The Profibrotic Effects of Hematopoietic Y Chromosome Loss in HFpEF

/ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is a prevalent, yet largely underserved condition. While females are diagnosed with HFpEF at a modestly higher frequency, males with HFpEF exhibit worse morbidity and mortality in highly phenotyped, well-powered studies. In clinical trials, males with HFpEF are starkly resistant to treatment while females with HFpEF tend to show some benefit, suggesting the possible existence of sex- specific pathological mediators. We hypothesize that the mosaic loss of the Y chromosome (mLOY) in the hematopoietic system plays a role in the etiology of HFpEF. mLOY describes the clonal loss of the Y chromosome in hematopoietic cells of males and represents the most prevalent postzygotic mutation in this sex. Similar to HFpEF, the incidence of mLOY increases with age. Notably, fibrosis is a hallmark of advanced HFpEF and predicts future adverse events, and pilot data show that mLOY in the hematopoietic system can induce cardiac fibrosis. Recent pilot data also indicate an association between mLOY and HFpEF in humans and exacerbated diastolic function in experimental mice, providing a compelling rationale for the sex differences in this condition. Thus, the clinical, causal and mechanistic relationships between mLOY and HFpEF will be explored. Project Number: 1R01AG092528-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: KENNETH WALSH | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $689,148 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295710