'Y' are men at higher risk of heart failure?

An international research team has shown that the loss of the male sex chromosome as many men age causes the heart muscle to scar and can lead to deadly heart failure. Published in the journal Science, the finding may help explain why men die on average several years younger than women.

While biological women have two X chromosomes, men have an X and a Y. But many men begin to lose their Y chromosome in a fraction of their cells as they age, predominantly in cells that undergo rapid turnover such as blood cells; this is called mosaic loss of Y chromosome (mLOY). Haematopoietic mLOY is known to increase with age and tobacco use; it is detectable in 40% of 70-year-old men and 57% of 93-year-old men, depending on the method of measurement.

Scientists have previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and to suffer age-associated maladies such as Alzheimer’s disease, solid tumours such as prostate and colon cancer, heart attacks and strokes. The new research, involving the University of Virginia (UVA), Uppsala University and Osaka Metropolitan University (OMU), is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men’s health.

A group led by OMU’s Dr Soichi Sano analysed data from the UK Biobank to determine the statistical relationship between mLOY and heart failure. The results showed that a 1% increase in the rate of mLOY resulted in a 1.0054-fold increase in mortality from cardiovascular disease. Furthermore, for mLOY>40% (when the percentage of cells without the Y chromosome is greater than 40%), the mortality rate due to cardiovascular disease was 1.31 times higher; within this category, the hypertensive heart disease rate was 3.48 times higher, the heart failure rate was 1.76 times higher (the congestive heart failure rate was 2.42 times higher), and the aortic aneurysm and dissection rate was 2.76 times higher.

Since this analysis could not determine whether mLOY is a direct cause of cardiovascular disease, the research team conducted experiments in mice to verify any causal relationship between the two. Having used CRISPR gene-editing technology to develop a special mouse model, the researchers found that mice in which blood cells had lost the Y chromosome (mLOY mice) experienced accelerated age-related diseases, which made the mice more prone to heart scarring and led to earlier death.

Subsequently, the team hypothesised that the excessive activation of fibroblasts observed in the mLOY mouse model of heart failure was due to some blood cells that did not have the Y chromosome acting on fibroblasts, so they then investigated the differences in the function of blood cells with and without the Y chromosome. In heart failure, leukocytes collect in the damaged heart, which leads to inflammation and fibrosis. Hence, the researchers removed hearts from each of the mLOY and control mice that had heart failure, separated the cells using an enzyme, and collected the leukocytes accumulated in the hearts. Then, they analysed the differences in properties of leukocytes with and without the Y chromosome.

The results showed that among cardiac macrophages, a type of immune cell classified as white blood cells, those without the Y chromosome produced more substances that acted on and activated fibroblasts than did normal macrophages. This suggests that cardiac macrophages without the Y chromosome promote fibrosis.

The team also investigated how fibroblast activation by mLOY macrophages affects the pathogenesis of heart failure. The results revealed a mechanism by which mLOY macrophages are involved in the overproduction of TGFβ1, a key effector molecule in the fibrosis process, and activate fibroblasts. This finding suggests that mLOY has a significant effect on the exacerbation of heart failure.

“Tissue fibrosis is associated significantly with severe heart failure, pulmonary fibrosis and renal failure, which are major causes of death in the elderly,” Sano said. “In this study, we found that mLOY promotes fibrosis in not only the heart but also other organs, including the lungs and kidneys. Currently, clinical trials using antifibrotic agents are being conducted to treat fibrosis-related diseases such as heart failure, idiopathic interstitial pneumonia and cancer. Understanding the mLOY status of patients could allow the detection of high-risk groups for certain diseases, contributing to better treatment decisions in the future.”

The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. Study co-leader Dr Kenneth Walsh, from UVA, notes that one potential treatment option might be a drug known as pirfenidone, which has already been approved by the US FDA for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine this.

While doctors currently have no easy way to determine which men suffer Y chromosome loss, Uppsala’s Lars A Forsberg has now developed an inexpensive PCR test that can detect Y chromosome loss. Walsh speculated, “If interest in this continues, and it’s shown to have utility in terms of being prognostic for men’s disease and can lead to personalised therapy, maybe this becomes a routine diagnostic test.”

Image caption: Approximately 40% of men will lose their male sex chromosome in certain cells by age 70, and that can lead to deadly heart failure. Illustration by Katriel E Cho.

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