Sex differences in amyloid transthyretin cardiomyopathy National Amyloidosis Centre staging at diagnosis: an analysis from a large single-center cohort

BACKGROUND: Amyloid transthyretin cardiomyopathy (ATTR-CM) is a progressive infiltrative cardiomyopathy that has seen significant advances in diagnosis and treatment over the last two decades. Sex differences in phenotype, treatment response, and long-term outcomes remain poorly understood. Our study aims to describe the factors that contribute to differences in phenotype and long-term outcomes between male and female patients. METHODS: This was a single-center retrospective analysis of 334 patients with ATTR-CM seen at Northwestern Memorial Hospital, Chicago, IL, USA. The study included adults >18 years with an ATTR-CM diagnosis (wild-type, variant). Immunoglobulin light chain (AL) amyloidosis patients were excluded. Patients were classified as male or female based on the biological gender described in the electronic medical record. Male patients with ATTR-CM were compared with female patients with ATTR-CM. The National Amyloidosis Centre (NAC) stage was calculated using clinical parameters at the time of diagnosis. The primary outcome was all-cause mortality. Baseline characteristics were compared using chi-squared analysis. Associations were determined using Kaplan-Meier estimation and restricted mean survival time analysis (RMST). RESULTS: The study included 334 patients with ATTR-CM-268 (80%) men and 66 (20%) women. Female patients were diagnosed at higher NAC stages (p = 0.002), had lower pre-albumin levels and a lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide levels, a higher prevalence of the ATTR variant genotype, and were more likely to be African American. During a median follow-up of 42 months (IQR 17-70), 74 deaths occurred. The unadjusted 60-month RMST difference between men and women was -2.2 months (p = 0.37). In our multivariable analysis, age at diagnosis (p < 0.001) and atrial fibrillation (p = 0.017) were the only factors associated with increased mortality. CONCLUSIONS: Female patients present with ATTR-CM at significantly later NAC stages than men. Despite this, they have a similar mortality rate. Our findings may demonstrate that the NAC stage overestimates disease severity in female patients or, alternatively, that biological mechanisms confer a less aggressive disease phenotype in female patients despite advanced disease staging.