SUMMARY/ABSTRACT Transthyretin cardiac amyloidosis (ATTR) is a prevalent, yet underappreciated and underdiagnosed condition that gives rise to a particularly lethal form of heart failure with preserved ejection fraction (HFpEF). An unusual aspect of ATTR is its strong male bias (94% male in wild-type ATTR and 72% in mutant ATTR). We hypothesize that the mosaic loss of the Y chromosome (mLOY) in the hematopoietic system plays a role in the etiology of ATTR. mLOY is the most prevalent postzygotic mutation in males. mLOY describes the clonal loss of the Y chromosome in cells that frequently arises in the hematopoietic system. Recent work by the Walsh lab has associated mLOY with incident cardiovascular disease in humans and demonstrated that experimental LOY in the hematopoietic system can lead to spontaneous heart failure in mice (Sano et al. Science 2022). More recently, we have found association between mLOY and TTR cardiac amyloidosis in the patient population, providing a compelling rationale for the strong sex bias that is common to this condition. Thus, the causal and mechanistic relationships between mLOY and cardiac amyloidosis will be explored.

NARRATIVE Transthyretin cardiac amyloidosis is a prevalent form of heart failure that is underdiagnosed and underappreciated. Because this condition predominantly occurs in elderly men, this research will explore the role of mosaic loss of the Y chromosome in the etiology of this disease.