Amyloid Polyneuropathy Research Articles

New therapies to treat cardiac amyloidosis.

Review advancements in therapies for transthyretin (ATTR-CM) and immunoglobulin light chain (AL-CM) cardiac amyloidosis. In ATTR-CM, tafamidis remains the cornerstone therapy, with Food and Drug Administration (FDA) approval for over 5 years. Acoramidis, another transthyretin stabilizer, has very recently been FDA-approved following positive results in the ATTRibute-CM trial. Vutrisiran, a transthyretin gene silencer, demonstrated efficacy in the HELIOS-B trial and awaits FDA review. Eplontersen's CARDIO-TTRansform trial, the largest ATTR-CM study to date, is expected to report by late 2025. Innovative approaches such as NTLA-2001 (a CRISPR-Cas9 therapy) and fibril depleters like ALXN2220 and coramitug are advancing in clinical trials. In AL-CM, daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) has established itself as the standard of care. Novel antiplasma cell therapies include CAR-T cells and bispecific antibodies (teclistimab) and fibril depleters. Birtamimab improved survival in advanced AL-CM during the VITAL trial and is under investigation in AFFIRM-AL. Anselamimab is in phase III CARES trials, whereas AT-02 undergoes early-phase testing for ATTR-CM and AL-CM. The therapeutic landscape for ATTR-CM and AL-CM is rapidly evolving, driven by novel therapies targeting diverse mechanisms. Ongoing clinical trials promise to further refine the standard of care and improve outcomes for patients with cardiac amyloidosis.

Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy

There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and -3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. ClinicalTrials.gov Identifier: NCT02510261.

Applications and Challenges of RNA Interference Technology in Therapeutic Development

RNA interference (RNAi) is a potent biological mechanism enabling the targeted silencing of specific genes, transforming gene regulation and therapeutic approaches in medical science. Using small RNA molecules such as small interfering RNAs (siRNAs) and microRNAs (miRNAs), RNAi allows for precise mRNA degradation or translational repression. Clinically, RNAi has been applied to treat genetic disorders such as hereditary transthyretin amyloidosis (hATTR) and acute hepatic porphyria (AHP). RNAi also holds promise in cancer therapies, targeting oncogenes like KRAS and pathways such as PI3K/AKT/mTOR to slow tumor growth. However, several challenges limit RNAi's broader clinical adoption. A significant barrier is the development of effective delivery systems beyond liver cells, as current methods, such as lipid nanoparticles, have limitations in targeting other tissues. Furthermore, issues such as immune activation, off-target effects, and ensuring RNAi stability must be addressed. Regulatory hurdles concerning long-term safety and gene-silencing specificity also pose challenges. Looking ahead, advancements in next-generation RNAi molecules and delivery platforms, alongside combination therapies, offer promising solutions to overcome these limitations. his review explores the fundamental mechanisms of RNAi, including its role in gene regulation and gene silencing, and highlights its clinical applications in treating genetic disorders, cancers, and viral infections

Minimal invasive biopsies are highly sensitive for amyloid detection in hereditary transthyretin amyloidosis with polyneuropathy.

To assess the effectiveness of labial minor salivary gland biopsy (LSGB) alone or in combination with punch skin biopsy (SB) for the detection of amyloid deposits in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). In this single-center retrospective study, Congo red staining of minimal invasive LSGB (4 mm) and SB (3 mm) was assessed in ATTRv-PN patients consecutively evaluated between 2012 and 2023. Histopathological data of 171 ATTRv-PN, including 49 early-onset p.Val50Met, 58 late-onset p.Val50Met, and 64 non-p.Val50Met, were reviewed. LSGB and SB identified amyloid deposits in 123/171 (72%) and 131/171 (77%) patients respectively (p = 0.2). Combining LSGB and SB increased the amyloid detection rate to 150/171 (88%), especially in late-onset p.Val50Met (48/58 [83%]) and non-p.Val50Met patients (55/64 [86%]). LSGB and SB have a similar rate of detection of amyloid depositions in early onset p.Val50Met patients (94%). Also, the LSGB/SB combination identified amyloidosis in 89% (55/62) of early-stage ATTRv-PN patients. In our study, combining LSGB and SB allowed the detection of amyloid deposits in 88% of ATTRv-PN patients. LSGB/SB analysis may be of major interest to confirm entry in the disease at very early-stage ATTRv-PN, with implications in disease-modifying treatment initiation.

Exploratory analyses from HELIOS-B, a phase 3 study of vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy

Exploratory analyses from HELIOS-B, a phase 3 study of vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy

Gender-related Outcome Differences In Patients With Transthyretin Amyloidosis (attr): Analysis From The National Inpatient Sample (nis)

Gender-related Outcome Differences In Patients With Transthyretin Amyloidosis (attr): Analysis From The National Inpatient Sample (nis)

Real-world tafamidis experience in hereditary transthyretin amyloidosis with peripheral neuropathy in Brazil.

Tafamidis is a kinetic stabilizer that binds to the transthyretin (TTR) gene, inhibiting its dissociation. It is the only disease-modifying treatment for hereditary TTR amyloidosis with peripheral neuropathy (ATTRv-PN) available in the National Therapeutic Form (Formulário Terapêutico Nacional, FTN, in Portuguese) of the Brazilian Unified Health System (Sistema Único de Saúde, SUS, in Portuguese). To assess if the efficacy and safety of tafamidis in the Brazilian real-world experience are comparable to the results of clinical trials. We retrospectively studied all patients with ATTRv-PN evaluated at our center from September 2011 to March 2022 (data cut-off) who were initiated on tafamidis and had at least 1 follow up visit 6 months after the initiation of the drug treatment. Neurologic and functional outcomes were compared from day 1 (D1) of the tafamidis treatment (baseline) to the last follow-up. In total, 33 patients were included, 18 (55%) of whom were female. All patients were carriers of the V30M mutation of ATTRv-PN, and 20 (61%) presented early onset (EO) ATTRv-PN. At baseline, the median age of the sample was of 40 (interquartile range [IQR]: 36-68) years, the median Neuropathy Impairment Score (NIS) was of 10 (6-24) points, and the median body mass index (BMI) was of 26 (23-28) kg/m2. The mean follow-up time was of 3.4 years. At the last follow-up, the BMI, the neurological impairment, and the level of disability slightly worsened compared with baseline, while the findings of the nerve conduction studies remained stable. These same results were observed across EO and late-onset (LO) ATTRv-PN patients. A total of 25 (75.8%) patients were considered responders, and 8 (24.2%), non-responders. The efficacy and safety of tafamidis reported in clinical trials is expandable to the Brazilian real-world scenario in EO and late-onset (LO) ATTRv-PN.

Outpatient heart failure worsening in patients with cardiac transthyretin amyloidosis: Results from the Apollo-B trial

Outpatient heart failure worsening in patients with cardiac transthyretin amyloidosis: Results from the Apollo-B trial

Early genetic screening and cardiac intervention in patients with cardiomyopathies in a multidisciplinary clinic.

Patients with cardiomyopathies are a heterogeneous group of patients who experience high morbidity and mortality. Early cardiac assessment and intervention with access to genetic counselling in a multidisciplinary Cardiomyopathy Clinic may improve outcomes and prevent progression to advanced heart failure. Our prospective cohort study was conducted at a multidisciplinary Cardiomyopathy Clinic with 421 patients enrolled (42.5% female, median age 58years), including 224 patients with dilated cardiomyopathy (DCM, 42.9% female, median age 57years), 72 with hypertrophic cardiomyopathy (HCM, 43.1% female, median age 60years), 79 with infiltrative cardiomyopathy (65.8% female, median age 70years) and 46 who were stage A/at risk for genetic cardiomyopathy (54.3% female, median age 36years). Patients were seen in follow-up at a median of 18months. A pathogenic/likely pathogenic variant was identified in 28.5% of the total cohort, including 33.3% of the DCM cohort (28% TTN mutations) and 34.1% of the HCM cohort (60% MYBPC3 and 20% MYH7) who underwent genetic testing. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (48.3-69.5% of total cohort, P<0.001), β-blockers (58.4-72.4%, P<0.001), mineralocorticoid receptor antagonists (33.9-41.4%, P=0.0014) and sodium/glucose cotransporter-2 inhibitors (5.3-27.9%, P<0.001) all increased at follow-up. Precision-based therapies were also implemented, including tafamidis for transthyretin amyloidosis (n=21), enzyme replacement therapy for Fabry disease (n=14) and mavacamten (n=4) for HCM. Optimization of medications and devices resulted in improvements in left ventricular ejection fraction (LVEF) from 27% to 43% at follow-up for DCM patients with reduced LVEF at baseline (P<0.001) and reduction in left ventricular mass index (LVMI) from 156g/m2 to 128g/m2 at follow-up for HCM patients with abnormal LVMI at baseline (P=0.009). Optimization of therapies was associated with stable plasma biomarkers in stage B patients while lowering levels of BNP (619-517.5pg/mL, P=0.048), NT-proBNP (777.5-356ng/L, P<0.001) and hsTropT (31-22ng/L, P=0.005) at follow-up relative to baseline values for stage C patients. Despite stage B patients having overt cardiomyopathy at baseline, stage A and B patients had a similarly high probability of survival (χ2=0.204, P=0.652). The overall cardiovascular mortality rate was low at 1.7% for the cohort (0.5% for stage B and 3.3% for stage C) over a median of 34-month follow-up. Our study demonstrates that a multidisciplinary cardiomyopathy clinic can improve the clinical profiles of patients with diverse genetic cardiomyopathies.

From Molecular to Radionuclide and Pharmacological Aspects in Transthyretin Cardiac Amyloidosis.

Amyloidosis is a rare pathology characterized by protein deposits in various organs and tissues. Cardiac amyloidosis (CA) can be caused by various protein deposits, but transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) are the most frequent pathologies. Protein misfolding can be induced by several factors such as oxidative stress, genetic mutations, aging, chronic inflammation, and neoplastic disorders. In ATTR cardiomyopathy (ATTR-CM), the amyloid fibrils can be found in the myocardium interstitial space and are associated with arrhythmias and heart failure. In pathological situations, the transthyretin (TTR) configuration is destroyed by proteolytic action, leading to monomers that further misfold and aggregate to form the amyloid fibrils. 99mTc-Pyrophosphate (99m-Tc-PYP), 99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid (99m-Tc-DPD) and 99m-Tc hydroxy-methylene-Dyphosphonate (99m-Tc-HMDP) are used to detect myocardium amyloid deposits due to their ability to detect calcium ions that are present in the amyloid fibrils through dystrophic calcification. ATTR-CM therapy acts on different stages of the amyloidogenic process, including liver TTR synthesis, TTR tetramer destabilization, and misfolding of the monomers. The main aim of this narrative review is to present ATTR-CM, starting with molecular changes regarding the protein misfolding process and radionuclide aspects and finishing with pharmacological approaches.

Cluster analysis and analysis of risk factors for hereditary transthyretin amyloidosis cardiomyopathy

Objective: To explore the clinical characteristics and prognostic value in hereditary transthyretin amyloidosis cardiomyopathy (hATTR-CM) patients based on cluster analysis, and to explore the risk factors for cardiovascular composite events. Methods: This retrospective cohort study included hATTR-CM patients who were admitted to Peking Union Medical College Hospital from January 2000 to January 2024. These patients were divided into two clusters using cluster analysis, based on genetic information, demographic information and clinical information. During the follow-up period, cardiovascular composite events were defined as all-cause death and hospitalization for heart failure. Both cardiovascular composite events and all-cause death were the endpoints. Kaplan-Meier survival curves and log-rank method were used to compare the prognostic significance of cluster analysis subgroups. Univariate and multivariate Cox proportional hazard regression models were used to analyze the risk factors affecting the incidence of cardiovascular composite events. Results: A total of 43 patients were included in this study, 30 were male (69.8%). In cluster 1 (n=27), whose age of onset was (49.9±13.9) years old, 24(88.9%) of them started with neuropathy or gastrointestinal symptoms, and all clinical phenotypes were mixed type (neurological and cardiac). In cluster 2 (n=16), whose age of onset was (59.0±10.6) years old, 15(93.8%) of them started with heart failure symptoms, and 13(81.3%) were pure cardiomyopathy. During the median follow-up time of 2.6 years, a total of 16 patients (37.2%) experienced composite cardiovascular events, and a total of 12 patients (27.9%) died. Kaplan-Meier survival curves showed a significantly lower cumulative survival rate for cardiovascular composite endpoint events (log-rank P=0.04) and all-cause death (log-rank P=0.04) in cluster 2 than in cluster 1. Univariate Cox proportional hazard regression model analysis showed that hATTR-CM patients with reduced estimated glomerular filtration rate, left ventricular ejection fraction≤40%, and moderate to severe mitral regurgitation were risk factors for vascular composite events (all P<0.05). Multivariate Cox proportional hazard regression analysis showed that left ventricular ejection fraction≤40% was an independent risk factor (P<0.01). Conclusions: Cluster analysis is a valuable prediction tool on the prognostic stratification of hATTR-CM. Cluster 2, which is late-onset with onset of heart failure symptoms has a worse prognosis during follow-up period. The occurrence of composite cardiovascular events in hATTR-CM is related to left ventricular ejection fraction≤40%. Cluster analysis is helpful for clinical identification of high-risk groups.

Disease-modifying therapies for amyloid transthyretin cardiomyopathy: Current and emerging medications.

Transthyretin amyloidosis (ATTR) is a rare disease that results in amyloid fibril misfolding and deposition in multiple organs, including the heart, leading to the development of ATTR cardiomyopathy (ATTR-CM), which is associated with poor outcomes. In the last decade, several disease-modifying medications are in advanced stages of clinical development or have been approved to treat ATTR-CM. The purpose of this review is to critically evaluate clinical trial data investigating the use of approved and investigational medications for the treatment of ATTR-CM. We performed a comprehensive literature search via PubMed and EMBASE to identify randomized controlled trials evaluating medications for the treatment of ATTR-CM published through August 2024. This narrative review describes the pathophysiology of ATTR-CM, highlights important screening and diagnostic work-up, and summarizes the existing clinical evidence resulting from our literature search. Several classes of disease-modifying medications are in development for ATTR-CM. The tetramer stabilizers and transthyretin silencers have proven to be the most effective therapies to date. Tafamidis and acoramidis are currently approved for ATTR-CM while vutrisiran approval for ATTR-CM may be forthcoming. Other disease-modifying medication classes in development include antisense oligonucleotides, gene editing therapies, and monoclonal antibodies. However, several unmet needs exist including the lack of cost-effectiveness due to the extremely high acquisition costs of these medications. Disease-modifying medications approved and in development to treat ATTR-CM offer hope for patients with this disease, but their lack of affordability is the biggest barrier to their use.

The features of cardiomyopathy in AL and ATTR amyloidosis

Amyloidoses are protein misfolding diseases characterized by the accumulation of amyloid fibrils in the interstitium leading to the damage of an affected organ. Cardiac involvement is quite common and results from light chain amyloidosis (AL) or transthyretin amyloidosis (ATTR), including two subtypes: wild type (ATTRwt) and variant ATTR (ATTRv), which can lead to hereditary cardiac amyloidosis. Heart damage leads to life-threatening cardiomyopathy (CM) with poor prognosis. Besides the alteration of the tissue caused by the deposition of amyloid fibrils, experimental studies reveal some complex molecular mechanisms of the cytotoxic effects of amyloid. Although these effects are more prominent and defined in AL amyloidosis, they can also take place in ATTR and somehow affect the disease course. Analyzing the mechanisms on different levels is necessary for understanding of the development of the heart damage and prevention of progression of cardiac amyloidosis (CA). This study aims to conduct a comparative analysis of heart lesions and biochemical characteristics of AL and ATTR amyloidosis. This review was performed by searching the PubMed and Scopus databases for articles published until December 2023, using keywords such as “cardiomyopathy”, “AL amyloidosis”, “mass effect”, “cytotoxicity” and “ATTR amyloidosis”. Exclusion criteria included irrelevant articles and duplicates, with selected studies undergoing comprehensive review.

Clinical differential factors in patients with hereditary transthyretin amyloidosis with Val142Ile and Ser43Asn mutations

BackgroundHereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant disease with high clinical variability, influenced by both genotype and the geographic origins of carriers. There is a limited understanding of the Val142Ile and Ser43Asn recognised mutations in Ecuador and Colombia. Therefore, the objective of this study is to describe the neurological and functional characteristics of patients with hATTR associated with the Val142Ile and Ser43Asn mutations, as well as to identify possible differentiating factors between the two mutations.MethodsThis cross-sectional, multicenter study included 35 hATTR patients from rehabilitation centers in Ecuador and Colombia. Patients had confirmed Val142Ile or Ser43Asn mutations. Neurological and functional assessments included the Neurological Impairment Scale, Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN), Composite Autonomic Symptom Score-31, and various motor function tests as nine-hole peg test (NHP). Quantitative Sensory Testing (QST) evaluating small fiber function, while ultrasound measured the cross-sectional area (CSA) of peripheral nerves. Statistical analysis employed nonparametric tests and random forest classifiers, using SHAP values to identify differentiating variables.ResultsVal142Ile carriers showed lower performance in the right NHP test and greater sensitivity to cold pain in hand and leg. Ultrasound revealed increased CSA of the median nerve at the elbow and arm and the ulnar nerve at the arm in Val142Ile carriers compared to Ser43Asn carriers. The final random forest model identified the NHP test, Norfolk QOL-DN score, and CSA of the median and ulnar nerves as key discriminating variables.ConclusionThis study identified significant neurophysiological and ultrasound markers differentiating Val142Ile and Ser43Asn mutations in hATTR-PN patients. Increased nerve CSA and specific motor and sensory impairments highlight the need for comprehensive evaluations to guide diagnosis and treatment.

Multiple Red Flags of Cardiac Amyloidosis in a Single Patient: Clinical Manifestations of an Underdiagnosed Disease.

Cardiac transthyretin amyloidosis is an underdiagnosed disorder with significant diagnostic difficulties due to its non-specific clinical manifestations. It is caused by the deposition of protein aggregates with an abnormal tertiary structure in the extracellular matrix. Their accumulation leads to the development of hypertrophic and restrictive cardiomyopathy and, at a later stage, heart failure with preserved ejection fraction syndrome. Depending on the pathogenesis, there are different types of the disease-hereditary and age-related wild-type transthyretin amyloidosis. We present the case of an 85-year-old woman who was referred to the department with a two-month history of exertional dyspnea in New York Heart Association functional class II. After reviewing the initial findings, several red flags for cardiac amyloidosis (CA) were identified. Following the diagnostic algorithm, scintigraphy was performed and showed significant radioisotope accumulation in the myocardium, confirming the suspected disease. In this manuscript, we present the current recommendations and diagnostic pathway, discussing in detail both available and emerging treatment options. As early diagnosis is essential to prevent the development of serious complications, we would like to highlight the pitfalls in diagnosing CA and emphasize the need to be aware of its variable clinical presentation and red flags.

Management of Hereditary Transthyretin Amyloidosis (ATTRv) Patients and Asymptomatic Carriers in Spain: The EMPATIa Study.

Background: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal-dominant systemic disease, where amyloid fibrils accumulate especially in the peripheral and autonomic nervous systems and in the heart. The aim of the present work was to outline the follow-up and type of management received by asymptomatic carriers (ACs) and Coutinho stage 1 ATTRv patients in Spain. Methods: A cross-sectional, non-interventional study was conducted throughout seven experienced hospitals in Spain. A total of 86 ACs without neurological symptoms and 19 Coutinho stage 1 ATTRv patients diagnosed 12 months before their enrollment were included. Clinical and demographic data, red flags, and neurological and cardiological evaluations were gathered. In addition, site variables were collected from four centers to describe the clinical management of ATTRv. Results: ATTRv clinical management varied depending on the center setting but was primarily overseen by neurology and internal medicine, which were responsible for the holistic follow-up of ACs and patients. Routinely, neurologists, neurophysiologists, cardiologists, and internal medicine conducted the follow-up. Specialties involved in initial AC assessment were neurophysiologists and cardiologists in 100% of cases, neurologists (75%), internists and geneticists (50%), and ophthalmologists (25%). A review of the medical tests performed proved an exhaustive management of the study population. Stable patients were followed up every 6 months, while those under evolution were monitored every 3-6 months. The frequency of monitoring of ACs was annual, and carriers classified with doubtful disease onset were visited every 3-6 months. Conclusions: The EMPATIa study provides valuable insights into the management of ATTRv in a real-world clinical setting in highly experienced hospitals in Spain. It demonstrates that multidisciplinary practice and enhanced disease awareness may lead to a reduction in diagnostic delay.

The Structural and Dynamic Insights into the Ala97Ser Amyloidogenic Mutation in Transthyretin.

Transthyretin (TTR), a homo-tetrameric protein encoded by the TTR gene, can lead to amyloid diseases when destabilized by mutations. The TTR-Ala97Ser (A97S) mutation is the predominant pathogenic variant found in Han-Taiwanese patients and is associated with late-onset familial amyloid polyneuropathy (FAP), which presents a rapid progression of symptoms affecting peripheral nerves and the heart. In this study, we combined nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to investigate how the A97S mutation impacts the structure and dynamics of TTR. Previous X-ray analyses indicated that the FG loop exhibits increased flexibility due to the mutation, evidenced by missing electron density and a reduced number of hydrogen bonds. Our NMR hydrogen-deuterium (H/D) exchange experiments provided additional insights, revealing that inter-residue hydrogen bonds among the FG loop residues are unstable in both wild-type (WT) and A97S TTR. Notably, the hydrogen bonds between G67 and S97 are unstable, influencing the stability of adjacent loops. This elongation of the FG loop is believed to contribute to increased flexibility and enhanced water-protein proton exchange, as observed in NMR relaxation and chemical exchange experiments. Our findings offer a comprehensive understanding of how the A97S mutation affects TTR structure and dynamics, providing new insights into its amyloidogenicity.

Progression and prognostic significance of electrocardiographic findings in patients with cardiac amyloidosis.

This study aimed to evaluate the change of the main electrocardiographic (ECG) characteristics and their prognostic role across the main subtypes of cardiac amyloidosis [light-chain amyloidosis (AL) and hereditary (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt)]. This multicentre, retrospective study was performed in six referral centres for cardiac amyloidosis. Clinical and ECG data were collected at the first and last evaluations. Three hundred fifty-six patients were included (AL, n=105; ATTRv, n=50; ATTRwt, n=201). The median age was 76 (67-81) years, and 271 (74%) were men. At baseline, patients with ATTRwt showed a higher prevalence of conduction abnormalities compared with those with AL [first-degree atrioventricular block, n=51 (40%) vs. n=13 (34%), P<0.01; left bundle branch block, n=23 (11%) vs. n=2 (2%), P<0.01], and patients with AL more often had low QRS voltage [n=58 (55%); in ATTRv, n=17 (34%); in ATTRwt, n=67 (33%), P value<0.01] and T wave inversion compared with those with ATTR [n=39 (37%); in ATTRv, n=9 (18%); in ATTRwt, n=37 (18%)]. After a median follow-up of 15 (8-26) months, the adjusted differences in mean PR, QRS interval, total, peripheral, and precordial QRS scores were similar across subtypes of amyloidosis (P value for linear regression>0.05). The adjusted odds ratios for the development of right bundle branch block were higher in AL compared with ATTRwt [odds ratio 4.7 (95% confidence interval 1.5-15), P<0.05]. QRS duration at baseline remained independently associated with patient survival in the overall population even after adjustment for relevant clinical variables [hazard ratio 1.78 (95% confidence interval 1.13-2.8), P<0.01]. The progression of the ECG abnormalities seems similar across amyloidosis subtypes. QRS duration could be a marker of more advanced disease.

Free-Breathing Ungated Radial Simultaneous Multi-Slice Cardiac T1 Mapping.

Modified Look-Locker imaging (MOLLI) T1 mapping sequences are acquired during breath-holding and require ECG gating with consistent R-R intervals, which is problematic for patients with atrial fibrillation (AF). Consequently, there is a need for a free-breathing and ungated framework for cardiac T1 mapping. To develop and evaluate a free-breathing ungated radial simultaneous multi-slice (SMS) cardiac T1 mapping (FURST) framework. Retrospective, nonconsecutive cohort study. Twenty-four datasets from 17 canine and 7 human subjects (4 males, years; 3 females, years). Canines were from studies involving AF induction and ablation treatment. The human population included separate subjects with suspected microvascular disease, acute coronary syndrome with persistent AF, and transthyretin amyloidosis with persistent AF. The remaining human subjects were healthy volunteers. Pre- and post-contrast T1 mapping with the free-breathing and ungated SMS inversion recovery sequence with gradient echo readout and with conventional MOLLI sequences at 1.5 T and 3.0 T. MOLLI and FURST were acquired in all subjects, and American Heart Association (AHA) segmentation was used for segment-wise analysis. Pre-contrast T1, post-contrast T1, and ECV were analyzed using correlation and Bland-Altman plots in 13 canines and 7 human subjects. T1 difference box plots for repeated acquisitions in four canine subjects were used to assess reproducibility. The PIQUE image quality metric was used to evaluate the perceptual quality of T1 maps. Paired t-tests were used for all comparisons between FURST and MOLLI, with indicating statistical significance. There were no significant differences between FURST and MOLLI pre-contrast T1 reproducibility ( and , ), FURST and MOLLI ECV ( and , ), or FURST and MOLLI PIQUE scores ( and , ). The ECV mean difference was with . FURST had similar quality pre-contrast T1, post-contrast T1, and ECV maps and similar reproducibility compared to MOLLI. 3 TECHNICAL EFFICACY: 1.

A Comparative Study of the Electroneurographic Findings in Amyloidotic Polyneuropathy in Patients with Light-Chain Amyloidosis and Glu54Gln Transthyretin Amyloidosis

Background and Objectives: Amyloidosis is a disorder characterized by the abnormal folding of proteins, forming insoluble fibrils that accumulate in tissues and organs. This accumulation disrupts normal tissue architecture and organ function, often with serious consequences, including death if left untreated. Light-chain amyloidosis (AL) and hereditary transthyretin-type amyloidosis (hATTR) are two of the most common types. In amyloidosis, peripheral nervous system involvement is a significant diagnostic feature, particularly when it manifests as polyneuropathy, carpal tunnel syndrome (CTS), and dysautonomia. These neurological symptoms often point to the involvement of amyloid deposits in the peripheral and autonomic nervous systems, which can help identify and differentiate between the various types of amyloidosis. Materials and Methods: This retrospective study focused on the evolution of electrophysiological parameters in two groups: AL (n = 22) and hATTR-Glu54Gln patients (n = 14), with mixed axonal polyneuropathy. Patients were followed for two consecutive years to assess disease progression. The PND scale (polyneuropathy disability) was also used to assess motor impairment for each patient. Results: In our study AL amyloidosis patients presented with mixed, axonal polyneuropathy associated with CTS in 63.6% of cases and cardiomyopathy (45.5%). Serial EMGs (electromyography) showed decreased motor amplitudes of the common peroneal and tibial nerves and sensory amplitude of the superficial peroneal nerve, with mostly preserved conduction velocities. The patients maintained stage I PND throughout the monitoring period. The entire hATTR group displayed mixed, axonal polyneuropathy and cardiomyopathy; 85.7% of them had CTS, and 42.9% had orthostatic hypotension. EMG data showed decreased motor amplitudes of the tibial and common peroneal nerves, decreased sensory amplitudes of the superficial peroneal nerve, and mildly reduced conduction velocities, with significant progression at 12 and 24 months. The patients displayed additional reduced muscle strength, some reaching stage 3A and 3B-PND at the end of the study. Conclusions: The amyloidotic polyneuropathy found in the groups was similar in its axonal, sensory-motor, and length-dependent characteristics, but the study showed significant differences in its progression, with more abrupt changes in the hATTR-Glu54Gln group. The amyloidosis AL patients remained in stage 1 PND, while the hATTR-Glu54Gln patients progressed to stage 3 PND at 24 months.