Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Science. 2022 Jul 15;377(6603):292-297. doi: 10.1126/science.abn3100. Epub 2022 Jul 14.


Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.

Keywords: clonal hematopoiesis.

MeSH terms

  • Aging* / genetics
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Antibodies, Neutralizing / therapeutic use
  • Chromosome Deletion*
  • Fibrosis
  • Heart Failure* / genetics
  • Heart Failure* / therapy
  • Hematopoietic Stem Cells*
  • Macrophages
  • Male
  • Mice
  • Mosaicism
  • Myocardium* / pathology
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Y Chromosome* / genetics


  • Antibodies, Neutralizing
  • Transforming Growth Factor beta