Background:Current guidelines for diagnosing cardiac transthyretin amyloidosis (ATTR-CM) rely on uniform disease characteristics and imaging thresholds irrespective of sex, including a septal wall thickness ≥12 mm. As existing evidence is derived from predominantly male collectives, there is a risk of underdiagnosing women due to systematic differences in disease characteristics that influence screening and diagnostic criteria. Aim:To assess sex-specific differences in the clinical presentation, diagnostic pathway, and outcomes of patients with ATTR-CM under transthyretin stabilizer therapy. Methods:All consecutive patients with confirmed ATTR-CM diagnosed between 2018 and 2024 at the West German Amyloidosis Center (Essen, Germany) were included. Baseline clinical, laboratory, and echocardiographic parameters as well as outcomes after 6 months of therapy were compared between sexes. Analyses were stratified by diagnostic period (2018–06/2021 vs. 07/2021–2024). Statistical significance was defined as p < 0.05. The study was approved by the local ethics committee (23-11500-BO). Results:Among 240 patients, 34 (14.2%) were women. Age, BMI, and time to diagnosis did not differ overall between sexes. The proportion of women increased from 8.7% in the early to 19.2% in the late diagnostic period (p = 0.019), with a shorter time to diagnosis in the later phase (86 vs. 750 days, p = 0.022). At diagnosis, women had thinner interventricular septum (15.9 ± 4.5 vs. 18.1 ± 4.5 mm, p = 0.026), lower LV mass (206 vs. 316 g, p = 0.004), higher LVEF (55% vs. 51.7%, p < 0.001), lower troponin I (30 vs. 45 ng/L, p = 0.049), and lower eGFR (47.6 vs. 60 mL/min, p = 0.026) compared with men. After 6 months of transthyretin stabilizer therapy, sex-based differences in LVEF, IVS thickness, and LV mass persisted.When indexed to body surface area, differences in interventricular septal thickness (IVSDi 9.3 ± 2.8 vs. 9.2 ± 2.4 mm, p = 0.838), LV mass (LVMMi 124 vs. 161 g/m², p = 0.104), and left atrial volume (LAVIi 25 vs. 27 ml/m², p = 0.562) were no longer significant, although absolute differences persisted.Regarding red-flag symptoms, women more frequently presented with carpal tunnel syndrome (58.8% vs. 40.8%, p = 0.049) but showed similar rates of polyneuropathy (32.4% vs. 23.0%, p = 0.242). Coronary artery disease was less frequent in women (32.4% vs. 53.4%, p = 0.023). After 6 months of transthyretin stabilizer therapy, sex-based differences in LVEF, IVS thickness, and LV mass persisted, even when indexed to body surface area. Conclusion:Women with ATTR-CM exhibit distinct phenotypic characteristics with less pronounced hypertrophy and higher ejection fraction despite similar functional impairment. These differences persist even when indexed to body surface area and are accompanied by a different pattern of red-flag manifestations, including a higher prevalence of carpal tunnel syndrome and lower rates of coronary artery disease. Current sex-neutral diagnostic thresholds may therefore contribute to underrecognition of ATTR-CM in women. Incorporating sex-specific reference values into screening algorithms could improve early detection and ensure equitable diagnostic accuracy
