Transthyretin Cardiac Amyloidosis in Women: Underdiagnosis, Sex-Specific Phenotypic Expression and Therapeutic Response

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of cardiac dysfunction in adults, resulting from extracellular deposition of misfolded transthyretin fibrils and progressive myocardial impairment. Clinical expression and diagnostic yield differ substantially between sexes, contributing to systematic underdiagnosis in women, who often present with subtler myocardial remodeling, heart failure with preserved ejection fraction (HFpEF)–dominant phenotypes, and nonspecific systemic manifestations that fall below conventional diagnostic thresholds, particularly in early disease stages. Female patients, particularly those with ATTRwt, tend to present at older ages and more frequently show HFpEF-dominant phenotypes and nonspecific extracardiac manifestations. Carpal tunnel syndrome (CTS) is an important extracardiac red flag for ATTR-CM, but its interpretation in women requires caution because of the high background prevalence of idiopathic CTS in the general population. Evidence also suggests sex-related differences in diastolic function, right ventricular involvement, and overall progression. Despite these biological and phenotypic distinctions, women are markedly underrepresented in trials of disease-modifying therapies, limiting conclusions about sex-specific treatment effects and leaving uncertainty about whether current pharmacologic interventions provide comparable benefit. Hormonal influences, genetic background, and age-related mechanisms, comorbidities, and diagnostic pathways may contribute to the distinctive female phenotype, but underlying mechanisms remain insufficiently defined. This narrative review examines sex-associated differences in ATTR-CA, focusing on mechanisms of underdiagnosis, principal clinical and imaging features, and implications for therapeutic response, with the goal of improving diagnostic accuracy, guiding individualized management, and ultimately enhancing outcomes for women and all affected patients worldwide in clinical practice.