Men with Y-chromosome hematopoietic mosaic loss have a worse prognosis for heart failure

A research group led by Dr. Soichi Sano, a specially appointed lecturer in the Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka Metropolitan University, found that men with Y-chromosome hematopoietic mosaic loss (mLOY) – that is, men with an increase in blood cells that have lost the male sex chromosome – have a worse prognosis for heart failure due to the progression of fibrosis in the heart. Additionally, in experiments using mice, which like humans have an increased mortality rate with age, they found that the presence of mLOY causes an overproduction of fibrosis-promoting substances, which leads to the progression cardiac fibrosis, a mechanism directly linked to a worse prognosis for heart failure.

Humans have both X and Y sex chromosomes, with the combination XY being male and XX being female. However, as men age, they lose their Y chromosome, primarily in blood cells. This is called mosaic Y chromosome loss in the blood (mLOY). Hematopoietic mLOY is known to increase with age and smoking; it is detectable in 40% of 70-year-old men and 57% of 93-year-old men, depending on the method of measurement. Men with mLOY are found to live shorter lives than men without mLOY, and are thought to be more prone to Alzheimer’s disease, solid tumors such as prostate and colon cancer, heart attacks and strokes.

A research group led by Dr. Soichi Sano, a specially appointed lecturer in the Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka Metropolitan University, analyzed participant data from the UK Biobank to determine the relationship statistics between mLOY and heart failure. The results showed that a 1% increase in mLOY level resulted in a 1.0054-fold increase in mortality from cardiovascular disease. Moreover, for mLOY > 40% (meaning the percentage of cells without the Y chromosome is greater than 40%), the mortality rate from cardiovascular disease is 1.31 times higher, and in this category, the hypertensive heart disease rate is 3.48 times higher, heart failure rate is 1.76 times higher (congestive heart failure rate is 2.42 times higher), and aneurysm and dissection rate aortic is 2.76 times higher.

However, since this analysis cannot 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. Results of an experiment in which mice developed heart failure showed that mice whose only blood cells had lost the Y chromosome (mLOY mice) had worse heart failure than mice transplanted with hematopoietic stem cells whose Y chromosome had not been removed (control mice). This result proves the causal relationship between mLOY and heart failure.

Subsequently, the team hypothesized that the excessive fibroblast activation seen in the mLOY mouse model of heart failure was due to certain blood cells that lacked the Y chromosome acting on the fibroblasts, so they then studied the differences in blood cell function with and without the Y chromosome. In heart failure, leukocytes accumulate in the damaged heart, leading to inflammation and fibrosis. Therefore, the researchers removed the hearts from each of the mLOY and control mice with heart failure, separated the cells using an enzyme, and collected the leukocytes accumulated in the hearts. Next, they analyzed the differences in leukocyte properties with and without the Y chromosome.

The results of the experiment showed that among cardiac macrophages, a type of immune cell classified as white blood cells, those without a Y chromosome produced more substances that act and activate fibroblasts than normal macrophages. These results suggest that cardiac macrophages lacking the Y chromosome promote fibrosis.

The team also investigated how activation of fibroblasts 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 heart failure exacerbation.

Tissue fibrosis is significantly associated with severe heart failure, pulmonary fibrosis and renal failure, which are the main causes of death in the elderly. In this study, we found that mLOY promotes fibrosis not only in the heart but also in 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.”

Dr. Soichi Sano, Specially Appointed Lecturer in the Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka Metropolitan University

Regarding future research, Dr. Sano explained: “There are only a limited number of genes present on the Y chromosome, most of which are only expressed in germ cells, and of which only a few a few are expressed in blood cells. Our future studies aim to clarify which genes deleted by mLOY are associated with worsening heart failure and fibrosis.”

Source:

Osaka Metropolitan University

Journal reference:

Sano, S. et al. (2022) Hematopoietic loss of the Y chromosome leads to cardiac fibrosis and heart failure mortality. Science. doi.org/10.1126/science.abn3100.

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