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2.
Arq. bras. cardiol ; 116(1): 75-76, Jan. 2021.
Artigo em Português | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1147466

RESUMO

A miocardiopatia chagásica (MC), descrita originalmente em 1909 por Carlos Chagas,1 segue nos dias atuais associada a elevada morbimortalidade e impacto socioeconômico, especialmente nos países da America Latina. Nesse sentido, a busca por marcadores epidemiológicos, clínicos, laboratoriais, eletrocardiográficos e de imagem associados ao prognóstico cumpre papel importante na estratificação de risco desses pacientes. O índice cardiotorácico (ICT), originalmente descrito em 1919 e calculado a partir da radiografia de tórax é uma das variáveis associadas à mortalidade na MC. Rodriguez-Salas et al.,2 identificaram o ICT>0,55 como variável independente associada à mortalidade em estudo que incluiu 960 pacientes. Notadamente, o diâmetro diastólico final do ventrículo esquerdo (DDVE) avaliado pelo ecocardiograma transtorácico não se associou à má evolução nesse estudo. Posteriormente, Salles et al.,3 detectaram associação entre o ICT>0,5 e mortalidade por todas as causas em estudo que incluiu 738 pacientes, mas o diâmetro sistólico final do ventrículo esquerdo medido pelo ecocardiograma transtorácico foi variável independente mais fortemente associada à morte por todas as causas, além de morte relacionada à MC e morte súbita. Esse achado possivelmente reflete melhor a relação entre disfunção sistólica ventricular esquerda e má evolução que o aspecto morfológico dessa câmara. Por outro lado, Bestetti et al.,4 identificaram o DDVE analisado pelo ecocardiograma transtorácico como preditor independente de morte súbita em estudo que incluiu 74 pacientes e não mostrou associação entre ICT alterado e o desfecho.


Assuntos
Ecocardiografia , Cardiomiopatia Chagásica , Cardiomegalia , Insuficiência Cardíaca/epidemiologia , Fatores Socioeconômicos , Radiografia Torácica , Indicadores de Morbimortalidade
3.
PLoS Negl Trop Dis ; 14(12): e0008889, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351798

RESUMO

Chronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFNγ, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-γ-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Doença Crônica , Genoma Humano , Humanos , MicroRNAs/genética , Análise de Componente Principal
4.
Mem Inst Oswaldo Cruz ; 115: e200110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33146244

RESUMO

We aimed to investigate the association of CD14 -260C/T (rs2569190) polymorphism and Chagas cardiomyopathy and the functional characteristics of CD14+ and CD14- monocytes upon infection with Trypanosoma cruzi. We observed an association between the T- genotype (absence of allele -260T) related to low CD14 expression and the dilated cardiomyopathy type of Chagas disease. Furthermore, we observed that CD14- monocytes showed a more activated profile upon in vitro infection with T. cruzi than CD14+ monocytes. Our findings suggest that T- genotype is associated with susceptibility to develop Chagas dilated cardiomyopathy, likely linked to the T. cruzi-induced inflammatory profile of CD14- monocytes.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Chagásica/genética , Receptores de Lipopolissacarídeos/genética , Doença de Chagas , Genótipo , Insuficiência Cardíaca , Humanos , Trypanosoma cruzi , Disfunção Ventricular Esquerda
6.
Trop. Med. Infect. Dis ; 5(3): 1-6, Aug., 2020. tab.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1121993

RESUMO

ABSTRACT: Background­Patients with Chagas cardiomyopathy (CC) have high mortality, and CC is a common indication for heart transplantation (HTx) in endemic countries. Chagas disease reactivation (CDR) is common after transplantation and is likely to cause adverse outcomes unless detected and treated appropriately. This study reviews our experiences with HTx among patients with CC, and the use of benznidazole (BZ) before transplantation. METHODS­During the 18-year period from 1996 through 2014, 70 of 353 patients who underwent HTx (19.8%) had CC, and 53 patients met the inclusion criteria. The e_ectiveness of prophylactic treatment with BZ (dose of 5 mg/kg/day, two times per day, for at least four weeks and for a maximum of eight weeks) was determined based on the observed reduction in the incidence of CDR during the post-HTx period. RESULTS­Prophylactic therapy was administered to 18/53 patients (34.0%). During the follow-up period, the incidence rate of CDR in our study was 34.0% (18/53). Based on logistic regression analysis, only prophylaxis (OR = 0.12; CI 0.02­0.76; p = 0.025) was considered to protect against CDR. CONCLUSION­Our study suggests that the use of BZ may reduce the incidence of CDR in patients undergoing HTx and warrants further investigation in a prospective, randomized trial.


Assuntos
Cardiomiopatia Chagásica , Transplante de Coração , Doença de Chagas
7.
Life Sci ; 257: 118067, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652140

RESUMO

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Diminazena/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Diminazena/administração & dosagem , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/parasitologia , Miócitos Cardíacos/parasitologia , Miosite/tratamento farmacológico , Miosite/parasitologia , Fragmentos de Peptídeos/metabolismo , Ratos , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia
8.
Rev Soc Bras Med Trop ; 53: e20200100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638887

RESUMO

Patients with Chagas cardiomyopathy (ChC) usually progress with fatigue and dyspnea. Exercise tests are valuable for the functional evaluation of these patients. However, information about the applicability of the exercise tests is scattered, and no studies have systematically reviewed the results. Thus, the present review explored the general aspects and prognostic value of exercise tests in patients with ChC. A literature search of the MEDLINE, Web of Science, CINAHL, Scopus, and LILACS databases was performed to identify relevant studies. There were no data restrictions, and articles that met the objective of the study were selected. Articles written in English, Portuguese, and Spanish were considered, and 25 articles were finally included. The peak oxygen uptake (VO2peak) was correlated with demographic and echocardiographic variables. Echocardiographic features of the left ventricular diastolic function and right ventricular systolic function appeared to be determinants of functional capacity, in addition to age and sex. VO2peak was associated with higher mortality, especially in patients with dilated ChC. The minute ventilation/carbon dioxide production slope (VE/VCO2 slope) was a strong predictor of survival; however, more studies are needed to verify this observation. Field tests showed moderate to strong correlation with VO2peak and thus may be inexpensive tools for the functional evaluation of patients with ChC. However, few studies have verified their prognostic significance. While exercise tests are useful tools for functional assessment, information is scarce regarding further considerations, and many of the criteria are based on guidelines for other heart diseases.


Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Teste de Esforço/métodos , Tolerância ao Exercício/fisiologia , Insuficiência Cardíaca/fisiopatologia , Função Ventricular Esquerda/fisiologia , Função Ventricular Direita/fisiologia , Ecocardiografia , Humanos , Prognóstico
9.
Int J Cardiovasc Imaging ; 36(11): 2209-2219, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32613382

RESUMO

Chagas' disease (CD), caused by the parasite Trypanosoma cruzi, is the leading cause of cardiac disability from infectious diseases in Central and South America. The disease progresses through an extended, asymptomatic form characterized by latency without clinical manifestations into a symptomatic form with cardiac and gastro-intestinal manifestations. In the terminal phase, chronic Chagas' myocarditis results in extensive myocardial fibrosis, chamber enlargement with aneurysms and ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) has proven useful in characterizing myocardial fibrosis (MF). Sub-epicardial and mid-wall fibrosis are less common patterns of MF in CHD than transmural scar, which resembles myocardial infarction. Commonly involved areas of MF include the left ventricular apex and basal infero-lateral wall, suggesting a role for watershed ischemia in the pathophysiology of MF. Electrophysiology studies have helped refine the relationship between MF and VT in this setting. This article reviews the patterns of MF in CHD and correlate these patterns with electrogram patterns to predict risk of ventricular arrhythmias and sudden death.


Assuntos
Potenciais de Ação , Cardiomiopatia Chagásica/diagnóstico por imagem , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Imagem por Ressonância Magnética , Miocárdio/patologia , Taquicardia Ventricular/diagnóstico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Progressão da Doença , Fibrose , Sistema de Condução Cardíaco/parasitologia , Humanos , Valor Preditivo dos Testes , Taquicardia Ventricular/parasitologia , Taquicardia Ventricular/fisiopatologia
10.
Am J Trop Med Hyg ; 103(4): 1480-1486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32700660

RESUMO

Chagas disease is an emerging infectious disease in Europe and other non-endemic areas, mainly owing to migration from endemic areas. We aimed at investigating the value of advanced echocardiography (ECHO) and cardiac magnetic resonance (CMR) in patients newly diagnosed with Chagas disease to compare findings with those of electrocardiogram (ECG) and conventional ECHO and thus detecting cardiac abnormalities. We included consecutive patients with newly diagnosed Chagas disease and registered cardiac test results (ECG, ECHO, and CMR). We divided ECHO parameters into three tiers: 1) left ventricular ejection fraction, regional wall motion abnormality, and left ventricular diastolic dimension (ECHO-1); 2) other common ECHO parameters (ECHO-2); and 3) global longitudinal strain (GLS) (ECHO-3). Cardiac magnetic resonance included global and segmental biventricular function, the presence of myocardial fibrosis, and edema. The study comprised 100 patients from South America. The mean age was 43.9 ± 0.9 years, and 66% were women. Mean time living in Spain was 9.7 ± 0.5 years. The ECG revealed ≥ 2 abnormal findings in 47% of patients. ECHO-1 was abnormal in 22% of patients, ECHO-2 in 52%, and GLS in 16%. Cardiac magnetic resonance was abnormal in 50% of cases, and in 3% of these, ECHO was normal. When ECG and conventional ECHO were taken together, abnormalities were detected in 83% of patients. This value increased to 86% and 92% for GLS and CMR, respectively. These findings suggest that ECG and conventional ECHO should be used routinely as standard cardiac tests for newly diagnosed cases of Chagas disease. The value of advanced ECHO techniques and CMR is low.


Assuntos
Cardiomiopatia Chagásica/diagnóstico , Doença de Chagas/patologia , Coração/fisiopatologia , Doenças Transmissíveis Emergentes , Ecocardiografia/métodos , Eletrocardiografia/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , América do Sul , Espanha , Função Ventricular Esquerda
11.
Mem Inst Oswaldo Cruz ; 115: e200056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32556037

RESUMO

BACKGROUND: Left ventricular aneurysm (LVA) is indicator of high morbidity in Chagas' disease. A cross-sectional study performed identified LVA in 18.8% of the chronic chagasic patients (CCP). OBJECTIVE: Determine the risk of death of patients with chronic chagasic cardiopathy (CCC) and LVA in 24-year interval. MATERIAL AND METHODS: In 1995 a cohort of 298 CCP was evaluated by anamnesis, physical examination, EKG and ECHO and classified in groups: G0 = 86 without cardiopathy; G1 = 156 with cardiopathy without LVA and G2 = 56 with cardiopathy and LVA. 38 patients of G0 and G1 used benznidazole. Information about the deaths was obtained in the notary, death certificates, hospital records and family members. FINDINGS: Were registered 113 deaths (37.9%): 107 (35.9%) attributed to cardiopathy and 6 (2.0%) to other causes (p < 0.05). Amongst these 107 deaths, 10 (11.6%) occurred in G0; 49 (31.4%) occurred in G1 and 48 (85.7%) occurred in G2 (p < 0.05). The risk of death was 2.7 and 7.4 times significantly higher in G2, than in G1 and G0, respectively. CONCLUSION: Chronic chagasic patients with LVA and ejection fraction < 45% have a higher risk of death than those without.


Assuntos
Cardiomiopatia Chagásica/mortalidade , Aneurisma Cardíaco/mortalidade , Ventrículos do Coração/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Cardiomiopatia Chagásica/complicações , Doença Crônica , Estudos Transversais , Eletrocardiografia , Feminino , Aneurisma Cardíaco/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Am J Trop Med Hyg ; 103(2): 745-751, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32431281

RESUMO

Chronic Chagas disease can progress to myocardial involvement with intense fibrosis, which may predispose patients to sudden cardiac death through ventricular arrhythmia. The associations of myocardial fibrosis detected by cardiac magnetic resonance (CMR) parameters with non-sustained ventricular tachycardia (NSVT) were evaluated. This cross-sectional study included patients in early stages of Chagas disease (n = 47) and a control group (n = 15). Patients underwent cardiac evaluation, including CMR examination. Myocardial fibrosis assessment by CMR with measurement of late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV) was performed. There was an increase in myocardial fibrosis CMR parameters and ventricular arrhythmias among different stages of Chagas disease, combined with a decrease in the left ventricular ejection fraction (LVEF) by CMR and also in the right ventricular systolic function by S' wave on tissue Doppler. Fibrosis mass and ECV were associated with the Rassi score, ventricular extrasystole, and E/e' ratio in a logistic regression model adjusted for age and gender. The ECV maintained an association with the presence of NSVT, even after adjustments for fibrosis mass and LVEF assessed by CMR. The receiver-operating characteristic area under the curve for global ECV (0.85; 95% CI: 0.71-0.99) and NSVT was greater than that for fibrosis mass (0.75; 95% CI: 0.54-0.96), although this difference was not statistically significant. Extracellular volume could be an early marker of increased risk of ventricular arrhythmia in Chagas disease, presenting an independent association with NSVT in the initial stages of chronic Chagas cardiomyopathy, even after adjustment for fibrosis mass and LVEF.


Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Coração/diagnóstico por imagem , Taquicardia Ventricular/fisiopatologia , Idoso , Área Sob a Curva , Estudos de Casos e Controles , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/diagnóstico por imagem , Doença de Chagas/complicações , Doença de Chagas/diagnóstico por imagem , Doença de Chagas/fisiopatologia , Estudos Transversais , Ecocardiografia , Eletrocardiografia Ambulatorial , Espaço Extracelular , Feminino , Fibrose , Humanos , Modelos Logísticos , Imagem por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Tamanho do Órgão , Curva ROC , Volume Sistólico , Taquicardia Ventricular/etiologia , Função Ventricular Direita
13.
PLoS Negl Trop Dis ; 14(5): e0007980, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433643

RESUMO

Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Animais , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/genética , Proteoma/metabolismo , Proteômica , Transdução de Sinais , Trypanosoma cruzi/fisiologia
14.
PLoS Pathog ; 16(4): e1008474, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315358

RESUMO

Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas cardiomyopathy. In the present study, we investigated the role of extracellular vesicles (Ev) in shaping the macrophage (Mφ) response in progressive Chagas disease (CD). We purified T. cruzi Ev (TcEv) from axenic parasite cultures, and T. cruzi-induced Ev (TEv) from the supernatants of infected cells and plasma of acutely and chronically infected wild-type and Parp1-/- mice. Cultured (Raw 264.7) and bone-marrow Mφ responded to TcEV and TEv with a profound increase in the expression and release of TNF-α, IL-6, and IL-1ß cytokines. TEv produced by both immune (Mφ) and non-immune (muscle) cells were proinflammatory. Chemical inhibition or genetic deletion of PARP1 (a DNA repair enzyme) significantly depressed the TEv-induced transcriptional and translational activation of proinflammatory Mφ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory Mφ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NFκB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NFκB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-α+ Mφ in the myocardium of CD wild-type mice. In comparison, chronically infected Parp1-/- mice exhibited low-to-moderate tissue inflammation, >80% decline in myocardial infiltration of TNF-α+ Mφ, and no change in immunoregulatory IL-10+ Mφ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-κB pathway of proinflammatory Mφ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the Mφ activation and controlling the chronic inflammation in CD.


Assuntos
Doença de Chagas/metabolismo , Vesículas Extracelulares/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , Nucleotidiltransferases/imunologia , Poli(ADP-Ribose) Polimerase-1/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/imunologia , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Rev Soc Bras Med Trop ; 53: e20190406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321089

RESUMO

This is a case report about the only confirmed death in the State of Espírito Santo due to acute Chagas-related myocarditis in a 2-year-old child living in the rural area of Guarapari. He presented with fever, abdominal pain, headache, and vomiting, resulting in death 21 days after the presentation of symptoms. Amastigote forms were observed in the myocardial fibers in histological examination. The boy's mother had reported finding "kissing bugs" in the child's hand. This case highlights the need to include Chagas disease in the differential diagnosis in health care to provide early treatment and avoid death in affected individuals.


Assuntos
Cardiomiopatia Chagásica/diagnóstico , Doença Aguda , Autopsia , Pré-Escolar , Evolução Fatal , Humanos , Masculino
16.
PLoS Negl Trop Dis ; 14(4): e0008162, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32275663

RESUMO

Chagas cardiomyopathy is the most severe manifestation of human Chagas disease and represents the major cause of morbidity and mortality in Latin America. We previously demonstrated diastolic Ca2+ alterations in cardiomyocytes isolated from Chagas' patients to different degrees of cardiac dysfunction. In addition, we have found a significant elevation of diastolic [Na+]d in Chagas' cardiomyocytes (FCII>FCI) that was greater than control. Exposure of cardiomyocytes to agents that enhance inositol 1,4,5 trisphosphate (IP3) generation or concentration like endothelin (ET-1) or bradykinin (BK), or membrane-permeant myoinositol 1,4,5-trisphosphate hexakis(butyryloxy-methyl) esters (IP3BM) caused an elevation in diastolic [Ca2+] ([Ca2+]d) that was always greater in cardiomyocytes from Chagas' than non- Chagas' subjects, and the magnitude of the [Ca2+]d elevation in Chagas' cardiomyocytes was related to the degree of cardiac dysfunction. Incubation with xestospongin-C (Xest-C), a membrane-permeable selective blocker of the IP3 receptors (IP3Rs), significantly reduced [Ca2+]d in Chagas' cardiomyocytes but did not have a significant effect on non-Chagas' cells. The effects of ET-1, BK, and IP3BM on [Ca2+]d were not modified by the removal of extracellular [Ca2+]e. Furthermore, cardiomyocytes from Chagas' patients had a significant decrease in the sarcoplasmic reticulum (SR) Ca2+content compared to control (Control>FCI>FCII), a higher intracellular IP3 concentration ([IP3]i) and markedly depressed contractile properties compared to control cardiomyocytes. These results provide additional and convincing support about the implications of IP3 in the pathogenesis of Chagas cardiomyopathy in patients at different stages of chronic infection. Additionally, these findings open the door for novel therapeutic strategies oriented to improve cardiac function and quality of life of individuals suffering from chronic Chagas cardiomyopathy (CC).


Assuntos
Cálcio/metabolismo , Cardiomiopatia Chagásica/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Miócitos Cardíacos/metabolismo , Adulto , Bradicinina/metabolismo , Permeabilidade da Membrana Celular , Endotelinas/metabolismo , Feminino , Humanos , Compostos Macrocíclicos/metabolismo , Masculino , Pessoa de Meia-Idade , Oxazóis/metabolismo , Qualidade de Vida , Retículo Sarcoplasmático/metabolismo , Sódio/metabolismo
17.
Parasitol Res ; 119(6): 1829-1843, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32206887

RESUMO

The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/ß transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1-/-), and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1-/- and Aif1+/+ mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+ HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1ß-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.


Assuntos
Cardiomiopatia Chagásica/patologia , Doença de Chagas/complicações , Dieta Hiperlipídica , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Coração/parasitologia , Inflamação/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/patologia , Carga Parasitária , Trypanosoma cruzi/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
18.
Am J Cardiol ; 125(9): 1413-1420, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171439

RESUMO

Chagas heart disease (HD) is a chronic fibrosing myocarditis with high mortality. The PEACH study aimed to evaluate if exercise training can improve the functional capacity of Chagas HD patients with left ventricular dysfunction and/or heart failure. The PEACH study was a single center, parallel-group, clinical trial that randomized 30 clinical stable Chagas HD patients with left ventricular ejection fraction <45% or heart failure symptoms to either supervised exercise training 3 times/week for 6 months or a control group. Both groups had the same monthly pharmaceutical and nutritional counseling and usual care. Primary end point was functional capacity assessed by peak exercise oxygen consumption (peak VO2) obtained by cardiopulmonary exercise test. Secondary end points included other cardiopulmonary exercise test variables, cardiac function by echocardiography, body composition, muscle respiratory strength, and metabolic biomarkers. Peak VO2 increased among patients in exercise group from 17.60 ± 4.65 mlO2 kg-1 min-1 to 19.40 ± 5.51 mlO2 kg-1 min-1 while decreased in controls from 15.40 ± 6.30 mlO2 kg-1 min-1 to 12.96 ± 4.50 mlO2 kg-1 min-1, resulting in significant difference in change in peak VO2 between groups after 6 months (ß = +4.6, p = 0.004). There were significant differences between groups in changes in anaerobic threshold (ß = 3.7, p = 0.05), peak oxygen pulse (ß = +2.7, p = 0.032) and maximum minute ventilation (ß = +13.9, p < 0.0001) after 6 months of intervention. In conclusion, exercise training improved functional capacity of chronic Chagas HD patients with left ventricular dysfunction and/or heart failure.


Assuntos
Cardiomiopatia Chagásica/terapia , Exercício Físico , Idoso , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/fisiopatologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
19.
PLoS Pathog ; 16(3): e1008379, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32160269

RESUMO

Chagas Disease (CD) is one of the leading causes of heart failure and sudden death in Latin America. Treatments with antioxidants have provided promising alternatives to ameliorate CD. However, the specific roles of major reactive oxygen species (ROS) sources, including NADPH-oxidase 2 (NOX2), mitochondrial-derived ROS and nitric oxide (NO) in the progression or resolution of CD are yet to be elucidated. We used C57BL/6 (WT) and a gp91PHOX knockout mice (PHOX-/-), lacking functional NOX2, to investigate the effects of ablation of NOX2-derived ROS production on the outcome of acute chagasic cardiomyopathy. Infected PHOX-/- cardiomyocytes displayed an overall pro-arrhythmic phenotype, notably with higher arrhythmia incidence on ECG that was followed by higher number of early afterdepolarizations (EAD) and 2.5-fold increase in action potential (AP) duration alternans, compared to AP from infected WT mice. Furthermore, infected PHOX-/- cardiomyocytes display increased diastolic [Ca2+], aberrant Ca2+ transient and reduced Ca2+ transient amplitude. Cardiomyocyte contraction is reduced in infected WT and PHOX-/- mice, to a similar extent. Nevertheless, only infected PHOX-/- isolated cardiomyocytes displayed significant increase in non-triggered extra contractions (appearing in ~75% of cells). Electro-mechanical remodeling of infected PHOX-/-cardiomyocytes is associated with increase in NO and mitochondria-derived ROS production. Notably, EADs, AP duration alternans and in vivo arrhythmias were reverted by pre-incubation with nitric oxide synthase inhibitor L-NAME. Overall our data show for the first time that lack of NOX2-derived ROS promoted a pro-arrhythmic phenotype in the heart, in which the crosstalk between ROS and NO could play an important role in regulating cardiomyocyte electro-mechanical function during acute CD. Future studies designed to evaluate the potential role of NOX2-derived ROS in the chronic phase of CD could open new and more specific therapeutic strategies to treat CD and prevent deaths due to heart complications.


Assuntos
Arritmias Cardíacas/metabolismo , Sinalização do Cálcio , Cardiomiopatia Chagásica/metabolismo , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doença Aguda , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo
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