• cardiac amyloidosis
• light chain amyloidosis
• mitochondria damage transthyretin amyloidosis

• Humans
• Amyloid Neuropathies, Familial/physiopathology
• Cardiomyopathies/physiopathology
• Cardiomyopathies/etiology
• Cardiomyopathies/therapy
• Heart Failure/physiopathology
• Heart Failure/etiology
• Immunoglobulin Light-chain Amyloidosis/physiopathology

• ATTRv amyloidosis
• Baseline NIS quartiles
• Disability
• Neuropathy severity
• Nutritional status
• Polyneuropathy
• Quality of life
• RNA interference
• Vutrisiran

• Alnylam Pharmaceuticals

• Gastroenterologists
• Gastrointestinal manifestations
• Hereditary transthyretin amyloidosis
• Patients management

• Humans
• Amyloid Neuropathies, Familial/diagnosis
• Amyloid Neuropathies, Familial/therapy
• Amyloid Neuropathies, Familial/genetics
• Italy
• Gastrointestinal Diseases/diagnosis
• Gastrointestinal Diseases/therapy
• Genetic Testing
• Surveys and Questionnaires
• Gastroenterology

• bone-avid tracer
• case report
• computed tomography
• core needle biopsy
• gluteus medius muscle
• wild-type transthyretin amyloidosis

• Humans
• Amyloid Neuropathies, Familial/pathology
• Amyloid Neuropathies, Familial/diagnostic imaging
• Amyloid Neuropathies, Familial/diagnosis
• Amyloid Neuropathies, Familial/metabolism
• Biopsy
• Buttocks/pathology
• Buttocks/diagnostic imaging
• Cardiomyopathies/pathology
• Cardiomyopathies/diagnostic imaging
• Cardiomyopathies/metabolism
• Cardiomyopathies/diagnosis
• Muscle, Skeletal/pathology
• Muscle, Skeletal/diagnostic imaging
• Muscle, Skeletal/metabolism
• Prealbumin/genetics
• Prealbumin/metabolism
• Radiopharmaceuticals
• Technetium Tc 99m Pyrophosphate
• Tomography, X-Ray Computed

• amyloid transthyretin
• amyloidosis treatment
• hereditary transthyretin amyloidosis
• management of hereditary amyloidosis
• rna interference therapeutic
• transthyretin amyloidosis

• Humans
• Male
• Female
• Hypertrophy, Left Ventricular/physiopathology
• Hypertrophy, Left Ventricular/etiology
• Middle Aged
• Hypertension/physiopathology
• Hypertension/surgery
• Hypertension/complications
• Biomarkers/blood
• Coronary Artery Disease/surgery
• Coronary Artery Disease/complications
• Echocardiography/methods
• Aged
• Kidney/innervation
• Blood Pressure/physiology
• Matrix Metalloproteinases/blood
• Sympathectomy/methods

• ATTRv amyloid neuropathy
• ATTRv amyloidosis with polyneuropathy
• diagnosis guidelines
• hereditary transthyretin-mediated (hATTR) amyloidosis
• treatment recommendations

• Humans
• Amyloid Neuropathies, Familial/complications
• Amyloid Neuropathies, Familial/diagnosis
• Amyloid Neuropathies, Familial/genetics
• Polyneuropathies/diagnosis
• Polyneuropathies/therapy
• Aggression
• Biopsy
• Prealbumin/genetics

• Alnylam® Pharmaceuticals

• transthyretin amyloidosis
• ocular and periocular tissues
• conjunctival ttr deposits

• Humans
• Animals
• Swine
• Aged
• Plaque, Amyloid
• Amyloid Neuropathies, Familial/diagnosis
• Amyloid Neuropathies, Familial/drug therapy
• Amyloid Neuropathies, Familial/genetics
• Congo Red/therapeutic use
• Conjunctiva

• ATTRv amyloidosis
• Nutritional status
• Physical function
• Polyneuropathy
• Quality of life
• RNA interference
• Vutrisiran
• hATTR amyloidosis

• Alnylam Pharmaceuticals

• ATTRv amyloidosis
• Amyloidotic polyneuropathy
• Diffusion tensor imaging
• Magnetic resonance neurography
• Transthyretin amyloidosis

• Humans
• Middle Aged
• Aged
• Diffusion Tensor Imaging/methods
• Cross-Sectional Studies
• Sciatic Nerve/diagnostic imaging
• Amyloid Neuropathies, Familial/complications
• Amyloid Neuropathies, Familial/diagnostic imaging
• Magnetic Resonance Imaging/methods
• Polyneuropathies
• Magnetic Resonance Spectroscopy

• Pfizer
• Università degli Studi di Brescia

• Amyloid fibril tissue
• Metabolite database
• Optical diagnostic
• Raman spectroscopy
• SAXS
• β-pleated amyloid

• AL
• Amyloidosis
• renal transplantation
• stem cell transplantation

• ATTRv amyloidosis
• RNA interference
• hATTR amyloidosis
• patisiran
• vutrisiran

• ATTR
• Amyloidosis
• Bone scintigraphy
• Polyneuropathy

• Humans
• Amyloid Neuropathies, Familial
• Carboxylic Acids/pharmacology
• Organotechnetium Compounds
• Polyneuropathies
• Prealbumin
• Retrospective Studies
• Tomography, X-Ray Computed

• Medical University of Vienna

• biopsy
• cardiac amyloidosis (CA)
• diagnosis
• pathology
• proteomics

Point mutations of the transthyretin (TTR) gene are related with hereditary amyloidosis (hATTR). The number of people affected by this rare disease is only partially estimated. The real impact of somatic mosaicism and other genetic factors on expressivity, complexity, progression, and transmission of the disease should be better investigated. The relevance of this rare disease is increasing and many efforts have been made to improve the time to diagnosis and to estimate the real number of cases in endemic and non-endemic areas. In this context, somatic mosaicism should be better investigated to explain the complexity of the heterogeneity of the hATTR clinical features, to better estimate the number of new cases, and to focus on early and personalized gene therapy. Gene therapy can potentially improve the living conditions of affected individuals and is one of the central goals in research on amyloidosis related to the TTR gene, with the advantage of overcoming liver transplantation as the sole treatment for hATTR disease.

• Amyloidosis
• autonomic nervous system
• neuropathy
• registry
• transthyretin

• ATTR variants
• TTR amyloidosis
• hereditary amyloidosis
• oligomer toxicity
• protein misfolding
• wild-type amyloidosis

• Amyloid/metabolism
• Amyloid Neuropathies, Familial/etiology
• Amyloid Neuropathies, Familial/metabolism
• Amyloid Neuropathies, Familial/pathology
• Animals
• Humans
• Mutation
• Prealbumin/genetics

• Monoclonal gammopathy
• POEMS syndrome
• Paraprotein
• Plasma cell dyscrasia
• Uncompacted myelin lamellae
• Widely spaced myelin

• Humans
• Neural Conduction
• POEMS Syndrome/diagnosis
• POEMS Syndrome/therapy
• Paraproteinemias/complications
• Paraproteinemias/diagnosis
• Paraproteinemias/therapy
• Peripheral Nerves
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy

• 20FC1030 the ministry of health, labour and welfare of japan

• Angiogenesis
• Cardiac amyloidosis
• Endothelial progenitor cells
• Transthyretin

• Amyloidosis/diagnosis
• Amyloidosis/therapy
• Cardiomyopathies/diagnostic imaging
• Cardiomyopathies/therapy
• Humans

Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer’s disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer’s disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.

• AA amyloidosis
• AL amyloidosis
• ATTR amyloidosis
• Alzheimer’s disease
• Parkinson’s disease
• amyotrophic lateral sclerosis
• dementia
• pathology
• prion
• transthyretin

• Amyloid/metabolism
• Amyloidosis/physiopathology
• Amyloidosis/therapy
• Animals
• Humans
• Organ Specificity
• Protein Aggregates
• Schwann Cells/pathology

Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

• chemotherapy
• diflunisal
• electron microscopy
• inotersen
• neurodegeneration
• pathogenesis
• pathology
• patisiran
• plasma cell dyscrasia
• tafamidis

• Alzheimer’s disease
• Amyloid-β oligomers
• ROS
• acetylcholinesterase
• antioxidant activity
• limonene
• neuroprotection
• potassium channels

Amyloidosis caused by systemic deposition of transthyretin (TTR) is called ATTR amyloidosis and mainly includes hereditary ATTR (ATTRv) amyloidosis and wild-type ATTR (ATTRwt) amyloidosis. Until recently, ATTRv amyloidosis had been considered a disease in the field of neurology because neuropathic symptoms predominated in patients described in early reports, whereas advances in diagnostic techniques and increased recognition of this disease revealed the presence of patients with cardiomyopathy as a predominant feature. In contrast, ATTRwt amyloidosis has been considered a disease in the field of cardiology. However, recent studies have suggested that some of the patients with ATTRwt amyloidosis present tenosynovial tissue complications, particularly carpal tunnel syndrome, as an initial manifestation of amyloidosis, necessitating an awareness of this disease among neurologists and orthopedists. Although histopathological confirmation of amyloid deposits has traditionally been considered mandatory for the diagnosis of ATTR amyloidosis, the development of noninvasive imaging techniques in the field of cardiology, such as echocardiography, magnetic resonance imaging, and nuclear imaging, enabled nonbiopsy diagnosis of this disease. The mechanisms underlying characteristic cardiac imaging findings have been deciphered by histopathological studies. Novel disease-modifying therapies for ATTR amyloidosis, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotides, were initially approved for ATTRv amyloidosis patients with polyneuropathy. However, the indications for the use of these disease-modifying therapies gradually widened to include ATTRv and ATTRwt amyloidosis patients with cardiomyopathy. Since the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, occurred, the minimization of hospital visits and telemedicine have become increasingly important. As older age and cardiovascular disease are major factors associated with increased disease severity and mortality of COVID-19, many ATTR amyloidosis patients are at increased risk of disease aggravation when they are infected with SARS-CoV-2. From this viewpoint, close interspecialty communication to determine the optimal interval of evaluation is needed for the management of patients with ATTR amyloidosis.

• Amyloid angiopathy
• Cardiac amyloidosis
• Inotersen
• Patisiran
• Positron emission tomography
• Protein misfolding disease
• Red flag
• Scintigraphy
• Tafamidis
• Treatment

• amyloidosis
• cardiomyopathy
• light chains
• peripheral neuropathy
• transthyretin

Hereditary transthyretin amyloidosis (ATTRv) is a condition with adult onset, caused by mutation of the transthyretin (TTR) gene and characterized by extracellular deposition of amyloid fibrils in tissue, especially in the peripheral nervous system (PNS) and heart. PNS involvement leads to a rapidly progressive and disabling sensory‐motor axonal neuropathy. Although awareness among neurologists increased in recent years thanks to new treatment options, ATTRv is frequently misdiagnosed, and thus a correct diagnosis can be delayed by several years. This review aims to draw the history and features of polyneuropathy in ATTRv based on pathological and electrophysiological correlates. We assessed original articles and case reports based on their relevance to ATTRv neuropathy and we included those appropriate for the scheme of this narrative review. Amyloid fibrils initially deposit in ganglia, causing an axonal neuropathy without amyloid deposits in distal segments (eg, sural nerve biopsy). Over time, amyloid fibrils spread along the nerves, leading to some demyelinating features in the context of severe axonal loss. This review highlights how the features of neuropathy change based on type of ATTRv (early vs late onset) and stage of disease.

• hereditary transthyretin-mediated amyloidosis
• neuropathology
• neuropathy
• review

Waste valorization represents one of the main social challenges when promoting a circular economy and environmental sustainability. Here, we evaluated the effect of the polyphenols extracted from apple peels, normally disposed of as waste, on the amyloid aggregation process of κ-casein from bovine milk, a well-used amyloidogenic model system. The effect of the apple peel extract on protein aggregation was examined using a thioflavin T fluorescence assay, Congo red binding assay, circular dichroism, light scattering, and atomic force microscopy. We found that the phenolic extract from the peel of apples of the cultivar “Fuji”, cultivated in Sicily (Caltavuturo, Italy), inhibited κ-casein fibril formation in a dose-dependent way. In particular, we found that the extract significantly reduced the protein aggregation rate and inhibited the secondary structure reorganization that accompanies κ-casein amyloid formation. Protein-aggregated species resulting from the incubation of κ-casein in the presence of polyphenols under amyloid aggregation conditions were reduced in number and different in morphology.

• fruit waste
• polyphenolic extract
• κ-casein amyloid aggregation

• Amyloid/chemistry
• Caseins/chemistry
• Malus/chemistry
• Microscopy, Atomic Force

• central sensitization
• gene silencing
• hereditary pain diseases
• pain mechanisms
• sensory modulation disorder
• sodium channelopathies

Systemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.

• Amyloidosis
• Endomyocardial biopsy
• Magnetic resonance imaging
• Myocardium
• Scintigraphy

• amyloid polyneuropathy
• carrier
• hereditary transthyretin amyloidosis
• intraepidermal nerve fiber
• median nerve
• transthyretin

Matrix metalloproteinases (MMPs) are identified as modulators of the extracellular matrix in heart failure progression. However, evidence for intracellular effects of MMPs is emerging. Pro- and anti-hypertrophic cardiac effects are described. This may be due to the various sources of different MMPs in the heart tissue. Therefore, the aim of the present study was to determine the role of MMPs in hypertrophic growth of isolated rat ventricular cardiac myocytes.

Cardiomyocytes were isolated form ventricular tissues of the rat hearts by collagenase perfusion. RT-qPCR, western blots, and zymography were used for expression and MMP activity analysis. Cross-sectional area and the rate of protein synthesis were determined as parameters for hypertrophic growth.

MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 mRNAs were detected in cardiomyocytes, and protein expression of MMP-2, MMP-9, and MMP-14 was identified. Hypertrophic stimulation of cardiomyocytes did not enhance, but interestingly decreased expression of MMPs, indicating that downregulation of MMPs may promote hypertrophic growth. Indeed, the nonselective MMP inhibitors TAPI-0 or TIMP2 and the MMP-2-selective ARP-100 enhanced hypertrophic growth. Furthermore, TAPI-0 increased phosphorylation and thus activation of extracellular signaling kinase (ERK) and Akt (protein kinase B), as well as inhibition of glycogen synthase 3β (GSK3β). Abrogation of MEK/ERK- or phosphatidylinositol-3-kinase(PI3K)/Akt/GSK3β-signaling with PD98059 or LY290042, respectively, inhibited hypertrophic growth under TAPI-0.

MMPs’ inhibition promotes hypertrophic growth in cardiomyocytes in vitro. Therefore, MMPs in the healthy heart may be important players to repress cardiac hypertrophy.

• Cardiomyocytes
• Hypertrophy
• Matrix metalloproteinase
• Signaling kinases

• Animals
• Cardiomegaly/metabolism
• Down-Regulation
• Male
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinases/metabolism
• Myocytes, Cardiac/metabolism
• Rats
• Rats, Wistar
• Signal Transduction
• Up-Regulation

• National Research, Development and Innovation Office of Hungary
• Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary

• amyloidosis
• bioequivalence
• pharmacokinetics
• tafamidis
• transthyretin

• Administration, Oral
• Adult
• Amyloid Neuropathies/drug therapy
• Amyloid Neuropathies, Familial/complications
• Benzoxazoles/administration & dosage
• Benzoxazoles/adverse effects
• Benzoxazoles/pharmacokinetics
• Brazil
• Canada
• Cardiomyopathies/drug therapy
• Cardiomyopathies/etiology
• Cardiomyopathies/genetics
• Cardiomyopathies/prevention & control
• Cross-Over Studies
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Compounding/methods
• Fasting/blood
• Female
• Healthy Volunteers/statistics & numerical data
• Humans
• Japan
• Male
• Middle Aged
• Prealbumin/drug effects
• Prealbumin/metabolism
• Safety
• Therapeutic Equivalency
• United States

• Pfizer

ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end products, may participate in the disease process. In addition to direct damage caused by amyloid fibrils, recent studies have suggested that the toxicity of nonfibrillar TTRs, such as TTR oligomers, participates in the process of tissue damage. Although liver transplantation has been performed for patients with ATTRv amyloidosis since 1990, late-onset patients were not eligible for this treatment. However, as the efficacy of orally administered tafamidis and diflunisal, which stabilize TTR tetramers, was suggested in the early 2010s, such late-onset patients have also become targets for disease-modifying therapies. Additionally, recent studies of small interfering RNA (patisiran) and antisense oligonucleotide (inotersen) therapies have demonstrated the efficacy of these gene-silencing agents. A strategy for monitoring patients that enables the choice of an appropriate treatment from comprehensive and long-term viewpoints should be established. As many patients with ATTR amyloidosis are aged and have heart failure, they are at increased risk of aggravation if they are infected by SARS-CoV2. The optimal interval of evaluation should also be considered, particularly in this COVID-19 era.

• Angiopathy
• Cardiac amyloidosis
• Electron microscopy
• Microangiopathy
• Pathogenesis
• Pathology
• Protein misfolding disease
• Schwann cell
• Therapy
• Ultrastructure

• Cardiac amyloidosis
• Cardiac magnetic resonance imaging
• Echocardiography
• Nuclear imaging

• amyloid neuropathies
• amyloid proteins
• amyloidosis
• chronic pain
• peripheral neuropathy
• type 2 diabetes mellitus

• Amyloidogenic Proteins/metabolism
• Humans
• Peripheral Nervous System Diseases/genetics