mLOY: Mosaic Loss of the Y Chromosome and Myocardial Remodeling in Severe Valvular Heart Disease

Mosaic loss of the Y chromosome (mLOY) in blood cells is one of the most common acquired genetic changes in aging men. It has been linked to higher cardiovascular risk and mortality and to fibrotic remodeling of the heart, partly through pro-fibrotic immune cells and enhanced TGF-β1 signaling. Whether the Y chromosome is also lost in the heart itself, and how this relates to mLOY in the blood, remains largely unknown.

This translational project studies mLOY in patients with severe valvular heart disease who undergo heart valve surgery. With the patients’ informed consent, blood samples and a small myocardial biopsy are collected during their routine surgery. LOY is then measured in both blood and heart tissue using digital PCR. This lets us link LOY in blood and heart tissue to myocardial remodeling and fibrosis in the same patients.

In parallel, induced pluripotent stem cells (iPSCs) derived from patients are turned into cardiomyocytes and cardiac fibroblasts and studied in 2D and 3D engineered cardiac tissue models. We use these models to find out whether LOY in heart cells comes from the cells’ own susceptibility under stress, such as ischemia or pro-fibrotic signaling, or from signals sent by LOY-affected immune cells. We also test whether blocking TGF-β1 can counteract fibrotic remodeling.

The project is a collaboration between three groups: the Department of Cardiac Surgery at the University Hospital Basel (Prof. Dr. med. Hassina Baraki), the Cardiac Surgery and Engineering Group of PD Dr. Anna Marsano (Department of Biomedicine, University of Basel), and the University Medical Center Göttingen (Prof. Dr. med. Elisabeth Zeisberg).