Mahshid Eslami

Background: Hereditary transthyretin amyloidosis (ATTRv) is a progressive multisystem disease, and some patients continue to deteriorate despite disease-modifying therapy. Real-world data on sequential treatment and on eplontersen after prior gene-silencing therapy are scarce. Case Presentation: A 60-year-old man with a family history suggestive of amyloidosis presented in early 2017 with heart failure (NYHA class II–III), chronic diarrhoea and carpal tunnel syndrome. Multimodality imaging, grade 3 bone scintigraphy, exclusion of a monoclonal protein (negative immunofixation and a normal serum free light chain ratio) and genetic testing established ATTRv amyloidosis due to the p.Thr80Ala variant, and colonic and duodenal biopsies showed gastrointestinal amyloid deposits. Between 2017 and 2025 he was treated sequentially with tafamidis, patisiran and vutrisiran. Over this period the disease progressed clinically, with weight loss, worsening axonal polyneuropathy on nerve conduction studies, rising NT-proBNP (up to 3808 pg/mL) and a decline in six-minute walk distance. In July 2025, vutrisiran was replaced by eplontersen. During 15 months of follow-up, eplontersen was well tolerated and body weight increased from 54 to 57 kg. NT-proBNP fluctuated without a sustained further rise (3093 pg/mL at the switch and 3141 pg/mL at 15 months), and troponin T and renal function were unchanged, whereas diarrhoea persisted and the six-minute walk distance was 360 m. Conclusions: This case shows clinical progression of p.Thr80Ala ATTRv amyloidosis despite sequential stabiliser and small interfering RNA therapy, followed by clinical stabilisation after a switch to eplontersen. Without serum TTR measurements and in a single patient, these observations do not allow conclusions about treatment efficacy.

Aims: To assess the association of 1-min heart rate recovery (HRR1) with clinical outcomes and its incremental contribution to model fit beyond peak VO2 and ventilatory efficiency (VE/VCO2 slope) in transthyretin cardiac amyloidosis (ATTR-CM). Methods and results: Consecutive adults with confirmed ATTR-CM undergoing symptom-limited cardiopulmonary exercise testing (CPET) were included in this single-centre observational study. During standardized active recovery at 24 W, HRR1 was defined as peak heart rate minus heart rate exactly 60 s after exercise. Cox proportional-hazards models evaluated all-cause mortality and the composite of mortality or first heart-failure hospitalization. Principal models adjusted for age, sex, peak VO2 and VE/VCO2 slope; NT-proBNP and National Amyloidosis Centre (NAC) stage were examined separately. Of 161 baseline patients, 11 with unverifiable heart-rate measurements were excluded, and exact HRR1 was available in 110. Mortality analysis included 105 patients with 33 deaths; composite-outcome analysis included 107 patients with 51 events. Median HRR1 was 15.5 bpm. In conventional CPET-adjusted models, each 10-bpm greater HRR1 was associated with lower hazards of mortality [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.44–0.95; P = 0.028] and the composite outcome (HR 0.74, 95% CI 0.57–0.97; P = 0.029). Adding HRR1 improved model fit (likelihood-ratio P = 0.017 and P = 0.021, respectively); apparent C-indices increased from 0.770 to 0.795 for mortality and from 0.695 to 0.699 for the composite outcome. Associations were non-significant after separate adjustment for NT-proBNP or NAC stage. Conclusion: HRR1 remained associated with outcomes after CPET adjustment and improved model fit. Discrimination gains were modest; value beyond biomarker staging was unproven.

Background: Transthyretin amyloidosis is a multi-system disease that may manifest as cardiomyopathy (ATTR-CM) and/or polyneuropathy. Both disease manifestations are associated with autonomic dysfunction. However, the prevalence of autonomic dysfunction in ATTR-CM remains to be evaluated. Methods: Within the scope of a prospective ATTR-CM registry, the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire was applied to consecutive patients between November 2022 and November 2024. Baseline characteristics are described, and associations of the COMPASS-31 score with markers of disease severity were assessed. Kaplan–Meier analysis was utilized to assess the COMPASS-31 score’s association with a combined endpoint of all-cause mortality and heart failure-related hospitalizations. Results: A total of 129 ATTR-CM patients [81.7 years (IQR: 77.4–84.3), 108 male (83.7%)] were included in the final study cohort. After stratification using the COMPASS-31 median [14 points, interquartile range (IQR): 6–29], statistically significant differences with regard to New York Heart Association (NYHA) stage and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were observed. Furthermore, the COMPASS-31 score was moderately correlated with the KCCQ score in Spearman correlation analysis (r = −0.55, p < 0.001). The primary endpoint occurred in 16 patients (13 HF-hospitalizations/3 deaths) after 6.3 (IQR: 2.8–17.1) months. In Kaplan–Meier analysis, a COMPASS-31 score above the median of 14 was also associated with the primary endpoint of all-cause mortality and HF-related hospitalization (log-rank p = 0.047). Conclusions: Autonomic dysfunction is highly prevalent in ATTR-CM, affecting almost two-thirds of patients. As the presence of autonomic dysfunction is likely associated with more severely impaired quality of life, routine screening for this disease manifestation of transthyretin amyloidosis may be advisable.

Background/Objectives: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) often experience significantly reduced functional capacity due to myocardial involvement. Cardiopulmonary exercise testing (CPET) is the gold standard to quantify functional capacity, and ^99mTc-DPD scintigraphy and SPECT/CT have proven to be highly effective tools for diagnostic and disease monitoring. We aimed to investigate the complementary role and correlation between both methods, focusing on their combined potential as a strong prognostic framework for monitoring disease progression and evaluating treatment efficacy. Methods: A total of 44 patients with diagnosed ATTR-CM, who underwent ^99mTc-DPD scintigraphy and SPECT/CT imaging as well as CPET, were included. All patients were divided into two groups based on the median DPD retention index (low DPD uptake: ≤5.0, n = 22; high DPD uptake: >5.0, n = 22). Results: The mean age was 78 years, with 82% of participants being male. Significant correlations were observed between peak VO₂ and DPD retention index (r = −0.355, p = 0.018) as well as between peak VO₂ at anaerobic threshold with DPD retention index (r = −0.391, p = 0.009). Interestingly, there was no strong correlation between VE/VCO₂ slope and the retention index. A strong association was identified between cardiac biomarkers and peak VO₂, specifically for NT-proBNP (r = −0.530, p < 0.001) and Troponin T (r = −0.431, p < 0.001). Conclusions: In ATTR-CM, significant correlations were observed between key CPET parameters and quantitative cardiac DPD uptake, which further reflects on disease severity and functional impairment. Our findings highlight the utility of integrating CPET and SPECT/CT for comprehensive patient assessment in ATTR-CM.