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1.
Rev Soc Bras Med Trop ; 52: e20190386, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800924

RESUMO

INTRODUCTION: Chronic chagasic cardiopathy (CCC) is essentially a dilated cardiomyopathy in which a subacute, but constant chronic inflammatory process causes progressive destruction of the heart tissue. The action of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and anti-inflammatory cytokines, like interleukin IL-10 and IL-17, plays a fundamental role in the immunopathogenesis and evolution of disease. Early anti-congestive therapy, aimed at changing the morbidity and mortality rate, has been shown to reduce disease progression and to alter patients' immune response pattern. METHODS: This cross-sectional study aimed to evaluate the profile of Th1 and Th17 cytokines and IL-17, TNF-α, and IFN-γ expressions in different stages of CCC. Forty patients affected by chronic Chagas disease were divided into different groups according to the stage of the pathology. In agreement with the Brazilian consensus on Chagas disease, patients were classified as presenting an undetermined form, a cardiac form and a digestive form. Serum IFN-γ, TNF-α, IL-10, and IL-17 were evaluated. RESULTS: Lower serum IFN-γ concentrations were detected in patients receiving angiotensin-converting enzyme inhibitors (p = 0.0182), but not in those using angiotensin receptor blockers (p = 0.0783). Patients using amiodarone and aldosterone antagonist presented higher serum TNF-α concentrations (p = 0.0106 and 0.0187, respectively). IL-10 and IL-17 levels did not differ between the study groups (p = 0.7273 and p = 0.6697, respectively). CONCLUSIONS: These results suggest that the cytokine profile and disease progression are altered by anti-congestive medications commonly prescribed for CCC.


Assuntos
Cardiomiopatia Chagásica/imunologia , Citocinas/sangue , Adulto , Idoso , Cardiomiopatia Chagásica/sangue , Cardiomiopatia Chagásica/tratamento farmacológico , Doença Crônica , Estudos Transversais , Citocinas/imunologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
2.
Int. j. cardiovasc. sci. (Impr.) ; 32(5): 546-550, Sept-Oct. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-1040097

RESUMO

We present a case of a female adolescent with severe acute Chagas myocarditis, acquired by oral transmission in an endemic area in the Brazilian western Amazon, who had electrocardiographic changes normalized after empirical treatment with the antiparasitic drug benznidazole combined with conventional treatment for severe heart failure


Assuntos
Humanos , Feminino , Criança , Cardiomiopatia Chagásica , Doença de Chagas/epidemiologia , Eletrocardiografia/métodos , Volume Sistólico , Trypanosoma cruzi , Ecocardiografia/métodos , Insuficiência Cardíaca , Antiparasitários/uso terapêutico
3.
Mem Inst Oswaldo Cruz ; 114: e180593, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433004

RESUMO

BACKGROUND: Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal transduction events during heart contraction-relaxation processes. Talin links integrins to the actin cytoskeleton and serves as a scaffold for the recruitment of other proteins, such as paxillin in focal adhesion formation and regulation. Chagasic cardiomyopathy is caused by infection by Trypanosoma cruzi and is a debilitating condition comprising extensive fibrosis, inflammation, cardiac hypertrophy and electrical alterations that culminate in heart failure. OBJECTIVES: Since mechanotransduction coordinates heart function, we evaluated the underlying mechanism implicated in the mechanical changes, focusing especially in mechanosensitive proteins and related signalling pathways during infection of cardiac cells by T. cruzi. METHODS: We investigated the effect of T. cruzi infection on the expression and distribution of talin/paxillin and associated proteins in mouse cardiomyocytes in vitro by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR). FINDINGS: Talin and paxillin spatial distribution in T. cruzi-infected cardiomyocytes in vitro were altered associated with a downregulation of these proteins and mRNAs levels at 72 h post-infection (hpi). Additionally, we observed an increase in the activation of the focal adhesion kinase (FAK) concomitant with increase in ß-1-integrin at 24 hpi. Finally, we detected a decrease in the activation of FAK at 72 hpi in T. cruzi-infected cultures. MAIN CONCLUSION: The results suggest that these changes may contribute to the mechanotransduction disturbance evidenced in chagasic cardiomyopathy.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Miócitos Cardíacos/parasitologia , Paxilina/metabolismo , Talina/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Western Blotting , Técnica Indireta de Fluorescência para Anticorpo , Immunoblotting , Mecanotransdução Celular/fisiologia , Camundongos , Reação em Cadeia da Polimerase em Tempo Real
4.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434314

RESUMO

Chagas disease (CD) affects approximately 6-7 million people worldwide, from which 30% develop chronic Chagas cardiomyopathy (CCC), usually after being asymptomatic for years. Currently available diagnostic methods are capable of adequately identifying infected patients, but do not provide information regarding the individual risk of developing the most severe form of the disease. The identification of biomarkers that predict the progression from asymptomatic or indeterminate form to CCC, may guide early implementation of pharmacological therapy. Here, six circulating microRNAs (miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p and miR-208a-3p) were evaluated and compared among patients with CCC (n = 28), CD indeterminate form (n = 10) and healthy controls (n = 10). MiR-19a-3p, miR-21-5p, and miR-29b-3p were differentially expressed in CCC patients when compared to indeterminate form, showing a positive correlation with cardiac dysfunction, functional class, and fibrosis, and a negative correlation with ejection fraction and left ventricular strain. Cardiac tissue analysis confirmed increased expression of microRNAs in CCC patients. In vitro studies using human cells indicated the involvement of these microRNAs in the processes of cardiac hypertrophy and fibrosis. Our study suggests that miRNAs are involved in the process of cardiac fibrosis and remodeling presented in CD and indicate a group of miRNAs as potential biomarkers of disease progression in CCC.


Assuntos
Biomarcadores/metabolismo , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Fibrose/patologia , MicroRNAs/metabolismo , Biomarcadores/química , Cardiomiopatia Chagásica/genética , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROC , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia
5.
PLoS Negl Trop Dis ; 13(7): e0007602, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365537

RESUMO

TGF-ß involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-ß signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TßR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-ß signaling pathway reduced TGF-ß/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-ß inhibitors.


Assuntos
Benzamidas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Coração/efeitos dos fármacos , Pirazóis/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Tripanossomicidas/uso terapêutico , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Coração/parasitologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Trypanosoma cruzi/efeitos dos fármacos
6.
Rev Soc Bras Med Trop ; 52: e20180512, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31340357

RESUMO

Heart transplantation is an effective treatment for Chagas disease patients with severe cardiomyopathy. However, Trypanosoma cruzi reactivation is of great concern. The T. cruzi parasite is classified into six discrete typing units (DTUs identified as TcI-TcVI). It is unknown whether there is an association between T. cruzi genetic lineages and the different clinical manifestations of the disease. We report the case of a 51-year-old man who received a heart transplantation and presented with a reactivation of the disease. The molecular characterization of the parasite showed that the reactivation was related to specific infection by a DTU I (TcISYL) parasite.


Assuntos
Cardiomiopatia Chagásica/cirurgia , Transplante de Coração/efeitos adversos , Imunossupressores/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , DNA de Protozoário , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
7.
Heart Lung Circ ; 28(9): 1427-1435, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31272827

RESUMO

The majority of global cardiovascular disease burden occurs in low- and middle-income countries (LMIC) and indigenous populations. Although common diseases, such as ischaemic heart disease, cause significant burden, there are also neglected diseases. Forgotten by many, these diseases-including rheumatic heart disease, endomyocardial fibrosis and Chagas cardiomyopathy-continue to take a tremendous toll on a large proportion of the world's population. Whilst the technology of echocardiography continues to evolve in many high-income countries, low resource countries are working out how to make this vital tool available and affordable for the most remote and poorest populations. This paper aims to highlight the neglected cardiovascular diseases and their echocardiographic features. It also highlights the latest research in relation to portable echocardiography, task shifting and disease screening. The authors make recommendations in relation to future directions, including making echocardiography an affordable and accessible tool for all.


Assuntos
Cardiomiopatia Chagásica , Ecocardiografia/economia , Fibrose Endomiocárdica , Pobreza , Cardiopatia Reumática , Cardiomiopatia Chagásica/diagnóstico por imagem , Cardiomiopatia Chagásica/economia , Fibrose Endomiocárdica/diagnóstico por imagem , Fibrose Endomiocárdica/economia , Humanos , Cardiopatia Reumática/diagnóstico por imagem , Cardiopatia Reumática/economia
8.
PLoS Negl Trop Dis ; 13(7): e0007597, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31356587

RESUMO

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNγ producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8+ T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8+ T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8+ T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies.


Assuntos
Vacinas contra Adenovirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Cardiomiopatia Chagásica/imunologia , Quimiotaxia de Leucócito , Miocárdio/metabolismo , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Apoptose , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/prevenção & controle , Feminino , Coração/parasitologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/imunologia , Receptores CCR2/metabolismo , Baço/imunologia , Regulação para Cima , Vacinas de DNA/imunologia
9.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 29(Suppl. 2b): 158-158, Jun. 2019.
Artigo em Português | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1009803

RESUMO

INTRODUÇÃO: A forma cardíaca é das mais letais da doença de Chagas, e métodos para sua estratificação de risco são necessários. O teste de esforço (TE) possui variáveis consagradas na avaliação de diversos grupos, sendo pouco estudado em chagásicos. O objetivo do estudo é avaliar se há associação entre variáveis do TE com desfechos clínicos na cardiopatia chagásica com fração de ejeção do ventrículo esquerdo (FEVE) reduzida. MÉTODOS: Estudo de coorte prospectivo incluindo pacientes com diagnóstico de doença de Chagas, estáveis e FEVE < 45%. O protocolo usado no TE foi de Bruce modificado e a recuperação passiva. Desfecho foi combinado de morte e implante de dispositivo cardíaco eletrônico (DCE). Estimativa de tamanho amostral de 14 pacientes (poder do teste de 95%). Os dados descritivos são apresentados como proporções e médias com desvio-padrão (DP). A associação entre variáveis e desfecho foi analisada pela regressão logística de Cox. RESULTADOS: Total de 46 pacientes, 25 mulheres (54,3%), com média de tempo de seguimento de 38,3 meses (DP 15). A média de idades foi de 57,6 anos (DP 9,2) e as proporções de hipertensos, diabéticos, dislipêmicos e tabagistas foram, respectivamente, 54,3%, 15,2%, 50% e 8,7%. A maioria estava em classe funcional II (69,6%), sendo que 42 (91,3%) pacientes usavam betabloqueadores, 41 (89,1%) usavam inibidores da ECA ou bloqueador de angiotensina e 14 (30,4%) usavam amiodarona. No eletrocardiograma, 25 (54,3%) tinham bloqueio de ramo direito, 5 (10,9%) tinham bloqueio de ramo esquerdo e a média da duração do QRS foi de 128,5 ms (DP 28,8). A média da FEVE foi 36,5% (DP 4,9) e do diâmetro diastólico do VE de 63,2 mm (DP 7,3) ao ecocardiograma. No TE, a média do tempo de esforço foi 9,6 minutos (DP 2,7) e em 10 (21,7%) pacientes foi induzida taquicardia ventricular não-sustentada (TVNS). O desfecho combinado ocorreu em 22 (47,8%) casos, sendo 14 óbitos e 8 implantes de DCE. Na regressão simples, 4 variáveis foram significativamente associadas ao desfecho: indução de TVNS no TE, diferença entre pressão sistólica no pico do esforço e repouso, recuperação da frequência cardíaca e a diferença entre pressão sistólica no minuto 1 e minuto 3 da recuperação. Permaneceram significativas na regressão múltipla a TVNS no TE (p= 0,005) e diferença entre pressão sistólica no minuto 1 e minuto 3 da recuperação (p= 0,01). CONCLUSÃO: Na amostra estudada, as variáveis significativamente associadas ao desfecho combinado foram a TVNS induzida no TE e a diferença entre pressão sistólica no minuto 1 e minuto 3 da recuperação. (AU)


Assuntos
Humanos , Cardiomiopatia Chagásica , Teste de Esforço
10.
PLoS Negl Trop Dis ; 13(5): e0007413, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31145733

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection.


Assuntos
Anticorpos Antiprotozoários/imunologia , Cardiomiopatia Chagásica/imunologia , Vacinas Protozoárias/administração & dosagem , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/prevenção & controle , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Interferon gama/genética , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/patologia , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/patologia , Parasitemia/prevenção & controle , Vacinas Protozoárias/imunologia , Células Th1/imunologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Vacinação
11.
Parasit Vectors ; 12(1): 260, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126327

RESUMO

BACKGROUND: Chagas disease is a protozoan infection caused by Trypanosoma cruzi. The disease has a chronic course in which 20-30% of the patients would develop progressive damage to the cardiovascular system and the gastrointestinal tube. We are still unable to predict who will develop end-organ damage but there are some acquired and genetic risk factors already known. RESULTS: We reviewed data from 833 patients with serologically confirmed Chagas disease in this retrospective study. Patients were classified as siblings or non-siblings (controls) and the results of pre-treatment blood PCR assay, end-organ damage (cardiac and/or gastrointestinal), and the presence of delayed type hypersensitivity (DTH) skin involvement in patients treated with benznidazole were analyzed. Siblings were grouped by family and we randomly generated groups of 2 or 3 persons with the remaining controls. We classified the results of each variable as concordant or discordant and compared the concordance in these results among the sibling groups with that among control groups. We identified 71 groups of siblings and randomly generated 299 groups of non-related patients. Pre-treatment blood PCR concordance was significantly higher (19%) among siblings compared to controls (P = 0.02), probably due to a higher frequency in pre-treatment positive results. No other statistically significant differences were found. CONCLUSIONS: A significant difference was found in the concordance of pre-treatment blood PCR for T. cruzi among siblings compared to non-related controls.


Assuntos
Doença de Chagas/etnologia , Doença de Chagas/genética , Irmãos , Adulto , Bolívia , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/etiologia , Doença de Chagas/complicações , Doença Crônica , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/parasitologia , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi
12.
Life Sci ; 230: 141-149, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129142

RESUMO

When administered alone, preinfection exercise training and benznidazole-based chemotherapy induce cardioprotection in Chagas disease. However, the effect of concomitant exercise and benznidazole treatment is unknown. We investigated whether exercise and specific chemotherapy could interact to modulate parasitemia, inflammation, redox status and heart damage in a murine model of T. cruzi infection. Wistar rats were randomized into an uninfected control group (CNT) and four groups infected with T. cruzi: sedentary untreated (SUN) and treated (STR), and trained untreated (TUN) and treated (TTR). Running training was administered 5 days/week for 4 weeks. Treated animals concomitantly received 100 mg/kg/day benznidazole. Heart inflammation and reactive damage were not detected in CNT animals. Compared to SUN, TUN animals presented increased levels of parasitemia, myocarditis, nitric oxide, hydrogen peroxide, protein carbonyl, malondialdehyde, cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10 and IL-17), catalase, superoxide dismutase and glutathione reductase activity, as well as reduced heart non-protein antioxidant levels (P < 0.05). TTR animals exhibited higher levels of parasitemia, myocarditis, hydrogen peroxide, malondialdehyde, IFN-γ, TNF-α and IL-6 than STR animals (P < 0.05), which showed the lowest levels of all analyzed parameters compared to the other groups (P < 0.05). Our findings indicate that exercise aggravates acute infection. When concomitantly administered with benznidazole, exercise training impaired parasitic control and chemotherapy-induced cardioprotection in T. cruzi-infected rats. Considering that exercise training and T. cruzi infection constitute independent metabolic challenges, the negative effects of concomitant treatment are potentially related to the overlapping oxidative and immunoinflammatory demands of exercise and the infection itself.


Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/metabolismo , Catalase/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Cardiomiopatia Chagásica/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Coração/fisiologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Masculino , Miocardite/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Nitroimidazóis/farmacologia , Parasitemia/parasitologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo
13.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936158

RESUMO

In chronic Trypanosoma cruzi infection, the cause of Chagas disease, life-threatening inflammatory diseases develop over time in the heart, esophagus, and colon of some patients. C57BL/6 mice infected with the myotropic Colombiana strain of T. cruzi model many of the immunological and parasitological features of human infection but succumb to chronic paralyzing myositis and skeletal muscle vasculitis, not cardiomyopathy or gastrointestinal disease. Here we show that T cell depletion in the chronic phase of this model increased tissue parasitism to acute-phase levels and induced neutrophilic skeletal muscle inflammation. Conversely, after daily treatment with the trypanocide benznidazole for 8 weeks during the chronic phase, viable parasites were no longer detectable, myositis completely resolved, vasculitis was ∼80% reduced, fibrosis was reduced, and myofiber morphology normalized. After the drug was discontinued, parasitism rebounded, and immunopathology recurred. The parasite load was statistically strongly correlated with the severity of inflammation. Thus, both T cell immunity and trypanocidal pharmacotherapy suppress to very low levels, but do not cure, T. cruzi infection, which is necessary and possibly sufficient to induce crippling chronic skeletal muscle myositis and vasculitis in the model.


Assuntos
Cardiomiopatia Chagásica/parasitologia , Músculo Esquelético/parasitologia , Miosite/parasitologia , Trypanosoma cruzi/fisiologia , Vasculite/parasitologia , Animais , Cardiomiopatia Chagásica/imunologia , Modelos Animais de Doenças , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Miosite/imunologia , Linfócitos T/imunologia , Vasculite/imunologia
14.
PET Clin ; 14(2): 281-291, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826025

RESUMO

Ventricular arrhythmias (VAs) are a major cause of morbidity and mortality, especially in patients with structural heart disease. In the last decade, advanced imaging modalities, such as cardiac MR and nuclear imaging, have progressively demonstrated to play a central role in the diagnosis and management of patients presenting with VAs. PET is acquiring a growing role thanks to its capability to assess different pathophysiologic aspects of the arrhythmogenic substrate by evaluating abnormal myocardial perfusion, presence of inflammation, myocardial viability, and sympathetic innervation. This review describes the principles and main clinical applications of PET imaging in the setting of VAs.


Assuntos
Arritmias Cardíacas/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Cardiomiopatia Chagásica/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Miocardite/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Recidiva , Sarcoidose/diagnóstico por imagem
15.
Hum Immunol ; 80(7): 517-522, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30853363

RESUMO

INTRODUCTION: Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4+CD25HighFOXP3+) to orchestrate the immune response in chronic Chagas disease. METHODS AND RESULTS: Patients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi-negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14+ cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L+ cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14+ Caspase3+ cells in the IND group. CONCLUSION: Our data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease.


Assuntos
Antígeno B7-H1/metabolismo , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Chagásica/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/imunologia , Trypanosoma cruzi/imunologia , Adulto , Idoso , Antígenos de Protozoários/imunologia , Apoptose/imunologia , Apirase/metabolismo , Antígenos CD4/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Sorológicos
16.
Infect Dis Clin North Am ; 33(1): 119-134, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30712757

RESUMO

American trypanosomiasis is caused by a parasite endemic of the Americas. Current migration has globalized Chagas disease. Acute infection usually resolves spontaneously. Nonetheless, 20% to 40% develop cardiomyopathy 20 to 30 years later. Progression to cardiomyopathy is devastatingly rapid, manifesting with heart failure and sudden death. Etiologic treatment is highly effective and recommended in those with acute infections, congenital infections, and parasite reactivation, and women of childbearing age, but in asymptomatic Trypanosoma cruzi carriers and patients with early cardiomyopathy remains controversial and under investigation. Progression of heart failure is rapid and accounts for most of the morbidity and related mortality.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/mortalidade , Doença de Chagas/complicações , Doença de Chagas/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Progressão da Doença , Vetores de Doenças , Humanos , Nitroimidazóis/uso terapêutico , Triatominae/parasitologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/isolamento & purificação
17.
Arq Bras Cardiol ; 112(2): 189-192, 2019 Feb.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30785584

RESUMO

Changes in iron metabolism in heart failure (HF) have been described as an important prognostic marker. To check if the markers of iron kinetics are related to the morbidity and etiology of chagasic cardiomyopathy. Patients with Chronic Chagasic Cardiomyopathy (CCC, n = 40), with indeterminate form (IND, n = 40), besides non-chagasic cardiomyopathy (NCh, n = 40). The mean age was 50.98 ± 5.88 in CCC, 50% were male, 49.68 ± 5.28 in IND, 52.2% were male, and 49.20 ± 10.09 in NCh, 12.5% were male. Lower levels of iron (FeSe) were observed in the CCC groups (93.15 ± 36.53), when compared to IND (125.30 ± 22.79) and NCh (114.77 ± 18.90) (p = 0.0004), lower IST transferrin saturation index in CCC (29.48 ± 6.59), when compared to IND (30.95 ± 7.06) and in the NCh group (39.70 ± 7.54) p = 0.0001), total binding capacity of the lower CTLF iron in the CCC group (297.30 ± 36.46), when compared to the IND group (196.52 ± 56.95) and the NCh group (275.18 ± 33, 48) (p = 0.0001), lower ferritin in the CCC group (134.55, 1.56-42.36), when compared to the IND group (156,25, 1,72-42,20) and the NCh group (112.95, 2.88-42.66) (p = 0.0004). It was also observed that FeSe (95% CI 1.00-1.04, p = 0.0014), IST (95% CI 1.02-1.22) (p = 0.0012) and gender (95% CI 1.07-14.43 p = 0.0038) were independently associated with the degree of ventricular dysfunction in chagasic cardiomyopathy. CCC patients showed greater change in iron metabolism regarding the indeterminate form and other forms of cariomyopathies.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Distúrbios do Metabolismo do Ferro/metabolismo , Ferro/sangue , Disfunção Ventricular Esquerda/metabolismo , Adulto , Anemia/metabolismo , Anemia/fisiopatologia , Cardiomiopatia Chagásica/fisiopatologia , Doença Crônica , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estatísticas não Paramétricas , Disfunção Ventricular Esquerda/fisiopatologia
18.
Life Sci ; 219: 336-342, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684542

RESUMO

Chagas disease (CD) is an important cause of cardiomyopathy in South America. The pathophysiology of CD is still a matter of debate. Renin Angiotensin System (RAS) components are clearly involved in cardiovascular diseases. RAS molecules interact with nitric oxide (NO) pathway in blood vessel and heart tissue. Thus, the aim of this study is to investigate possible changes in RAS molecules during the infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, l-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received l-NAME or tap water from one day before the infection until 13 or 17 days post infection (dpi). Angiotensin converting enzyme 1 (ACE1) levels were significantly higher at day 17 when compared to baseline in atrium, whereas, in ventricle, ACE2 levels were significantly higher in 13 dpi when compared to baseline. In response to l-NAME treatment, atrium tissue levels of ACE1 were significantly reduced in treated animals at day 17, while Angiotensin-(1-7) concentration in atrium significantly increased in this group at the same time-point. No changes were detected in RAS components in the ventricle. ACE2 levels in Soleus muscle were significantly reduced in treated animals at day 13. In conclusion, changes in RAS molecules were detected during acute phase of T. cruzi infection and the inhibition of NO synthesis clearly interfered with expression of ACE1 and Angiotensin-(1-7) in the atrium.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/antagonistas & inibidores , Sistema Renina-Angiotensina , Animais , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Peptidil Dipeptidase A/metabolismo , Ratos Sprague-Dawley , Trypanosoma cruzi
19.
PLoS Negl Trop Dis ; 13(1): e0007033, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650073

RESUMO

Several studies have proposed different genetic markers of susceptibility to develop chronic Chagas cardiomyopathy (CCC). Many genes may be involved, each one making a small contribution. For this reason, an appropriate approach for this problematic is to study a large number of single nucleotide polymorphisms (SNPs) in individuals sharing a genetic background. Our aim was to analyze two CCR2 and seven CCR5 SNPs and their association to CCC in Argentina. A case-control study was carried out in 480 T. cruzi seropositive adults from Argentinean Gran Chaco endemic region (Wichi and Creole) and patients from Buenos Aires health centres. They were classified according to the Consensus on Chagas-Mazza Disease as non-demonstrated (non-DC group) or demonstrated (DC group) cardiomyopathy, i.e. asymptomatic or with CCC patients, respectively. Since, after allelic analysis, 2 out of 9 studied SNPs did not fit Hardy-Weinberg equilibrium in the unaffected non-DC group from Wichi patients, we analyzed them as a separate population. Only rs1800024T and rs41469351T in CCR5 gene showed significant differences within non-Wichi population (Creole + patients from Buenos Aires centres), being the former associated to protection, and the latter to risk of CCC. No evidence of association was observed between any of the analyzed CCR2-CCR5 gene polymorphisms and the development of CCC; however, the HHE haplotype was associated with protection in Wichi population. Our findings support the hypothesis that CCR2-CCR5 genes and their haplotypes are associated with CCC; however, depending on the population studied, different associations can be found. Therefore, the evolutionary context, in which the genes or haplotypes are associated with diseases, acquires special relevance.


Assuntos
Cardiomiopatia Chagásica/genética , Predisposição Genética para Doença , Receptores CCR2/genética , Receptores CCR5/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Argentina , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
20.
J. Am. Soc. Echocardiogr ; 32(2): 286-295, Fev. 2019. tabela, gráfico
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1023938

RESUMO

Serial echocardiographic studies in chronic Chagas cardiomyopathy are scarce. The aims of this study were to evaluate whether therapy with benznidazole modifies the progression of cardiac impairment and to identify baseline echocardiographic parameters related to prognosis. METHODS: A prospective sub study was conducted in 1,508 patients with chronic Chagas cardiomyopathy randomized to benznidazole or placebo, who underwent two-dimensional echocardiography at enrollment, 2 years, and final follow-up (5.4 years). Left ventricular (LV) ejection fraction, LV wall motion score index (WMSI), indexed left atrial volume, and chamber dimensions were collected and correlated to all-cause death and a composite hard outcome using univariate and multivariate analyses. RESULTS: At enrollment, most patients had normal chamber dimensions, and 70.5% had preserved LV ejection fractions. During follow-up, all chamber dimensions increased similarly in both treatment arms. LV ejection fraction was comparably reduced (55.7 ± 12.7% to 52.1 ± 14.6% vs 56.3 ± 12.7% to 52.8 ± 14.1%) and LV WMSI similarly increased (1.31 ± 0.41 to 1.49 ± 0.03 and 1.27 ± 0.38 to 1.51 ± 0.03) for the benznidazole and placebo groups, respectively (P > .05). A higher baseline LV WMSI was identified in subjects who died compared with those alive at final echocardiography (1.76 ± 0.517 vs 1.271 ± 0.393, P < .0001). There was a significant (P < .0001) graded increase in the risk for the composite outcome with worsening LV WMSI (hazard ratios, 2.27 [95% CI, 1.69-3.06] and 6.42 [95% CI, 4.94-8.33]) and also of death (hazard ratios, 2.45 [95% CI, 1.62-3.71] and 8.99 [95% CI, 6.3-12.82]) for 1 < LV WMSI < 1.5 and LV WMSI > 1.5, respectively. Both LV WMSI and indexed left atrial volume remained independent predictors in multivariate analysis. CONCLUSIONS: Trypanocidal treatment had no effect on echocardiographic progression of chronic Chagas cardiomyopathy over 5.4 years. Despite normal global LV systolic function, regional wall motion abnormalities and indexed left atrial volume identified patients at higher risk for hard adverse clinical outcomes. Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved. KEYWORDS: Chagas cardiomyopathy; Echocardiography; Prognosis; Trypanocidal therapy. (AU)


Assuntos
Humanos , Prognóstico , Tripanossomicidas/uso terapêutico , Ecocardiografia , Cardiomiopatia Chagásica
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