Abstract Body (Do not enter title and authors here): Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a restrictive cardiomyopathy characterized by deposition of misfolded transthyretin in the myocardium. Untreated individuals with ATTR-CM have a median survival of 2-4 years after diagnosis. Individuals with clonal hematopoiesis, including clonal hematopoiesis of indeterminate potential (CHIP), mosaic chromosomal alterations (mCAs), and loss of Y (LOY), have heightened risk of adverse cardiovascular outcomes. It is unknown whether the presence of clonal hematopoiesis is associated with mortality in ATTR-CM.

Methods: We tested the association between clonal hematopoiesis and all-cause mortality among individuals with ATTR-CM in the Mass General Brigham Biobank (MGBB). ATTR-CM status was determined by pyrophosphate scintigraphy (PYP) scan. CHIP was called from whole exome sequencing; mCAs and LOY were called from genotype array data. Key exposures were the presence of any CHIP (defined as a variant allele fraction [VAF] ≥2%), large CHIP (VAF ≥10%), CHIP driver mutations (DNMT3A, TET2, and non-DNMT3A), mCA, and LOY. Cox models were used to generate hazard ratios (HRs) for all-cause mortality with adjustment for age at scan, sex, type 2 diabetes, and coronary artery disease.

Results: Among 54 genotyped individuals in the MGBB with a positive PYP scan (mean [SD] age 79.1 [6.7], 48 [89%] male), any CHIP was identified in 16 (29%) individuals, large CHIP in 9 (17%), LOY in 11 (23% of males), and mCAs in 10 (19%). The most common CHIP clones were DNMT3A (11 [20%] individuals), TET2 (3 [6%] individuals), and ASXL1 (2 [4%] individuals). Over a median [interquartile range] follow-up of 2.89 [1.48-4.37] years, non-DNMT3A CHIP was significantly associated with risk of all-cause mortality (HR 5.97 [95% CI 1.13-31.55], P =0.036). TET2 CHIP had a suggestive association with all-cause mortality (HR 5.94 [0.79-44.68], p = 0.08). Neither any CHIP, large CHIP, nor DNMT3A CHIP was significantly associated with all-cause mortality, though effect estimates were directionally consistent with increased risk (any CHIP: HR 2.06 [0.60-7.12], P=0.25; large CHIP HR 2.57 [0.53-12.60], P=0.24; DNMT3A CHIP HR 1.76 [0.47-6.57], P=0.40). In addition, mCAs, but not LOY, were associated with mortality (mCA HR 4.75 [1.33-16.96], P=0.017; LOY HR 2.79 [0.74-10.59], P=0.13).

Conclusions: In a small observational study of individuals with ATTR-CM, non-DNMT3A CHIP and mCAs were associated with increased risk of all-cause mortality.