Is There a Link Between Heart Failure and Y Chromosome in Men?

It is now a little clearer why a condition that often occurs in older men, showing a large number of hematopoietic cells showing loss of the Y chromosome, is associated with a higher risk of death and age-related diseases, thanks to mice.

This condition – known as mosaic loss of Y chromosome or mLOY – is a major risk factor for heart failure and cardiac fibrosis in older men, according to a study involving prospective data from UK Biobank. The study also showed that a neutralizing antibody could reverse some of the cardiac effects caused by mLOY.

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‘This condition – known as mosaic loss of Y chromosome or mLOY – is a major risk factor for heart failure and cardiac fibrosis in older men and a neutralizing antibody could reverse some of the cardiac effects caused by mLOY.’

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"(M)en with mLOY could represent a patient subpopulation that exhibits a superior response to this class of therapeutic agents," the study’s authors say.

Research of mLOY and Heart Failure

The Y chromosome has been long considered a ’genetic wasteland’, and beyond biological sex determination, there is little understanding of its functional role. Nevertheless, mLOY in blood cells has been linked to increased risk for mortality, cardiovascular disease, and other age-related disorders.

In human somatic cells, mLOY is the most commonly acquired mutation in the male’s genome. However, a relationship between mLOY and pathogenesis has not yet been established. Using CRISPR-Cas9, Soichi Sano and colleagues developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome.

Sano et al. discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function. According to the findings, bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β1 (TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis.

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Treatment with a TGF-β1 neutralizing antibody was shown to ameliorate these harmful effects. What’s more, a prospective study in human patients showed that those with mLOY in blood were also at a greater risk for cardiovascular dysfunction and associated mortality, suggesting the potential clinical relevance of Sano et al.’s findings in mice.

“Indeed, several unexpected links between the Y chromosome, immune system, and complex polygenic traits have been discovered, suggesting an influence of the Y chromosome on immune and inflammatory responses in men,” writes Andreas Zeiher and Thomas Braun in a related Perspective. “The study of Sano et al. reinforces this view and uncovers a crucial function of the Y chromosome in maintaining a healthy innate immune system, but further research is required to elucidate the mechanisms.”

Source-Eurekalert