Objectives: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive condition that predominantly affects older adults  a population that is at higher risk of morbidity and mortality. In HELIOS-B, vutrisiran reduced all-cause mortality and recurrent cardiovascular events compared with placebo in patients with ATTR-CM. This analysis aims to evaluate the efficacy and safety outcomes by age categories (<75, 75-79, and ≥80 years) in the HELIOS-B trial. Methods: The HELIOS-B trial randomized patients with ATTR-CM 1:1 to receive vutrisiran 25 mg or placebo subcutaneously every 12 weeks up to 36 months. In this analysis, clinical outcomes were assessed across age categories, for the primary endpoint (a composite of all-cause mortality and recurrent cardiovascular events), three secondary endpoints (all-cause mortality up to 42 months, and changes from baseline to month 30 in both 6-minute walk test [6MWT] and KCCQ-Overall Summary Score [KCCQ-OSS]), as well as safety outcomes. Results: Among 654 randomized patients (aged 45-85 years, mean age 75.33±6.74 years), 257 (39.3%) were <75 years, 201 (30.7%) were 75-79 years, and 196 (30.0%) were ≥80 years. Reduction of the risk of the primary composite outcome with vutrisiran compared with placebo was consistent in all age categories (Pinteraction= 0.56). Similar benefits were observed for the components of the primary outcome as well as the secondary endpoint of all-cause mortality (up to 42 months). Across all endpoints evaluated, interaction tests (randomized treatment assignment x age) were not significant, suggesting these benefits were consistent across age groups. Vutrisiran was associated with consistent preservation of functional status and quality of life across all age groups (Pinteraction= 0.35 and 1.00 for KCCQ-OSS and 6MWT, respectively). Safety profiles were consistent across all age categories, with no clinically significant increase in adverse events in older patients. Conclusion: In patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events compared with placebo and preserved functional capacity and quality of life across different age groups. These findings support vutrisiran treatment in elderly patients, including those who are 80 years or older.

Background: Hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) is a rare multisystemic disease caused by mutations in the TTR gene, leading to amyloid deposits in nerves, progressive disability, and death. Nexiguran ziclumeran (nex-z) is an investigational, in vivo, CRISPR-based, one-time therapy designed to precisely target the TTR gene to provide lifelong knockdown of serum TTR. Objective: To report the safety, pharmacodynamics (PD), and efficacy of nex-z in patients with ATTRv-PN from the Phase 1 study (NCT04601051) after 24 months of follow-up. Methods: Adult patients with ATTRv-PN received a weight-based (0.1, 0.3, 0.7, or 1.0 mg/kg) or fixed dose (55 or 80 mg) of nex-z as a one-time intravenous infusion. Primary objectives were assessment of safety and PD (serum TTR levels). Secondary objectives were evaluation of efficacy, neurologic biomarkers, and patient-reported outcomes, including changes from baseline in Neuropathy Impairment Score (NIS), modified NIS+7 (mNIS+7), modified body mass index (mBMI), neurofilament light chain (NfL) levels, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire (Norfolk QOL-DN). Results: As of XX Month 2025, 36 patients (male, 72%; median [range] age, 61 [19-75] years; 6 previously received patisiran and had a history of disease progression while on treatment) were dosed with nex-z. Mean±SD follow-up was XX±XX months. Mean (95% CI) percent change from baseline in serum TTR levels at Day 28 (n=XX), Month 12 (n=XX), and Month 24 (n=XX) were XX% (XX, XX), XX% (XX, XX), and XX% (XX, XX), respectively. Mean±SD change from baseline to Month 24 in NIS (n=XX), mNIS+7 (n=XX), and mBMI (n=XX) was XX±XX, XX±XX, and XX±XX kg/m2×g/L, respectively. NfL analysis is ongoing and will be reported through Month 24. Mean±SD change from baseline to Month 24 in Norfolk QoL-DN scores was XX±XX. The most common adverse events were [placeholder] (XX%) and [placeholder] (XX%); [placeholder for additional safety details]. Conclusions: A single therapeutic dose of nex-z was well tolerated and associated with rapid, deep, and sustained reductions in serum TTR. Compared with the natural history of disease, these data demonstrate that nex-z can stabilize or improve multiple disease-relevant measures in patients with ATTRv-PN, including those who progressed on prior silencer treatment. Further investigations on the effects of nex-z on clinical outcomes in ATTRv-PN are advancing with the ongoing Phase 3 MAGNITUDE-2 trial (NCT06672237).

Introduction: The extent of missed opportunities for early diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) is unknown. In this study using data from the National Readmission Database (NRD), we aimed to determine the cause and frequency of hospitalizations within the 6-month period prior to the index admission with ATTR-CM as a surrogate for potential missed opportunities. Our secondary objectives were to establish the impact of sex on hospitalizations and determine the factors associated with in-hospital all-cause mortality and hospital length of stay. Methods: We conducted a retrospective cohort study of the National Readmissions Database to evaluate the 6-month admissions to hospital preceding the index hospitalization with a diagnosis of ATTR-CM. We determined the rate and causes of admissions, and identified factors associated with in-hospital mortality. Results: Between 2018 and 2020, there were 10,975 patients hospitalized with ATTR-CM of whom 4,545 (41.1%) had one or more hospital admission within the preceding 6-months. The total number of hospital admissions during this time period was 15,520. A total of 1,995 patients (9.6%) had 2 admissions and 605 patient (5.5%) had 3 admissions within the 6-months prior to hospitalization with ATTR-CM. The most common primary diagnoses for the 6-month admissions before hospitalization with ATTR-CM were hypertensive heart disease and chronic kidney disease (22.6%), hypertensive heart disease (9.9%), sepsis (4.9%), atrial fibrillation and flutter (4.1%) and heart failure (3.6%). The factors associated with an increased risk of previous admission included female sex (OR 1.39 95%CI 1.14-1.69, p=0.001), chronic lung disease (OR 1.56 95%CI 1.26-1.94, p<0.001), and hypertension (OR 1.40 95%CI 1.04-1.88, p=0.026). A previous 6-month hospitalization was associated with a 2-fold increased risk of mortality during the index admission with ATTR-CM (OR 2.06 95%CI 1.32-3.20, p=0.001). The predictors of in-hospital all-cause mortality included the presence of liver failure (OR 8.96 95%CI 3.46-23.21, p<0.001) and palliative care input (OR 11.05 95%CI 6.13-19.94, p<0.001). Conclusions: Hospitalization occurs in nearly half (41.1%) of patients in the 6 months prior to their readmission with a new diagnosis of ATTR-CM. Prior hospitalization is associated with a 2-fold increase in mortality and is more common among females. The commonest reasons for prior hospitalization include hypertensive heart and chronic kidney disease, sepsis, atrial arrhythmia, and heart failure.

Background: Hereditary transthyretin amyloidosis (ATTRv), is a progressive and heterogeneous disease marked by length-dependent axonal and autonomic neuropathy, cardiomyopathy, or mixed phenotypes. Timely intervention is critical to mitigate irreversible tissue damage. Identifying early neurophysiological markers in asymptomatic gene carriers offers a potential path toward preemptive diagnosis and treatment. Objective: To validate neurophysiological tools as early markers of neuropathy in ATTRv amyloidosis by examining changes from baseline (T0) to symptom onset (T1) in individuals with ATTRv amyloidosis. Methods: A retrospective analysis was conducted on 35 asymptomatic carriers of the ATTRV30M mutation who developed symptomatic disease during follow-up evaluations as asymptomatic carriers. Participants underwent longitudinal neurophysiological evaluations, including nerve conduction studies (sural and median Σ SNAP and Σ CMAP), small fiber assessments with Quantitative Sensory Testing (CDT, HP5, HP05), sympathetic skin response (Σ SSR), and electrochemical skin conductance (ESC feet and hands). Wilcoxon Signed-Rank and Mann-Whitney U tests assessed intra-individual changes and symptom associations. Spearman’s correlation was used to evaluate the relationship between Predictided Age of Onset (PADO) and age of onset. Results: At symptom onset, significant neurophysiological changes included increased CDT, HP5, and HP05 thresholds (p < 0.001, p = 0.001, p < 0.001 respectively), reduced Σ SSR (p < 0.001), and decreased ESC in the feet (p = 0.026). No significant changes were noted in Σ SNAP, Σ CMAP or ESC in the hands. Sensory symptoms were present in 80% of participants and were significantly associated with CDT thresholds at T1. A positive linear correlation was found between PADO and age at symptom onset. Conclusion: Small fiber dysfunction markers—particularly CDT, HP5, HP05, SSR, and ESC feet—are sensitive indicators of early neuropathic change in ATTRv carriers. These neurophysiological tools may serve as early diagnostic biomarkers, supporting timely intervention with disease-modifying therapies to improve patient outcomes.

Introduction: The efficacy of treatment with transthyretin silencers for variant transthyretin amyloidosis with polyneuropathy (A-ATTRv PNP) has been widely demonstrated in the literature in different clinical trials. In Spain, there are no real-life studies available to evaluate the response to treatment. Methodology: an ambispective multicenter observational drug study in patients who have received patisiran or inotersen for at least 6 months. The following hospitals participate: Hospital Son Llàtzer, Hospital Vall D\\\'Hebron, Hospital Clinic Barcelona, Hospital Bellvitge, Hospital Basurto and Hospital Donosti. Responders are those patients who during follow-up showed no progression of sensory, autonomic or motor signs and symptoms and did not increase the NIS > 2 points in 6 months. Non-responders are those patients who during follow-up showed disease progression similar to that expected without treatment defined by meeting at least 2 of the following criteria: clinical worsening, change of FAP stage from I to II or from II to III, ENG: drop of at least 50% in CMAP and/or SNAP amplitude and/or NIS progression (≥10 points in 6 months). Partial responders are defined as patients not classifiable as responders or non-responders, with dysautonomic clinical stability. Objectives: to describe the real-life efficacy of patisiran and inotersen in patients with A-ATTRv PNP in Spain. Results: A total of 53 patients were included, 81% Val30Met, 60.4% were male, 50.9% had mixed phenotype, 35.8% neurological ¨late onset¨ and 13.2% neurological ¨early onset¨. Treatment was in 44 patients (83%) patisiran and in 9 (17%) inotersen. In the inotersen group, 33.3% were total responders, 44.4% partial responders and 22.2% non-responders. In the patisiran group 68.2% were total responders, 15.9% partial responders and 15.9% non responders. No differences in response were observed according to the time of disease onset. There were no statistically significant differences between response groups in prealbumin levels (p= 0.1693), however total responders tended to have higher prealbumin levels compared to the other groups. The percentage change in SNAP was comparable between patisiran and inotersen and independent of the response group to which they belonged. Patients with patisiran had a decrease in NTProBNP levels and with inotersen an increase (mean change -247.29 (-15.9%) vs 308.38 (17.72%) respectively. Conclusions: Silencer treatment delays neuropathy progression. Patisiran shows a higher percentage of total response of polyneuropathy compared to inotersen. Prealbumin levels do not predict treatment response. NT-ProBNP is modified throughout treatment, which may suggest an impact on cardiac function. The impact of treatment on NTProBNP was better in the Patisiran group compared to Inotersen. Further long-term studies with larger numbers of patients are needed to confirm these data.

Background: Therapies for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), including transthyretin (TTR) stabilizers and silencers, have demonstrated mortality benefit in three randomized trials. However, the timing of this benefit—often appearing delayed—has been debated, and has broad implications for clinical use and trial design. Methods: We extracted time-to-event mortality data from the published Kaplan-Meier curves of three ATTR-CM outcomes trials: ATTR-ACT (tafamidis), ATTRIBUTE-CM (acoramidis), and HELIOS-B (vutrisiran). Using flexible parametric survival models, we estimated instantaneous hazard ratios and assessed the time-varying treatment effects across trials. These were compared to analogous analyses from two heart failure trials—PARADIGM-HF and DAPA-HF. Results: Mortality curves in each ATTR-CM trial began to diverge between 12–18 months after therapy initiation (Figure, panel A). Instantaneous hazard ratios showed consistent time-varying treatment effects across trials (p=0.99), with a pooled model confirming a delayed but progressively strengthening benefit (p for treatment effect <0.001; p for time interaction = 0.008). No differences were found between the 3 trials in the instantaneous hazard ratios. In contrast, standard GDMT heart failure therapies (sacubitril/valsartan and dapagliflozin) exhibited immediate and sustained mortality benefit over time. Conclusions: Despite differences in trial design and event rates, mortality benefits with TTR silencers and stabilizers in ATTR-CM emerged in a delayed but consistent fashion with no apparent differences between trials. This pattern likely reflects the mechanism of action—attenuation of further amyloid accumulation—rather than rapid reversal of disease burden. These findings underscore the importance of early intervention clinically, and adequate trial duration to capture delayed therapeutic effects in ATTR-CM.

Objectives Acoramidis is an oral, highly selective transthyretin (TTR) stabilizer that achieves a rapid increase in serum TTR (sTTR) levels and near-complete (≥90%) TTR stabilization, and is approved in the US, Europe, and Japan for the treatment of adult patients with TTR amyloid cardiomyopathy. Results from the phase 3 ATTRibute-CM study demonstrated that acoramidis treatment significantly increased sTTR levels in participants with TTR amyloid cardiomyopathy, resulting in improved clinical outcomes. Here we assess the effect of tafamidis (TAF) taken concomitantly with acoramidis on sTTR levels in participants from ATTRibute-CM. Methods Participants from ATTRibute-CM were randomized 2:1 to receive acoramidis or placebo (PBO). After 12 months, participants could initiate concomitant TAF treatment; sTTR levels were monitored over 30 months. Results At Month 12, mean (standard error of the mean, SEM) change from baseline (CFB) in sTTR levels for acoramidis was 7.9 (0.31) mg/dL and for PBO was −0.6 (0.33) mg/dL. At Month 30, mean (SEM) CFB in sTTR levels for acoramidis was 9.1 (0.38) mg/dL, for PBO+TAF was 6.4 (1.24) mg/dL, and for acoramidis+TAF was 8.9 (0.79) mg/dL. In the PBO only group, a mild decrease in sTTR levels was observed at Month 30 (CFB: −0.4 [0.49] mg/dL) (Figure). Acoramidis was well tolerated across all groups. Conclusions In participants with TTR amyloid cardiomyopathy, treatment with acoramidis significantly increased sTTR levels compared with PBO and PBO+TAF. Addition of TAF to acoramidis did not show any further increase in sTTR levels, indicating no additional stabilization of sTTR. Safety of concomitant acoramidis+TAF was similar to the overall safety profile of acoramidis. Overall, addition of TAF to acoramidis may not provide further pharmacologic effects as measured by sTTR levels.

Objectives Individuals with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) generally have lower serum TTR (sTTR) levels than those with wild-type (ATTRwt-CM), likely from greater TTR destabilization, which causes earlier disease onset and more rapid clinical progression. Acoramidis is an oral, highly selective TTR stabilizer that achieves a rapid increase in sTTR levels and near-complete (≥90%) TTR stabilization, and is approved in the US, Europe, and Japan for the treatment of adult patients with ATTR-CM. Here, we report the effects of acoramidis on sTTR levels and clinical outcomes in participants with ATTRv-CM and ATTRwt-CM. Methods Outcomes were analyzed using a stratified Cox proportional hazards model. Results Figure 1A shows baseline characteristics; sTTR was lower at baseline in participants with ATTRv-CM vs those with ATTRwt-CM. Participants with ATTRv-CM had greater increases in, yet similar absolute achieved, sTTR levels as participants with ATTRwt-CM; this increase was stable through Month 30 (Figure 1B). The Cox proportional hazards ratio in a pre-specified subgroup analysis of time to all-cause mortality or cardiovascular-related hospitalization was statistically significant in both participants with ATTRv-CM and participants with ATTRwt-CM (hazard ratio [95% confidence interval]: 0.41 [0.21–0.81] and 0.69 [0.52–0.90], respectively; Figure 1C). Conclusions Despite greater TTR destabilization and lower baseline sTTR in participants with ATTRv-CM, acoramidis treatment induced a greater proportional increase in sTTR and achieved similar absolute sTTR levels as in participants with ATTRwt-CM. In a pre-specified analysis this resulted in statistically significant better outcomes in both participants with ATTRv-CM and with ATTRwt-CM. These rapid and sustained increases in sTTR levels in participants with ATTRv-CM and similar absolute levels in participants with ATTRwt-CM are consistent with near-complete TTR stabilization with acoramidis treatment. Acoramidis is the only disease-modifying therapy that statistically improves clinical outcomes in both participants with ATTRv- and with ATTRwt-CM. 

Objectives: Hereditary transthyretin (ATTRv) amyloidosis is a rare, progressive and often fatal autosomal dominant disorder caused by transthyretin gene variants, leading to motor, sensory and autonomic impairment, which worsens overall disability and gait speed. Methods: In the pivotal NEURO-TTRansform study (NCT04136184), change from baseline of Rasch-built Overall Disability Scale (R-ODS) for overall disability (as assessed by limitation to activity and social participation) and 10-Meter Walk Test (10MWT) for gait speed were measured as prespecified exploratory endpoints in eplontersen-treated patients with ATTRv-polyneuropathy (PN), and results were compared with an external placebo from the APOLLO study (NCT01960348). R-ODS and 10MWT were assessed at baseline and weeks 37 and 81 in the eplontersen group. In the placebo group, R-ODS was assessed at baseline and weeks 39 and 78, while 10MWT was assessed only at baseline and week 78. Results: In eplontersen-treated patients (n=144), R-ODS remained stable compared with baseline at weeks 37 and 81 (baseline mean [standard deviation] 35.8 [10.35]; unadjusted mean change from baseline (CFB) [standard error of the mean; SEM] 0.6 [0.41] at week 37 and −0.5 [0.45] at week 81). The placebo group (n=77) had deterioration in R-ODS at weeks 39 and 78 with an adjusted least-squares mean (LSM) CFB (SEM) −4.0 (0.69) and −8.9 (0.88), respectively. In eplontersen-treated patients, 10MWT results (metre/second [m/s]) improved for both fast (CFB [SEM] 0.098 [0.57] at week 37 and 0.047 [0.50] at week 81) and comfortable (CFB [SEM] 0.036 [0.43] at week 37 and 0.013 [0.36] at week 81) walking speeds. In the placebo group, walking speed (m/s) declined at week 78 (LSM CFB mean [SEM] −0.24 [0.04]). Conclusions: In this prespecified exploratory analysis from the NEURO-TTRansform study, eplontersen prevented disability progression and observed deterioration of gait speed, in contrast to the worsening that was observed with placebo. This supports the benefit of eplontersen treatment for patients with ATTRv-PN.

Background: In hereditary transthyretin amyloidosis (ATTRv) polyneuropathy is a hallmark, driven by Wallerian degeneration and progressive axonal loss, initially affecting small sensory fibers and leading to impaired pain and temperature sensation, as well as autonomic dysfunction. This study explores the relationship between neuropathic pain intensity and clinical and neurophysiological measures in symptomatic ATTRv patients. Methods: We analyzed 106 symptomatic ATTR V30M patients (46 males, mean age 47.5 ± 13.2 years), categorized based on neuropathic pain (NP) severity according to Norfolk QOL questionnaire. Clinical and neurophysiological measures included the Neuropathy Impairment Score (NIS), sensory sural and motor peroneal nerve amplitudes, sympathetic skin response (SSR), and electrochemical skin conductance (ESC) in hands and feet. Statistical analysis included the Kruskal-Wallis test with Dunn’s post-hoc test and Bonferroni correction. A cumulative odds ordinal logistic regression was used to assess associations under the proportional odds assumption. Results: Patients with NP showed significant differences in NIS (p < .001), sural (p = .009) and peroneal (p = .001) amplitudes, hand ESC (p = .036), and foot ESC (p = .003). While neurophysiological measures distinguished patients with and without NP, they did not differentiate NP severity levels. NIS was the only independent predictor of NP intensity (OR = 1.058, 95% CI: 1.010–1.108, p = .018). Conclusion: Incorporating tools such as the NIS, alongside selective neurophysiological tests and validated patient-reported outcome measures, provides a more holistic approach for evaluating the multifaceted nature of neuropathic pain in ATTRv.

Objectives: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) can have lower circulating serum transthyretin (sTTR) levels; this is associated with a greater risk of mortality. Acoramidis is an oral, highly selective TTR stabilizer that achieves near-complete (≥90%) TTR stabilization and is approved in the US, Europe, and Japan for the treatment of adult patients with ATTR-CM. In a phase 3 study, ATTRibute-CM, acoramidis treatment resulted in a rapid (by Day 28) and sustained increase in sTTR levels, and reduced the risk of cardiovascular hospitalizations (CVH) and mortality (CVM). In this post-hoc analysis of ATTRibute-CM, we evaluated the association between acoramidis-mediated early increase in sTTR levels with the risk of CVM and of first CVH. Methods: Analyses were conducted in the ATTRibute-CM modified intent-to-treat population (acoramidis: 409; placebo: 202). Relationships between change from baseline in TTR at Day 28 and subsequent risk of CVM and of first CVH over 30 months were analysed as separate endpoints using a stratified Cox proportional hazards model. Results: A 1 mg/dL increase in sTTR levels at Day 28 mediated by acoramidis was associated with a risk reduction of 5.5% in CVM and 4.1% for first CVH over 30 months (Table). Conclusions: Incremental increases in sTTR levels on Day 28 achieved with acoramidis may independently predict greater reduction in risks of CVM and of first CVH in patients with ATTR-CM. This study will help enable cardiovascular clinicians to understand that greater increases in serum tetrameric TTR (measured as serum prealbumin) levels through stabilization of the TTR tetramer by acoramidis is associated with better clinical outcomes in patients with ATTR-CM.

Introduction and objectives Hereditary Transthyretin-mediated Amyloidosis with Polyneuropathy (ATTRv-PN) is a progressive disease caused by transthyretin (TTR)-derived amyloid deposits. This study explores the relationship between serum TTR levels and neuropathy severity according to Polyneuropathy Disability (PND) score and Neuropathy Impairment Score (NIS), aiming to assess its potential as a biomarker for early diagnosis and disease progression. Methods We studied 239 individuals, of which 120 had ATTRv-PN and 119 were asymptomatic carriers of a TTR amyloidogenic variant followed at the reference center of ULS Santa Maria, Lisbon. TTR levels were compared between asymptomatic carriers and symptomatic patients, as well as before and after disease onset in a subset of individuals. Associations with neuropathy severity were assessed using non-parametric tests (Mann-Whitney U, Wilcoxon signed-rank, Kruskal-Wallis) and multiple linear regression models adjusted for key confounders. Results Symptomatic ATTRv patients had significantly lower TTR levels than asymptomatic carriers (median TTR 24 mg/dL vs 25 mg/dL, p = 0.015). However, no significant difference was observed in TTR levels before and after symptom onset. Additionally, lower TTR values were significantly associated with higher NIS scores (median TTR: 24 mg/dL for NIS ≤ 8 vs. 22.5 mg/dL for NIS > 8, p = 0.014) and across PND stages (median TTR: 24.5 mg/dL in PND 0, 24 mg/dL in PND 1, and 21 mg/dL in PND ≥ 2, p = 0.001). In both multiple linear regression models, lower TTR levels were significantly associated with higher PND scores (p = 0.006) and NIS (p = 0.016), after adjusting for confounders, indicating a consistent relationship between TTR levels and neuropathy severity. Gender and modified body mass index were also significantly associated with TTR levels in both models. Conclusions TTR levels decline with disease progression in ATTRv amyloidosis, consistent with its underlying pathophysiology. While TTR appears insufficiently sensitive as a biomarker for early disease detection, it may hold potential for monitoring disease progression in treated patients, an area that warrants further investigation.

Introduction: Portugal has a high prevalence of hereditary ATTR (ATTRv) amyloidosis, especially the V30M variant, which can manifest as early or late-onset, and has high penetrance.1 Despite this, there is limited information on the sociodemographic characteristics of affected individuals and how these may relate to clinical manifestations and disease features. Objectives: This study aimed to explore trends over time in mutation types, family history, sex distribution, and age at symptoms and diagnosis among individuals with ATTRv amyloidosis. Methods: This multicentric retrospective cohort study included adult Portuguese individuals with a confirmed TTR mutation who attended to at least one appointment at an ATTRv amyloidosis reference centre (CoE) between 2011 and 2023. Anonymized data were extracted from electronic health records, with follow-up from the first appointment until the last recorded visit, loss to follow-up, or death. The study was approved by the Institutional Ethics Committees of both centers. Results: A total of 2605 individuals with confirmed TTR mutations were identified, of whom 52.3% were female and 98.6% had the V30M variant. The prevalence of V30M slightly declined over time. Most individuals (91.1%) had a known family history, though the proportion without family history increased in recent decades. Notably, 82.1% of those without family history were male. Female predominance in the total cohort declined over time, with recent years showing balanced sex distribution. Of those diagnosed with ATTR amyloidosis (63.6%), 53.0% were male. Mean age at symptoms and at diagnosis increased over time, with an overall mean of 39.5 and 41.5 years, respectively. At the end of follow-up, 31.5% were asymptomatic carriers, 63.6% had developed ATTR amyloidosis, and 4.9% remained undefined (requiring further clinical evaluation). Conclusions: This analysis of the CARDINAL highlights evolving trends in ATTRv amyloidosis in Portugal, including a slight decline in V30M mutation prevalence, a rising proportion of cases without family history, particularly among males, and an increasing age at symptoms and diagnosis. These shifts underscore the need for heightened clinical awareness in patients without a known family history and in older individuals. Further research is needed to understand the drivers of these changes and their impact on disease management. References: 1. Inês M et al. Neuroepidemiology 2018;51:177–182

Objectives This study aimed to characterize spinal structural changes in patients with histologically confirmed amyloid deposits in the ligamentum flavum by comparing radiographic parameters at operated levels with adjacent non-operated levels. Methods Preoperative MRI and CT imaging were retrospectively analyzed in patients who underwent lumbar decompression surgery and were biopsy-positive for amyloidosis. For each patient four parameters were measured at both the operated level and a superior healthy reference level: average disc height (calculated as the mean of anterior, middle and posterior measurements), cross-sectional area (CSA) of the dural sac, anteroposterior (AP) diameter of the bony spinal canal, and ligamentum flavum thickness (average of both sides). As all data had a normal distribution paired sample t-tests were performed to assess statistical differences between levels. Results A total of 24 patients were included in the analysis. Ligamentum flavum thickness was significantly greater at operated levels compared to control levels (mean difference: 1.32 mm, p < 0.001), indicating pronounced ligamentous hypertrophy in amyloidosis-associated stenosis. CSA was significantly reduced at operated levels (mean difference: –87.14 mm², p < 0.001), consistent with central canal narrowing compared with healthy levels. No significant difference was found in disc height (mean difference: –0.22 mm, p = 0.594), suggesting that intervertebral disc degeneration does not play a primary role in this subtype of spinal stenosis. Likewise, the bony AP diameter remained unchanged (mean difference: –0.74 mm, p = 0.219), further supporting the notion that spinal narrowing occurs predominantly through posterior soft tissue expansion rather than anterior-posterior bony remodeling. Conclusions These findings suggest that lumbar spinal stenosis in amyloidosis-positive patients is primarily caused by ligamentum flavum hypertrophy and not by disc degeneration. The observed decrease in CSA combined with stable disc height and AP diameter supports a different degenerative mechanism compared to classic degenerative stenosis. These insights highlight the importance of preoperative MRI evaluation of ligamentum flavum thickness and disc height in patients with suspected spinal amyloidosis, potentially aiding in earlier diagnosis.

Objective: Transthyretin amyloidosis (ATTRv) is a rare, inherited disorder caused by mutations in the TTR gene, leading to progressive amyloid deposition and multisystem disease. The Balearic Islands are recognized as an endemic region for the p.Val30Met (V30M) variant, but the genetic landscape and founder effects in this population have not been fully characterized. The aim of this project is to comprehensively define the genetic architecture of ATTRv in the Balearic population, assess the frequency and geographic distribution of key TTR variants, and explore the presence of potential founder effects. Methods: A retrospective analysis was conducted using 23 years of genetic testing data from the Balearic Islands' public health system. Genetic analysis included both Sanger sequencing and whole-exome sequencing to identify TTR gene variants. The study specifically investigated the co-occurrence of the V30M and p.Gly6Ser (G6S) variants to evaluate potential founder effects in this population. Prevalence calculations were performed for each island within the archipelago. Results: From the total cohort of 1,478 individuals who underwent genetic testing, 320 tested positive for pathogenic TTR variants. The V30M variant was predominantly identified in 308 cases, representing 96% of all positive results. Geographic distribution analysis revealed the highest prevalence in Mallorca and Menorca, with rates of 1 in 2,900 and 1 in 4,700 respectively, while Ibiza and Formentera showed lower frequencies. A significant finding was the co-occurrence of V30M and G6S variants on the same chromosome in 93% of V30M carriers, providing strong evidence for a unique founder effect in this population. Conclusions: This comprehensive genetic analysis establishes the Balearic Islands as a major global focus for the V30M variant of ATTRv, characterized by a distinct genetic signature suggesting a founder effect. These findings have immediate clinical implications, emphasizing the necessity for region-specific genetic screening protocols and tailored clinical management strategies. The high prevalence and unique genetic profile underscore the importance of early identification of at-risk individuals and enhanced clinical awareness in this population. Future research directions should focus on integrating these genetic insights with clinical outcomes to optimize treatment approaches for this genetically distinct population.

Objectives Amyloid polyneuropathy (A-PN) is a progressive peripheral neuropathy caused by amyloid deposits in nerves, most often due to hereditary transthyretin amyloidosis (ATTRv-PN) or light-chain (AL) amyloidosis. This study aimed to estimate the incidence of A-PN in England and to describe patient characteristics and clinical outcomes using electronic health records (EHRs). Methods In this retrospective observational study, anonymised, linked primary and secondary care data (Clinical Practice Research Datalink [CPRD] and Hospital Episode Statistics [HES]) were used to describe individuals diagnosed with A-PN. Patients aged 18 years and older with diagnosis codes for A-PN from either primary or secondary care in the period between January 2004 to March 2023 were included. The primary outcome was all-cause mortality (ACM), described using crude event rates (per 1,000 person-years, PY) and analysed using Cox proportional hazards models. Demographic and clinical data were summarised using descriptive statistics. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated to account for risks of ACM. Results: There were 2,505 patients coded with incident A-PN (mean age: 69 years; 39% females), including 45 coded for ATTRv-PN, of whom 17 had mixed polyneuropathy and cardiac amyloidosis phenotypes. In the 12 months to first diagnosis code or by prescription, dyspnoea, heart failure, and gastrointestinal dysfunction were the most common clinical presentations recorded, across the patient groups (Table). Antidepressants were prescribed in 19.6% of the A-PN patients and gabapentinoids in 24.4% of the ATTRv-PN group. The incidence of coded A-PN increased from 0.93 in 2004 to a peak of 2.42 in 2023, per 100,000 PY, a 2.6-fold increase; males had higher rates than females (Figure 1). Over a median follow-up of 2.3 years, 1,144 (46%) A-PN patients died of any cause (crude event rate: 123 per 1,000 PY). Over time, females had higher survival probabilities compared to males (Figure 2). Prominent independent significant risk predictors of ACM in A-PN patients included severe anaemia (HR=24.9 [95% CI: 2.8-222.0]), severe thrombocytopenia (HR=8.7 [95% CI: 1.9-38.6]), and very high serum monoclonal protein (HR=7.2 [95% CI: 2.3-22.4]). Conclusions: In this large EHR-based study, amyloid polyneuropathy was confirmed to be rare but increasingly recognised in clinical practice. The incidence rate of newly coded A-PN increased overall in the past two decades, with higher rates in males than in females. Mortality among A-PN patients was high and was associated with known and unknown risk factors. There is now an urgent need for increased awareness, enhanced methods of detection, characterisation and robust data capture to influence further pathway developments.

Objectives Acoramidis, a near-complete transthyretin stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM), demonstrated efficacy and safety in the Phase 3 ATTRibute-CM study (NCT03860935), leading to its approval in the United States, Europe, and Japan. The ACO-REAL study aims to generate real-world evidence on acoramidis in Europe, complementing data from the ATTRibute-CM study. Methods ACO-REAL is a prospective, open-label, multicentre, single-arm, observational study in approximately 2000 treatment-experienced or treatment-naive participants with either wild-type or variant ATTR-CM initiating treatment with acoramidis in real-world clinical settings across approximately 20 European countries. Results The primary objective is to assess the characteristics and treatment patterns of participants with wild-type or variant ATTR-CM receiving acoramidis across real-world patients observed in contemporary clinical practice. Demographic and clinical characteristics will be collected from medical records or through participant questionnaires. The secondary objective is to evaluate the safety profile of acoramidis in a “real world” setting. Further objectives will evaluate cardiac function and course of the disease (key biomarkers and echocardiographic and electrocardiographic parameters), as well as functional capacity and health status (New York Heart Association classification and 6-minute walk test), using data collected as available in routine clinical practice. Health-related quality of life will be assessed using the Kansas City Cardiomyopathy and the EuroQol-5 Dimensions-5 Levels questionnaires. Patient-reported outcomes will be provided by all participants during the initial study site visit and subsequently via telephone interviews at months 3, 6, 9, and 12. In addition, healthcare resource utilization (ATTR-CM-related hospitalizations, intensive care unit stays, emergency room visits, and outpatient visits) will be assessed. A list of primary, secondary, and further study objectives can be found in Table 1. Statistical analyses will be exploratory and descriptive, with no pre-defined hypotheses. Categorical variables will be presented as frequencies and continuous variables as sample statistics. Conclusions ACO-REAL is a prospective observational study with acoramidis with near-complete transthyretin stabilization, in a population with ATTR-CM. This study aims to provide meaningful insights into the treatment of ATTR-CM using real-world evidence from European healthcare systems, and may potentially help in decision-making for initiating treatment with acoramidis in people with ATTR-CM.

OBJECTIVES: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by deposition of misfolded transthyretin protein in the heart. Vutrisiran, a subcutaneously administered RNA interference therapy, inhibits the production of hepatic transthyretin leading to rapid knockdown of the pathogenic protein. Over the 33–36-month (M), double-blind (DB) period of HELIOS-B (NCT04153149), vutrisiran treatment lowered the risk of the primary composite endpoint of all-cause mortality (ACM) and recurrent cardiovascular (CV) events vs placebo in both the overall population and the monotherapy population (patients not on tafamidis at baseline). Patients completing the DB period were eligible to enter a 2-year open-label extension (OLE). The objective of this analysis is to present 1-year efficacy and safety data from the OLE of HELIOS-B. METHODS: Following completion of the DB period (up to 36 months), patients could enter the 2-year OLE period in which all patients received vutrisiran 25 mg q3M. Efficacy endpoints evaluated over the OLE period include mortality and CV events (collected at M6, 12, 18, and 24). The ACM secondary endpoint was prespecified for analysis up to M42 from the start of the DB period, which included data from up to 6M of the OLE; this was expected to increase statistical precision and power since former placebo patients in the OLE would not yet have experienced mortality benefit. RESULTS: Overall, 654 patients received treatment in HELIOS-B (vutrisiran n=326; placebo n=328). Of 477 patients who completed DB treatment, 462 (96.9%; vutrisiran n=241; placebo n=221) entered the OLE period (96.9% of eligible patients who completed HELIOS-B study). A vital status sweep at OLE M6 (November 2024) resulted in 99% data ascertainment, consistent with the primary analysis ascertainment of >99%. Efficacy and safety results at OLE M12 will be presented. CONCLUSIONS: During the DB period of HELIOS-B, vutrisiran demonstrated significant clinical benefit versus placebo in patients with ATTR-CM. The impact of early vs delayed initiation of vutrisiran in this population will be elucidated in the OLE M12 data. Originally presented at ESC 2025. This study is funded by Alnylam Pharmaceuticals.

Background: Cardiac amyloidosis is a progressive and life-threatening disease where early diagnosis and appropriate treatment are critical. It manifests as hereditary transthyretin-related (ATTRv) amyloidosis with cardiomyopathy (ATTRv-CM), polyneuropathy (ATTRv-PN), or a mixed phenotype (ATTRv-mixed), or as wild-type variant (ATTRwt-CM), primarily affecting the heart. This study assessed real-world amyloidosis care pathways across seven countries to identify barriers and opportunities for improvement. Methods: From June 2024 to April 2025, qualitative data was collected by AstraZeneca Medical Science Liaisons in 6 European countries and Canada. A 20-item questionnaire captured insights into care delivery from 59 centers (56 tertiary amyloidosis centers, 3 referral centers) across the seven countries including: Austria (n=9), Germany (n=17), Italy (n=18), Nordics (n=3), Portugal (n=3), Switzerland (n=7) and Canada (n=2). Results: The centers collectively diagnosed 10,207 patients with ATTR amyloidosis, of which the majority were ATTRwt-CM patients (n=6,383; 63%). Of the patients with hereditary ATTR amyloidosis (n= 3,824), 54% were diagnosed with ATTRv-PN (n=2,066; 4-80% across countries), followed by 24% ATTRv-mixed phenotype (n=920, 2-39% across countries) and 22% ATTRv-CM (n=838, 1-20% across countries). Reported time from suspected ATTR amyloidosis at the expert center to diagnosis was captured in 54-69% of centers: ATTRwt-CM (n=40), ATTRv-PN (n=38), ATTRv-mixed (n=31), and ATTRv-CM (n=34). The weighted median time in months [IQR] from suspicion to diagnosis within the center was 4 months [2-8] for all patients. For the different phenotypes, this was 5 months [3-8] for ATTRwt-CM, 4 months [3-10] for ATTRv-PN, 2 months [2-8] for ATTRv-mixed, and 5 months [3-8] for ATTRv-CM. Diagnosis within a year was reported in 89% of cases. Multidisciplinary team (MDT) meetings were held in only 14 centers, largely on a monthly basis. Diagnostic protocols existed in 76% of centers, and a treatment protocol in 66%. Adherence to diagnostic guidelines was 71% (ESC: n=29, ISA: n=8); adherence to treatment guidelines was lower at 50% (ESC: n=19, ISA: n=6). Top reported barriers to optimal care included: (1.) low awareness of amyloidosis in referring centers (n=30/34), (2.) lack of structured referral (n=11/30), (3.) absence of formal management protocols in local referring centers (n=9/30). Conclusions: In this international multicenter study, ATTRwt-CM was the most prevalent phenotype, with one in four ATTRv-mixed phenotypes among hereditary ATTR amyloidosis patients. The low number of center-held MDT meetings leaves room for improvement. Guideline usage was widespread but varied in frequency and consistency. Substantial gaps remain in referral and diagnosis processes, particularly due to low disease awareness and inconsistent protocol implementation, suggesting the need for novel quality standards including the patients’ perspectives. Strengthening awareness, promoting adherence to international guidelines, and establishing structured referral pathways are essential to improving timely diagnosis and management of cardiac amyloidosis globally.

Objectives: Hereditary and wild-type transthyretin-mediated amyloidosis (ATTRv and ATTRwt) are caused by the misfolding of transthyretin proteins, leading to the formation of amyloid plaques that accumulate in various organs. Notably, the prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has increased, thanks to advancements in non-invasive diagnostic tools. As a result, the disease has become more treatable with the continued development of new therapies. However, diagnosing ATTR amyloidosis remains challenging, often delayed due to its heterogeneous and non-specific symptoms.This review explores the connection between a range of musculoskeletal (MSK) manifestations and ATTR amyloidosis, and suggests a screening tool to help clinicians in the diagnosis of this condition Methods: This review was conducted following the PRISMA guidelines. A comprehensive search was carried out in PubMed on March 1, 2025, yielding a total of 2,345 results. No restrictions were applied regarding the publication date. Both abstracts and full-text articles were screened for relevance based on the topic, patient population, and study design. Reviews, case reports, and articles available only as abstracts were excluded from the final analysis. Results: We identified 86 relevant articles discussing the relationship between ATTR amyloidosis and a range of musculoskeletal comorbidities. The most frequently reported associations were with carpal tunnel syndrome (48 studies) and spinal canal stenosis (26 studies). Other musculoskeletal issues linked to amyloidosis included distal biceps tendon rupture (2 studies), rheumatoid arthritis (16 studies), trigger finger (6 studies), revision surgery following carpal tunnel release (2 studies), rotator cuff rupture (2 studies), hip osteoarthritis (2 studies), and shoulder pain (1 study). In addition, risk factors such as older age, male gender, and a family history of carpal tunnel syndrome or amyloidosis were also noted. Conclusions: These findings highlight the potential role of orthopedic surgeons in the early diagnosis and referral for treatment of ATTR amyloidosis. Based on the prevalence of various musculoskeletal manifestations, we have developed a screening tool that could facilitate earlier diagnosis and the timely initiation of effective treatments, ultimately helping to prevent disease progression.

Objectives: Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous, progressive, potentially fatal disease, resulting in multi-system dysfunction predominantly in the heart (ATTR cardiomyopathy; ATTR-CM) and peripheral nerves (ATTR polyneuropathy; ATTR-PN). Many patients present with a mixed phenotype (CM and PN symptoms). The diverse presentation of ATTR amyloidosis frequently leads to delays in diagnosis and treatment initiation, while large-scale real-world data remain limited. Methods: MaesTTRo is a prospective, non-interventional, multi-country cohort study designed to comprehensively assess patient characteristics, disease course, treatment patterns and outcomes in patients with ATTR amyloidosis. The first phase will enrol patients with ATTR-PN and with mixed phenotype. This first interim analysis will describe the demographic and clinical characteristics of patients in the initial 6 months. Results (Table): The cohort included 53 patients primarily in the USA (74%). It predominantly comprised patients with ATTR amyloidosis with mixed phenotype (81%), followed by ATTR-PN (19%). Most were hereditary ATTR amyloidosis (79%) and 21% were non-hereditary; 51% of the former had a family history of ATTR amyloidosis. Patients were typically male (70%), Black (53%) and elderly, with a mean (standard deviation) age of 71 (10) years. Most common comorbidities at or within 12 months of baseline were hypertension in 42% of patients, hyperlipidaemia (34%) and atrial fibrillation (23%). History of carpal tunnel surgery was present in 25%, pacemaker use in 19% and aortic valve replacement in 4% of patients. Among 26 patients (49% of the total cohort) in whom baseline New York Heart Association (NYHA) assessments were performed, all had mild-to-moderate cardiac symptoms (NYHA Class I, II or III). ATTR-PN amyloidosis staging was insufficiently performed to report. Baseline clinical manifestations including peripheral neuropathy (64%), numbness in extremities (45%), carpal tunnel syndrome (42%), dyspnoea (38%), fatigue (32%), erectile dysfunction (29%), heart failure with preserved ejection fraction (23%) and chronic kidney disease Stage 3 (21%) were most frequently and consistently observed pre- and post-ATTR amyloidosis diagnosis. Prescribed treatment classes for ATTR amyloidosis were stabilisers in 45%, silencers in 28% and both in 23% of patients. The most frequently prescribed concomitant medication was loop diuretics (32%). Additional data will be included in the presentation, as enrolment continues. Conclusions: Early MaesTTRo results reveal a dynamic and evolving clinical landscape for ATTR amyloidosis, highlighting the increasing recognition of mixed phenotype among a predominantly hereditary cohort with neuropathic symptoms. Such patients present with multiple comorbidities, demanding a more comprehensive and proactive approach to care. Future analyses with expanded cohorts will extend understanding of this disease and inform the development of optimised treatment strategies for this challenging and primarily mixed-phenotype patient population.

Objectives: This study aimed to analyze 5,000 cases for hereditary transthyretin amyloidosis (ATTRv), focusing on patients with pathogenic or likely pathogenic (P/LP) TTR gene variants and differentiating clinical manifestations of ATTRv: predominantly neurologic, predominantly cardiac, or mixed phenotypes. Methods: The analysis population included all patients enrolled between October 2020 and May 2025 in the TRAMmoniTTR (ClinicalTrials.gov ID NCT03237494) study. A total of 141 cases were genetically diagnosed with hereditary transthyretin amyloidosis (ATTRv), classified into major subtypes: ATTRv-PN (polyneuropathy; n=38) and ATTRv-CM (cardiomyopathy; n=19). Classification was based on the electronic Case Report Form (eCRF) data captured by the study centers, using information related to the diagnosed clinical disease (PN or CM) from study centers or symptoms indicating neuropathic or cardiac involvement. A mixed phenotype (n=68) was identified when both features were present. Sixteen cases were classified as \"unclear\" due to missing data or insufficient symptoms. Results: In the ATTRv-PN group, the most reported symptoms included numbness or tingling (21/38), burning feet (9/38), and diarrhea (9/38). For ATTRv-CM, shortness of breath (8/19) and chest pain (7/19) were most prevalent, followed by arrhythmia and palpitations (6/19). The mixed group showed an even distribution of symptoms, with numbness (51/68) and dyspnea (39/68) being most frequent (Table 1). Male predominance in the cohort was approximately 60%. The age at diagnosis of ATTR amyloidosis is depicted in Figure 1. Genotypic analysis detected 16 different P/LP variants, with p.Val142Ile being most frequent in ATTRv-CM (7/19) and p.Val50Met predominant in ATTRv-PN (16/38) and mixed cases (32/68). The unclear phenotype cohort consisted mainly of younger individuals, indicating potential bias towards oligosymptomatic screening in TTR families. (Table 2). Conclusion: This analysis highlights the clinical and genetic diversity within ATTRv patients. Differentiating between ATTRv-PN and ATTRv-CM based on clinical symptoms is crucial for treatment strategies. The findings emphasize the need for comprehensive genetic screening and symptom characterization, particularly in at-risk cohorts like relatives of known ATTRv patients. Further studies are warranted to explore the implications of these findings on management and therapeutic approaches in ATTRv. The study was supported from a funding from Alnylam Pharmaceuticals.

Objectives: Changes in autonomic symptom impairment and overall disability (e.g. limitations to participation in physical and social activities) that are clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) have not been established. This study aimed to describe the magnitude of treatment differences that are clinically meaningful to patients for these measures and assess whether changes in these measures with eplontersen exceeded the estimated thresholds. Methods: Data from NEURO-TTRansform, which studied patients with ATTRv-PN who were treated with eplontersen (n=141), were evaluated as these measures were only ascertained for this group. Anchor-based approaches were used to estimate thresholds for meaningful differences in the 31-question Composite Autonomic Symptoms Score (COMPASS-31) and the Rasch-built Overall Disability Scale (R-ODS). For example, to determine meaningful improvement for COMPASS-31 based on the Patient Global Impression of Change (PGIC), the difference in mean COMPASS-31 was calculated between patients who reported feeling 'a little better' compared with those reporting 'no change' on PGIC. Results: Mean baseline values (standard deviation; SD) for COMPASS-31 and R-ODS scores were 19.4 (SD, 11.3; range, 0.0–51.0) and 35.8 (SD, 10.3; range, 1.0–48.0), respectively. Absolute range for meaningful difference in COMPASS-31 was estimated as 0.5–3.2 points. Estimated absolute range for meaningful difference in R-ODS was 0.1–2.3 points. In unadjusted indirect comparisons between eplontersen in NEURO-TTRansform and a placebo group from an external study of ATTRv-PN (APOLLO; NCT01960348), differences between eplontersen and placebo in COMPASS-31 (4.8 points) and R-ODS (9.4 points) exceeded the estimated thresholds of clinically meaningful difference in these scores. Conclusions: Thresholds for clinically meaningful differences in COMPASS-31 and R-ODS instruments were successfully ascertained for ATTRv-PN for the first time to inform future studies. When applying these thresholds to the effect of eplontersen in the NEURO-TTRansform study, eplontersen demonstrated clinically meaningful improvements for autonomic symptoms and overall disability compared with an external placebo.

Objectives: This study aims to assess the feasibility, acceptance, and preliminary efficacy data of a structured psychological support program for patients with hereditary transthyretin amyloidosis, presymptomatic carriers, and caregivers. The primary objectives are to evaluate the feasibility and acceptance of the program, delivered both in-person and remotely. Secondary objectives include analyzing its impact on anxiety and depression (Hospital Anxiety and Depression Scale, HADS), caregiver burden (Caregiver Burden Inventory, CBI), resilience (Resilience Scale, RS-14), and perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS). The exploratory objective is to examine associations between clinical-medical variables and mental health indicators scores in patients and presymptomatic carriers. Methods: This is a single-arm, monocentric, interventional pilot study enrolling 150 participants divided into three groups: patients, presymptomatic carriers and caregivers. The study protocol includes three assessment time points (T0, T6, T12), during which participants complete psychological questionnaires (HADS, MSPSS, RS-14, CBI) and clinical monitoring tools (ROD-S, Norfolk QoL-DN, SF-36, KCCQ, EQ-5D-3L, NYHA class, NIS, 6MWT, and COMPASS-31). Monthly psychological support sessions are also offered on a voluntary basis. Results: To date, 136 participants have been enrolled (67 patients, 41 presymptomatic carriers, 28 caregivers). Participation in psychological support sessions was 46% among patients and 35% among both carriers and caregivers, with a dropout rate below 2%. A total of 322 psychological support sessions have been conducted so far. MSPSS scores are in the medium-to-high range (60–62), and resilience levels (RS-14) are good (80–83). No clinically significant depressive symptoms were detected; presymptomatic carriers showed borderline anxiety levels. Caregiver burden was mild (mean CBI score: 14.58/96). To date, 49 participants have completed the 6-month follow-up assessment. Conclusions: Preliminary data indicate good feasibility and acceptance of the psychological support program. Despite medium-to-high emotional well-being levels reported in psychometric tests, the support program addresses a concrete need among participants, highlighting the importance of safe spaces for listening and processing personal and family-related experiences. The 12-month analysis will allow for a deeper evaluation of clinical efficacy and potential integration into care pathways.

Lower mitochondrial DNA copy number in Swedish carriers of hereditary transthyretin amyloidosis Gabriella Johannson1, Marina Rubio Garcia1, Malin Olsson1, Anders Olofsson2, and Intissar Anan1 1Department of Public health and clinical medicine and 2Department of Microbiology, Umeå University, Umeå, Sweden Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a progressive systemic disease characterized by peripheral neuropathy, gastrointestinal and renal dysfunction, and cardiac involvement leading to arrythmias and cardiac failure. The most common mutation, Val30Met (ATTRV30M), is endemic in Japan, Portugal, and Sweden. Although these populations share the same mutation, the age of onset varies significantly, and not all carriers develop symptoms. For instance, in Sweden, onset is typically after age 50, whereas in Portugal it occurs before 40. The reason for these differences remains unclear. Mitochondrial DNA (mtDNA) copy number is a biomarker of mitochondrial dysfunction, with abnormal levels linked to many pathological conditions, including neurodegenerative diseases. Prior research in Portuguese ATTRV30M population showed increased mtDNA copy number in symptomatic patients compared to non-carriers. We aimed to investigate whether mtDNA copy number also differs in Swedish ATTRV30M carriers, potentially identifying mitochondrial mechanisms contributing to symptom development and offering a biomarker for disease onset. Methods: 304 individuals from northern Sweden were included in this study. They were divided into three groups: symptomatic and asymptomatic ATTRV30M carriers, respectively, and healthy non-carrier controls. Relative mtDNA copy number was quantified from buffy coat samples using multiplex qPCR and calculated 2(-ΔΔCq) value. Statistical analyses were performed using Kruskal-Wallis and Mann-Whitney U tests. Results: Symptomatic ATTRV30M carriers showed a significantly lower relative mtDNA lower relative mitochondrial copy number compared to control group. Additionally, among healthy non-carrier controls, women had a significantly higher mtDNA copy number than men. Conclusion: These findings indicate a potential role for mitochondrial dysfunction in the development of symptoms among Swedish ATTRV30M carriers. The observed sex-related differences in mtDNA copy number may also help explain the higher incidence of disease in males, suggesting a possible avenue for future biomarker development and targeted intervention.

Background: Serum neurofilament light chain (sNfL) serves as a biomarker for peripheral neuropathy, with levels correlating with the severity of polyneuropathy in hereditary transthyretin (ATTRv) amyloidosis. However, it remains unclear whether sNfL levels also correlate with autonomic neuropathy, and potentially serve as a biomarker for detection and follow-up of autonomic neuropathy in ATTRv amyloidosis. Objective: To investigate the relationship between sNfL levels and autonomic neuropathy in ATTRv amyloidosis. Methods: sNfL levels were retrospectively measured in 38 patients with ATTRv amyloidosis who visited the University Medical Center Groningen between November 2007 and April 2018. Single-molecule array technology was used to measure sNfL levels. All subjects underwent autonomic function testing, including iodine-123 labelled metaiodobenzylguanidine ([123I]mIBG) scintigraphy, Ewing battery test, and sympathetic skin response (SSR). Autonomic neuropathy was defined as an abnormal [123I]mIBG scintigraphy, Ewing battery test and/or SSR. Peripheral neuropathy was assessed using nerve conduction studies and quantitative sensory testing. The severity of polyneuropathy was graded according to the polyneuropathy disability score. Cardiac involvement was assessed using [99mTc]Tc-hydroxymethylene diphosphonate bone scintigraphy. Results: The median sNfL level was 3.4 times higher in 20 patients with autonomic neuropathy compared to eighteen patients without autonomic neuropathy (p<0.001) (Figure 1). Univariate regression analysis demonstrated a relation between sNfL levels and the presence of autonomic neuropathy, polyneuropathy, and cardiomyopathy. Multivariate regression analysis revealed that polyneuropathy was the only independent predictor of sNfL levels (Table 1). Conclusion: This study demonstrates that sNfL levels are increased in ATTRv amyloidosis patients with autonomic neuropathy. However, the elevation in sNfL levels is primarily due to the concurrent presence of polyneuropathy. Therefore, sNfL is not a useful biomarker for detecting autonomic neuropathy in ATTRv amyloidosis.

Objectives: Hereditary transthyretin (ATTRv) amyloidosis is a rare, progressive and often fatal autosomal dominant disorder that is caused by transthyretin gene variants. It leads to motor, sensory and autonomic neuropathies, and significantly impacts quality of life. The efficacy and safety of eplontersen were demonstrated to week 65/66 in the pivotal NEURO-TTRansform trial (NCT04136184) compared with a historical placebo from NEURO-TTR (NCT01737398) in patients with ATTRv amyloidosis with polyneuropathy (ATTRv-PN). The ongoing NEURO-TTRansform open-label extension (OLE) study is evaluating the long-term efficacy and safety of continued eplontersen treatment through 3 years (week ≥157). Methods: Patients who satisfactorily completed NEURO-TTRansform were eligible to enrol in the OLE study (NCT05071300). Efficacy assessments included change from baseline in the Neuropathy Impairment Score (NIS), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire, Neuropathy Symptom and Change (NSC) score, serum transthyretin (TTR) concentration, Physical Component Summary (PCS) score from the 36-Item Short Form Survey, modified body mass index (mBMI), Composite Autonomic Symptom Score-31 (COMPASS-31), 5 Dimension 5 Level EuroQoL (EQ-5D-5L), and Polyneuropathy Disability (PND) score. Safety was also assessed. The OLE study did not include a placebo control group. Results: The OLE study included 127 patients who were treated with eplontersen for 84 weeks in the index study; mean eplontersen exposure in the OLE was 89.5 weeks. Patients who received eplontersen in NEURO-TTRansform continued to show benefit in the OLE study relative to the index study baseline up to OLE week 77 in all efficacy parameters that were measured (Table). Decreases of >80% in serum TTR were observed through OLE week 77 with eplontersen. Mean (standard deviation; SD) NIS composite score increased from 45.31 (28.94) at index study baseline by 4.59 (15.56), 4.84 (16.66) and 2.99 (13.99) at OLE weeks 25, 53 and 77, respectively. Mean (SD) changes from index study baseline in Norfolk QoL-DN were −4.77 (19.91), −4.90 (20.93) and −2.86 (20.12) at OLE weeks 25, 53 and 77, respectively. mBMI remained stable, with mean changes from the index study baseline of between 1.67 and −8.30 during the OLE study through week 77. Other efficacy variables persisted unchanged during the OLE period with eplontersen (Table). The safety profile of eplontersen in the OLE study was consistent with that of NEURO-TTRansform and no new safety concerns were identified. Conclusions: In patients with ATTRv-PN, the benefits gained from eplontersen treatment during NEURO-TTRansform were maintained with continued eplontersen treatment from week 66 through 3 years from treatment initiation. Eplontersen slowed disease progression, reduced deterioration in quality of life exhibited during the placebo phase of the index study, and no new safety signals were identified.

Background: Diflunisal, an non-steroidal anti-inflammatory drug, has been used for years as an off-label TTR stabilator drug in ATTR-amyloidosis with polyneuropathy (ATTR-PN). Although some good results have been reported, even in a placebo-controlled clinical trial (PC-CT), high abandonment tases have been reported, mainly due to adverse effects. A deep insight in the real experience with diflunisal is then needed to uncover it real efficacy and safety. Methods: A review of published data of efficacy and safety of diflunisal in ATTR-PN was carried using diflunisal as the keyword on PubMed, MEDLINE and EMBASE (cut-off: November 2024). Randomized placebo-controlled trials and clinical cohorts were included if showed enough data. Cases reports were excluded. Study characteristics were systematically extracted including author, year of publication, study design, sample sizes, and clinical parameters. Primary variables analyzed included demographic, clinical and electroneurographical data (age, sex, Kumamoto Score, PND, NIS, NIS+7, mBMI, TTR levels, CMAP/SMAP). Descriptive statistics, between-group comparisons and changes from baseline to follow-up were assessed. For meta-analytic approaches, weighted means were calculated based on sample sizes. Results: Of the initial 898 articles founded, 19 articles fulfilled the inclusion criteria. Of those, 5 were focused in ATTR-PN and 2 in both ATTR-PN and ATTR-CM, and were published between 2013 and 2024. All articles except the PC-CT had a high risk of bias. Globally, 279 A-ATTR-PN patients were studied. All patients had A-ATTRv [V30M (142; 50.9%), of whom 12 (8.4%) were V30M domino liver recipients; A97S (34; 12.2%), T60A (15; 5.3%) and L58H (15; 5.3%)] Patients were followed for a mean of 25.9  9.3 months. Treated patients were older than untreated (62.31 ± 10.90 vs 59.20 ± 12.20 years; p= 0.038). There was a non-significant trend of increasing Kumamoto mean score during follow up (n=137; 17.9 ± 12.9 vs 20.4 ± 11.3), but in lower rate than untreated patients. There was a significant decrease in mean mBMI (n=137; 954.9  97.9 vs 928,8  106,8, p=0.04). There was a non-significant increase in median NIS during follow up (n= 76; 21.5 vs 27.7; median change 6.23), and it was significantly lower than untreated patients. There was a non-significant decrease in CMAP during follow up (n= 81; 4.9  4.5 vs 3.8  4), with a significant lower rate than in untreated patients. Finally, there was a significant increase in serum TTR concentration (n= 28; 21.8 ± 5.2 mg/dL at baseline, 28.1 ± 6.8 mg/dL at 12 months of treatment, p=0.000002). There was a mean treatment discontinuation rate of 20.5%, mainly due to adverse effects. However, serious adverse effects were infrequent (5.1% of reported eGFR deterioration, and 1.5% of reported gastrointestinal bleeding). Conclusion: Diflunisal treatment slows ATTR-PN disease progression according to clinical and electrophysiological published data. Although a relatively high rate of treatment discontinuation (20.5%), serious adverse effects were uncommon.

Objectives: To assess the clinical evolution and biomarker response in patients with hereditary transthyretin amyloidosis (ATTRv) receiving Vutrisiran in a third-level Neuromuscular Clinic setting. Methods: we retrospectively reviewed all ATTRv patients at our Neuromuscular Clinic who had received Vutrisiran for at least 6 months. We obtained baseline and follow-up values (every 6 months) of Familial Amyloidotic Polyneuropathy (FAP) and Polyneuropathy Disability (PND) scores, Neuropathy Impairment Score (NIS), as well as serum transthyretin (TTR) and NT-proBNP levels. Complete TTR supression was defined as <5 mg/dl. One patient was excluded because enrollment in a clinical trial. Results: 26 patients were evaluated (11 women, age range 45-85, median follow-up 15 months (interquartile range (IQR) 12-18); median baseline NIS 31.0 (IQR 14.0–68.25). The most frequent mutation was Val50Met (15 patients; 57.7%). At last follow-up, 17 patients (65%) had stable or improved NIS (median NIS improvement was 5.63 [IQR: 4.75–10.25]); 2 patients (7.7%) had improved PND score (from PND-II to PND-I and from PND-IIIB to PND-IIIA) and 19 (73%) remained stable. All but one patient (96%) achieved complete TTR suppression. NT-proBNP levels remained stable or decreased in 18 patients (69%; median NT-proBNP improvement was 60 [IQR: 24–154]). One patient discontinued treatment because of clinical progression. Conclusions: in this single-center cohort of 26 ATTRv patients treated with Vutrisiran, more than half of the individuals demonstrated stability or improvement in clinical scores and biomarker profile after a median follow-up of 12 months. These findings support the effectiveness of Vutrisiran in the treatment of ATTRv neuropathy in a real-world setting.

Abstract Objectives: Variant transthyretin (TTR) amyloidosis (ATTRv) is a systemic disease. The most prevalent mutation in Sweden, TTR V30M, is characterized by two different phenotypes: early-onset disease with polyneuropathy, and late-onset disease that also causes cardiomyopathy. The different phenotypes have been shown to correlate with different amyloid fibril compositions, fibril types A and B. Type A contains both fragmented and full-length TTR, whereas in type B only full-length TTR is found. Fibril type has also been shown to correlate with cardiac 99mTc-DPD scintigraphy uptake. The aim of the study was to investigate the relationships between clinical phenotype, cardiac 99mTc-DPD uptake, and amyloid fibril composition found in abdominal fat tissue in a larger patient population. Methods: We identified 152 ATTRv patients seen at the Amyloid Centre at Norrland University Hospital, Umeå, Sweden, in whom amyloid fibril composition had been determined in adipose tissue biopsies and who had undergone cardiac investigations with 99mTc-DPD scintigraphy, echocardiography, troponin T, and NT-proBNP. Degree of cardiac involvement, defined by biomarkers and echocardiographic findings, was analysed in relation to amyloid fibril composition and scintigraphic findings. Results: Among the patients, 85 had type A and 67 had type B fibrils. Patients with type B fibrils were significantly younger at symptom onset and diagnosis and exhibited a higher frequency of negative 99mTc-DPD investigations, as well as lower interventricular septum thickness, troponin T, and NT-proBNP levels (p < 0.001, respectively). Ten patients (15%) with type B fibrils displayed cardiac uptake on 99mTc-DPD scintigraphy. These individuals demonstrated higher interventricular septum thickness, troponin T, and NT-proBNP levels than type B patients without uptake (p ≤ 0.01). Conclusion: ATTR fibril type analysed in abdominal fat tissue correlates well with clinical phenotype. However, our findings suggest that 99mTc-DPD scintigraphy may be an even better predictor of ATTR cardiomyopathy in ATTR V30M patients.

Objectives Transthyretin amyloidosis (ATTR) is a progressive and life-threatening disease caused by the deposition of amyloid fibrils derived from misfolded transthyretin (TTR) protein. ATTR is classified into two main types: hereditary/variant-type ATTR (ATTRv), resulting from mutations in the TTR gene, and wild-type ATTR (ATTRwt), which occurs without genetic mutations and is associated with aging. The clinical manifestations of ATTR vary depending on the phenotype with ATTR cardiomyopathy (ATTR-CM) primarily affecting the heart and ATTR polyneuropathy (ATTR-PN) predominantly involving peripheral and autonomic nerves. To investigate the risk of incident polyneuropathy in patients diagnosed with ATTR-CM in German routine care. Methods This longitudinal, retrospective cohort study utilized the InGef Database (from January 2019 and December 2023), encompassing anonymized claims data from ~14% of Germany's 73 million statutory health insurance beneficiaries. Newly diagnosed ATTR-CM was identified based on a combination of diagnoses codes for amyloidosis, cardiomyopathy, and diagnostic procedures. ATTR-CM patients without polyneuropathy at the time of diagnosis were followed to detect incident polyneuropathy. Polyneuropathy was defined by both a specific ATTR polyneuropathy code (ICD-10: E85.1) as well as other unspecific codes indicating symptoms indicative of polyneuropathy (ICD-10: G60-G64). In additional analysis, incident polyneuropathy was defined only based on the specific ICD-10 code E85.1 indicating confirmed neuropathic hereditary amyloidosis. We calculated incidence rates with corresponding 95%-confidence intervals (CI). Results The study included 309 patients with ATTR-CM with unknown etiology (ATTRv/ATTRwt) free of polyneuropathy at the time of diagnosis (mean age 72 ± 13 years; 17% women). Comorbidities such as hypertensive disease (91%), ischemic heart disease (65%), atrial fibrillation (59%), chronic kidney disease (45%) and diabetes mellitus (27%) were most frequently observed (Table 1). Frequently used medications in the year prior to ATTR-CM diagnosis were beta blockers (75%), loop diuretics (72%), renin-angiotensin-system inhibitors (79%), statins (56%), and direct oral anticoagulants (49%). During a median follow-up period of 430 days (Q1-Q3: 175-936 days), confirmed/suspected neuropathic symptoms newly occurred in 48 patients, translating into an incidence of 10.8 per 100 person years (PYs) (95%-CI: 7.9-14.3). An analysis using confirmed polyneuropathy only led to an incidence of 2.2 per 100 PYs (95%-CI: 1.1-3.9). Conclusions The risk for a new ATTR polyneuropathy diagnosis in patients with ATTR-CM of unknown etiology observed in routine care in Germany is relatively low at 2.2 cases per 100 PYs. The risk of polyneuropathy using a broader symptom-based definition in this population is 10.8 cases per 100 PYs.

Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a potentially fatal disease due to variants in the transthyretin gene, leading to multisystem dysfunction primarily affecting the heart and the peripheral nervous system. The challenge of clinical heterogeneity may lead to delayed diagnosis and suboptimal care. The OverTTuRe study aims to comprehensively describe patient characteristics, treatment patterns, and disease outcomes of ATTRv. This current regional sub-analysis reported results from China. Methods: OverTTuRe is a multi-country study generating real-world evidence on adult symptomatic patients with ATTR amyloidosis. This cohort was extracted from a retrospective chart review of electronic medical records from 2013 to 2024 in 6 selected hospitals across China, which are ranked as leading hospitals in ATTR diagnosis in China. Eligible patients were ≥18 years old and had confirmed diagnosis of ATTR amyloidosis. Demographic/clinical characteristics, treatment patterns, and outcomes in ATTRv patients were analysed both overall and by phenotype (polyneuropathy [ATTR-PN]; cardiomyopathy [ATTR-CM]; mixed). Results: A total of 209 ATTRv patients were included. Overall mean (SD) age at onset and diagnosis was 53.6 (11.8) and 57.2 (12.0) years, respectively. Among these, 134 (65.7%) patients were classified as late onset (≥50 years). Patients were predominantly male (n=151, 72.2%) and of Han ethnicity (n=197, 94.3%; Table). Most ATTRv patients (n=152, 72.7%) had a mixed phenotype. A family history of ATTR amyloidosis was present in 45.0% (94/209) of overall patients and 73.7% (14/19) of ATTR-PN patients. The most common variant in patients with recorded genetic variants was Ala97Ser (27.5%, 56/204). Before diagnosis, the most common first clinical manifestations included numbness (28.2%), muscle weakness (15.0%), and chronic diarrhoea (14.1%), while the most common manifestation at diagnosis was cardiomyopathy (46.4%). Overall median time from first clinical manifestation to diagnosis was 2.7 years (IQR, 1.1–4.8), with longer delays in patients with mixed phenotype versus other phenotypes. After diagnosis, 40.7% (85/209) of patients were lost to follow-up, with a median follow-up duration of 595.0 days (IQR, 192.0–980.0). During follow-up, 59.3% (124/209) of patients received ATTR-related treatment. Overall median time (95% CI) from diagnosis to initiation of ATTR-related treatment, new manifestation, all-cause hospitalisation, and all-cause mortality was 44.5 (2.0-200.0), 11.7 (7.6–15.3), 25.0 (17.9–35.1), and 84.0 (82.6–NE) months, respectively. Conclusions: Chinese ATTRv patients show high clinical heterogeneity, delayed recognition, suboptimal ATTR treatment, and poor follow-up in real-world practice, indicating potential challenges in definitive diagnosis, and the critical need for early detection, timely access to ATTR-specific treatments, and enhanced care.

Background: In the past decade, growing awareness of transthyretin cardiac amyloidosis (ATTR-CM), along with the availability of non-invasive diagnostic tools and disease-modifying therapies, has led to an increased number of diagnoses and recognition of milder clinical phenotypes. Cardiac magnetic resonance (CMR) plays a key role in amyloid burden quantification and prognostic assessment. Methods: We retrospectively analyzed all consecutive patients referred to the CMR unit at the University Hospital of Padua who received a final diagnosis of ATTR-CM. Patients were stratified by year of CMR (before vs. after 2020), as a surrogate for evolving diagnostic awareness and phenotypic shift. Morphological, functional, and late gadolinium enhancement (LGE) features were compared between the two groups. Results: A total of 75 patients were included [70 (93%) male, median age 75 years (IQR 71–79)]. The number of ATTR-CM diagnoses increased over time. No significant differences were observed in interventricular septal thickness (18 mm vs. 17 mm, p = 0.43), left ventricular ejection fraction (50% vs. 48%, p = 0.36), or right ventricular ejection fraction (53% vs. 47%, p = 0.1). Tissue characterization showed similar patterns of left ventricular LGE, although a trend toward more frequent atypical LGE patterns was noted post-2020 (11% vs. 23%, p = 0.12). Conclusions: In recent years, CMR referrals for ATTR-CM have increased, with a shift toward milder phenotypes, as suggested by the rise in atypical LGE patterns. These findings highlight the importance of a nuanced and comprehensive CMR interpretation to avoid false-negative diagnoses in early-stage or atypical presentations.

Objectives Atrial fibrillation (AF) is a common manifestation observed in up to 70% of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). The coexistence of AF and ATTR-CM is associated with an increased risk of cardiovascular-related hospitalizations (CVH). Acoramidis is an oral, highly selective transthyretin stabilizer that achieves a rapid increase in serum transthyretin levels and near-complete (≥90%) transthyretin stabilization, and is approved in the US, Europe, and Japan for the treatment of adult patients with ATTR-CM. In the pivotal phase 3 ATTRibute-CM study (NCT03860935), acoramidis demonstrated significant clinical efficacy, including a 50% relative risk reduction in the annual frequency of CVH. To date, the effects of acoramidis on AF-related events (AF, atrial flutter [AFL]) in patients with ATTR-CM have not been explored. Post-hoc analyses of AF and AFL were conducted to evaluate the effects of acoramidis, relative to placebo, in participants with ATTR-CM enrolled in ATTRibute-CM. Methods The design and methodology of the ATTRibute-CM study have been previously described. Post hoc descriptive analyses of CVH and treatment-emergent adverse events (TEAEs) were conducted to evaluate the impact of acoramidis on AF/AFL. These included an analysis of CVH due to AF/AFL in the efficacy analysis population (modified intention-to-treat, N = 611) and an assessment of the incidence of TEAEs related to AF/AFL in the overall safety population (N = 632) and in the subgroup of subjects with no prior history of AF reported at study entry (No-prior-AF subgroup). CVHs due to AF/AFL were determined in a blinded manner by an independent clinical events committee, and the annual frequency of these events was calculated. AF/AFL TEAEs were identified in the ATTRibute-CM clinical trial database using three Medical Dictionary for Regulatory Activities preferred terms (atrial fibrillation, atrial flutter, cardiac flutter). Results Baseline characteristics in the No-prior-AF subgroup (n = 264, i.e. 42% of the overall safety population) and the overall safety population are shown in Table 1A. Participants in the No-prior-AF subgroup tended to have lower N-terminal prohormone B-type natriuretic peptide levels and a higher Kansas City Cardiomyopathy Questionnaire overall summary score and 6-minute walking distance compared with the overall safety population (Table 1A). A 43% relative risk reduction in the annual frequency of CVH due to AF/AFL was observed with acoramidis relative to placebo (Table 1B). In both the overall safety population and the No-prior-AF subgroup, a 17% lower incidence of AF/AFL TEAEs was reported in the acoramidis group compared with the placebo group (Table 1C). Conclusions In ATTRibute-CM, acoramidis treatment was associated with reduced hospitalizations and adverse events due to AF/AFL compared with placebo. This may lead to potential benefits on arrhythmia-associated morbidity that is frequently observed in patients with ATTR-CM.

Background: Carpal tunnel syndrome (CTS) has emerged as an early clinical manifestation of cardiac amyloidosis (CA) caused by transthyretin-associated (ATTR) mutations. With recent advances in disease-modifying therapies for ATTR-CA, early detection is critical for improving patient outcomes. Bone tracer cardiac scintigraphy offers a noninvasive, precise, and sensitive method for diagnosing ATTR-CA, and may serve as a valuable screening tool in patients with idiopathic CTS using the Perugini grading system. Objectives: The CarPoS study (NCT05409833) is a cross-sectional clinical study designed to investigate the relationship between idiopathic CTS and ATTR amyloidosis, and to evaluate the diagnostic and therapeutic implications of screening for ATTR-CA in this population. Methods: Fifty patients with idiopathic CTS underwent clinical evaluation, laboratory testing, and bone scintigraphy with 99mTc-DPD. Selected patients were further assessed with histopathological analysis of tenosynovial tissue and transthyretin genotyping when indicated. Results: Scintigraphy revealed Perugini grade 2 or 3 uptake in 13 patients (26%), consistent with ATTR-CA. Among the 35 patients with negative scintigraphy, 10 underwent histopathological analysis post-surgery; two patients (20%) showed amyloid deposits; in one case, ATTR was confirmed by mass spectrometry. Of the 14 patients with confirmed ATTR, 4 were genetically tested, and all were found to have wild-type transthyretin (ATTRwt). Conclusions: In patients with idiopathic CTS, screening with cardiac scintigraphy and histology may uncover early-stage amyloidosis, particularly ATTRwt, highlighting CTS as a red flag for systemic disease. These findings support the integration of targeted amyloidosis screening in selected CTS cases to enable timely diagnosis and treatment.

Objectives: Changes in autonomic symptom impairment and overall disability (e.g. limitations to participation in physical and social activities) that are clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) have not been established. This study aimed to describe the magnitude of treatment differences that are clinically meaningful to patients for these measures and assess whether changes in these measures with eplontersen exceeded the estimated thresholds. Methods: Data from NEURO-TTRansform, which studied patients with ATTRv-PN who were treated with eplontersen (n=141), were evaluated as these measures were only ascertained for this group. Anchor-based approaches were used to estimate thresholds for meaningful differences in the 31-question Composite Autonomic Symptoms Score (COMPASS-31) and the Rasch-built Overall Disability Scale (R-ODS). For example, to determine meaningful improvement for COMPASS-31 based on the Patient Global Impression of Change (PGIC), the difference in mean COMPASS-31 was calculated between patients who reported feeling 'a little better' compared with those reporting 'no change' on PGIC. Results: Mean baseline values (standard deviation; SD) for COMPASS-31 and R-ODS scores were 19.4 (SD, 11.3; range, 0.0–51.0) and 35.8 (SD, 10.3; range, 1.0–48.0), respectively. Absolute range for meaningful difference in COMPASS-31 was estimated as 0.5–3.2 points. Estimated absolute range for meaningful difference in R-ODS was 0.1–2.3 points. In unadjusted indirect comparisons between eplontersen in NEURO-TTRansform and a placebo group from an external study of ATTRv-PN (APOLLO; NCT01960348), differences between eplontersen and placebo in COMPASS-31 (4.8 points) and R-ODS (9.4 points) exceeded the estimated thresholds of clinically meaningful difference in these scores. Conclusions: Thresholds for clinically meaningful differences in COMPASS-31 and R-ODS instruments were successfully ascertained for ATTRv-PN for the first time to inform future studies. When applying these thresholds to the effect of eplontersen in the NEURO-TTRansform study, eplontersen demonstrated clinically meaningful improvements for autonomic symptoms and overall disability compared with an external placebo.

OBJECTIVES: Transthyretin amyloidosis (ATTR) is a progressive, fatal disease caused by misfolded transthyretin protein accumulating as amyloid fibrils in multiple organs, often leading to a mixed phenotype with polyneuropathy and cardiomyopathy. ATTR with cardiomyopathy (ATTR-CM) results in progressive heart failure, a decline in health status and quality of life, and increased hospitalisation rate and mortality. The objective of this analysis is to assess clinical characteristics and the treatment landscape of patients with ATTR-CM (wild-type [wtATTR-CM] or hereditary [hATTR-CM]) from real-world clinical practice across 6 different countries. METHODS: This primary market research study was conducted in France, Germany, Italy, Japan, Spain, and the UK between September–October 2023. Cardiologists completed a 45-minute online survey, reporting data for ≥1–6 patients with ATTR-CM they had seen in the previous 12 months. The qualifying criteria for cardiologists from the IQVIA database included ≥3 years practicing medicine, ≥20% time in patient care, and ≥1 wtATTR-CM patient followed in the last 12 months. Medical records based on data from patient record forms were aggregated and fully anonymised. RESULTS: Data from 242 cardiologists and 965 patient record forms (Spain n=180, France n=175, Germany n=170, Japan n=159, Italy n=156, and the UK n=125) were included. Overall, 63–71% of patients were male, 78–86% had wtATTR-CM, and the majority (59–90%) were aged ≥65 years at their most recent consultation. For patients with hATTR-CM, the most common variant was V30M in France (58%) and Spain (42%); V122I in Italy (37%) and the UK (44%); and V30M and V122I in Germany (both 32%). The most common clinical presentation was heart failure (35–58%) with most patients in New York Heart Association class II (48–66%). More than 47% of patients reported at least one neuropathy symptom. Reported symptoms were generally similar across countries (Figure 1). The proportion of patients on pharmacological treatment ranged from 39% in Spain to 73% in France. Of patients on TTR targeted treatment, the majority received tafamidis 61 mg (ranging from 47% in the UK to 82% in Germany). For most patients, physicians reported an inadequate response to treatment, with cardiologists often reporting a persistence or progression of symptoms (Figure 2). CONCLUSIONS: These data show reported clinical characteristics of real-world patients and the treatment landscape of the respective patients with ATTR-CM in 5 European countries and Japan. Characteristics were generally similar across countries and reflect the multi-organ impairment in ATTR. Most patients showed persistence or progression of heart failure symptoms, considered a partial or no response to their current treatment by the reporting physicians, reflecting an unmet need for more available and effective treatment options in ATTR-CM. Originally presented at HFA 2025. This study was funded by Alnylam Pharmaceuticals.

Objectives: Misdiagnosis and delay in diagnosis are frequent in patients with transthyretin cardiac amyloidosis (ATTR-CA). Methods from simple and accessible tests such as ECG are needed to better identify and treat patients. We sought to develop and optimize a deep-learning model based on the Willem AI platform to identify patients with ATTR-CA from 12-lead electrocardiograms (ECGs). Methods: We analyzed ECGs from all subjects undergoing 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy for routine care assessment of ATTR-CA at Hospital Universitario Puerta de Hierro Majadahonda from 2009 to 2023. 523 patients exhibited cardiac uptake and after complete assessment were diagnosed with ATTR-CA, whereas 2117 patients without DPD uptake constituted the control group. The Willem AI platform was optimized to discriminate between ATTR-CA patients and controls from 10 seconds 12-lead ECGs. A total of 9183 ECG records from all recruited subjects were used for model development and evaluation (ATTR-CA: 5237, 57.03%; controls: 3946, 42.97%), considering ECGs independently. 3707 ECGs from ATTR-CA and 2753 ECGs from controls were used for training and validation (70.30% of the total), and 1530 ECGs from ATTR-CA and 1193 ECGs from controls for testing (29.70%). The model generated its binary output based on features learned from ECG signals in the training dataset. Each ECG signal was normalized on a per-lead basis. Class weighting technique was used to adjust the loss function to cope with class imbalance, and the area under the Area Under the Receiver Operating Characteristic curve (AUROC) was considered as the main evaluation metric. Results: Demographic and clinical data from both groups is summarized in Table 1. In the test dataset, AUROC for correct ATTR-CA classification was 0.841 (CI 95%: 0.826–0.856). Other performance metrics are represented in Table 2. The ROC curve is displayed in Figure 1. These results suggest the model has a good discriminative power to identify patients with ATTR-CA. Conclusions: Willem AI platform identifies ATTR-CA patients using standard 12-lead ECGs with positive preliminary performance in this single-center study with a large dataset. Future work includes external validation in an ongoing multicenter european study to further evaluate model robustness and generalizability. Funding: This study is funded by AstraZeneca

Objectives. Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive and life-limiting disease characterized by diverse genotypes and phenotypes globally. The V30M mutation is most frequent among Portuguese and Swedish patients, but with differences between age of onset and penetrance. Misfolded transthyretin (TTR) accumulates as amyloid fibrils in various body tissues and organs, such as nerves, eyes and heart, with varying clinical symptoms. However, autonomic dysfunction is in general common among ATTRv patients and often develops early after disease onset. As the vagal nerve (VN) is frequently affected in the presence of autonomic dysfunction and the progress of arrhythmias, VN ultrasound may serve as a valuable tool for assessing autonomic dysfunction. The aim of this study was, for the first time, to evaluate the cervical VN cross-sectional area (CSA) in Swedish patients with V30M-ATTRv, and in gene carriers. Methods. Bilaterally cervical VN ultrasound with a high frequency probe were performed in transversal view below the carotid bifurcation at the level of the thyroid gland, and were assessed by one a single sonographer on six late onset V30M-ATTRv patients (>50 years), early after disease onset, and within ten V30M gene carriers and 40 healthy controls. Results. The VN CSA were significantly larger on the right side compared to the left side in controls (p<0.001) and gene carriers (p=0.002). However, in V30M-ATTRv patients no such side difference was noted (p=0.423). Further, a significantly wider VN CSA was found in V30M-ATTRv patients compared with controls (right side p=0.032, left side p=0.006), and V30M-ATTRv patients also demonstrated significantly wider VN compared with gene carriers (left side p=0.004). As controls were significantly younger than both V30M-ATTRv patients (p<0.001) and gene carriers (p<0.001), additional evaluations with an age-matched control group (n=9) were performed still revealing wider VN CSA in V30M-ATTRv patients compared with controls (right side p=0.045, left side p=0.035). Conclusions. This pilot-study suggests that VN ultrasound may be considered as an additional method within V30M-ATTRv patients as they revealed wider VN-CSA compared with controls and gene carriers. Interestingly, there were no side differences of the VN among the V30M-ATTRv patients, although wider right VN-CSA were seen in both controls and gene carriers. However, further studies with more patients need to be done to confirm this finding. Furthermore, as arrhythmias in ATTRv might be caused by amyloid infiltration within the heart, and/or by VN dysfunction, this study underscores the usefulness of VN ultrasound as an additional method within these patients, and in diseases causing autonomic dysfunction in general.

Background: Hereditary transthyretin amyloidosis is a progressive disease that demands timely and effective treatment to delay progression. Early prediction of therapy failure is essential to enable prompt intervention and prevent further neurological decline. This study aims to identify clinical and neurophysiological markers predictive of treatment failure, determine how early they emerge, and develop a predictive model for patients receiving disease-modifying treatments. Methods: We retrospectively analysed clinical and neurophysiological data from 119 ATTRV30M polyneuropathy patients who had been receiving a stabilizer treatment for at least one year. Each evaluation was treated as a distinct data point. Features were engineered to capture baseline status, current values, and changes over time. After removing variables with high missingness and post-treatment evaluations, we applied multiple feature selection methods, including XGBoost importance, to identify robust predictors. Key variables included NIS, Sural and Median SNAP amplitudes, Peroneal and Median CMAP amplitudes, SSR (Hand and Foot), and BMI. Results A total of 119 ATTR V30M patients were included in the study, 65 female (53,7%). All were ambulatory at baseline, and 90% had a PND score of 1 or less. The final model achieved 78.2% accuracy and 77.8% recall. Compared to a baseline logistic regression (80.0% accuracy, 70.1% recall), our model demonstrated improved sensitivity, especially in high-risk periods (e.g., within 0–180 days of therapy failure). SHAP analysis showed that dynamic features—such as changes in NIS, Foot SSR, CMAP peroneal, and Sural SNAP amplitudes—were the most predictive of progression. A leave-one-out test confirmed the model\'s ability to monitor rising risk over time. Conclusion This dynamic model shows strong potential for real-time risk stratification in ATTRv amyloidosis. Despite limitations due to sample size and historical treatment context, it offers a foundation for clinical decision support. Future work will focus on cohort expansion, baseline risk factor development, and creating an integrated risk tool.

Background: Amyloidosis is a progressive, systemic condition, often involving the heart, kidneys and nervous system. It can have a debilitating impact on people with amyloidosis and their families, making early diagnosis and treatment critical. Yet despite existing guidelines, delayed diagnosis and inefficiencies in care delivery continue to impact quality of life and prognosis. There is evidence that some people with amyloidosis with cardiac involvement experience a delay of approximately six years before diagnosis is confirmed, leading to worse patient outcomes.1 A comprehensive framework to support care improvement across diverse health systems is lacking. We aimed to develop quality standards and indicators to provide a set of clear goals for the delivery of high-quality amyloidosis care. Methods: Eighteen experts were recruited to join a quality standards development group, including patient representatives (n=6) and clinicians with expertise in amyloidosis diagnosis and management (n=12), including specialists in cardiology, neurology, haematology and internal medicine. The study group focused on the two principal types of amyloidosis –transthyretin (ATTR) and immunoglobin light chain (AL) – in the context of high-income, publicly funded health systems. The study was informed by initial qualitative exploratory research, involving a scoping literature review and semi-structured interviews with experts, to identify critical points in the amyloidosis care pathway for quality standard development. A nominal group technique (NGT) was used to formally achieve a consensus on the quality standards. This structured method was selected for the generation and prioritisation of ideas, over alternative approaches such as Delphi, to facilitate inclusive, in-depth discussion among the expert group. The NGT was delivered via: silent generation of ideas, thematic analysis, prioritisation, and discussion and finalisation. Each quality standard was constructed to be applicable to both ATTR and AL amyloidosis, and was paired with a measurable indicator to support performance tracking. Indicators were submitted by the expert group, with consensus modelled on a vote. Results: Twenty-nine quality standard statements were developed during silent generation. These were iteratively refined by the expert group, with consensus ultimately reached on eight quality standards that span the amyloidosis care pathway (Figure), including red flag identification, diagnostic work-up, treatment initiation, interdisciplinary care, follow-up, and care optimisation. While 63 indicators were originally submitted, 20 were selected to accompany the final quality standards (Table), to support monitoring of health system performance. Conclusions: This set of quality standards establishes a consensus-based goal for improving the delivery of high-quality, equitable amyloidosis care, providing a framework for use across diverse health system contexts. Widespread adoption could support pathway transformation to optimise outcomes for people with amyloidosis, improving diagnostic efficiency, care delivery and quality of life. References: 1. Rozenbaum MH, Large S, Bhambri R, et al. 2021

Objectives The description of transthyretin amyloid cardiomyopathy (ATTR-CM) in South-East Asia (SEA) is sparse. We sought to describe the clinical characteristics of ATTR-CM patients in a tertiary academic centre in Singapore. Methods We included ATTR-CM patients on follow up with our center from March 2017 to April 2025. Clinical, laboratory and genetics data were obtained from electronic medical records. Results Baseline demographics and clinical characteristics are summarized in Table 1 and number of newly diagnosed ATTR-CM cases are illustrated in Figure 1. Among 61 patients (86.9% male), median age was 74 years-old. Majority were of Chinese ethnicity (93.4%). 44 patients (72%) consented for TTR genetic testing, of which 36 genetic test results were available at time of analysis. 20 of the 36 (56%) had hereditary ATTR-CM and 16 (44 %) were wild type ATTR-CM. The most common TTR gene mutation in our cohort was the Ala117Ser mutation (N=12; 60%). The majority of patients, 32 (52.5%) were diagnosed with Modified NAC stage 1 disease, 14 (23%) with stage 2 disease, 10 (16.4%) with stage 3 disease and 5 (8.2%) with stage 4 disease. We further divided our analysis into 3 time periods of years 2017-2019, 2020-2023 and 2024-2025. This corresponds with a period of lack of awareness of cardiac amyloidosis prior to 2019 locally. Followed by our institution’s effort to increase awareness through physician and public education during the period of 2020 to 2023. Lastly, from 2024 onwards, there was increased accessibility of Tafamidis locally due to increased healthcare subsidies. There were significantly more elderly patients diagnosed in the most recent time period of 2024-2025 compared to earlier periods, p = 0.027 and more genetic tests performed during the same period, p = 0.043. Conclusion Our study provides important information on the clinical characteristics and TTR genotypes of ATTR-CM patients in a multiracial South-East Asia country. We the authors feel the increased elderly population diagnosed with ATTR-CM in recent years likely reflects an increased awareness of this condition amongst physicians and patients in Singapore. Provision of financial subsidy for Tafamidis in symptomatic ATTR-CM patients likely also reduced fatalistic attitudes among the elderly patients and their physicians, with a greater impetus in diagnosis, leading to a spike in diagnosis during time period 2024-2025. Furthermore, with the increased awareness in ATTR-CM and accessibility to genetic testing, there is a corresponding uptake as demonstrated here. We plan to follow up with further assessment of genetic results when available for better understanding in our population.

Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a progressive neuropathic disease where disease-modifying treatments are approved only after clinical conversion. Identifying asymptomatic carriers at highest risk of short-term progression is essential to optimize follow-up and inform timely therapeutic decisions. We aimed to evaluate whether early quantitative changes in electrochemical skin conductance (Sudoscan®) and sensory nerve conduction studies (ENG) over six months could predict near-term neurological conversion in ATTRv carriers. Methods: We conducted a prospective observational study of 15 asymptomatic ATTRv carriers, mean age 49 yo (39-60), 66% female, 44% male, Regarding the mutations 66.7% were Val50Met, 20% Val142 Ile, 6.7% Glu109Lys, 6.7% Ser43Asn .Participants underwent baseline and six-month assessments using Sudoscan® and sensory ENG (sural or peroneal nerves). Clinical conversion was defined using established symptomatic and neurophysiological criteria. Retrospective analysis determined whether six-month quantitative changes predicted subsequent clinical progression. Results: During follow-up, 3 carriers (20%) progressed to symptomatic neuropathy. All three had shown significant quantitative deterioration during the first six months: Sudoscan® decline ≥10% (100% converters vs. 15.4% non-converters, p=0.047) and ≥20% reduction in sensory nerve amplitudes (66.7% converters vs. 10% non-converters, p=0.041). These early changes anticipated later clinical conversion and were absent in stable carriers, underscoring their predictive value. Conclusions: A six-month quantitative assessment combining Sudoscan® and sensory nerve conduction studies identifies asymptomatic ATTRv carriers at elevated risk of near-term neurological conversion. Incorporating this early checkpoint into routine clinical practice could enhance risk stratification, optimize monitoring intensity, and inform preventive strategies before symptom onset.

Objective: To describe health-related quality of life (HRQoL), and underlying components/drivers, among patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN) in a real-world setting. Methods: Interim data were drawn from the Adelphi Real World Disease Specific Programme™, a cross-sectional survey of physicians and their patients with ATTR-PN. Data were collected in France, Germany, Italy, Spain, the United Kingdom (Europe), and the United States (US) between October 2024 – March 2025. Physicians completed electronic record forms for consecutively consulting patients they saw during this period, capturing their demographic and clinical characteristics including Polyneuropathy Disability (PND) score. The patients were invited to complete a questionnaire, containing the 35-item Norfolk Quality of Life-Diabetic Neuropathy questionnaire (Norfolk QoL-DN) and EQ-5D-5L. Analyses were descriptive. Results: One-hundred-and-sixty-nine physicians reported data for 811 patients with ATTR-PN, of whom 170 provided self-reported questionnaire data (France: 41, Germany: 81, Italy: 19, Spain: 19, US: 10). Physicians reported 120 of these patients had ATTR-PN and 50 had a mixed phenotype (France: 9, Germany: 26, Italy: 7, Spain: 4, US: 4). Mean (standard deviation; SD) age was 59.4 (12.3) years, and 70.0% were male. Median (interquartile range) disease duration was 1.9 (0.9–3.9) years. Complete Norfolk QoL-DN data (measured from -4 to 136, with higher scores indicating worse quality of life [QoL]) were provided by 152 patients, who reported a mean (SD) total score of 36.13 (28.60). Scores ranged from 12.33 (18.08) at PND 0, to 109.67 (7.09) at IV (Table 1). Additionally, the majority of patients reported an impact of different aspects of ATTR-PN on their quality of life (Figure 1). EQ-5D-5L health utilities (where 1 corresponds to perfect health and 0 corresponds to death) were derived using the value set for Germany. Mean (SD) health utilities ranged from 0.94 (0.07) at PND 0, to 0.24 (0.18) at IV (Table 1). Conclusions: These real-world data show the negative impact of ATTR-PN and mixed phenotypes on the quality of life of those affected, particularly those at higher PND scores. As well as physical manifestations such as pain and fatigue, many patients reported being impacted by loss of their independence, or fears about disease progression. Early disease detection and prompt treatment intervention are vital to attempt to preserve patient QoL in the face of advancing symptoms.

Objectives: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) can have significant impacts on physical, mental, and psychosocial well-being. There is consequently a need to characterise the current provision of holistic clinical management for ATTR-CM, identify areas of high unmet need, and develop potential solutions to enhance clinical practice. These solutions will be published in a subsequent full article. Methods: Narrative review and consensus from a multidisciplinary group comprising cardiologists, specialist nurses, patient advocates, patients and primary care (for continuation of care in the community). Results: Multiple areas of unmet holistic need were identified. The journey through healthcare systems for patients with ATTR-CM can be long and complex, with multiple opportunities for holistic intervention. Organisation of care: The multidisciplinary team (MDT) is critical to holistic management, helping to identify and address current and evolving health and well-being issues. However, the structure and dynamics of the MDT can vary substantially by practice type, institution, and country. Furthermore, as the needs of patients with hereditary ATTR-CM can be substantially different from those with wild-type disease this requires recognition and dedicated competence in the MDT. The proposed article will describe some of the disciplines who should be involved in the holistic management of ATTR-CM. Disease monitoring: There is a need for clinically feasible and practical tools for frequent monitoring, along with a better understanding of how treatment and other factors influence clinical status. The proposed article includes suggestions to guide and inspire development of future tools. Maintenance of physical and mental health: The provision of services for physical and psychological assessment and support is often limited. Given the impact of ATTR-CM on physical and mental well-being and psychosocial functioning, we aim to provide suggestions about how this support could be enhanced. Communication: As ATTR-CM is a complex disease with varied presentation, prognosis, and treatment options, patients can benefit from improved communication and shared decision-making that allows for a patient-centred approach with individual preferences incorporated into treatment decisions. Improved understanding can help patients to navigate the disease, treatment, and care. Other professions, such as specialized nurses, have a role to play in this regard as they may be able to communicate differently. Beyond medical support: Referral to support groups can play a key part in helping patients to maintain or enhance their well-being. Gender differences: Evidence of gender differences in prevalence, clinical manifestations, and patient well-being suggests more research is needed. Conclusions: There is a large degree of heterogeneity and complexity in the holistic management of ATTR-CM. This multidisciplinary review identifies and/or confirms key unmet needs and knowledge gaps, and provides recommendations to help ensure an holistic care management according to best practices for patients with ATTR-CM.

Background/Introduction The body of evidence on amyloid transthyretin cardiomyopathy (ATTR-CM) derived from real world data (RWD) has increased sharply in recent years. Since specific codes for the documentation of ATTR-CM are lacking in Europe, algorithms have been developed to identify such patients based on other specific information indicating ATTR-CM. However, the accuracy of these algorithms in correctly identifying ATTR-CM patients has not yet been investigated. Purpose To evaluate the accuracy of established algorithms to identify ATTR-CM patients based on RWD compared to expert clinician assessment. Methods This retrospective cross-sectional study utilized data from the PHARMO Data Network, encompassing anonymized hospital data and outpatient pharmacy data of 3,054,433 patients in the Netherlands, with additional linkages to general practitioner, inpatient pharmacy, laboratory, and pathology data. Based on a previously published ATTR-CM algorithm implemented on a French healthcare database (1) and adapted for use in the context of Dutch healthcare data, patients with any diagnosis of amyloidosis and cardiac involvement (heart failure, arrhythmia, cardiomyopathy, conduction disorder) and without any diagnosis, drug dispensing, or procedure indicative of light chain amyloidosis, secondary amyloidosis, or amyloid angiopathy from January 2013 to December 2022 were included for this analysis. Four independent clinical experts reviewed the medical records of a subsample of algorithm-identified ATTR-CM patients and classified each case as true positive or false positive. The positive predictive value (PPV) was calculated to assess the performance of the algorithm compared to expert clinician assessment. Results on a random sample of 200 ATTR-CM patients are included in this abstract. Results Overall, 367 ATTR-CM cases were identified based on the implemented algorithm in the PHARMO Data Network (mean age 72.8 ± 13.0 years; 31.3% women) (Table 1). Heart failure and arrhythmia were the most frequent cardiac involvements observed in these patients (60% and 63%, respectively). Among the sample of 200 algorithm-identified ATTR-CM cases reviewed by the clinical experts, 43 (22%) patients were excluded due to insufficient available data for the clinical validation. Of the remaining 157 patients, 143 patients were classified as true positive, leading to a PPV of 91.1% (Table 2). The PPV was broadly consistent across reviewing expert clinicians and type of cardiac involvement. PPV increased slightly among older age groups and in more recent calendar years. Conclusion The current algorithm implemented on Dutch RWD performed well in identifying true ATTR-CM patients according to expert clinician assessment. Consequently, the implementation of this algorithm in RWD studies will enable an accurate understanding of the ATTR-CM disease burden including patient characteristics, treatment patterns, long-term outcomes, healthcare utilization and costs. Reference (1) Damy T, et al. Orphanet J Rare Dis, 2023; 18, 345.

Objectives Hereditary Transthyretin amyloidosis (ATTRv) is a rare, progressive, and presumed underdiagnosed disease where amyloidogenic fibrils of the misfolded protein Transthyretin accumulates in various tissues, leading to organ failure and death. Different fibril types (A or B) have been shown to contribute to the different main phenotypes of the disease; neurologic and cardiac manifestations. Less has been investigated how the inheritance pattern affects the course of the disease. The aim of this study is to increase the understanding of early disease manifestations in ATTRv in relation to gender and inheritance pattern. Methods This retrospective study was based on data collected from medical records from first-time “baseline” visits of Swedish patients with verified ATTRv (tissue biopsy from abdominal fat or myocardium) from their initial clinical examinations at Norrland University Hospital, Umeå, Sweden between 2006 – 2024. Data collection included information of subjects’ sex, length and weight, age at diagnosis, gene mutation, fibril type, inheritance pattern (maternal, paternal or homozygous), initial clinical symptoms (defined as described symptom leading to first health care contact (categorised as neurological, cardiac, gastrointestinal, renal or ocular)), time from symptom onset to diagnosis. Results 152 ATTRv patients (50 females, 102 males) with determined fibril type were included, of which 118 had mapped inheritance patterns (56 maternal, 60 paternal, 2 homozygous – the latter excluded in the statistics). Age at diagnosis ranged from 24 - 88 years. All types of mutations were included in the materials (95% with V30M). Descriptive demographics can be seen in table 1. The main manifestation of the disease was neurological symptoms, for both maternal (40%) and paternal (39%) inheritance. However, no significant relationship (p=0.094) was found between inheritance patterns and “age at diagnosis” (i.e. early/late onset). When investigating “time of symptoms before diagnosis” a significant relationship with inheritance pattern was found (p=0.040), after excluding a presumed outlier, no significance was noted (p=0.072). There was no significant difference (p=0.479) in aspects of fibril types and inheritance pattern. Conclusions - Heredity could have an effect of age of onset, although this was not significant. More late onset patients had paternal inheritance, and more early onset patients had maternal inheritance patterns. - In line with earlier studies, twice as high penetrance was seen for men compared with women. - Initially, a significant difference in the relationship between “time of symptoms before diagnosis” and inheritance pattern, indicating that individuals with a paternal inheritance would go a longer time with symptoms before diagnosing the disease. However, when a presumed outlier was excluded, no significant relationship was found (p=0.072). - The main initial clinical manifestation was neuropathic, and future studies with more detailed description will be done, as this is sparsely investigated in Swedish ATTRv patients.

Communicating accurate, accessible, and relevant information to individuals affected by amyloidosis presents significant challenges. Amyloidosis is a rare, complex, and multisystem disease with numerous subtypes, each associated with different abnormal protein deposits and varied clinical outcomes. Despite these challenges, the past decade has seen a marked increase in the availability of patient-focused resources, driven by advancements in diagnostics, therapeutic development, and the proliferation of omnichannel communication platforms. While greater information accessibility is beneficial, important questions remain: How useful is this information? Who is it reaching? And at what point in the patient journey is it most impactful? Objectives To identify and address unmet informational needs among individuals affected by all types of amyloidosis in the UK. Methods Amyloidosis UK, in collaboration with the Patient Information Forum (PIF) is conducting the Perfect Patient Information Journey (PPIJ) project for the UK amyloidosis community. The PPIJ is a validated methodology developed by PIF to identify patient and public information needs and gaps. The project is structured in two phases. Phase 1 involves mapping the current patient information experience by gathering insights from individuals living with amyloidosis and their care teams to identify opportunities for improvement. Phase 2 will focus on implementing and evaluating the impact of targeted information interventions. Results Phase 1 is currently in progress and includes semi-structured interviews with three healthcare professionals and three individuals affected by amyloidosis (two patients and one spouse/caregiver). These will be followed up with further interviews and focus groups. Conclusions Phase 1 findings and the proposed framework for Phase 2 will be presented at ATTR2025 in September.

Objectives: The landscape of transthyretin amyloidosis (ATTR) is rapidly evolving. Enhanced diagnostic capabilities and the introduction of innovative therapies have ushered in a new era of improved prognosis. A nuanced understanding of ATTR amyloidosis care enables healthcare professionals to tailor management strategies, optimize treatment regimens, and monitor disease progression. The objective of this analysis is to assess the treatment patterns and outcomes post-diagnosis across multiple healthcare systems and populations with different genetic compositions. Methods: OverTTuRe is a multi-country study generating real-world evidence on adult symptomatic patients with ATTR amyloidosis. The study cohort included patients diagnosed between 2014 and November 2024 from the Swedish Transthyretin Amyloidosis Registry (SveATTR) linked with three national healthcare databases. Analyses from the Amyloid Registry of the Charité University Hospital in Germany, the national clinic-based Canadian Registry for Amyloidosis Research (CRAR), and chart reviews from six hospitals in China and from 11 hospitals in Spain are ongoing and will also be presented. Results: Preliminary data are shown in Table 1 from 547 patients from Sweden predominantly diagnosed with variant-type ATTR amyloidosis (n=341, 62.3%) who tended to be younger, more often female, and more likely to have a medical history of (poly)neuropathy, versus patients with wild-type disease (n=164, 30.0%) who were more likely to have a history of heart failure, cardiomyopathy, arrhythmia, atrial fibrillation, and carpal tunnel syndrome. Post-diagnosis, 80% received an ATTR-specific treatment over an average follow-up time of 4.2 years. The median time to stabilizer treatment initiation was 3 months (median (IQR) 92 (15, 391) days). Considerable variation was observed with greater than one-quarter of patients waiting more than a year before receiving treatment with a stabilizer (Table 2). The population with wild-type ATTR amyloidosis had higher rates of mortality and hospitalization. Conclusions: These results illustrate the substantial complexity of people diagnosed with ATTR amyloidosis, irrespective of genotype. Opportunities exist to elevate the profile of clinical suspicion, diagnose early, and implement a personalised and multidisciplinary approach to care with guideline-concordant treatment to improve the lives of affected individuals.

Objectives: Non-clinical attributes of treatments can impact clinicians’ treatment preferences when selecting between treatment options. Given the advent of effective treatments with different administration, dosing, and pharmacodynamic profiles in the management of Transthyretin amyloidosis (ATTR), clinicians’ preference based on these non-clinical attributes when selecting a disease-modifying treatment in ATTR was evaluated. Methods: Three non-clinical attributes, speed of TTR knockdown, medication administration approach (where and by whom doses are administered) and dosing frequency, were identified as potential preference drivers in qualitative interviews of ATTR-treating clinicians and tested in a discrete choice experiment (DCE). After pretesting, the finalized DCE survey was used to quantify clinicians’ preferences for different levels of each attribute (spanning a clinically and practically meaningful range) in the context of treating hypothetical ATTR patients. Results: Two hundred clinicians (100 neurologists; 100 cardiologists) in the United States, who have been treating ATTR for 11.8 years on average, completed the DCE survey; mean age was 51.2 years, 17.5% were female, and mean number of ATTR patients seen per clinician was 39 annually. The most important attribute, conditional on the attributes and levels evaluated, was speed of TTR knockdown, with a conditional relative importance (CRI) of 42.9%, versus 31.7% for medication administration approach and 25.4% for dosing frequency. Conclusions: DCE results showed that speed of TTR knockdown was a key driver of clinicians’ treatment choice, having the greatest positive influence on clinicians selecting a disease-modifying therapy for ATTR, with rapid knockdown being preferred to address the rapidly progressive and debilitating manifestations of the disease.

OBJECTIVES: Transthyretin amyloidosis (ATTR) is a progressive and fatal condition caused by deposition of misfolded transthyretin (TTR) as amyloid fibrils in multiple tissues. ATTR is classified as either hereditary (hATTR) or wild-type (wtATTR), depending on the presence or absence of amyloidogenic TTR gene variants, and manifests as either primarily cardiomyopathy (ATTR-CM), polyneuropathy, or a mixed phenotype. RNA interference (RNAi) therapeutics suppress the hepatic production of TTR by targeting wild-type and variant TTR mRNA for degradation. Previous studies showed that rapid TTR knockdown with RNAi therapeutics improves outcomes for ATTR patients regardless of etiology or manifestation.[1-3] Most recently, vutrisiran was shown to improve outcomes for patients with ATTR-CM across multiple domains in the HELIOS-B study, including reducing cardiovascular events and all-cause mortality, and improving functional capacity and quality of life.[3] Larger reductions in TTR levels correlated with greater clinical benefit in patients with hATTR and polyneuropathy,[1] suggesting that greater TTR knockdown may offer similar benefits in ATTR-CM. Nucresiran (ALN-TTRsc04) is a next-generation RNAi therapeutic designed for the treatment of ATTR. In a Phase 1, ascending-single-dose study in healthy adults (NCT05661916), nucresiran led to rapid and sustained knockdown of TTR. Up to 95% knockdown by Day 15 and >90% mean reductions through Month 6 was achieved with subcutaneously administered doses ≥300 mg that were well tolerated.[4] We aim to describe the rationale and design of a global phase 3, randomised, placebo-controlled study to evaluate the efficacy, safety and pharmacokinetics/pharmacodynamics (PK/PD) of nucresiran in patients with ATTR-CM. METHODS: The study design, including inclusion and exclusion criteria, will be finalised in Q1 2025. Enrolment of adult patients with ATTR-CM is expected to begin in 2025. Key endpoints will assess mortality and cardiovascular events. RESULTS: The nucresiran phase 3 ATTR-CM study design and rationale will be presented. CONCLUSIONS: The phase 3 study will investigate the efficacy, safety and PK/PD of nucresiran in patients with ATTR-CM. Nucresiran has the potential to provide greater and more sustained TTR knockdown with lower inter-patient variability and less frequent dosing than current TTR-lowering therapies. REFERENCES [1.] Adams D, et al. N Engl J Med 2018; 379: 11–21. [2.] Adams D, et al. Amyloid 2023; 30: 1–9. [3.] Fontana M, et al. N Engl J Med 2024; DOI: 10.1056/NEJMoa2409134. [4.] Murad A, et al. American Heart Association 2024, 16–18 November. Originally presented at HFA 2025. This study is funded by Alnylam Pharmaceuticals.