We read with great interest the study “Clinical, imaging, and disease progression sex-related differences in transthyretin cardiac amyloidosis” by Decotto et al. The authors present one of the first national registries specifically addressing this topic and report findings consistent with international experience: women represent a minority of diagnosed patients, are diagnosed at older ages, and have lower wall thickness and better-preserved ventricular function at the time of diagnosis, with no significant differences in clinical course during follow-up. (1) Far from settling the debate, these results prompt us to reconsider several questions regarding the true impact of sex on this disease.

The first question is whether the marked epidemiological difference reflects a lower true prevalence or, at least in part, underdiagnosis in women. International registries such as THAOS and other contemporary cohorts show a clear male predominance, although the magnitude of this difference varies across studies. (2-4) The SCAN-MP study, which used an active screening strategy with nuclear scintigraphy in minority populations, found that women accounted for 31.3% of the active ascertainment cohort, compared with 13.3% of referral clinical cohorts. (5) Suspicion of transthyretin cardiac amyloidosis (ATTR-CA) continues to rely heavily on increased wall thickness, with absolute cutoffs derived from predominantly male populations. In this context, it is particularly interesting that, in the cohort presented, differences in wall thickness disappear after indexing these measurements to body surface area, and that a significant proportion of women have a septal thickness <12 mm at the time of diagnosis. These findings support the need to reassess whether current echocardiographic criteria might delay clinical suspicion and, consequently, access to confirmatory testing such as scintigraphy.

However, diagnostic bias likely does not fully account for the observed difference. In hereditary ATTR-CA, penetrance is clearly influenced by sex, with lower clinical expression and later disease onset in women carrying several pathogenic variants. This difference in penetrance suggests that biological mechanisms—possibly related to hormonal factors and transthyretin tetramer stability—also contribute to the natural history of the disease. The lower representation of women is likely the result of an interaction between these biological differences and lower clinical recognition.

Another relevant aspect is prognosis. Although some early series suggested a more unfavorable course in men, contemporary analyses adjusted for disease stage, including THAOS and other recent registries, have not demonstrated consistent differences in mortality or heart failure hospitalizations, in line with the results reported by the authors. (2,3) This suggests that the differences observed at the time of diagnosis do not necessarily translate into differences in disease course once the disease is established.

Finally, these observations should be interpreted in light of a persistent limitation in clinical research: the underrepresentation of women in pivotal ATTR-CA trials. Studies such as ATTR-ACT (6) and more recent trials of transthyretin-stabilizing or -silencing therapies included a markedly lower proportion of women, limiting the ability to perform sex-specific analyses. In this context, clinical practice registries are particularly valuable, as they provide a more precise understanding of the actual disease burden in women and help identify opportunities to optimize diagnostic and therapeutic strategies.

The study by Decotto et al. represents a valuable contribution to the regional literature. Rather than confirming that women present a different form of the disease, their findings prompt us to ask whether we are using diagnostic tools that are sufficiently sensitive to recognize a presentation that is likely to be different as well.