and TET2 in 705 male patients with established chronic heart failure across the entire spectrum of left ventricular ejection fraction. Both, LOY and DNMT3A/TET2 mutations, increased with age, and LOY co-occurred with DNMT3A/TET2 mutations in 27.1% of men at age > 70 years. LOY was an independent predictor of death during 3-years of follow-up across the entire spectrum of left ventricular ejection fraction. The co-occurrence of harboring LOY and DNMT3A/TET2 mutations significantly contributed to the observed increased mortality observed in carriers of DNMT3A/TET2 mutations. The detrimental effect of LOY on prognosis was confirmed in a validation cohort of patients with ischemic heart disease. scRNA sequencing of peripheral blood cells in patients with chronic ischemic heart failure showed increased profibrotic signaling in LOY monocytes with elevated markers of monocyte mediated inflammation and profibrotic cardiac remodeling (S100A8, TLR2, CLEC4D) and reduced expression of TGF-beta inhibiting genes (SMAD7, TGIF2). The proinflammatory phenotype of LOY monocytes was further amplified in LOY monocytes of patients simultaneously harboring DNMT3A mutations, who displayed heightened expression of alarmins (S100A8, HMGB2) and interferon signaling related genes (IFNGR1, TRIM56, CD84) compared to patients without CHIP mutations. Thus, the age-associated acquisition of somatic mutations in blood cells of men with chronic heart failure is associated with increased mortality, with loss of Y chromosome emerging as an independent predictor of all-cause death across the entire spectrum of left ventricular function.

The authors have declared no competing interest.

S.C. is supported by the DFG (SFB1531, project code 456687919 and FOR 5643, project code 515629962). M.S. is supported by an excellence grant of the German Center for Cardiovascular Research (DZHK-81X3600506), the German CHIP Registry (Deutsches CHIP Register e.V.), and a Junior Research Group Cardiovascular Diseases Grant of the CORONA Foundation (S199/10085/2021). S.M.-P. received support by a Cardiopulmonary Institute (CPI) Excellence Cluster Start-up Grant and a Center for Cardiovascular Research (DZHK) Postdoc Start-up Grant and the DFG FOR 5643, project code 515629962). T.S. is supported by the Else Kroener-Fresenius Foundation and DFG (SFB TRR 219, Project-ID 322900939). S.D. is supported by the DFG (SFB1531, project code 456687919 and FOR 5643, project code 515629962). AMZ is funded/co-funded by the European Union (ERC-2021-ADG, GAP - 101054899, CHIP AVS) and the DFG (FOR 5643, project code 515629962). WA is funded by the DFG (FOR 5643, project code 515629962). We would like to thank Dr. Gregor Hoermann, Dr. Manja Meggendorfer and Prof. Torsten Haferlach for their support from the Munich Leukemia Laboratory (MLL). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

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