One of the major causes of increased heart failure in older men is the loss of the Y chromosome in immature blood cells called hematopoietic cells. Now, researchers have suggested an already approved drug could be the solution.
The Y chromosome has been long considered a “genetic wasteland,” with little understanding of its role beyond determining sex in mammals, researchers at the University of Virginia said. But losing the chromosome in hematopoietic cells—a condition called mosaic loss of Y chromosome, or mLOY—is the most commonly acquired mutation in the human male’s genome. It is linked to increased risk for mortality, cardiovascular disease and other age-related disorders in men, and has been suggested as one of the reasons women live on average five years longer than their male counterparts.
Using CRISPR gene editing technology, Kenneth Walsh, Ph.D., of the University of Virginia’s Division of Cardiovascular Medicine and a team developed a mouse model of mLOY by reconstituting the bone marrow of mice with cells lacking the Y chromosome. They discovered that these mice suffered from increased mortality and were likely to display heart problems, the team wrote in a study published July 14 in the journal Science.
What’s more, they realized that mLOY macrophages from bone marrow that then infiltrate the heart can trigger high transforming growth factor β1 (TGF-β1) activity, which in turn leads to the scarring of the heart muscle. After identifying the problem, they could then test treatment with a TGF-β1 neutralizing antibody—which was shown to ameliorate these harmful effects.
A related study by the team offered clues as to how this discovery could be translated to humans. They analyzed a massive biomedical database called the U.K. Biobank and noted that Y chromosome loss was indeed associated with cardiovascular disease, heart failure and ultimately an increased risk of death.
Based on these two research routes, Walsh suggested that an FDA-approved treatment might already exist that could target the effects of Y chromosome loss. Pirfenidone, sold by Roche as Esbriet, has been on the market to treat a form of lung scarring since 2014, and Walsh suggested in his study that this drug—which has undergone trials for heart failure—could benefit men with mLOY.
"In view of recent efforts to treat heart failure, idiopathic pulmonary fibrosis and some cancers with antifibrotic approaches, men with mLOY could represent a patient subpopulation that exhibits a superior response to this class of therapeutic agents," the study's authors said.
Even if pirfenidone turns out to be a therapeutic solution, there is still the issue of identifying patients with mLOY. But Walsh also has his eyes on a solution for that problem. Scientists at Uppsala University in Sweden have developed a PCR test to detect Y chromosome loss and, while at the moment its use is limited to a few labs, Walsh suggests it has a larger potential.
“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 personalized therapy, maybe this becomes a routine diagnostic test,” he said.