The investigators reconstituted the bone marrow of mice with cells lacking the Y chromosome to model the process of haematopoietic mLOY. This process often occurs with age and has been associated with a variety of medical conditions. However, the causal link between the one and the other had yet to be demonstrated.
The research team reported increased mortality, fibrosis, and cardiac dysfunction in the mice with mLOY in haematopoietic cells, in particular in the setting of pressure overload. Furthermore, it was shown that the Y chromosome-lacking cardiac macrophages of the reconstituted mice displayed polarisation towards a more fibrotic phenotype and that cardiac dysfunction could be targeted with a transforming growth factor β1-neutralising antibody.
Consequently, the investigators evaluated the blood samples of 223,000 men who donated blood to the UK biobank. In line with the results that were found in mice, men who had lost >40% of the Y-chromosomes in their white blood cells had a 31% increased risk of fatal heart conditions in the next 12 years, compared to those who did not display loss of Y-chromosomes.
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