Causes life-threatening heart scarring; an existing drug may offer a treatment option

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Loss of the male sex chromosome as many men age causes heart muscle to scar and can lead to fatal heart failure, according to a new study from the University of Virginia School of Medicine. This finding may help explain why men die, on average, many years younger than women.

UVA researcher Kenneth Walsh, PhD, says the new finding suggests that men who suffer from Y-chromosome loss – who are estimated to include 40% of people aged 70 – could particularly benefit from a drug. existing that targets dangerous tissue scars. The drug, he suspects, may help counteract the harmful effects of chromosome loss – effects that can manifest not only in the heart, but also in other parts of the body.

On average, women live five years longer than men in the United States. The new finding, Walsh believes, may explain nearly four of the five-year difference.

“Particularly after age 60, men die faster than women. It’s like they age biologically faster,” said Walsh, director of UVA’s Center for Hematovascular Biology. “There are more than 160 million men in the United States alone. The years of life lost due to male survival disadvantage are staggering. This new research provides clues as to why men have a shorter lifespan than women.”

Loss of chromosomes and heart health

While women have two X chromosomes, men have an X and a Y. But many men start losing their Y chromosome in a fraction of their cells as they age. This seems to be especially true for smokers. The loss occurs primarily in cells that undergo rapid turnover, such as blood cells. (Y-chromosome loss does not occur in male reproductive cells, so it is not inherited by children of men who have Y-chromosome loss.) Scientists have previously observed that men who suffer from Y chromosome loss are more likely to die at a younger age. and suffer from age-related diseases such as Alzheimer’s disease. Walsh’s new research, however, is considered the first hard evidence that chromosome loss directly causes harmful health effects in men.

Walsh, of UVA’s Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of the loss of Y chromosome in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring, and led to earlier death. It was not the result of simple inflammation, the scientists determined. Instead, the mice underwent a complex series of responses in the immune system, leading to a process called fibrosis throughout the body. According to the researchers, this showdown within the immune system could accelerate the development of the disease.

Scientists have also looked at the effects of Y chromosome loss in humans. They performed three analyzes of data compiled from the UK Biobank, a massive biomedical database, and found that loss of the Y chromosome was associated with cardiovascular disease and heart failure. As the loss of chromosomes increased, the scientists found that the risk of death also increased.

Potential treatment

The findings suggest that targeting the effects of Y-chromosome loss could help men live longer, healthier lives. Walsh notes that a potential treatment option could be a drug, pirfenidone, which has already been approved by the federal Food and Drug Administration 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. Based on his research, Walsh believes that men with Y-chromosome loss may respond particularly well to this drug and other classes of antifibrotic drugs currently in development, although more research is needed to determine this.

Currently, doctors have no easy way to determine which men are suffering from Y-chromosome loss. Walsh collaborator Lars A. Forsberg of Uppsala University in Sweden has developed a Inexpensive polymerase chain reaction (PCR) test, like those used for COVID-19 testing, that can detect Y chromosome loss, but the test is largely confined to his and Walsh’s labs. Walsh, however, can foresee that this will change: “If interest in this continues and it proves useful in terms of prognosis for men’s disease and can lead to personalized therapy, perhaps this will become a test routine diagnosis,” he said.

“The DNA in all of our cells inevitably accumulates mutations as we age. This includes the loss of the entire Y chromosome in a subset of cells in humans. Understanding that the body is a mosaic of acquired mutations provides clues to age-related diseases and the aging process itself,” said Walsh, a member of UVA’s Department of Biochemistry and Molecular Genetics. “Studies that examine Y chromosome loss and other acquired mutations hold great promise for the development of personalized drugs tailored to these specific mutations.”

The work was supported by the National Institutes of Health (Grants AG073249, AG072095, HL141256, HL139819, HL142650, HL152174, 21K20879, C 22K08162, and HL146056); the MSD Life Sciences Foundation; the Ichiro Kanehara Foundation; the Kenzo Suzuki Memorial Foundation; YOKOYAMA Foundation for Clinical Pharmacology; the Cardiovascular Research Fund; the Japanese Heart Failure Society; the Osaka Medical Research Foundation for Incurable Diseases; the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grants 679744 and 101001789); the Swedish Research Council (grant 2017-03762); the Swedish Cancer Society (grant 20-1004); Kjell and Märta Beijers Stiftelse; Marcus Borgströms stiftelse; and the American Heart Association (grant 20POST35210098).

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