Key Information
Abstract
Aims
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure. With a male:female ratio of approximately 10:1, current evidence including diagnostic criteria is largely based on male-dominant collectives. Sex-specific differences may contribute to delayed diagnosis in women. This study investigates these differences in a real-world setting.
Methods and results
In this retrospective single-centre cohort study, all patients at West German Amyloidosis Center diagnosed with ATTR-CM between 2018 and 2024 were analysed. Clinical, echocardiographic, and laboratory parameters as well as outcomes under transthyretin stabilizer therapy at 6 and 12 months were evaluated. Among 240 patients, 34 (14.2%) were women. Compared to men, women had lower interventricular septal diameter, left ventricular mass, and stroke volume, but higher ejection fraction. Troponin I levels were lower and renal function was worse in women. Diagnostic delay was significantly longer in women (median 750 vs. 86 days, P = 0.022). Despite therapy, sex-specific echocardiographic differences persisted, and functional capacity remained lower in women, although NYHA functional class was comparable.
Conclusion
Transthyretin amyloid cardiomyopathy presents with persistent sex-specific differences that may contribute to diagnostic delay in women. Current diagnostic thresholds may not adequately reflect female disease patterns, underscoring the need for sex-adapted diagnostic criteria to improve early detection and management.
Keywords: Amyloidosis, ATTR, Cardiomyopathy, Gender, Heart failure, Transthyretin
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive infiltrative cardiomyopathy characterized by the deposition of misfolded transthyretin amyloid fibrils in the myocardium.1external link, opens in a new tab Transthyretin amyloid cardiomyopathy can result from either a wild-type (ATTRwt) or variant (ATTRv) TTR gene with distinct disease phenotypes.2external link, opens in a new tab Diagnosis of ATTR-CM relies on suggestive symptoms, so-called red flag symptoms and imaging modalities, with interventricular septum diameter (IVSD) ≥ 12 mm serving as a key criterion.3external link, opens in a new tab Currently, transthyretin stabilizers represent the only approved disease-modifying therapy for ATTR-CM4external link, opens in a new tab,5external link, opens in a new tab while novel therapeutic approaches including gene silencers and antibodies are under investigation.6external link, opens in a new tab
Unfortunately, the diagnosis of ATTR-CM is often delayed due to its overlapping symptoms with common heart failure. While studies have shown that the time to ATTR-CM diagnosis has improved in recent years, nearly 1 year still passes from the onset of symptoms until patients receive therapy.7external link, opens in a new tab Approximately 13% of HFpEF patients have underlying cardiac amyloidosis,8external link, opens in a new tab yet the condition remains underrecognized. While women are more frequently diagnosed with HFpEF, they appear to be underrepresented in ATTR-CM diagnoses.9external link, opens in a new tab Most large studies to date have predominantly included male patients, which may have contributed to diagnostic criteria and disease recognition patterns that are more reflective of the male phenotype.5external link, opens in a new tab,10external link, opens in a new tab Sex-specific differences in cardiac anatomy and normative values may further obscure diagnosis, making early detection particularly challenging in female patients. Although individual studies have shown that at the time of diagnosis, women are older, have a higher New York Heart Association (NYHA) functional class, and more frequently present with red flag symptoms like carpal tunnel syndrome and aortic valve stenosis, there is currently no standardized recommendation to individualize or alter diagnostic criteria in screening of female patients.11external link, opens in a new tab Recently, no overt sex-specific differences were observed in a large, well-characterized ATTR-CM cohort, but a significant risk of selection bias by delayed or missed diagnosis in women remains.