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The design of a potent amyloid-β protein (Aβ) inhibitor plays a pivotal role in the prevention and treatment of Alzheimer's disease (AD). Despite endogenous transthyretin (TTR) being recognized as an Aβ inhibitor, the weak inhibitory and blood brain barrier (BBB) crossing capabilities hinder it for Aβ aggregation inhibition and transport. Therefore, we have herein designed a recombinant TTR by conjugating a cationic cell penetrating peptide (penetratin, Pen), which not only enabled the fusion protein, TTR-Pen (TP), to present high BBB penetration but also greatly enhanced the potency of Aβ inhibition. Namely, the protein fusion made TP positively charged, leading to a potent suppression of Aβ 40 fibrillization at a low concentration (1.5 μM), while a TTR concentration as high as 12.5 μM was required to gain a similar function. Moreover, TP could mitigate Aβ-induced neuronal death, increase cultured cell viability from 72% to 92% at 2.5 μM, and extend the lifespan of AD nematodes from 14 to 18 d. Thermodynamic studies revealed that TP, enriched in positive charges, presented extensive electrostatic interactions with Aβ 40 . Importantly, TP showed excellent BBB penetration performance, with a 10 times higher BBB permeability than TTR, which would allow TP to enter the brain of AD patients and participate in the transport of Aβ species out of the brain. Thus, it is expected that the fusion protein has great potential for drug development in AD treatment.

Background: Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR-CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium-99m-pyrophosphate in individuals diagnosed with hATTR-CM., Methods and Results: We retrospectively analyzed a prospective cohort from the NEURO-TTRansform trial, including patients with hATTR-CM receiving eplontersen (45 mg/4 weeks). A control group comprised patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis, or patisiran. Technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography was conducted at baseline and during follow-up. Thirteen patients with hATTR-CM were enrolled, with 6 receiving eplontersen and 7 serving as the control group. The median follow-up time was 544 days. The eplontersen group exhibited a significant decrease in volumetric heart and lung ratio (3.774 to 2.979, P =0.028), whereas the control group showed no significant change (4.079 to 3.915, P =0.237). Patients receiving eplontersen demonstrated a significantly greater reduction in volumetric heart and lung ratio compared with the control group (-20.7% versus -3.4%, P =0.007)., Conclusions: The volumetric heart and lung ratio used to quantify technetium-99m-pyrophosphate uptake showed a significant reduction subsequent to eplontersen treatment in individuals diagnosed with hATTR-CM. These findings suggest the potential efficacy of eplontersen in treating hATTR-CM and highlight the value of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography as a tool for monitoring therapeutic effectiveness.

Background: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo., Methods: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m 2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level., Results: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients., Conclusions: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.)., (Copyright © 2024 Massachusetts Medical Society.)

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underrecognized cause of heart failure (HF). ATTR-CM can lead to a number of cardiovascular manifestations including HF, rhythm disturbances, and valvular disease that ultimately limit quality of life and prognosis. Due to advances in diagnostic modalities and therapeutic options, the prevalence of ATTR-CM is rising. There are several classes of medications under active investigation, though most therapies are most efficacious if instituted early on in the disease course. As such, early clinical recognition and prompt diagnosis are crucial to improving disease related outcomes. In this review, we highlight clinical manifestations of ATTR-CM as well as contemporary diagnostic and treatment approaches to the disease., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a mutation-based genetic disorder due to the accumulation of unstable transthyretin protein and presents with symptoms of congestive heart failure (CHF) and numerous extracardiac symptoms like carpal tunnel syndrome and neuropathy. Two subtypes of ATTR-CM are hereditary and wild-type, both of which have different risk factors, gender prevalence and major clinical symptoms. Timely usage of imaging modalities like echocardiography, cardiac magnetic imaging resonance, and cardiac scintigraphy has made it possible to suspect ATTR-CM in patients presenting with CHF. Management of ATTR-CM includes appropriate treatment for heart failure for symptomatic relief, prevention of arrhythmias and heart transplantation for nonresponders. With the recent approval of tafamidis in the successful management of ATTR-CM, numerous potential therapeutic points have been identified to stop or delay the progression of ATTR-CM. This article aims to provide a comprehensive review of ATTR-CM and insights into its novel therapeutics and upcoming treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aim: Radical esophagectomy after preoperative neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, careful treatment selection is required when considering organ function in elderly patients. Prealbumin, a rapid turnover protein, is a short-term dynamic nutritional index, and its relationship with long-term postoperative survival in various cancers has been previously reported. However, the association between serum prealbumin level before NAC and survival in elderly patients remains unclear. This study investigated the clinical significance of prealbumin level measurement before NAC in elderly patients with locally advanced ESCC who underwent surgery after NAC., Patients and Methods: Eighty patients aged ≥65 years diagnosed with cStage II/III ESCC and undergoing radical esophagectomy after cisplatin and 5-fluorouracil therapy as NAC, were included. The cutoff value of the serum prealbumin level before NAC was set at 18.2 mg/dl using receiver operating characteristic curve analysis, and postoperative complications, recurrence, and overall survival were compared between the low and high prealbumin groups., Results: There were no differences in patient background, clinicopathological characteristics, postoperative complications, or recurrence-free survival between the two groups. Overall survival (OS) was significantly worse in the low prealbumin group than in the high prealbumin group (5-year survival, 33.3% vs. 67.0%; p=0.0341). Furthermore, on univariate and multivariate analysis, low prealbumin level was an independent poor OS factor (p=0.036)., Conclusion: In elderly patients with locally advanced ESCC, serum prealbumin level before NAC may be a useful prognostic factor and may be important in selecting a treatment strategy that considers individual organ function., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To investigate the conditions of occurrence and factors influencing liver injury caused by molecular targeted drugs and immune checkpoint inhibitors combined with hepatic arterial chemoembolization (TACE) in the treatment of primary liver cancer. Methods: 105 cases of primary liver cancer admitted to the Third Hospital of Hebei Medical University from January 2020 to June 2023 were selected. Patients liver biochemical indicators conditional changes before and after treatment with targeted drugs+TACE and targeted drugs+immune checkpoint inhibitors (ICIs)+TACE were analyzed. Liver injuries above grade 2 and its independent risk factors to predict and evaluate model accuracy were established. Independent samples t-test, analysis of variance, and rank sum test were used for comparison of measurement data between groups. Count data were compared with a χ (2) test between groups. Results: A total of 50 (47.62%) of the 105 cases developed liver injury during the treatment course, with 26 (52%) cases of first-grade liver injury, 16 (32%) cases of second-grade liver injury, 8 (16%) cases of third-grade liver injury, and none of fourth-grade liver injury. There was no statistically significant difference in the incidence of liver injury between the two groups of patients ( χ (2)=1.299, P = 0.637). Multivariate logistic regression analysis showed that total bilirubin, prealbumin, and prothrombin activity were independent risk factors for the occurrence of liver injury. The total bilirubin-prealbumin-prothrombin activity (TAP) model was established. TAP diagnosis of grade 2 or higher liver injury had an area under the receiver characteristic curve of 0.935, sensitivity of 84.35%, and specificity of 92.31% at a cut-off value of 1.24, and significantly better diagnostic performance than albumin-bilirubin (ALBI) grade. Conclusion: The occurrence of severe liver injury is minimal and well tolerated in the targeted drug + TACE treatment group and targeted drug + ICIs + TACE treatment group. The TAP model can be used as a new method to assess the risk of liver injury above grade 2 in patients treated with targeted immunotherapy combined with TACE.

Background: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate., Areas of Uncertainty: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data., Data Sources: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal.", Therapeutic Advances: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72)., Conclusion: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; P =0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; P =0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; P <0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; P =0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; P =0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; P <0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.

Background: The study investigates the nutritional status in children with acute lymphoblastic leukemia (ALL) during chemotherapy treatment because nourishment is substantial, as much as chemotherapy in children with malignant diseases., Material and Method: We enrolled 17 children with ALL (between 1 to 16 year-old, mean age 6.03 ± 4.04 y) from 5 different centers in Istanbul between September 2013 and May 2014. Anthropometric data, prealbumin, B12, and folate levels were assessed, at diagnosis, after the induction phase of chemotherapy, and before maintenance phases of chemotherapy in a longitudinal and prospective study., Results: Patients remarkably lost weight at the end of the induction phase ( P =0.064) and regained this loss before maintenance chemotherapy ( P =0.001). At the end of induction chemotherapy serum prealbumin level ( P =0.002), weight for height ratios ( P =0.016), weight for age ratios ( P =0.019) significantly decreased. From the end of the induction phase to the beginning of maintenance chemotherapy, weight ( P =0.001) and weight for age ( P =0.017) significantly, and weight for height were remarkably elevated ( P =0.076). At the end of the induction phase, serum prealbumin levels were significantly lower ( P =0.048) and below laboratory reference values ( P =0.009) in children younger than 60 months compared with those older. Serum folate levels increased from the end of the induction phase to the beginning of the maintenance phase ( P =0.025). Serum vitamin B12 levels did not alter significantly., Conclusion: There is malnutrition risk at the end of the induction phase of the ALL-BFM chemotherapy regimen; therefore, clinicians should follow up on nutrition closely, especially in under 5-year-old patients. However, before the beginning of the maintenance phase, children start to gain weight, and obesity risk occurs. Thus , further studies are needed to evaluate nutritional status during childhood ALL chemotherapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A recently published expert consensus document recommended a multiparametric tool to monitor cardiac disease progression in patients with transthyretin cardiac amyloidosis (ATTR-CA). We aimed to evaluate the effect of the transthyretin stabiliser drug, tafamidis, by applying this integrative tool., Methods: We retrospectively applied a multiparametric tool in a group of ATTR-CA patients who were given tafamidis between the years 2019-2021 and were followed in a dedicated clinic. We used three pre-specified follow-up timepoints: at 6, 12 and 18 months., Results: We included 16 ATTR-CA patients (wild-type ( n  = 14) and mutant ( n  = 2)). The median age at the initiation of tafamidis was 76 (IQR 70, 84) years and 75% of study patients were classified as NYHA functional class 2 or 3. All patients had elevated levels of high-sensitive troponin T (median 92 (IQR 63, 115) ng/L) and NT-proBNP (median 3784 (2290, 8773) pg/mL). At the end of 18-month follow-up, two patients have suffered from high-grade atrioventricular block and required permanent pacing, and one patient had heart-failure-related admission. Twenty-five percent and 50% of patients were classified as NYHA Class 1 at the initiation of tafamidis and at 18-months treatment, respectively. No patient was defined with disease progression at 6- or 12-month follow up; however, one patient (14%) was defined with a deteriorated disease status at 18-month follow-up., Conclusions: Based on a multiparametric tool, the use of tafamidis promoted disease stabilisation in the majority of patients at 18-month follow-up. Further study should focus on monitoring disease improvement in patients with ATTR-CA.

Background: Cardiac amyloidosis (CA) is a chronic progressive disease caused by the deposition of amyloid fibrils in cardiac tissues. Diagnosis and management of CA are complicated and have developed over the years., Hypothesis: Middle Eastern countries have significant knowledge disparities in diagnosing, managing, and treating different subtypes of CA., Methods: An online survey was sent to cardiologists in four countries (Saudi Arabia, Lebanon, Egypt, and Iraq) interested in heart failure and practicing for more than a year. The survey questioned the characteristics of the participants and their institutions. It addressed their knowledge and practices in CA specifically diagnostic modalities, treatment options, and interest in education and knowledge exchange., Results: A total of 85 physicians participated in the survey. There was a variation in the participating cardiologists' knowledge, experience level, and readiness of their institutes to manage patients with ATTR-CM. Most participants believed that a high rate of ATTR-CM misdiagnosis existed. Participants' knowledge of the diagnostic modalities and "red flags" raising suspicion about ATTR-CM varied. Another challenge was the availability of essential diagnostic modalities among various cardiology centers. A knowledge gap was also observed regarding updates in ATTR-CM management. However, there was a high endorsement of the need for more education, physician networking, and knowledge exchange., Conclusions: This survey highlighted the need for increasing awareness levels among cardiologists in the four selected Middle Eastern countries. Cardiologists are most likely to benefit from additional training and knowledge exchange on the latest management advances of this disease. Thus, measures must be taken to focus on the physician's awareness of ATTR-CM patient journey to achieve a better quality of care and outcome., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis., Research Design and Methods: Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI)., Results: Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: -5.3 [95% confidence interval (CI): -9.4, -1.2; p  = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: -18.3 [95% CI: -28.6, -8.0; p  < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p  = 0.020])., Conclusions: This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Cardiac amyloidosis, in the three forms of immunoglobulin light chain (AL), transthyretin (ATTR) wild type (ATTRwt) and mutated (ATTRv) amyloidosis, is an increasingly known and recognized disease in the cardiovascular setting. The first stage of the patient's journey is the clinical suspicion of the disease, which is placed, in presence of a hypertrophic phenotype, by the identification of red flags, both extracardiac and cardiac clues whose presence increase the probability of being faced with a patient with this disease. The second stage is represented by diagnosis, which occurs with certainty through the identification of amyloid substance in cardiac tissue. This stage is spotted in wo parts, i.e. disease confirmation and disease etiology definition (AL vs ATTRwt vs ATTRv). However, it is possible in some selected cases to make a diagnosis of ATTR without the need for tissue assessment, in presence of a positive grade 2-3 bisphosphonate scintigraphy and absence of monoclonal component. Once the diagnosis has been made, the third stage is the assessment of prognosis, the fourth is the patient therapy pathway and fifth is the follow-up plan. Prognosis evaluation is based on different staging systems at the onset of the disease, whose applicability in the era of new effective therapies is still to be defined. To date, the transthyretin tetramer stabilizer tafamidis is the only approved treatment for both wild-type and mutant ATTR cardiomyopathy without polyneuropathy, while ATTRv with associated neuropathy can benefit from treatment with patisiran, an inhibitor of hepatic protein synthesis. Therapies for complications and comorbidities, must be addressed individually, due to the lack of specific clinical trials on this category of patients. In fact, it is important to take into consideration the risks linked to the use of some drugs due to the infiltration of the conduction tissue by the amyloid substance, which increases the risk of bradycardia and heart blocks, the tendency towards hypotension and the increased thromboembolic risk. It is also essential to follow the course of the disease and the efficacy of the treatment in affected patients with a standardized follow-up, and to identify early the signs/symptoms of the disease in asymptomatic TTR mutation carriers.This ANMCO position paper on amyloidosis aims to provide the clinical cardiologist with a practical summary of the disease, to accompany the patient with amyloidosis in the various stages of his journey.

Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin (ATTR), either in its hereditary (ATTRh) or acquired (ATTRwt) forms. Cardiac amyloidosis has a very poor prognosis if therapy is not started promptly. Therefore, it is very important to recognize cardiac amyloidosis early in order to immediately start a treatment capable of modifying the prognosis. Treatment of cardiac amyloidosis is not easy, often requiring a multidisciplinary team. New RNA-interfering drugs (such as patisiran) have been devised and are effective in the treatment of ATTRh amyloidosis. Tafamidis (a stabilizer of the native tetramer structure of TTR) is recommended to treat patients with genetic testing-proven hereditary hTTR-cardiomyopathy or wild-type TTR cardiomyopathy and NYHA Class I or II to reduce symptoms, CV hospitalization and mortality (Class I, level of evidence B). Patisiran should be considered in ATTRh cardiomyopathy with polyneuropathy. Thus, this review is intended to be a simple practical guide for the treatment of ATTR cardiac amyloidosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

What Is This Plain Language Summary About?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results., What Did Researchers Find Out?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study., What Do the Results Mean?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration : NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration : NCT02791230 (ClinicalTrials.gov).

Background: Domino liver transplantation (DLT) has been commonly used during the last two decades to partly meet the high need for liver transplants. However, the recipients of grafts from patients with noncirrhotic inherited metabolic disorders may ultimately develop metabolic syndrome, and management is usually intricate, being complicated by the underlying initial disorder, other comorbidities, and post-transplantation conditions., Case: We report here the management and the outcome in a patient with acquired transthyretin amyloidosis after DLT and significant comorbidities. Final treatment with a transthyretin gene silencing agent, patisiran, was well tolerated and resulted in remission of the aggravating neurological deficits in a follow-up period of 2 years., Conclusions: The case presented here supports the concept that patisiran can target the hepatocytes producing the mutated transthyretin in acquired transthyretin amyloidosis, as efficiently as in hereditary transthyretin amyloidosis (hATTR), and can be used to treat patients with transthyretin amyloidosis after DLT., (© 2022 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic gain-of function (GOF) disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited and consisted mainly in liver transplantation and TTR-stabilizers. In the last few years, ATTRv has been at the center of major therapeutic breakthroughs, including development of effective small interfering RNA (siRNA) and antisense oligonucleotide (ASO) treatments targeting liver TTR mRNA. Both siRNA (patisiran) and ASO (inotersen) treatments are now commercially available and have dramatically improved ATTRv neurological outcome. Ongoing clinical trials currently evaluate another siRNA, vutrisiran and a novel ASO formulation, eplontersen. A CRISPR-Cas9-based TTR gene editing treatment is also currently evaluated, with encouraging preliminary results. These recent therapeutic developments demonstrate the shifting paradigm of ATTRv, a previously untreatable and lethal disorder and provide a proof-of-concept for developing siRNA, ASO and CRISPR-Cas9 treatments for other GOF genetic disorders., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, rapidly progressing, and potentially life-threatening disease caused by one of more than 120 mutations in the transthyretin (TTR) gene. As a result of the cumulative amyloid deposits, especially in the peripheral nerves and the heart, the majority of patients develop progressive, peripheral sensorimotor polyneuropathy and biventricular cardiomyopathy over time.Since TTR - and its amyloidogenic variants too - is predominantly synthesized in the liver, early, orthotopic liver transplantation (LTx) is a treatment option that can be used to potentially stop the progression of hATTR amyloidosis.The actual case shows a patient with hepatocellular carcinoma who received the organ of a patient with hATTR as part of a domino liver transplantation. After approximately 10 years, the patient started to develop the characteristic symptoms of the metabolic disorder. Because of a further progression of the amyloidosis, therapy with the RNA interference therapeutic patisiran was initiated, which temporarily halted the progression., Competing Interests: Ali Yilmaz: Vorträge und Berater bei Pfizer, Alnylam, Akcea Matthias Schilling: Berater (Advisory Board) bei Pfizer, Alnylam, Akcea Christoph Röcken: Vorträge und Berater bei Pfizer, Alnylam, Akcea Hartmut Schmidt: Vorträge und Berater bei Pfizer, Alnylam, Akcea, (Thieme. All rights reserved.)

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 10 13 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly widespread medical condition, with excessive morbidity and mortality. Recently, for the first time in HFpEF, a reduction in the primary composite outcome of cardiovascular death or HF hospitalization was shown with empagliflozin. The failure of previous clinical trials in HFpEF might have resulted from suboptimal patient selection and inclusion of patients without "true" or clinically significant HFpEF. Another important factor might be the heterogeneity of HFpEF, and thus there is a growing interest in HFpEF phenotyping. This phenotyping can be based on clinical presentation (e.g., subtypes with predominant atrial fibrillation, obesity, pulmonary hypertension and right ventricular failure, coronary artery disease (CAD), or noncardiac comorbidities), but also on HFpEF etiology. Specific therapies, such as tafamidis in transthyretin-related amyloidosis (ATTR) or mavacamten in hypertrophic cardiomyopathy, have demonstrated their efficacy. However, pathomechanisms leading to the development of different phenotypes of HFpEF seem more complex and subtle. Machine learning and neural network models might help identify specific subgroups within the HFpEF population that either cluster patients with similar genetic, biochemical, echocardiographic or clinical characteristics, or respond similarly to a given treatment. Herein, we review different approaches to HFpEF phenotyping and present some distinct HFpEF subtypes.

Introduction/aims: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures., Methods: The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms., Results: Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item "Pain kept you awake at night") to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and "Pain kept you awake at night" (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001)., Discussion: Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain., (© 2022 Wiley Periodicals LLC.)

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver and secreted into the plasma. TTR molecules can misfold and form amyloid fibrils in the heart and peripheral nerves, either as a result of gene variants in TTR or as an ageing-related phenomenon, which can lead to amyloid TTR (ATTR) amyloidosis. Some of the proposed strategies to treat ATTR amyloidosis include blocking TTR synthesis in the liver, stabilizing TTR tetramers or disrupting TTR fibrils. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) technologies have been shown to be highly effective for the blockade of TTR expression in the liver in humans. The siRNA patisiran and the ASO inotersen have been approved for the treatment of patients with ATTR variant polyneuropathy, regardless of the presence and severity of ATTR cardiomyopathy. Preliminary data show that therapy with patisiran improves the cardiac phenotype rather than only inducing disease stabilization in patients with ATTR variant polyneuropathy and concomitant ATTR cardiomyopathy, and this drug is being evaluated in a phase III clinical trial in patients with ATTR cardiomyopathy. Furthermore, ongoing phase III clinical trials will evaluate another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR variant polyneuropathy or ATTR cardiomyopathy. In this Review, we discuss these approaches for TTR silencing in the treatment of ATTR amyloidosis as well as the latest strategy of genome editing with CRISPR-Cas9 to reduce TTR gene expression., (© 2022. Springer Nature Limited.)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a debilitating and life-threatening condition with a heterogeneous clinical presentation. Recent guidelines from the United States and Europe have been published to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies for patients with ATTR-CM. These guidelines highlight the importance of an early diagnosis to optimize therapeutic outcomes, specifying the use of tests and imaging techniques to allow accurate, noninvasive diagnosis of ATTR-CM. However, as regional practice variations across Asia may limit access to healthcare, availability of specific tests, and expertise in assessing diagnostic images, there is an ongoing need to provide an Asian perspective on these clinical guidelines. This review article provides practical recommendations for the diagnosis and monitoring of patients with ATTR-CM in Asia, highlighting the need for additional guidelines to support a broad and diverse population, consider differing healthcare systems and diagnostic testing availability, and provide a flexible yet robust algorithm., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Aim: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed that tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to estimate the impact of tafamidis on survival and quality-adjusted life-years (QALYs)., Methods and Results: A multi-state, cohort, Markov model was developed to simulate the disease course of ATTR-CM throughout a lifetime. For survival extrapolation, survival curves were fitted by treatment arm and New York Heart Association (NYHA) Class I/II (68% of patients) and NYHA Class III (32% of patients) cohorts using the individual patient-level data from both the ATTR-ACT and the corresponding long-term extension study. Univariate and multivariate sensitivity analyses were conducted. The predicted mean survival for the total population (NYHA Class I/II + III) was 6.73 years for tafamidis and 2.85 years for the standard of care (SoC), resulting in an incremental mean survival of 3.88 years [95% confidence interval (CI) 1.32-5.66]. Of the 6.73 life-years, patients on tafamidis spend, on average, 4.82 years in NYHA Class I/II, while patients on SoC spend an average of 1.60 life-years in these classes. The combination of longer survival in lower NYHA classes produced a QALY gain of 5.39 for tafamidis and 2.11 for SoC, resulting in 3.29 incremental QALYs (95% CI 1.21-4.74) in favour of tafamidis., Conclusion: Based on the disease simulation model results, tafamidis is expected to more than double the life expectancy and QALYs of ATTR-CM patients compared to SoC. Longer-term follow-up data from the ATTR-ACT extension study will further inform these findings., Clinical Trials.gov Identifier: NCT01994889 (date of registration: 26 November 2013)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multi-systemic disease with clustering areas in, for example, northern Sweden. Until the 1990s, only symptomatic treatments were available but liver transplantation has, in selected patients, been a good therapeutic option since. The first disease-modifying drug for ATTRv amyloidosis was approved in 2011 and since then, the development of new therapeutic drugs has been rapid and successful. Two gene silencing therapies were approved for the disease in 2018, both showing a robust reduction in serum transthyretin levels and a satisfactory safety profile. Recently, CRISPR-Cas9 gene editing has also shown promising results in patients with ATTRv amyloidosis. The recent developments have had a paramount effect on the management of these patients, and will probably also have a significant positive effect on their life expectancy. However, treatment costs have skyrocketed, which implies future challenges.

Hereditary transthyretin-related amyloidosis (ATTRv) is a rare autosomal dominant disease and is fatal if left untreated. It is caused by mutations in the transthyretin gene. All known mutations induce misfolding of the tetrameric transthyretin molecule and protein deposits in multiple organs. In peripheral nerves this result in sensorimotor and autonomic polyneuropathy and in cardiac muscle it causes cardiomyopathy. Untreated ATTRv is characterized by an irreversible and progressive course and death 7-11 years after symptom onset. Treatment options consist of TTR stabilizing drugs, such as tafamidis and active agents that selectively interfere at the mRNA level, the so-called gene silencers patisiran and inotersen. All forms of treatment aim to prevent amyloid tissue deposition in tissues and organ dysfunction. Patisiran works by RNA interference on endogenous mechanisms of gene expression. It results in the cleavage of TTR-mRNA using the cytoplasmatic RNA-induced silencing complex. Inotersen, an antisense oligonucleotide, degrades TTR-mRNA via activation of nuclear RNase H. Both mechanisms result in a significant reduction of TTR protein serum levels. The efficacy could be demonstrated by slowing or improving neuropathy progression in the phase III study APOLLO (patisiran) or the NEURO-TTR study (inotersen). Furthermore, the use of both agents led to an improvement in the quality of life in patients with ATTRv. Both forms of treatment are approved in Germany since August 2018 for polyneuropathy stages 1 and 2 according to Coutinho. The choice of treatment should be carried out individually considering drug formulation, contraindications and the necessary safety monitoring controls., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Aims: Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring., Methods and Results: ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0-11.0] months, 20 mg: 11.0 (IQR 8.0-18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m2, P = 0.304; 20 mg: 114.5 vs. 115.4 g/m2, P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0-21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m2, P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]., Conclusion: Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807)., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: This review aims to serve as a practical guide for differentiating the two most common forms of cardiac amyloidosis, as well as reviewing the approach to diagnosis and management, particularly as it pertains to transthyretin cardiac amyloidosis., Recent Findings: Emerging literature continues to unravel new understandings and challenges in the field of cardiac amyloidosis. Although cardiac amyloidosis has historically been thought of as a 'zebra diagnosis', current evidence has shown that this is a common cause of heart failure. Furthermore, it has become increasingly apparent that earlier diagnosis leads to improved outcomes and quality of life for patients., Summary: By leveraging an understanding of the pathophysiology leading to amyloid fibril formation, new drug therapeutics are under investigation as promising candidates for the treatment of amyloid cardiomyopathy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Advancement in the diagnosis and treatment of transthyretin amyloid cardiomyopathy has made great strides in recent years. Novel therapeutics for transthyretin amyloidosis such as tafamidis, patisiran, and inotersen have shown significant benefits in a not-so-rare disease but come with high listing price tags ranging from a quarter to more than a half million dollars per year. These costs create significant financial barriers for the majority of patients, especially those with existing Medicare insurance plans. Of 72 patients reviewed, 67% were Medicare beneficiaries. Financial assistance was explored for the majority, and 37 (51%) patients with Medicare Part D received financial assistance that reduced their copayments to $0. Only one-third of our patients were able to afford these medications without any forms of financial assistance. Of these patients, 4 (6%) had the highest copayments ranging from $13 000 to $15 000 per year. To navigate the complexities of prescribing and affordability in amyloidosis, a multidisciplinary team including a dedicated clinical pharmacist is crucial in guaranteeing patients' success to secure these novel therapeutics. In this article, we discuss our experiences with prescribing, acquiring insurance authorizations, and financing these life-saving medications based on patient-specific insurance plans and socioeconomic status.

Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA). The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene ( TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials., Competing Interests: Jignesh Patel is a consultant for Pfizer, Alnylam, Akcea, and BridgeBio. Lily Stern has no competing interests to declare., (Copyright: © 2022 The Author(s).)

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy is a rare, inherited, multisystem, and often fatal disease caused by a variant in transthyretin (TTR) gene. Baseline characteristics of patients, especially anthropometric data, are scarce in the literature, and they are relevant to define effective treatment strategies., Objective: This study aimed to describe baseline demographic, anthropometric, and disease characteristics in a cohort of patients from a reference center in Brazil., Methods: Symptomatic patients not previously included in clinical trials and eligible for treatment were enrolled. Ethnicity, state of residence, age, sex, weight, height, body mass index (BMI), TTR variant, and Polyneuropathy Disability Score (PND) at diagnosis were analyzed., Results: Among the 108 patients enrolled, 58.33% were male, 60.19% were Caucasian, and 83.33% lived in the Southeast region. Mean age was 51.61 (±16.37) years, mean weight was 65.76 (±15.16) kg, mean height was 168.33 (±10.26) cm, and mean BMI was 23.11 (±4.45) kg/m2. The most prevalent variant was V30M (86.11%). Patients with PND score 0 presenting autonomic neuropathy were 14.81%. Patients with PND score I-II and III-IV were 52.78 and 32.41%, respectively. Mean weight and BMI were significantly lower in patients with sensory-motor manifestations., Conclusions: This is the largest cohort of patients in Brazil for whom anthropometric characteristics have been described. Baseline demographic, anthropometric, and disease data indicate that delay in diagnosis of hATTR amyloidosis with polyneuropathy is still a problem and that efforts must be made to expedite diagnosis and maximize opportunities for new disease-modifying treatments.

This plain language summary describes the results of a study called ATTR-ACT, which was published in the American Journal of Cardiology . In ATTR-ACT, researchers looked at the effects of tafamidis treatment in people with transthyretin amyloid cardiomyopathy (called ATTR-CM for short). Tafamidis is currently available in the USA and other countries as an oral treatment for adults with ATTR-CM. In ATTR-ACT, 441 people with ATTR-CM from 13 different countries took either tafamidis or placebo by mouth for 30 months. First, researchers looked at the effects of tafamidis on the risk of death and hospitalization due to heart problems between the start and the end of the study; they found that these risks were about one-third lower with tafamidis compared with placebo. As described in this summary, researchers also looked at the effects of tafamidis on people's heart failure symptoms, quality of life, and general health over the 30-month study. People who took part in ATTR-ACT rated these effects using questionnaires filled out before, during, and after the study. More people who took tafamidis saw improvement or no change in their heart failure symptoms and quality of life than people who took placebo. In addition, compared with people taking placebo, people taking tafamidis had less worsening of their general health during the study. These results show the benefits of tafamidis in reducing the declines in quality of life and health that often occur with this debilitating disease. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov).

Objective: To investigate a potential association between beta-blocker exposure and survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM)., Methods: In this real-world prospective registry of 128 consecutive patients with ATTR-CM recruited in 7 institutions in Galicia (Spain), survival of 65 patients who received beta blockers on registry enrollment was compared with that of 63 untreated controls by means of both unweighted Cox regression and Cox regression with inverse probability of treatment weighting. Tolerance to and adverse effects of beta blockers were recorded. Median study follow-up was 520 days., Results: Patients with ATTR-CM who received beta blockers showed statistically significant lower all-cause mortality than untreated controls as evaluated by either unweighted Cox regression (hazard ratio, 0.31; 95% CI, 0.12 to 0.79) or Cox regression with inverse probability of treatment weighting (hazard ratio, 0.18; 95% CI, 0.08 to 0.41; P<.001). Several sensitivity analyses confirmed the internal validity of these results. The overall frequency of beta-blocker suspension due to adverse effects was 25% (95% CI, 15.5% to 34.5%)., Conclusion: In this real-world, prospective, multi-institutional registry, patients with ATTR-CM who received beta blockers had lower all-cause mortality than untreated controls., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

This clinical practice guideline for treating transthyretin amyloid (ATTR) cardiomyopathy is based on the best available evidence of clinical effectiveness. The PICO format was used to generate a list of questions focused on the effectiveness and safety of the specific treatment of patients with ATTR cardiomyopathy. The search was conducted in PubMed, Cochrane and Epistemokus, between July-August 2020, and selected articles between 2000-2020, in English and Spanish. The level of evidence and recommendations were analyzed and classified by the GRADE system. The following drugs were included in the analysis: tafamidis, diflunisal, inotersen, patisiran y doxycycline and ursodeoxycholic acid. The expert panel had an agreement that tafamidis 80mg/daily is the only available drug with moderate evidence and weak recommendation for the reduction of total mortality, cardiovascular morbidity, heart failure hospitalization and progression of the disease in patients with ATTR cardiomyopathy and NYHA class = 3. In contrast, tafamidis 20 mg/daily had low-quality evidence in this group of patients. The expert panel did not recommend inotersen, patisiran and diflunisal in patients with ATTR cardiomyopathy due to the lack of supporting evidence, local drug availability, and the potential risk of toxicity. When patients did not have access to tafamidis, the expert panel stated a weak recommendation to use doxycycline and ursodeoxycholic acid in patients with ATTR cardiomyopathy.

This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evidence of clinical effectiveness. A list of questions was generated with a PICO format focused on the effectiveness and safety of the treatment of familial amyloid polyneuropathy. The search was carried out in PubMed, Cochrane and Epistemonikos. The levels of evidence and grades of recommendation were based on the GRADE system. Recommendations were graded according to their direction and their strength and were evaluated with the GLIA tool for their implementation. In patients with familial amyloid polyneuropathy and stage I and II neuropathy, it is suggested: inotersen 300 mg subcutaneous weekly or patisirán 0.3 mg/kg intravenously once every 3 weeks, since they probably stabilize or slow the progression of neuropathy and worsening quality of life (moderate quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and stage I neuropathy, treatment with tafamidis 20 mg orally, once a day, is suggested, as it could slow the progression of neuropathy and worsen quality of life (low quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and symptomatic neuropathy and in the absence of other treatments with approved efficacy, treatment with oral diflunisal 250 mg twice daily is suggested, as it could prevent the progression of neuropathy (quality evidence low; strength of recommendation weak).

The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis. Recently approved agents and drugs currently under investigation not only represent a major breakthrough in this field but also provide validation of the therapeutic potential of innovative approaches, like RNA interference and CRISPR-Cas9-mediated gene editing, in rare inherited disorders. In this review, we describe the evolving therapeutic landscape for hereditary transthyretin amyloidosis and discuss how this highly disabling and fatal condition is turning into a treatable disease. We also provide an overview of the molecular mechanisms involved in transthyretin (TTR) amyloid formation and regression, to highlight how a deeper understanding of these processes has contributed to the identification of novel treatment targets. Finally, we focus on major areas of uncertainty and unmet needs that deserve further efforts to improve long-term patients' outcomes and allow for a brighter future., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Autonomic neuropathies represent a complex group of disorders that preferentially target autonomic fibers and can be classified as either acute/subacute or chronic in onset. Acute-onset autonomic neuropathies manifest with such conditions as paraneoplastic syndromes, Guillain-Barre syndrome, Sjögren syndrome, infection, or toxins/chemotherapy. When the presentation is acute, immune-mediated, and without a secondary cause, autoimmune autonomic ganglionopathy is likely, and should be considered for immunotherapy. Of the chronic-onset forms, diabetes is the most widespread and disabling, with autonomic impairment portending increased mortality and cardiac wall remodeling risk. Acquired light chain (AL) and transthyretin (TTR) amyloidosis represent two other key etiologies, with TTR amyloidosis now amenable to newly-approved gene-modifying therapies. The COMPASS-31 questionnaire is a validated outcome measure that can be used to monitor autonomic severity and track treatment response. Symptomatic treatments targeting orthostatic hypotension, among other symptoms, should be individualized and complement disease-modifying therapy, when possible., (© 2020 by the American Association of Neuromuscular & Electrodiagnostic Medicine, Inc. All rights reserved.)

Objective: To evaluate the clinical value of serum amyloid A (SAA1/2) and misfolded transthyretin (TTR) for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients., Methods: 30 R/R DLBCL patients were enrolled as observation group, 20 remission/stabilization DLBCL and 10 chronic lymphadenitis patients were enrolled as control group. SELDI technique, Tris-Tricine sodium dodecyl sulfate-polyacrylamide gel electro-phoresis, the shotgun-LTQ-MS method, and bioinformatics technique were used to detected and analyzed SAA and TTR in R/R DLBCL patients. SPSS 21.0 software was used to analyze the relationship between the high expression of SAA, misfolded TTR in serum and the clinicopathological features, survival time of R/R DLBCL. patients Chi-square test was used to analyze clinical count data, Kaplan-Meier curve was used for survival analysis, and Log-Rank test was used to compare single-factor survival differences., Results: The high expression of SAA and TTR (SAA + TTR + ) was significantly associated with extranodal lesion, high level of LDH, and NCCN-IPI scores, and also correlated with non-GCB type. TTR + was correlated with C-MYC in pathological tissue, while SAA + was also associated with B-symptoms. The survival time of patients in SAA + , TTR + , and SAA + TTR + group were shorter than that in control group., Conclusion: Both SAA and misfolded TTR are poor prognosis factors of R/R DLBCL patients.

Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis., Competing Interests: Competing interests: AMR has received support from Alnylam UK Limited to attend scientific meetings and an honorarium for speaking at a sponsored symposium., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Ocrelizumab (Ocrevus), an anti-CD20 monoclonal antibody, has been approved for the treatment of multiple sclerosis. Eculizumab (Soliris) has been approved in several countries for refractory forms of generalized seropositive severe myasthenia gravis. A form of gene therapy, patisiran, has shown positive results in transthyretin familial amyloidosis. In the treatment of headaches, particularly migraines, non-pharmacological approaches have shown some interesting results. The criteria for Lewy body dementia have been revised. Generic use of lamotrigine does not result in recrudescence of epileptic seizures or adverse effects., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The heart is an organ often occupied by various forms of amyloidosis; cardiomyopathies are the leading cause of mortality in patients with amyloidosis. Cardiac amyloidosis is often diagnosed late because of nonspecific symptoms and missed early signs in the imaging routine. A method for treating cardiac amyloidosis depends on the type of amyloid protein. In the treatment of amyloidosis associated with immunoglobulins systemic chemotherapy is used without transplant or stem cell transplantation and in the treatment of familial transthyretin amyloidosis liver transplantation is used. There are still clinical studies on the use of siRNA for the treatment of cardiomyopathy associated with transthy retin amyloidosis, and on the use of amyloid protein stabilizers. The prognosis depends on the type of amyloid protein; worse results observed in the case of light chain amyloidosis. Care support is the cornerstone of treatment; it is expected that advances in cardiac imaging and proteomics positive impact on our ability to diagnosis, prognosis and treatment outcomes of amyloidosis of the heart.

Transthyretin (TTR) is a 127-residue homotetrameric beta-sheet-rich protein that transports thyroxine in the blood and cerebrospinal fluid. The deposition of fibrils and amorphous aggregates of TTR in patients' tissues is a hallmark of TTR amyloid disease. Familial amyloidotic polyneuropathy is a hereditary form of TTR amyloidosis that is associated with one among 80 different variants of TTR. The most aggressive variants of TTR are V30M, L55P, and A25T, and the propensity to undergo aggregation seems to be linked to tetramer stability. T119M is a very stable, non-amyloidogenic variant of TTR. Here we show that the combination of high hydrostatic pressure with subdenaturing concentrations of urea (4 m) at 1 degrees C irreversibly dissociates T119M into monomers in less than 30 min in a concentration-dependent fashion. After pressure and urea removal, long lived monomers are the only species present in solution. We took advantage of the slow reassociation kinetics of these monomers into tetramers to produce heterotetramers by mixing the T119M monomers with the tetramers of the aggressive mutants of TTR. Our data show that T119M monomers can be successfully incorporated into all of these tetramers even when the exchange is performed in a more physiological environment such as human plasma; these monomers render the resultant heterotetramers less amyloidogenic. The data presented here are relevant for the understanding of T119M folding and association reactions and provide a protocol for producing T119M monomers that function as inhibitors of TTR aggregation when incorporated in to tetramers. This protocol may provide a new strategy for treating TTR diseases for which there is no therapy available other than liver transplantation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid beta-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T(4) and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1-14) and (15-42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an alphaAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted alphaAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology.

Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (Abeta(1-42)) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with Abeta in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and Abeta aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic Abeta aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.