Unraveling gender differences in hereditary transthyretin amyloidosis: insights from the REACT registry

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Abstract Introduction Hereditary transthyretin amyloidosis (ATTRh) presents a variable clinical spectrum, affecting both the heart and the nervous system. However, gender differences remain underexplored due to the male predominance in clinical registries. Hormonal, genetic, and metabolic factors may influence the age of onset, clinical phenotype, and time to diagnosis. The REACT, a brazilian multicenter registry, has a higher proportion of women compared to other registries, allowing a more detailed analysis of gender differences in ATTRh. Identifying these patterns may improve diagnostic strategies and optimize patient management. Objective To compare clinical characteristics, age of onset, predominant phenotype, time to diagnosis and access to treatment, between men and women with ATTRh in a Brazilian multicenter registry. Methods This was a cross-sectional study based on REACT data, including 752 patients diagnosed between 02/11/2022 and 07/03/2023. We analyzed age at diagnosis, time to diagnosis, the most frequent mutations (TTR_p.Val50Met and TTR_p.Val142Ile), predominant phenotype (cardiac, neurological, or mixed), cardiac biomarkers (NT-proBNP and troponin), septal thickness on cardiac magnetic resonance, and use of Tafamidis. Statistical analysis was performed using Student’s t-test or Mann-Whitney test for continuous variables and the chi-square test for categorical variables, with significance set at p < 0.05. Results Among the 752 patients included, 279 (37.1%) were women and 473 (62.9%) were men. Women were diagnosed at a younger age. They also had a longer time to diagnosis, but this wasn't statistically significant. The TTR_p.Val50Met mutation was more frequent in women. The predominant cardiac phenotype was more common in men, whereas the mixed phenotype was more frequent in women. No significant difference was observed in isolated neuropathy. Cardiac biomarkers were lower in women, reflecting the lower prevalence of the cardiac phenotype in this group. Additionally, septal thickness was higher in men. Tafamidis use was more frequent among men, but did not reach statistical significance. Conclusions Our study highlights significant gender differences in ATTRh, with women being diagnosed at a younger age and more frequently presenting with a mixed phenotype, while the cardiac phenotype predominated in men. These findings suggest potential hormonal and genetic influences on disease expression and emphasize the need for gender-specific screening and management strategies. Future studies should investigate disease progression and treatment response in both genders to improve early diagnosis and develop more personalized therapeutic approaches. Investigating sex-related disparities in amyloid burden, autonomic dysfunction, and comorbidities could further refine risk stratification and guide targeted interventions.

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