Y chromosome loss causes heart failure and death from cardiovascular disease

Loss of the Y chromosome in blood cells of men is associated with disease and mortality, but no clear causal relationship has previously been identified. Now, researchers from Uppsala University show in an international study in the journal Science that loss of the Y chromosome in white blood cells causes development of fibrosis in the heart, impaired heart function and death from cardiovascular diseases in men.

The mouse models used in the study, the mouse Y chromosome was eliminated to mimic the human mLOY condition and we analysed the direct consequences that this had. Examination of mice with mLOY showed an increased scarring of the heart, known as fibrosis. We see that mLOY causes the fibrosis which leads to a decline in heart function, said researchers.

The researchers were also able to corroborate the causal effect in mouse via epidemiological studies in humans, where they found mLOY to be a new significant risk factor for death from cardiovascular disease in men. These studies were performed using data from UK Biobank, a database with genomic and health information from half a million normally ageing individuals aged 40–70 years at the start of the study. Men with mLOY in their blood at the start of the study displayed an approximately 30% increased risk of dying from heart failure and other types of cardiovascular disease during approximately 11 years of follow-up.

The study describes for the first time a mechanism by which mLOY in blood causes disease in other organs and further identifies a possible treatment. It is shown that mLOY in a certain type of white blood cell in the heart of mice, so-called cardiac macrophages, stimulates a known signalling pathway that leads to increased fibrosis. When the researchers blocked this signalling pathway, the pathological changes in the heart caused by mLOY could be reversed.

The link between mLOY and fibrosis is very interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis and certain cancers that aim to counteract the onset of fibrosis. Men with mLOY could be a patient group that responds particularly well to such treatment ended researchers.

Reference: "Y chromosome loss causes heart failure and death from cardiovascular disease";UPPSALA UNIVERSITY; JOURNAL-Science; -DOI:10.1126/science.abn3100.