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Gender disparities exist in various aspects of ATTR-CA, a condition predominantly affecting males.

Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by abnormal transthyretin deposition in cardiac tissue. Recent research suggests that sex differences may play a significant role in the disease’s clinical manifestations, progression, and outcomes. 

A study in the journal Heart Failure Reviews examined the available literature exploring sex differences in ATTR-CA.

ATTR-CA Primarily Affects Males, Especially as Age Increases.

Males account for >80% of cases, with the rate increasing with age. Age at diagnosis impacts the male-to-female ratio in wild-type ATTR-CA, with a male proportion of 69.5% and 92.7% in patients aged 80 and <80 years, respectively. Emerging evidence also highlights the effect of age at diagnosis on hereditary ATTR-CA, with a higher female prevalence of transthyretin mutations among older patients.

Different Transthyretin Mutations Show Varying Gender Prevalence

There is a greater male prevalence in the non-Val30Met cardiac mutations and in the Phe64Leu and Ile107Val mutations, while the Val30Met mutation is more prevalent in females. Estrogen may exert a cardioprotective effect, but estrogen signaling in transthyretin expression is poorly understood.

Women Typically Have More Severe Symptoms and Are Diagnosed Later

A study by Takashio et al. found that women were older at diagnosis and more often in New York Heart Association class III than men (57% vs. 35%, respectively) or IV (7% vs. 1%, respectively). A large survey also showed that female patients represented a greater proportion of IIIa or higher modified polyneuropathy disability scores than men (23% vs. 7%, respectively). 

Carpal tunnel syndrome, a red flag for ATTR-CA, occurs in the general population with a higher female prevalence. One study detected amyloid deposits in six males and four females out of 98 patients undergoing carpal tunnel surgery. A Japanese study found moderate to severe aortic stenosis was significantly more frequent in women than men.

Women with ATTR-CA show a higher frequency of heart failure with preserved ejection fraction than men and mostly present with it at diagnosis. Conversely, the hypertrophic phenotype is more common in men.      

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Gender-Based Diagnostic Challenges in ATTR-CA

Females might be underdiagnosed due to low clinical suspicion. In a retrospective study of wild-type ATTR-CA, those diagnosed post-mortem were more likely to be female than those diagnosed antemortem. One study demonstrated that interventricular septum and posterior wall thickness were lower in female ATTR-CA patients but that most differences were abolished when accounting for their smaller body size.

Adoption of such one-size-fits-all cutoff values may lead to underdiagnosis in women. Another large study demonstrated that overall functional and structural phenotypes were similar between sexes when indexed for body size. Research shows that female patients have a significantly higher left ventricular ejection fraction and lower left ventricular diastolic diameter than males. A study on wild-type ATTR-CA found that women showed echocardiographic signs of more advanced disease at diagnosis. Sex differences may also exist in bone tracer cardiac uptake, with one study showing a significantly lower heart-to-contralateral ratio with 99mTc-pyrophosphate in women. Evidence regarding N-terminal pro-B-type natriuretic peptide is contradictory.

Treatment and Prognosis

Most studies on tafamidis and other novel agents include mostly males, with no further evaluation of sex differences in the treatment response. Available data suggests no sex-related differences in the clinical outcomes, such as reduction in mortality and functional decline, with tafamidis. Moreover, recent studies have not demonstrated any significant sex-related differences in overall prognosis.

Source:

Aimo, A., Panichella, G., Garofalo, M., Gasparini, S., Arzilli, C., Castiglione, V., Vergaro, G., Emdin, M., & Maffei, S. (2023). Sex differences in transthyretin cardiac amyloidosis. Heart Failure Reviews. https://doi.org/10.1007/s10741-023-10339-w