Unraveling sex differences in transthyretin amyloidosis: Insights from the REACT-SP registry

Purpose Sex-based differences in transthyretin amyloidosis (ATTR), encompassing hereditary (ATTRv) and wildtype (ATTRwt) forms, remain underexplored due to male predominance in registries. The REACT-SP cohort, with a higher proportion of women (37.1%), provides an opportunity to assess sex-specific differences in a genetically diverse population. To evaluate sex-specific differences in clinical presentation, genotype distribution, biomarkers, cardiac involvement, diagnostic delay, and treatment access. Methods Cross-sectional analysis of 752 patients from the REACT-SP registry. Variables included age at diagnosis, time to diagnosis, phenotype, TTR mutations, biomarkers, septal thickness, and disease-modifying therapy. Sexbased comparisons were performed for the overall cohort and the ATTRv subgroup. Results Women (n=279) were diagnosed younger than men (58 vs. 68 years; p<0.003), with similar diagnostic delay. Cardiac (63.0% vs. 43.4%) and mixed phenotypes (29.8% vs. 16.8%) were more frequent in men, whereas neurological involvement showed no difference. Women had lower troponin positivity (29.3% vs. 58.8%) and septal thickness (11.0 vs. 16.5 mm; p<0.001). In ATTRv, women had lower cardiac involvement and septal thickness, and Val142Ile mutation was less frequent. Conclusion Sex significantly influences ATTR phenotype. These findings highlight the need for sex-aware diagnostic strategies, including reconsideration of septal thickness thresholds in women, to improve recognition and equitable care. Clinical trial registration Not applicable. This study is an observational analysis of data derived from a multicenter registry.