Scientist Daily: Heart scarring could be deadly; an existing drug may offer a treatment option

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New research by the University of Virginia School of Medicine has shown that the loss of the male sexual chromosome can cause scarring of the heart muscle and lead to fatal heart failure. This finding could help explain why men often die several years earlier than women.

Kenneth Walsh, PhD, a UVA researcher, has revealed that the drug used to treat tissue scarring may be particularly beneficial for men suffering from Y chromosome damage. This is a condition that affects 40% of 70-year olds. He believes the drug may be able to counteract the negative effects of chromosome losses, which can manifest in different parts of the body.

The average American woman lives five years longer than the average man. Walsh believes that the new findings could explain almost four years of the difference in five-year life expectancy.

“Men die faster than women, especially after age 60.” It’s almost as if biologically they age faster,” Walsh, director of UVA’s Hematovascular Biology Centre. “There are over 160 million males living in the United States. The loss of years due to maleness’ survival disadvantage is alarming. The new research reveals the reason men live shorter lives than women.

Loss of the Chromosomes, and Heart Health

Women have two Xchromosomes while men have one Xchromosome. As they age, many men lose their Y-chromosomes in a small percentage of their cells. This is especially true for smokers. Cells that undergo rapid turnover like blood cells are most at risk. The loss of the Y chromosome is not inherited. Scientists had previously discovered that men with Y chromosome damage are more likely die younger and to develop age-related diseases like Alzheimer’s. Walsh’s latest research is the first to show that chromosome damage directly affects men’s health.

Walsh of UVA’s Division of Cardiovascular Medicine, the Robert M. Berne Cardiovascular Research Center and his team used the cutting-edge CRISPR technology to create a mouse model that could better understand the effects of Y chromosome reduction in blood. They discovered that the loss caused age-related illnesses to accelerate, increased the risk of heart scarring, and lead to earlier death. Scientists determined that this was not due to inflammation. Instead, the mice were subject to complex immune system responses that led to fibrosis throughout the body. Researchers believe that this tug-of-war in the immune system may speed up disease development.

They also examined the effects of Y chromosome deletion on human men. The scientists conducted three analyses on data compiled by the UK Biobank. This massive biomedical database contains a large amount of data. They discovered that Y chromosome damage was associated with heart disease, stroke, and other health problems. The scientists discovered that as chromosome loss increased so did the death risk.

Potential Treatment

According to the findings, men who target the effects of Y chromosome losses could live longer, more healthy lives. Walsh suggests that pirfenidone could be one possible treatment. It has been approved by federal Food and Drug Administration as a treatment for idiopathic pneumonia fibrosis. It is also being studied for chronic kidney disease and heart disease. Both of these conditions are known to cause tissue scarring. Walsh’s research suggests that men suffering from Y chromosome deletion could be particularly responsive to the drug. However, more research is needed to confirm this.

Doctors have no way to tell which men are affected by Y chromosome losses at this time. Lars A. Forsberg (a collaborator of Walsh) has created a cheap polymerase chain reactions (PCR), test that can detect Y chromosome losses. It is similar to the COVID-19 test. However, it is limited to Walsh’s and Walsh’s labs. Walsh can see that things will change. He said, “If this interest continues and it’s proven to have utility in terms being prognosticative for men’s disease, and can lead into personalized therapy, maybe this is becoming a routine diagnostic tool.”

“As we age, mutations are inevitable in all of our DNA. This includes the loss or partial deletion of the entire Y-chromosome in a subset cells of men. Understanding the body as a mosaic of acquired mutations can provide clues about aging-related diseases and the aging process in general,” Walsh, a member of UVA’s Department of Biochemistry and Molecular Genetics said. “Studies that focus on Y chromosome losses and other acquired mutants are promising for personalized medicine that is tailored to these particular mutations,” Walsh said.

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 Science 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 Intractable 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 och Märta Beijers Stiftelse; Marcus Borgströms stiftelse; and the American Heart Association (grant 20POST35210098).

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