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

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. Description A disheartening loss Although the Y chromosome is the smallest and contains few genes, its functions are not fully understood. It has been observed, however, that mosaic loss of the Y chromosome in blood cells frequently occurs with age, and this alteration is associated with various medical conditions. Sano et al. modeled this process in mice by reconstituting their bone marrow with cells lacking the Y chromosome (see the Perspective by Zeiher and Braun). The resulting mice were prone to fibrosis and decreased cardiac function, especially in the setting of pressure overload, but they benefited from treatment with a transforming growth factor β1–neutralizing antibody. Human patients with loss of chromosome Y in their blood were also at greater risk of cardiac pathology, supporting the clinical relevance of these findings. —YN Mosaic loss of the Y chromosome in blood cells is linked to heart failure mediated by accelerated tissue fibrosis.