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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361762

RESUMO

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.


Assuntos
Doença de Alzheimer/patologia , Neuropatias Amiloides Familiares/patologia , Amiloide/imunologia , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Miocárdio/patologia , Nervos Periféricos/patologia , Doenças Priônicas/patologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Amiloide/antagonistas & inibidores , Amiloide/genética , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/imunologia , Benzoxazóis/uso terapêutico , Diflunisal/uso terapêutico , Humanos , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/imunologia , Fatores Imunológicos/uso terapêutico , Miocárdio/imunologia , Fármacos Neuroprotetores/uso terapêutico , Oligonucleotídeos/uso terapêutico , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/imunologia , Pré-Albumina/antagonistas & inibidores , Pré-Albumina/genética , Pré-Albumina/imunologia , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/genética , Doenças Priônicas/imunologia , RNA Interferente Pequeno/uso terapêutico
2.
Front Immunol ; 12: 650269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093538

RESUMO

Inflammation is a hallmark of several neurodegenerative disorders including hereditary amyloidogenic transthyretin amyloidosis (ATTRv). ATTRv is an autosomal dominant neurodegenerative disorder with extracellular deposition of mutant transthyretin (TTR) aggregates and fibrils, particularly in nerves and ganglia of the peripheral nervous system. Nerve biopsies from ATTRv patients show increased cytokine production, but interestingly no immune inflammatory cellular infiltrate is observed around TTR aggregates. Here we show that as compared to Wild Type (WT) animals, the expression of several chemokines is highly downregulated in the peripheral nervous system of a mouse model of the disease. Interestingly, we found that stimulation of mouse Schwann cells (SCs) with WT TTR results in the secretion of several chemokines, a process that is mediated by toll-like receptor 4 (TLR4). In contrast, the secretion of all tested chemokines is compromised upon stimulation of SCs with mutant TTR (V30M), suggesting that V30M TTR fails to activate TLR4 signaling. Altogether, our data shed light into a previously unappreciated mechanism linking TTR activation of SCs and possibly underlying the lack of inflammatory response observed in the peripheral nervous system of ATTRv patients.


Assuntos
Neuropatias Amiloides Familiares/imunologia , Quimiocinas/metabolismo , Regulação para Baixo/imunologia , Pré-Albumina/genética , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Transgênicos , Mutação , Pré-Albumina/isolamento & purificação , Pré-Albumina/metabolismo , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Células de Schwann/imunologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/imunologia , Nervo Isquiático/patologia , Receptor 4 Toll-Like/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 321(1): H149-H160, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34018852

RESUMO

Age-related wild-type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton was disorganized, focal adhesion formation was decreased, and nuclear shape was flattened. Fibroblasts had faster collective and single-cell migration velocities on TTR-deposited substrates. In addition, fibroblasts cultured on microposts with TTR deposition had reduced attachment and increased proliferation above untreated. Transcriptomic and proteomic analyses of fibroblasts grown on glass covered with TTR showed significant upregulation of inflammatory genes after 48 h, indicative of progression in TTR-based diseases. Together, results suggest that TTR deposited in tissue extracellular matrix may affect the structure, function, and gene expression of cardiac fibroblasts. As therapies for wtATTR are cost-prohibitive and only slow disease progression, better understanding of cellular maladaptation may elucidate novel therapeutic targets.NEW & NOTEWORTHY Transthyretin (TTR) cardiac amyloidosis involves deposition of fibrils of misfolded TTR in the aging human heart, leading to cardiac dysfunction and heart failure. Our novel in vitro studies show that TTR fibrils alter primary cardiac fibroblast cytoskeletal and nuclear structure and focal adhesion formation. Furthermore, both fibrillar and tetrameric TTR significantly increased cellular migration velocity and caused upregulation of inflammatory genes determined by transcriptomic RNA and protein analysis. These findings may suggest new therapeutic approaches.


Assuntos
Neuropatias Amiloides Familiares/metabolismo , Amiloide/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Inflamação/genética , Miocárdio/metabolismo , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Matriz Extracelular/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Miocárdio/patologia
4.
Nat Commun ; 12(1): 3142, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035264

RESUMO

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Cardiomiopatias/tratamento farmacológico , Macrófagos/imunologia , Pré-Albumina/antagonistas & inibidores , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Cardiomiopatias/patologia , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Mutação , Miocárdio/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/imunologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Heterólogo
5.
Transplant Proc ; 53(4): 1313-1316, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33836864

RESUMO

BACKGROUND: Carpal tunnel syndrome is the most common compression syndrome of the peripheral nerve. Transthyretin amyloidosis and dialysis-related ß2-microglobulin amyloidosis are known causes of carpal tunnel syndrome. CASE REPORT: A Japanese woman showed carpal tunnel syndrome 16 years after a domino liver transplantation (DLT) from the donor with hereditary transthyretin amyloidosis. DLT indication was congenital extrahepatic portosystemic shunt, and the patient had been put on maintenance hemodialysis because of chronic kidney disease 6 years before DLT. Moreover, the amyloid precursor protein of the patient was histologically confirmed not to be ß2-microglobulin, but transthyretin. CONCLUSIONS: The existence of amyloid was speculated when the patient who underwent DLT from hereditary transthyretin amyloidosis showed carpal tunnel syndrome. Additionally, elucidating the amyloid precursor protein when the patient has another cause of amyloidosis is necessary.


Assuntos
Neuropatias Amiloides Familiares/patologia , Síndrome do Túnel Carpal/diagnóstico , Transplante de Fígado/efeitos adversos , Neuropatias Amiloides Familiares/genética , Articulações do Carpo/patologia , Síndrome do Túnel Carpal/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Albumina/genética , Diálise Renal , Insuficiência Renal Crônica/patologia , Doadores de Tecidos
6.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922648

RESUMO

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.


Assuntos
Neuropatias Amiloides Familiares/patologia , Amiloide/química , Pré-Albumina/química , Dobramento de Proteína , Neuropatias Amiloides Familiares/metabolismo , Animais , Humanos
7.
BMC Neurol ; 21(1): 70, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579211

RESUMO

BACKGROUND: We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT). METHODS: Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies. RESULTS: Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001). CONCLUSIONS: Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.


Assuntos
Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/patologia , Progressão da Doença , Polineuropatias/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros
8.
J Clin Neurosci ; 84: 33-37, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33485595

RESUMO

BACKGROUND: Wild-type transthyretin (ATTRwt) amyloid deposits have been found in the ligamentum flavum of patients undergoing surgery for spinal stenosis. The relationship between ATTRwt and ligamentum flavum thickness is unclear. We used pre-operative magnetic resonance imaging (MRI) to analyze ligamentum flavum thickness in lumbar spinal stenosis patients with and without ATTRwt amyloid. METHODS: We retrospectively identified 178 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 253 specimens was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and ATTRwt was confirmed using mass-spectrometry and gene sequencing. RESULTS: Twenty four of the 178 patients (13.5%) were found to have ATTRwt in the ligamentum flavum. Forty ATTRwt specimens and 213 non-ATTRwt specimens were measured. Mean ligamentum flavum thickness was 4.92 (±1.27) mm in the ATTRwt group and 4.00 (±1.21) mm in the non-ATTRwt group (p < 0.01). The ligamentum flavum was thickest at L4-L5, with a thickness of 5.15 (±1.27) mm and 4.23 (±1.29) mm in the ATTRwt and non-ATTRwt group, respectively (p = 0.007). There was a significant difference in ligamentum flavum thickness between ATTRwt and non-ATTRwt case for both patients younger than 70 years (p = 0.016) and those older than 70 years (p = 0.004). ATTRwt patients had greater ligamentum flavum thickness by 0.83 mm (95% confidence interval (CI): 0.41-1.25 mm, p < 0.001) when controlled for age and lumbar level. CONCLUSION: Patients with ATTRwt had thicker ligamentum flavum compared to patients without ATTRwt. Further studies are needed to investigate the pathophysiology of ATTRwt in ligamentum flavum thickening.


Assuntos
Neuropatias Amiloides Familiares/patologia , Ligamento Amarelo/patologia , Adulto , Feminino , Humanos , Região Lombossacral/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estenose Espinal/cirurgia
9.
Am J Med ; 134(2): e98-e100, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32866461

RESUMO

BACKGROUND: Transthyretin (TTR) gene mutations are the most common cause of hereditary amyloidosis. Valine replaced by isoleucine in position 122 (V122I) variant is common, particularly in the black population. Carriers of V122I have increased risk for developing cardiac amyloidosis. Despite a relatively high prevalence, the penetrance of V122I is not firmly established. This study sought to determine the prevalence of clinically apparent cardiac amyloidosis among carriers of the TTR V122I variant. METHODS: BioVU, a Vanderbilt University resource linking DNA samples and pre-existing genetic data to de-identified electronic medical records was used to identify TTR V122I mutation carriers. Automated billing code queries (International Classification of Diseases, 9th revision codes), problem list searches, and manual chart reviews were used to identify subjects with clinically diagnosed cardiac amyloidosis. RESULTS: Among 28,429 subjects with available genotype data, 129 were V122I carriers. Carriers had a median age of 42 years (interquartile range 16-64). Noncarriers had a median age of 62 years, (interquartile range 41-77). The carrier rate was 3.7% in blacks and 0.02% in whites. Overall, the prevalence of clinically apparent cardiac amyloidosis was 0.8% in carriers and 0.04% in noncarriers (P = .05). Above age 60, the prevalence of cardiac amyloidosis was 2.6% in carriers and 0.06% in noncarriers (P = .03). CONCLUSION: Carriers of the TTR V122I variant are at a higher risk for development of cardiac amyloidosis, particularly at age>60 years. However, clinically apparent cardiac amyloidosis in this population was uncommon. These results support that the penetrance of TTR V122I is age dependent and suggest it may be significantly lower than previously reported.


Assuntos
Neuropatias Amiloides Familiares/genética , Cardiopatias/patologia , Pré-Albumina/genética , Adolescente , Adulto , Idoso , Neuropatias Amiloides Familiares/patologia , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Cardiopatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
FEBS J ; 288(1): 310-324, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32324953

RESUMO

Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis. DATABASES: PDB codes for A25T-TTR, V30G-TTR, and Y114C-TTR bound to tolcapone are 6TXV, 6TXW, and 6XTK, respectively.


Assuntos
Amiloide/antagonistas & inibidores , Antiparkinsonianos/química , Fármacos Neuroprotetores/química , Pré-Albumina/química , Agregados Proteicos/efeitos dos fármacos , Tolcapona/química , Amiloide/química , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Antiparkinsonianos/farmacologia , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Reposicionamento de Medicamentos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Cinética , Modelos Moleculares , Mutação , Fármacos Neuroprotetores/farmacologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Desnaturação Proteica , Dobramento de Proteína/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tolcapona/farmacologia , Ureia/química
11.
Rev Esp Cardiol (Engl Ed) ; 74(2): 149-158, 2021 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32317158

RESUMO

INTRODUCTION AND OBJECTIVES: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. METHODS: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. RESULTS: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CONCLUSIONS: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.


Assuntos
Amiloidose/patologia , Cardiomiopatias/patologia , Diagnóstico Tardio/estatística & dados numéricos , Insuficiência Cardíaca/etiologia , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/patologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/terapia , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio , Pré-Albumina
12.
Am Heart J ; 232: 137-145, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33212046

RESUMO

BACKGROUND: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed. OBJECTIVES: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard. METHODS: Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression. RESULTS: The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m2]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity). CONCLUSION: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Fatores Etários , Idoso , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/fisiopatologia , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/patologia , Amiloidose/fisiopatologia , Biópsia , Velocidade do Fluxo Sanguíneo , Cardiomiopatias/sangue , Cardiomiopatias/patologia , Regras de Decisão Clínica , Ecocardiografia , Eletrocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peptídeo Natriurético Encefálico/sangue , Tamanho do Órgão , Fatores Sexuais , Troponina I/sangue
13.
J Cardiovasc Magn Reson ; 22(1): 84, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33287829

RESUMO

BACKGROUND: Cardiovascular magnetic resonance (CMR) is part of the diagnostic work-up for cardiac amyloidosis (CA). Deep learning (DL) is an application of artificial intelligence that may allow to automatically analyze CMR findings and establish the likelihood of CA. METHODS: 1.5 T CMR was performed in 206 subjects with suspected CA (n = 100, 49% with unexplained left ventricular (LV) hypertrophy; n = 106, 51% with blood dyscrasia and suspected light-chain amyloidosis). Patients were randomly assigned to the training (n = 134, 65%), validation (n = 30, 15%), and testing subgroups (n = 42, 20%). Short axis, 2-chamber, 4-chamber late gadolinium enhancement (LGE) images were evaluated by 3 networks (DL algorithms). The tags "amyloidosis present" or "absent" were attributed when the average probability of CA from the 3 networks was ≥ 50% or < 50%, respectively. The DL strategy was compared to a machine learning (ML) algorithm considering all manually extracted features (LV volumes, mass and function, LGE pattern, early blood-pool darkening, pericardial and pleural effusion, etc.), to reproduce exam reading by an experienced operator. RESULTS: The DL strategy displayed good diagnostic accuracy (88%), with an area under the curve (AUC) of 0.982. The precision (positive predictive value), recall score (sensitivity), and F1 score (a measure of test accuracy) were 83%, 95%, and 89% respectively. A ML algorithm considering all CMR features had a similar diagnostic yield to DL strategy (AUC 0.952 vs. 0.982; p = 0.39). CONCLUSIONS: A DL approach evaluating LGE acquisitions displayed a similar diagnostic performance for CA to a ML-based approach, which simulates CMR reading by experienced operators.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Aprendizado Profundo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/fisiopatologia , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Masculino , Miocárdio/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Função Ventricular Esquerda , Remodelação Ventricular
14.
Int J Mol Sci ; 21(22)2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33212973

RESUMO

Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in ß-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR ("kinetic stabilization") and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer's disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers.


Assuntos
Doença de Alzheimer , Neuropatias Amiloides Familiares , Pré-Albumina , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/terapia , Humanos , Pré-Albumina/genética , Pré-Albumina/metabolismo , Estabilidade Proteica
15.
BMC Cardiovasc Disord ; 20(1): 466, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121442

RESUMO

BACKGROUND: Amyloidosis is a rare systemic disease due to the extracellular tissue deposition of a fibrillar-shaped misfolded protein, called amyloid. Only two types of proteins commonly affect the heart leading to an infiltrative cardiomyopathy: immunoglobulin light chain and transthyretin (TTR) cardiac amyloidosis (CA). Despite the promising role of emerging imaging modalities, such as strain echocardiography, cardiac magnetic resonance and bone scintigraphy, its diagnosis is still often missed or delayed due to their inherent limitations and to a nonspecific clinical scenario with frequent concomitance of cardiac comorbidities. The gold standard for a definite diagnosis still remains endomyocardial biopsy, but in rare cases Congo Red staining could provide false negative results, as in our case, requiring immunoelectron microscopy. CASE PRESENTATION: A middle-aged male adult presented to the emergency department for relapse of heart failure. Echocardiography and cardiac magnetic resonance, along with the history of bilateral carpal tunnel syndrome, were suspicious for TTR-CA. The diagnosis, however, was hampered by concomitant cardiac comorbidities and conflicting results of imaging modalities. In fact bone scintigraphy was negative, as well as Congo Red Staining on myocardial tissue samples obtained by endomyocardial biopsy. Given the high clinical suspicion, immunoelectron microscopy was performed, showing TTR amyloid fibrils deposits, that confirmed the diagnosis. A genetic analysis excluded and hereditary form. The patient was then referred to a specialist center for specific treatment. CONCLUSIONS: This is a rare case of a TTR-CA with a negative Bone Scintigraphy and Congo red staining, which demonstrated that CA is frequently misdiagnosed because of the low specific clinical manifestations and the results of imaging modalities that sometimes could be misleading, with subsequent delayed diagnosis and correct treatment.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Cintilografia , Idoso , Neuropatias Amiloides Familiares/patologia , Biópsia , Cardiomiopatias/patologia , Corantes , Vermelho Congo , Humanos , Masculino , Microscopia Imunoeletrônica , Miocárdio/patologia , Valor Preditivo dos Testes , Coloração e Rotulagem
16.
Methods Mol Biol ; 2176: 87-98, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865784

RESUMO

Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant condition in which mutations in the transthyretin gene cause amyloid fibrils to develop and deposit into tissues, affecting primarily the nerves and heart causing polyneuropathy and cardiomyopathy respectively. Standard treatment has been liver transplants to try and eliminate the mutated transthyretin products as the liver is the main source of transthyretin production. A new drug named inotersen (brand name Tagsedi), also known as IONIS-TTRRX, has been approved by the United States Food and Drug Agency, Health Canada, and European Commission in 2018, and introduced to the market for patients in stage 1 and stage 2 hATTR polyneuropathy. Inotersen is a second-generation antisense oligonucleotide with 2'-O-methoxyethyl modification designed to bind to the 3' untranslated region of the transthyretin mRNA in the nucleus of the liver cells. By doing so, it prevents the production of the mutant and wild-type forms of transthyretin, impeding the progression of the disease. In this article, the mechanism of action and safety profile of inotersen will be discussed along with some future directions following its approval.


Assuntos
Neuropatias Amiloides Familiares/terapia , Oligonucleotídeos/uso terapêutico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Animais , Progressão da Doença , Desenvolvimento de Medicamentos/métodos , Humanos , Oligonucleotídeos/síntese química , Oligonucleotídeos/genética , Oligonucleotídeos/farmacocinética , Pré-Albumina/genética , Qualidade de Vida
17.
Dtsch Med Wochenschr ; 145(16): 1162-1168, 2020 08.
Artigo em Alemão | MEDLINE | ID: mdl-32791553

RESUMO

Cardiac amyloidosis is a rare cause of cardiomyopathy, however, it is part of an underdiagnosed underlying systemic disease. For transthyretin (ATTR) amyloidosis, which is caused by the deposition of incorrectly folded transthyretin, either as the wild-type (wtATTR) or mutated (mATTR) form, novel evidence-based treatment options were recently shown to reduce disease progression as well as hospitalisation rates for heart failure. Thus, it is important to establish early and reliable diagnosis of cardiac involvement with ATTR amyloidosis.Modern non-invasive imaging (cardio magnetic resonance (CMR) and scintigraphic methods) together with immune fixation with determination of free light chains allow fast and reliable clinical screening for cardiac amyloidosis, whereas endomyocardial biopsy and genetics are used for confirmation of the underlying diagnosis. Interdisciplinary teams including hemato-oncology, neurology, nephrology in addition to cardiology are essential to enable personalized targeted treatment strategies.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/terapia , Amiloidose/genética , Amiloidose/patologia , Amiloidose/terapia , Biópsia , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/terapia , Diagnóstico Diferencial , Diagnóstico por Imagem , Diagnóstico Precoce , Medicina Baseada em Evidências , Humanos , Comunicação Interdisciplinar , Colaboração Intersetorial , Programas de Rastreamento , Miocárdio/patologia
19.
Stem Cell Reports ; 15(2): 515-528, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32735824

RESUMO

The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of hepatocyte-like cells (HLCs) to the proteotoxicity of secreted transthyretin (TTR). To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We combined this tool with single-cell RNA sequencing to identify hepatic proteostasis factors correlating with destabilized TTR production in iPSC-derived HLCs. By generating an ATF6 inducible patient-specific iPSC line, we demonstrated that enhancing hepatic ER proteostasis preferentially reduces the secretion of amyloidogenic TTR. These data highlight the liver's capacity to chaperone misfolded TTR prior to deposition, and moreover suggest the potential for unfolded protein response modulating therapeutics in the treatment of diverse systemic amyloidoses.


Assuntos
Neuropatias Amiloides Familiares/patologia , Amiloide/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Fígado/patologia , Modelos Biológicos , Pré-Albumina/metabolismo , Proteostase , Fator 6 Ativador da Transcrição/metabolismo , Neuropatias Amiloides Familiares/genética , Edição de Genes , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mutação/genética , Pré-Albumina/genética , Regiões Promotoras Genéticas/genética , Estabilidade Proteica , Análise de Sequência de RNA , Transdução de Sinais , Análise de Célula Única , Estresse Fisiológico , Transferrina/metabolismo , Resposta a Proteínas não Dobradas
20.
Sci Rep ; 10(1): 12437, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709875

RESUMO

It is significant to understand the earliest molecular events occurring in the nucleation of the amyloid aggregation cascade for the prevention of amyloid related diseases such as transthyretin amyloid disease. We develop chemical master equation for the aggregation of monomers into oligomers using reaction rate law in chemical kinetics. For this stochastic model, lognormal moment closure method is applied to track the evolution of relevant statistical moments and its high accuracy is confirmed by the results obtained from Gillespie's stochastic simulation algorithm. Our results show that the formation of oligomers is highly dependent on the number of monomers. Furthermore, the misfolding rate also has an important impact on the process of oligomers formation. The quantitative investigation should be helpful for shedding more light on the mechanism of amyloid fibril nucleation.


Assuntos
Neuropatias Amiloides Familiares/patologia , Modelos Biológicos , Pré-Albumina/metabolismo , Agregação Patológica de Proteínas/patologia , Algoritmos , Humanos , Cinética , Agregados Proteicos , Dobramento de Proteína , Processos Estocásticos
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