Sex-based differences in phenotypic expression and prognosis of transthyretin cardiac amyloidosis associated with the Val122Ile variant

Background Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction (HFpEF), resulting from either the wild-type (ATTRwt) or hereditary (ATTRv) form. The valine-to-isoleucine substitution (Val122Ile) is the most common inherited cardiac variant and is frequent among afro-caribbeans indivudals. However, data on gender differences in phenotype, prognosis, and the impact of tafamidis treatment in patients with Val122Ile-associated ATTR-CA remain limited. Methods From 5151 ATTR patients of the Healthcare European Amyloidosis Registry (HEAR), 830 (16.1%) were ATTRv including 513 (9.9%) with symptomatic ATTRv Val122Ile who were included in this study. Gender differences in clinical presentation, echocardiographic parameters at diagnosis, and prognosis were studied. A 48 months survival analysis stratified by sex and treatment, using a propensity score-adjusted method (PSAM) was performed (including 11 variables : age , cardiac function, kidney function ). Results Among the 513 symptomatic ATTRv Val122Ile patients, 150 (29.2%) were women and were significantly older than men at diagnosis (83 [77–87] vs. 77 [72–82] years; P<0.001, respectively). Neuropathy symptoms and carpal tunnel syndrome were more frequent in women than men ( 69 vs 56% , p=0.002 and 38 vs 27% , p=0.03 respectively ) . Women also had lower septal wall thickness than men, even after adjusting for body mass index , 8.7[8.1-10.1] vs 9.1[8.2-10.3], p=0.02 . Regarding left ventricular function, women exhibited higher left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) compared to men (LVEF: 54 [44–62] vs. 48 [38–56]%, P=0.001 and GLS: -10.6 [-8.7 - -13.1] vs. -9.7 [-7.5 - -12.4]%, P=0.003). NT-proBNP and Troponin T HS levels were similar between genders. The 48-month mortality rate did not differ between women and men. Tafamidis treatment was associated with an improvement in survival, whatever the gender but women treated with Tafamidis had a significantly better 48-month survival than men treated by Tafamidis. After 48 months, the reduction in the risk of all cause in mortality was more significant in women treated with Tafamidis compared to men after adjustment (0.452 [0.332–0.614] vs 0.767 [0.356-0.877], P=0.02). Conclusions ATTRv Val122Ile women are underrepresented in this dominant autosomal genetic disease (< 30%) and diagnosed at an older age with a better cardiac function than men. Tafamidis treatment is associated with a better benefit in survival in women than men. These findings suggest an under diagnosis and/or a less aggressive disease in ATTRv Val122Ile women, highlighting potential gender-based differences in disease progression and treatment response.