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2.
Curr Heart Fail Rep ; 21(3): 224-237, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38635117

RESUMO

PURPOSE OF REVIEW: Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection fraction (HFmrEF). Since patients with CA show early exhaustion, we aimed to investigate whether non-exertional variables of cardiopulmonary exercise testing (CPET) provide additional information in comparison to traditional peak oxygen consumption (VO2peak). RECENT FINDINGS: We retrospectively investigated CPET variables of patients with HFpEF and HFmrEF with (n = 21) and without (n = 21, HF) CA at comparable age and ejection fraction. Exertional and non-exertional CPET variables as well as laboratory and echocardiographic markers were analyzed. The primary outcome was the difference in CPET variables between groups. The secondary outcome was rehospitalization in patients with CA during a follow-up of 24 months. Correlations between CPET, NTproBNP, and echocardiographic variables were calculated to detect patterns of discrimination between the groups. HF patients with CA were inferior to controls in most exertional and non-exertional CPET variables. Patients with CA were hospitalized more often (p = 0.002), and rehospitalization was associated with VE/VCO2 (p = 0.019), peak oxygen pulse (p = 0.042), the oxygen equivalent at the first ventilatory threshold (p = 0.003), circulatory (p = 0.024), and ventilatory power (p < .001), but not VO2peak (p = 0.127). Higher performance was correlated with lower E/e' and NTproBNP as well as higher resting heart rate and stroke volume in CA. Patients with CA displayed worse non-exertional CPET performance compared to non-CA HF patients, which was associated with rehospitalization. Differences between correlations of resting echocardiography and CPET variables between groups emphasize different properties of exercise physiology despite comparable ejection fraction.


Assuntos
Amiloidose , Teste de Esforço , Insuficiência Cardíaca , Consumo de Oxigênio , Volume Sistólico , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/complicações , Teste de Esforço/métodos , Volume Sistólico/fisiologia , Amiloidose/fisiopatologia , Amiloidose/complicações , Amiloidose/diagnóstico , Estudos Retrospectivos , Consumo de Oxigênio/fisiologia , Masculino , Feminino , Idoso , Ecocardiografia/métodos , Tolerância ao Exercício/fisiologia , Pessoa de Meia-Idade , Cardiomiopatias/fisiopatologia , Cardiomiopatias/diagnóstico
3.
Eur J Heart Fail ; 26(3): 598-609, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38247182

RESUMO

AIMS: Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. METHODS AND RESULTS: Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. CONCLUSION: Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.


Assuntos
Amiloidose , Cardiomiopatias , Circulação Coronária , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Circulação Coronária/fisiologia , Idoso , Cardiomiopatias/fisiopatologia , Cardiomiopatias/diagnóstico , Amiloidose/fisiopatologia , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/diagnóstico , Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/complicações , Imagem de Perfusão do Miocárdio/métodos , Vasos Coronários/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Biópsia
4.
Rom J Intern Med ; 61(1): 28-34, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36278951

RESUMO

Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from severe cardiomyopathy, prevalence and incident rates are often underreported. As global longevity is increasing and rates of amyloidosis are also increasing, there is a need to improve diagnostic and therapeutic interventions. Previously, symptom management and transplantation were the mainstay of treatment for heart failure symptoms, but studies using RNAi and siRNA technologies have shifted the paradigm of therapeutic strategy in amyloid cardiomyopathy management. Additionally, early detection and clinical monitoring with numerous imaging and non-imaging techniques are being increasingly investigated. Here, we review the epidemiology, pathophysiology, diagnosis, and management of transthyretin amyloid cardiomyopathy.


Assuntos
Amiloidose , Cardiomiopatias , Humanos , Amiloidose/diagnóstico , Amiloidose/epidemiologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Arritmias Cardíacas/etiologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Pré-Albumina/genética
5.
Cells ; 11(2)2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35053352

RESUMO

For Alzheimer's disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Potenciais de Ação/fisiologia , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Amiloidose/complicações , Amiloidose/patologia , Amiloidose/fisiopatologia , Animais , Ritmo Delta/fisiologia , Progressão da Doença , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiopatologia , Placa Amiloide/complicações , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia
7.
J Am Coll Cardiol ; 78(22): 2177-2192, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34823661

RESUMO

BACKGROUND: Cardiac amyloidosis (CA) is a set of amyloid diseases with usually predominant cardiac symptoms, including light-chain amyloidosis (AL), hereditary variant transthyretin amyloidosis (ATTRv), and wild-type transthyretin amyloidosis (ATTRwt). CA are characterized by high heterogeneity in phenotypes leading to diagnosis delay and worsened outcomes. OBJECTIVES: The authors used clustering analysis to identify typical clinical profiles in a large population of patients with suspected CA. METHODS: Data were collected from the French Referral Center for Cardiac Amyloidosis database (Hôpital Henri Mondor, Créteil), including 1,394 patients with suspected CA between 2010 and 2018: 345 (25%) had a diagnosis of AL, 263 (19%) ATTRv, 402 (29%) ATTRwt, and 384 (28%) no amyloidosis. Based on comprehensive clinicobiological phenotyping, unsupervised clustering analyses were performed by artificial neural network-based self-organizing maps to identify patient profiles (clusters) with similar characteristics, independent of the final diagnosis and prognosis. RESULTS: Mean age and left ventricular ejection fraction were 72 ± 13 years and 52% ± 13%, respectively. The authors identified 7 clusters of patients with contrasting profiles and prognosis. AL patients were distinctively located within a typical cluster; ATTRv patients were distributed across 4 clusters with varying clinical presentations, 1 of which overlapped with patients without amyloidosis; interestingly, ATTRwt patients spread across 3 distinct clusters with contrasting risk factors, biological profiles, and prognosis. CONCLUSIONS: Clustering analysis identified 7 clinical profiles with varying characteristics, prognosis, and associations with diagnosis. Especially in patients with ATTRwt, these results suggest key areas to improve amyloidosis diagnosis and stratify prognosis depending on associated risk factors.


Assuntos
Amiloidose/classificação , Cardiomiopatias/classificação , Ecocardiografia/métodos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Análise por Conglomerados , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Fenótipo , Prognóstico , Estudos Prospectivos , Fatores de Tempo
9.
Am J Cardiol ; 160: 99-105, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610875

RESUMO

Cardiac amyloidosis is an important clinical entity associated with significant morbidity and mortality. Although the signs and symptoms can be apparent early in the disease course, diagnoses are often made late because of inadequate recognition. A diagnosis of cardiac amyloidosis requires careful scrutiny of a patient's symptoms, an electrocardiogram, and imaging studies, including echocardiography and magnetic resonance imaging. Further evaluation is required through the measurement of serum and urine light chains and the use of bone scintigraphy imaging to differentiate transthyretin amyloidosis from light-chain cardiac amyloidosis. The available treatments have expanded tremendously in recent years and have improved outcomes in the population with this disorder. Thus, it has become increasingly important to diagnose cardiac amyloidosis and provide timely therapies. This article will clarify the various misconceptions about cardiac amyloidosis and provide a framework for primary care providers to better identify this disease in their practice.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/terapia , Amiloidose/epidemiologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Compostos de Anilina , Circulação Assistida , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Técnicas de Imagem Cardíaca , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Etilenoglicóis , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estilbenos
10.
Molecules ; 26(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641582

RESUMO

The accumulation of amyloid plaques, or misfolded fragments of proteins, leads to the development of a condition known as amyloidosis, which is clinically recognized as a systemic disease. Amyloidosis plays a special role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and rheumatoid arthritis (RA). The occurrence of amyloidosis correlates with the aging process of the organism, and since nowadays, old age is determined by the comfort of functioning and the elimination of unpleasant disease symptoms in the elderly, exposure to this subject is justified. In Alzheimer's disease, amyloid plaques negatively affect glutaminergic and cholinergic transmission and loss of sympathetic protein, while in RA, amyloids stimulated by the activity of the immune system affect the degradation of the osteoarticular bond. The following monograph draws attention to the over-reactivity of the immune system in AD and RA, describes the functionality of the blood-brain barrier as an intermediary medium between RA and AD, and indicates the direction of research to date, focusing on determining the relationship and the cause-effect link between these disorders. The paper presents possible directions for the treatment of amyloidosis, with particular emphasis on innovative therapies.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/fisiopatologia , Amiloidose/fisiopatologia , Artrite Reumatoide/fisiopatologia , Sistema Imunitário/fisiopatologia , Doença de Parkinson/fisiopatologia , Placa Amiloide/fisiopatologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Citocinas/metabolismo , Humanos
11.
Pacing Clin Electrophysiol ; 44(12): 2092-2099, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34632598

RESUMO

Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure, characterized by extracellular deposition of insoluble protein fibrils leading to progressive myocardial dysfunction. The most common types of cardiac amyloidosis are immunoglobin light-chain (AL) and transthyretin (ATTR). Conduction abnormalities are commonly encountered among patients with cardiac amyloidosis and are an important cause of morbidity and mortality. Abnormalities range from infra-Hisian intraventricular conduction delay and bundle branch block to complete atrioventricular block. Pacemaker placement in CA patients follows established guidelines, similar to those for patients without CA, with generally good efficacy. The role and appropriate timing of pacemakers for primary prevention of brady-arrhythmias in CA remains uncertain. While biventricular (BiV) pacing has been shown to improve clinical outcomes in patients with systolic heart failure without CA, there are few data examining the utility of BiV pacing in patients with CA. With the advent of effective treatments for AL and ATTR, appropriate application of pacing is important to support patients with CA and conduction disease through therapeutic trials. This systematic review summarizes the current literature examining the utility of pacing in CA.


Assuntos
Amiloidose/fisiopatologia , Amiloidose/terapia , Estimulação Cardíaca Artificial/métodos , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/terapia , Sistema de Condução Cardíaco/fisiopatologia , Humanos
12.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502397

RESUMO

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.


Assuntos
Pré-Albumina/metabolismo , alfa 1-Antitripsina/metabolismo , Fatores Etários , Amiloide/metabolismo , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Amiloidose/genética , Amiloidose/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Fibrinolisina , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pré-Albumina/genética , Pré-Albumina/fisiologia , Proteólise , alfa 1-Antitripsina/fisiologia
13.
Medicine (Baltimore) ; 100(32): e26843, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397890

RESUMO

INTRODUCTION: Secondary amyloidosis is a rare complication of rheumatoid arthritis (RA) that is histologically characterized by the deposition of amyloid fibrils in target organs, such as the kidneys and gastrointestinal tract. Controlling the inflammatory response is essential to prevent organ dysfunction in amyloid A (AA) amyloidosis secondary to RA, and no clear treatment strategy exists. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old woman with RA, who had been treated with disease-modifying anti-rheumatic drugs for 1 year, presented with recurrent abdominal pain and prolonged diarrhea. Endoscopy showed chronic inflammation, and colon tissue histology confirmed AA amyloidosis. INTERVENTIONS AND OUTCOMES: After tocilizumab therapy was begun, her diarrhea and abdominal pain subsided, and articular symptoms improved. Biologic drugs for RA have been used in patients with secondary AA amyloidosis, including tumor necrosis factor and Janus kinase inhibitors, interleukin 6 blockers, and a T cell modulator. Here, we systematically review existing case reports and compare the outcomes of RA-related AA amyloidosis after treatment with various drugs. CONCLUSION: The data indicate that biologic drugs like tocilizumab might be treatments of choice for AA amyloidosis secondary to RA.


Assuntos
Amiloidose , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide , Terapia Biológica/métodos , Colo , Proteína Amiloide A Sérica/análise , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Idoso , Amiloidose/etiologia , Amiloidose/imunologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Produtos Biológicos/administração & dosagem , Colo/imunologia , Colo/patologia , Diarreia/diagnóstico , Diarreia/etiologia , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
14.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443678

RESUMO

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 (Aß). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aß 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 Aß, 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.


Assuntos
Amiloide/metabolismo , Amiloidose/fisiopatologia , Amiloidose/terapia , Animais , Humanos , Especificidade de Órgãos , Agregados Proteicos , Células de Schwann/patologia
15.
PLoS One ; 16(7): e0254104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242301

RESUMO

AIM: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) with preserved left ventricular ejection fraction (LVEF), typically presenting as restrictive cardiomyopathy. The potential co-existence of ATTR-CA with systolic heart failure has not been studied. The aim of this study is to describe the prevalence of ATTR-CA and its clinical characteristics in HF patients with reduced LVEF. METHODS: Patients with an unexplained cause of LV systolic dysfunction were screened for ATTR-CA by a 99mTc-PYP planar scintigraphy. Patients in whom presence of ≥ 2 uptake was confirmed by SPECT imaging were included. Their clinical, laboratory and echocardiographic data were collected. RESULTS: Out of 75 patients (mean age 65±12 years, LVEF 35.8±7.9%) included in this study, 7 (9.3%) patients (mean age 75±6 years, LVEF 32.0±8.3%) had ATTR-CA. Patients with ATTR-CA were more symptomatic at diagnosis (NYHA FC 3-4 (86% vs 35% (p = 0.03)) and had a more severe clinical course evident by recurrent hospitalizations for HF, and a need for intravenous diuretic treatment (p = 0.04 and p<0.01, respectively) at follow-up, compared with patients with no ATTR-CA. Patients with ATTR-CA had similar LVEF but a clear trend for larger LV mass index (157.1±60.6 g/m2 vs. 121.0±39.5 g/m2, p = 0.07) and a larger proportions of ATTR-CA patients had IVS thickness >13 mm (57.1% vs 13.1%, p = 0.02) as compared to HF patients with no ATTR-CA. CONCLUSION: In our study, a meaningful percentage of patients with unexplained LV dysfunction had a co-existing ATTR-CA indicating that the clinical heterogeneity of ATTR-CA is much broader than previously thought.


Assuntos
Amiloidose/complicações , Amiloidose/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Pré-Albumina/metabolismo , Sístole/fisiologia , Função Ventricular Esquerda/fisiologia , Idoso , Amiloidose/diagnóstico por imagem , Ecocardiografia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Patentes como Assunto , Tecnécio
17.
Brain Res ; 1768: 147579, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233173

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD. METHODS: We used an APPPS1 transgenic model of senile ß-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, ß-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics. RESULTS: Treatment with DMF had no influence on water maze performance, ß-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice. DISCUSSION: Our results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.


Assuntos
Amiloidose/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/fisiopatologia , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/fisiopatologia , Fumarato de Dimetilo/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Doenças Neuroinflamatórias/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo
18.
Clin Lymphoma Myeloma Leuk ; 21(8): 545-548, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34024744

RESUMO

BACKGROUND: Cardiac involvement and dysfunction are common in patients presenting with AL and ATTR Amyloidosis. Cardiopulmonary exercise testing (CPET) performance is the gold standard to quantify functional capacity. PATIENTS AND METHODS: In this study, we evaluated CPET measurements in 41 patients with cardiac Amyloidosis and their correlation with current amyloid specific staging criteria. RESULTS: In both AL and ATTR cardiac Amyloidosis, percent predicted peak VO2 is significantly reduced and correlates with biomarker abnormalities. The association of cardiac biomarkers with peak VO2 is stronger for AL Amyloidosis (NT-proBNP (r = -0.57, P=0.006), Troponin (r = -0.70, p < 0.001) than ATTR (NT-proBNP (r = -0.4, P = 0.04) and Troponin (r = -0.57, P = 0.002) despite lower left ventricular mass in the former, suggesting that this may be further evidence for light chain toxicity in AL amyloidosis. CONCLUSION: Our findings suggest further evidence for AL toxicity.


Assuntos
Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Idoso , Amiloidose/patologia , Biomarcadores/sangue , Cardiomiopatias/patologia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Consumo de Oxigênio , Fragmentos de Peptídeos/sangue , Prognóstico , Análise de Sobrevida , Troponina/sangue
19.
Circ Res ; 128(10): 1554-1575, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33983835

RESUMO

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.


Assuntos
Amiloidose/etiologia , Amiloidose/terapia , Cardiomiopatias/etiologia , Cardiomiopatias/terapia , Envelhecimento , Alquilantes/uso terapêutico , Amiloide/química , Amiloide/metabolismo , Neuropatias Amiloides Familiares/diagnóstico , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Anticorpos Monoclonais/uso terapêutico , Benzoatos/uso terapêutico , Benzoxazóis/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Transplante de Coração , Humanos , Agentes de Imunomodulação/uso terapêutico , Oligonucleotídeos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Dobramento de Proteína , Pirazóis/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Transplante de Células-Tronco , Sulfonamidas/uso terapêutico , Tolcapona/uso terapêutico
20.
Prion ; 15(1): 53-55, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33876719

RESUMO

The severe course of COVID-19 causes systemic chronic inflammation and thrombosis in a wide variety of organs and tissues. The nature of these inflammations remains a mystery, although they are known to occur against the background of a high level of cytokine production. The high level of cytokines provokes overproduction of the Serum amyloid A (SAA) protein. Moreover, the number of studies has shown that the severe COVID-19 causes SAA overproduction. The authors of these works regard a high level of SAA exclusively as a biomarker of COVID-19. However, it should be borne in mind that overproduction of SAA can cause systemic AA amyloidosis. SAA forms cytotoxic amyloid deposits in various organs and induces inflammation and thrombosis. The consequences of COVID-19 infection are surprisingly similar to the clinical picture that is observed in AA amyloidosis. Here I present the hypothesis that AA amyloidosis is a factor causing systemic complications after coronavirus disease.


Assuntos
Amiloidose , COVID-19 , Proteína Amiloide A Sérica , Amiloidose/sangue , Amiloidose/fisiopatologia , Amiloidose/virologia , Biomarcadores , COVID-19/complicações , COVID-19/fisiopatologia , Humanos , Inflamação
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