March 2023

European Heart Journal

Mas-Peiro S, Abplanalp WT, Rasper T, Berkowitsch A, Leistner DM, Dimmeler S, Zeiher AM.

Hematopoeitic mosaic loss of Y chromosome (LOY) is the most common acquired mutation; it increases with age and is associated with increased cardiovascular disease.

Murine studies revealed that LOY enhances cardiac fibrosis following left ventricular pressure overload by TAC, which mimicks aortic valve stenosis (AVS), the prototypical age-related disease. Since cardiac fibrosis is the major determinant of impaired survival even after successful transcatheter aortic valve replacement (TAVR), we hypothesized that LOY affects long-term outcome in men undergoing TAVR.

The extent of LOY (Y/X ratio) was assessed using digital PCR in DNA of peripheral blood cells, and the genetic signature of monocytes showing LOY was assessed by scRNAseq in 362 men with AVS undergoing successful TAVR. LOY values ranged from -4 to 83.4%, and 48% of the patients had LOY >10%. Three-year mortality increased with LOY and LOY remained an independent predictor during follow-up. ROC curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. scRNAseq analyses disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of TGFß-associated signalling, while expression of TGFß-inhibiting pathways was down-regulated.

This study shows for the first time that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. The pro-fibrotic gene signature with enhanced TGFß signaling in patient-derived circulating monocytes supports a prominent role for cardiac fibrosis to contribute to the effects of LOY observed in male patients with severe AVS