Gender differences in cardiac transthyretin amyloidosis: diagnostic gap in female patients

Current guidelines for diagnosing cardiac transthyretin amyloidosis (ATTR-CM) recommend a screening threshold of a septal wall thickness ≥12 mm, irrespective of sex. However, echocardiographic reference values differ between men and women, potentially leading to diagnostic delays in women.

This study examines sex-based differences in the diagnostic presentation and outcomes of ATTR-CM, thus exploring new potential implications for early detection and management.

All consecutive patients with confirmed ATTR-CM at a center with first diagnoses between 2018-2024 were screened for inclusion. Baseline characteristics, echocardiographic and laboratory parameters and outcomes after 6 months of transthyretin stabilizer therapy were compared. Cases were stratified into two periods of first diagnosis (2018-06/2021 and 07/2021-2024). Normally distributed variables were reported as mean ± standard deviation and non-normally distributed data as median (quartile 1-3). Statistical analyses involved two-sided t-tests, Mann-Whitney U tests, and Chi-square tests, with p < 0.05 deemed significant. Ethics approval was granted by the University of Duisburg-Essen (23-11500-BO).

We included 240 patients with ATTR-CM, including 34 (14.2%) women. Age (82 (78-84) versus (vs.) 80 (76-83) years), BMI (25 (23-25) vs. 26 (24-28) kg/m²) and time to diagnosis (212 (97-1056) vs. 286 (74-754) days, p=0.659, all women vs. men) did not differ. When dividing the diagnostic periods into an early phase (2018–06/2021) and a late phase (07/2021–2024), fewer women were diagnosed in the early phase (8.7% vs. 19.2%, p = 0.019). Additionally, the time to diagnosis in women was shorter in the later phase (median 86 (23–284) days vs. 750 (128-1058) days, p = 0.022).

Women had thinner interventricular septum thickness (IVS) (15.9 ± 4.5 mm vs. 18.1 ± 4.5 mm, p = 0.026), lower stroke volumes (49 (42-59) mL vs. 55 (46-69) mL, p = 0.022), higher left ventricular ejection fractions (LVEF) (55% vs. 51.7%, p < 0.001) and lower left ventricular mass (LVM) (206 (151-317) vs. 316 (165-377), p = 0.004) compared to men. Laboratory findings also differed, with women showing lower troponin I levels (30 (14–81) ng/L vs. 45 (27–70) ng/L, p = 0.049) and lower renal function (eGFR 47.6 (39–66) mL/min vs. 60 (47–73) mL/min, p = 0.026). After 6 months of transthyretin stabilizer therapy, differences in echocardiographic parameters between men and women persisted (LVEF: p=0.014, IVS: p=0.001, LVM: p=0.002).

These findings highlight a potential underdiagnosis of women with ATTR-CM, suggesting that current screening recommendations based on septal wall thickness may not adequately account for the unique characteristics of women. Adjusted criteria for women are essential to improve early diagnosis and management of ATTR-CM.