Mosaic loss of the Y chromosome in transthyretin (ATTR) cardiac amyloidosis

/ABSTRACT Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is associated with aging and is a commonly encountered, treatable cause of heart failure that affects over 150,000 older Americans. With an average age of onset of 75-80 years, ATTRwt-CA is characterized by the cardiac accumulation of misfolded TTR amyloid protein deposits. ATTRwt-CA has been mostly identified in men, with a male:female ratio of 4:1. While therapies improve survival and reduce heart failure hospitalizations in ATTRwt-CA, the mechanisms that underlie disease pathogenesis are incompletely understood. Mosaic loss of the Y chromosome (mLOY) in circulating white blood cells, a condition where the Y-chromosome is spontaneously deleted, is also a commonly observed feature in older men. Indeed, approximately 40% of men over the age of 70 years will have detectable mLOY, and the genetic abnormality has been associated with mortality from heart failure in large population studies. Given that both mLOY and ATTRwt-CA are diseases of older men, we demonstrated that, compared to patients with non-amyloid heart failure, ATTRwt-CA patients had almost a 2-fold higher prevalence of mLOY (58% vs. 30%). When ATTRwt-CA patients were divided into high and low burden of mLOY, those with high mLOY had a 2.8-fold increased risk of death and a 5-year mortality of 66% vs. 32% for those with low mLOY. Finally, using proteomics and single-cell RNA sequencing, our preliminary data suggests that mLOY is associated with dysregulation of immune pathways that impair macrophage scavenger functioning in the heart. Our central hypothesis is that the adverse outcomes observed in ATTRwt-CA with high mLOY are caused by a mechanism of immune dysregulation and impaired amyloid fibril clearance. In Aim 1 we will measure mLOY in archived blood samples from patients with ATTRwt-CA who were treated at the Boston University Amyloidosis Center and from non-amyloid patients with heart failure who are participants in the NIH- funded SCAN-MP study, directed by MPIs Ruberg and Maurer. We hypothesize that ATTRwt-CA patients will have higher mLOY and that mLOY will associate with survival, heart failure hospitalization, and quality of life both at baseline and over time. In Aim 2, we will describe the dysregulation of immune-mediated pathways using plasma proteomics from blood samples from Aim 1, and single-cell RNA sequencing transcriptomics using isolated white blood cells prospectively collected from patients with ATTRwt-CA and non-amyloid heart failure control patients. In Aim 3, we will collaborate with colleagues at the National Amyloidosis Centre (London, UK) to use cardiac magnetic resonance imaging to measure extracellular volume fraction (ECV), a clinical measure that captures the cardiac amyloid burden and predicts prognosis in ATTRwt-CA. We will demonstrate that mLOY is associated with increased ECV at baseline and increases over time. Successful completion of these Aims will provide critical insights into the course and prognosis of ATTRwt-CA, a common disease that impacts the health of older Americans, and inform treatment decisions. Project Number: 1R01AG093132-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Frederick Ruberg (+1 co-PI) | Institution: BOSTON MEDICAL CENTER, BOSTON, MA | Award Amount: $763,561 | Activity Code: R01 | Study Section: Clinical Integrative Cardiovascular and Hematological Sciences Study Section[CCHS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294611