Abstract Body (Do not enter title and authors here): Introduction: Transthyretin (TTR) dissolution into monomer form and subsequent misfolding causes amyloidosis through deposition of beta-pleated sheets in end organs. Genetic sequence variations can decrease the stability of TTR leading to earlier disease manifestation, a condition known as hereditary TTR amyloidosis (hATTR). The most common variant in the U.S. - V142I, is most prevalent in individuals of African descent. We sought to explore the relationship of V142I and cardiac manifestations of hATTR, using the Million Veteran Program (MVP) dataset.

Methods: We identified all V142I carriers in the MVP dataset who had a first visit before January 2008. Carriers were matched with controls at a 1:5 ratio based on age, sex, and race. The outcome studied was development of heart failure (HF)/cardiomyopathy (CM). Cumulative incidence and multivariable Cox proportional hazards regression models were performed to compare V142I carriers with the matched control group.

Results: A total of 2,658 V142I carriers (3.1% of veterans of African descent in MVP) and 13,467 matched control patients were included in our final study cohort. Carriers at baseline had a median age of 53 [46-60] years, 87.2% were male, 3.5% had HF, 34.0% had type 2 diabetes mellitus (T2DM), 8.0% had bilateral carpal tunnel syndrome (BCTS), 5.2% had spinal stenosis (SS), and 19.4% had neuropathy. Patients in the control group at baseline had a median age of 53 [46-60] years, 87.2% were male, 3.4% had HF, 33.6% had T2DM, 7.9% had BCTS, 5.0% had SS, and 19.6% had neuropathy. Cumulative incidence of HF/CM at age 70, 80 and 90 years was 23.8%, 48.0%, and 68.8% for cases, and 23.7%, 40.5%, and 56.7% for controls (p=0.006), respectively (Figure). In a multivariable Cox proportional hazards regression model, carrier status was associated with higher incidence of HF/CM - HR of 1.13 (CI: 1.03-1.23, p=0.004). T2DM, hypertension, Charleston comorbidity index and current smoking were also associated with the outcome.

Conclusions: We report on higher risk of developing HF/CM in V142I variant carriers compared to controls in the MVP cohort. Further research is needed to determine the most effective diagnostic and treatment approaches in veterans who may be V142I carriers at risk of developing HF/CM.