Age- and sex-associated cardiac features and diagnostic latency in patients with ATTR-mixed and PN phenotypes assessed in a prospective multi-national real-world study

Background

Age and sex influence the clinical expression of transthyretin (ATTR) amyloidosis, but limited evidence exists on their real-world impact across disease phenotypes. The prospective, multi-national MaesTTRo study, currently enrolling patients from the USA, Canada, the UK, Germany and Spain, provides a uniquely comprehensive opportunity to explore age- and sex-associated differences in routine practice. The aim of this analysis was to quantify the associations between these factors and diagnostic delay and cardiac findings.

Methods

Baseline data from 230 consecutively enrolled patients were analysed. Cohorts were stratified by age at diagnosis (<60 y, n = 45; ≥60 y, n = 185) and separately by sex (female n = 70; male n = 161). Clinical characteristics, laboratory values, echocardiographic parameters and Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores were compared descriptively. Additional data will be included in the presentation as enrollment continues.

Results

Younger patients exclusively expressed a hereditary genotype (100% vs 63%), and experienced a longer mean (+SD) diagnostic delay than older patients (48 ± 61.5 vs 40.9 ± 64.4 months). Cardiac involvement was markedly age-dependent: median NT-proBNP was 91.5 pg ml⁻¹ (IQR 48.5–307) in the <60 yrs group versus 1,393.5 pg ml⁻¹ (457–3,065) in the ≥60 yrs group. Older patients were more likely to experience New York Health Association (NYHA) class II–IV limitation than younger patients (88% vs 44%). Nonetheless, LV ejection fraction remained preserved in both cohorts (51 ± 14.8 vs 55.6 ± 9.3%). Older patients also reported a higher burden of cardiac symptoms (52% vs 33%). Patient-reported KCCQ scores were lower in the ≥60 yrs group vs <60 years (68.4 ± 22.3 vs 73.3 ± 27.4).

Females were more often diagnosed with ATTRv (84% vs 63%) after longer delays (51.3 ± 80.9 vs 38.3 ± 54.6 months), despite a stronger family history (61% vs 34%), and had lower biomarkers (NT-proBNP: 589 pg ml⁻¹ [111–2,509] vs 1,220 pg ml⁻¹ [386–2,941]) and wall thickness (LV wall thickness >12 mm: 58% vs 73%), although there was no difference in LV mass index. Males reported better health status (KCCQ: 70.7 ± 22.2 vs 64.7 ± 24.4). Neurologic manifestations were common in both sexes (~70%), while musculoskeletal symptoms were more commonly reported in females (33% vs 23%).

Conclusions

Age and sex may independently modulate the diagnostic trajectory and cardiac presentation of ATTR amyloidosis. Advanced age and male sex are associated with more pronounced structural biomarker evidence of myocardial damage, whereas younger age and female sex are linked to delayed diagnosis of primarily hereditary ATTR amyloidosis with polyneuropathy and less cardiac involvement, especially when non-indexed echo measurements are used. These results underscore the need for age- and sex-specific approaches to prompt early clinical suspicion and diagnosis in order to enable treatment to mitigate disease progression.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.