Rethinking wall thickness in transthyretin amyloid cardiomyopathy: sex-specific difference in the multinational SMART cohort

Background In transthyretin amyloid cardiomyopathy (ATTR-CM), increased wall thickness represents a central diagnostic red flag. Whether observed sex differences in wall thickness reflect intrinsic biological variation or differences in body size, and whether structural remodeling translates differently into electrical, biomarker, and functional consequences across sexes and different geographic populations remains incompletely defined. Objectives To evaluate sex-specific differences in cardiac wall thickness and in structural–electrical, structural–biomarker, and structural–functional relationships in ATTR-CM within a multinational European-Asian cohort (Sex and Multi-ethnic Assessment of Risk in Transthyretin amyloid cardiomyopathy, SMART). Methods We retrospectively enrolled patients with confirmed ATTR-CM from Taiwan and Italy. Clinical characteristics, laboratory test, electrocardiography, and echocardiography were assessed. Wall thickness was evaluated as absolute, body surface area (BSA)-indexed, and height-indexed measurements. Associations between left ventricular posterior wall thickness (LVPWd) and QRS duration, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and left ventricular ejection fraction (LVEF) were evaluated using sex-stratified correlations and multivariable interaction models adjusted for age, geographic region, and ATTR subtype. Results A total of 461 patients with confirmed ATTR-CM were included, of whom 393 (85.2%) were men and 68 (14.8%) were women. Women exhibited lower absolute wall thickness than men (all p≤0.05); however, these differences were no longer significant after normalization to body surface area or height. In multivariable models, LVPWd was positively associated with QRS duration without significant sex interaction, indicating similar structural–electrical coupling between sexes. LVPWd was likewise inversely associated with LVEF without evidence of sex interaction, supporting comparable structural–functional relationships across sexes. In contrast, a significant sex interaction was observed between LVPWd and NT-proBNP (absolute p=0.008; BSA-indexed p=0.040; height-indexed p=0.007). For a given indexed LVPWd, women demonstrated a more pronounced increase in NT-proBNP independent of age, geographic region, and ATTR subtype. Conclusions In ATTR-CM, lower absolute wall thickness observed in women is largely attributable to differences in body size. Structural–electrical and structural–functional relationships appear similar between sexes. However, women demonstrate a stronger association between wall thickness and NT-proBNP, independent of age, region, and genotype. These findings suggest that reliance on absolute wall thickness thresholds may contribute to under-recognition of ATTR-CM in women and highlight the need for sex-aware diagnostic assessment.