Size matters - redefining sex differences among patients with transthyretin amyloid cardiomyopathy – have we been wrong all along?
Authors: Patel R , Ioannou A , Razvi Y , Chacko L , Venneri L , Martinez-Naharro A , Masi A , Lachmann H , Wechalekar A , Petrie A , Whelan C , Hawkins P , Gillmore J , Fontana M 
Published: October 2022

Abstract

Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is most often diagnosed in men (1–5). The few available studies suggest affected women have a more favourable cardiac phenotype (5–8), but remain unclear regarding differences in outcomes.

Objectives and methods
To characterise sex differences among consecutive patients with non-hereditary and two prevalent forms of hereditary ATTR-CM diagnosed over a 20-year period at our specialist centre through analysis of deep phenotyping at presentation, changes on serial echocardiography and overall prognosis.

Results
In total, 1732 patients were studied, comprising: 1095 with wild-type (wt)ATTR-CM; 206 with T60A-hATTR-CM; and 431 with V122I-hATTR-CM. Female prevalence was greater in T60A-hATTR-CM (29.6%) and V122I-hATTR-CM (27.8%) compared to wtATTR-CM (6%). At presentation, females were 3.3 years older than males (81.9 vs 77.8 years for wtATTR-CM; 68.7 vs 65.1 years for T60A-hATTR-CM; 77.1 vs 74.9 years for V122I-hATTR-CM). At diagnosis, non-indexed measures of wall thickness were significantly greater in males (interventricular septum in diastole (IVSd) of 17.13mm in males & 16.15mm in females; p&lt;0.001). When indexed for body surface area (BSA), we observed that the mean indexed IVSd was fairly constant in males throughout the study period, but in females, had a tendency to decrease over the same study period. Furthermore, BSA significantly influenced measures of disease severity. When indexed for BSA, overall structural and functional phenotype was similar between sexes; the few observed significant differences including indexed IVSd (9.62mm/m2 in females & 8.88mm/m2 in males; p&lt;0.001), indexed left ventricular (LV) end-diastolic volume (35.07ml/m2 in females & 41.05ml/m2 in males; p&lt;0.001) and indexed LV end-systolic volume (17.95ml/m2 in females & 21.74ml/m2 in males; p&lt;0.001) suggested a mildly worse phenotype in females. No significant differences were observed in disease progression on serial echocardiography and mortality across the overall population (p=0.459) and when divided by genotype (p=0.730 for wtATTR-CM; p=0.161 for T60A-hATTR-CM; p=0.056 for V122I-hATTR-CM).

Conclusion
This study of a well-characterized large cohort of ATTR-CM patients, contrary to previous dogmas, did not demonstrate overall differences between sexes in either clinical phenotype, when indexed, or with respect to disease progression and prognosis. The analysis highlighted the deficiencies in using non-indexed values which can not only lead to the inaccurate perception of a milder clinical phenotype in women compared to men, but has been shown to result in female patients presenting at an older age and with a worse phenotype compared to men. These findings indicate the need for revision of existing clinical guidelines regarding awareness and diagnosis of ATTR-CM in women, and modification of clinical trials which currently use single non-indexed threshold for wall thickness as key inclusion criterion.

Funding Acknowledgement
Type of funding sources: Foundation.