Roza Badr Eslam

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: Cardiac transthyretin amyloidosis (ATTR‐CA) is frequently underdiagnosed and commonly presents as heart failure with preserved ejection fraction (HFpEF). Early identification enables disease‐modifying therapy but remains challenging in routine practice, so simple, widely available screening tools are needed. Methods: In this multicenter validation study, 885 patients with HF from 2 European centers were included. The internal validation cohort comprised 560 patients with preserved ejection fraction and analyzable ECGs: 149 with ATTR‐CA, 318 with HFpEF, and 93 with hypertrophic cardiomyopathy. External validation used an independent cohort of 107 patients (72 ATTR‐CA, 31 HFpEF, 4 hypertrophic cardiomyopathy). Standard 12‐lead ECGs were analyzed blindly by 3 independent observers using a previously developed, 2‐step, artificial intelligence–derived, visually interpretable ECG algorithm. Results: The ECG pattern was present in 82.6% of patients with ATTR‐CA, versus 10.2% with HFpEF and 6.5% with hypertrophic cardiomyopathy ( P P P =0.007). Conclusions: A visually interpretable, artificial intelligence–derived ECG algorithm enables effective screening for ATTR‐CA among patients with HFpEF. Its simplicity and compatibility with standard ECG systems support broad clinical implementation.

Aims: To evaluate the applicability of the RoMa classification in patients with transthyretin cardiac amyloidosis (ATTR-CM) and to assess its association with functional capacity and key cardiopulmonary exercise testing (CPET) parameters. Methods and results: Consecutive adults (≥18 years) with confirmed ATTR-CM from two tertiary centres who completed symptom-limited maximal CPET were included. RoMa classes were defined using predefined cut-offs for per cent-predicted peak heart rate (HRpp ≥80%) and per cent-predicted peak O2-pulse (O2pp ≥100%): RoMa I (high HRpp/high O2pp), RoMa II (high HRpp/low O2pp), RoMa III (low HRpp/high O2pp), and RoMa IV (low HRpp/low O2pp). We evaluated 165 patients (90% male; 77% wild-type ATTR, 20% variant ATTR). RoMa distribution was as follows: RoMa I, n = 33; RoMa II, n = 73; RoMa III, n = 30; and RoMa IV, n = 29. Age did not differ across classes (P = 0.36). Functional capacity declined across the RoMa strata: median 6-min walk distance (6MWD) decreased from 420 (RoMa I) to 313 m (RoMa IV) (overall P = 0.009; P-trend = 0.005), and NYHA class worsened (overall P = 0.003; P-trend = 0.005). Peak VO2 (% predicted) differed between groups (RoMa I: 93.0; II: 70.8; III: 75.2; IV: 51.9; overall P < 0.001; P-trend < 0.001), and ventilatory inefficiency increased (VE/VCO2 slope: 34; 39; 37; 47, respectively; overall P < 0.001; P-trend < 0.001; peak PetCO2: 30; 27; 29; 25, respectively; overall P < 0.001; P-trend = 0.003). 6MWD correlated with peak VO2 (r = 0.626; P < 0.001; n = 131) and inversely with VE/VCO2 slope (ρ = −0.484; P < 0.001; n = 130). Conclusion: In ATTR-CM, application of the RoMa classification was feasible and identified distinct CPET-derived exercise-response profiles associated with functional impairment. These findings support RoMa as a promising exploratory framework for functional phenotyping in ATTR-CM.

Fibroblast growth factor 23 (FGF23), a bone-derived hormone, is emerging as a potential biomarker in cardiovascular disease. However, its role in transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive infiltrative cardiomyopathy, remains poorly defined. This study examined the relationship between circulating FGF23 levels and cardiac and renal function markers in patients with ATTR-CM. In 114 patients with confirmed ATTR-CM, intact FGF23 levels were measured in venous ethylenediaminetetraacetic acid blood samples using a chemiluminescent immunoassay on the DiaSorin LIAISON XL system. Associations between FGF23 levels, cardiac biomarker levels, and disease severity were evaluated across FGF23 tertiles and National Amyloidosis Centre (NAC) stages. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin T levels were significantly associated with FGF23 tertiles. NT-proBNP medians across tertiles were 1,608, 2,920, and 1,948.5 pg/mL, respectively (P = 0.0084). Higher FGF23 levels were significantly associated with advanced NAC classification, and cumulative probability modeling supported its association with disease stage. After adjustment for eGFR, FGF23 remained significantly associated with NT-proBNP (Spearman's ρ = 0.16; p = 0.084). However, the association with troponin T did not reach statistical significance (ρ = 0.19; p = 0.043), representing a non-significant trend. This is the first study to demonstrate a significant association between FGF23 and established markers of cardiac injury and disease staging in ATTR-CM, supporting FGF23 as a potential complementary biomarker for risk stratification.

Aim: This study aimed to characterize circulating renin–angiotensin–aldosterone system (RAAS) profiles in transthyretin amyloid cardiomyopathy (ATTR-CM), examine their relationship with clinical and echocardiographic parameters and determine their prognostic value. Methods: In this prospective study, ATTR-CM patients underwent serum quantification of classical (angiotensin I–IV, aldosterone) and alternative (angiotensin 1–7, angiotensin 1–5) RAAS peptides and angiotensin-converting enzyme 2 (ACE2) activity using mass spectrometry. RAAS inhibitor use was recorded. Associations of RAAS peptides with N-terminal pro brain natriuretic peptide (NT-proBNP) and echocardiographic parameters were analysed. Prognostic associations with the composite endpoint of HF hospitalization or cardiac death were assessed using Kaplan–Meier curves stratified by median peptide values. Results: Among 137 patients, RAAS inhibitor use included ACEi (21.2%), ARBs (34.3%), ARNIs (7.3%), and none (26.0%). RAAS profiles were consistent with the expected effects of the respective RAAS inhibitors. During a median follow-up of 1.6 years, 49 patients (36%) experienced the composite endpoint. Patients with adverse cardiac events had higher ACE2 activity (P < .001) and alternative RAAS peptides (angiotensin 1–7: P = .007; angiotensin 1–5: P < .001). Higher ACE2 activity was associated with higher NT-proBNP (P < .001) and more advanced echocardiographic parameters of biventricular dysfunction. In Kaplan–Meier analysis, ACE2 above median predicted adverse cardiac outcomes (P = .017), while classical RAAS peptides were not predictive. Conclusion: ATTR-CM patients exhibit distinct RAAS profiles, with increased ACE2 activity and a shift towards the alternative RAAS axis in more advanced disease. Higher ACE2 activity is associated with higher NT-proBNP, biventricular dysfunction and adverse cardiac outcomes, suggesting that ACE2 may represent a promising marker for risk stratification in ATTR-CM.

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a heterogeneous multisystem disease caused by pathogenic transthyretin gene (TTR) variants. Increased awareness and availability of disease-modifying therapies have resulted in increased diagnoses, even in previously nonendemic regions. The aim of this study was to update the nationwide Austrian ATTRv registry by characterizing the clinical, genetic, and regional distribution of TTR variants. Methods: This multicenter, observational analysis examined ATTRv cases diagnosed in Austria between 2014 and 2025. Individuals were included according to the presence of pathogenic or likely pathogenic variants or variants of uncertain significance (VUSs) in TTR. Results: In total, 100 individuals were identified, including symptomatic and asymptomatic carriers. Compared with our previously presented data, the number of genetically confirmed ATTRv cases has more than doubled. Twenty-three TTR variants were identified. The most frequent pathologic variants were p.His108Arg (26%), p.Ile127Phe (11%), and p.Thr69Ile (9%), while p.Val113Leu (9%) represented the most frequent VUS. Significant regional clustering of p.His108Arg was documented in Vienna and Lower Austria. Other findings included a rising number of p.Val142Ile carriers and phenotypically relevant VUSs in 20 patients. Conclusions: Our findings revealed an increasing detection rate of ATTRv in a nonendemic European region. These data underscore the importance of multidisciplinary evaluation, cascade testing, and long-term monitoring to improve early diagnosis and timely management in hereditary amyloidosis.

Introduction The one-minute sit-to-stand test (1-min STST) is a simple and reproducible measure of functional capacity. Recently, cut-off values for the 1-min STST equivalent to guideline-recommended six-minute walk test (6MWT) thresholds have been proposed for risk stratification in patients with pulmonary hypertension (PH). However, the prognostic value of the 1-min STST for long-term outcomes remains unclear. Aim To assess the association between the 1-min STST performance and long-term adverse outcomes in patients with PH. Methods Consecutive patients with PH were prospectively enrolled and underwent both the 1-min STST and 6MWT. The primary endpoint was a composite of heart failure hospitalization, heart-lung transplantation or all-cause mortality. Associations between 1-min STST performance and long-term adverse outcomes were assessed using Cox regression. Patients were stratified into three groups based on previously published 1-min STST cut-offs (≤ 14, 15–19, ≥ 20 repetitions), aligned with 6MWT thresholds. Kaplan-Meier curves were used to compare event rates between groups. Results A total of 117 patients (mean age 66 ± 14 years, 56% female) were included. Over a median follow-up of 2.7 years [IQR 1.0–3.9], 60 (51%) patients experienced an adverse event. Lower 1-min STST performance was significantly associated with a higher risk of long-term adverse outcomes (HR per repetition: 0.94, 95% CI: 0.90–0.98, p < 0.001). This association remained significant after adjusting for age, sex, BMI and NT-proBNP levels (adjusted HR = 0.95; 95% CI: 0.91–0.99; p = 0.016) and major comorbidities (adjusted HR = 0.94; 95% CI: 0.90–0.98; p = 0.003). Kaplan-Meier analysis showed significantly worse long-term outcomes in patients performing ≤ 14 repetitions (log-rank p = 0.001). Conclusion The 1-min STST is a predictor for long-term adverse events in PH patients. Performing ≤ 14 repetitions on the 1-min STST indicates a significantly higher risk of long-term adverse outcomes. Therefore, the 1-min STST may be used for risk stratification in clinical practice.

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.