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1.
Basic Res Cardiol ; 114(5): 33, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31312919

RESUMO

Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.


Assuntos
Armadilhas Extracelulares , Fibroblastos/patologia , Leucócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Remodelação Ventricular/fisiologia , Adulto , Idoso , Feminino , Fibrose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia
2.
Medicine (Baltimore) ; 98(17): e15194, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027064

RESUMO

INTRODUCTION: While the role of inflammation in acute coronary events is well established, the impact of inflammatory-mediated vulnerability of coronary plaques from the entire coronary tree, on the extension of ventricular remodeling and scaring, has not been clarified yet. MATERIALS AND METHODS: The present manuscript describes the procedures of the VIABILITY trial, a descriptive prospective single-center cohort study. The main purpose of this trial is to assess the link between systemic inflammation, pan-coronary plaque vulnerability (referring to the plaque vulnerability within the entire coronary tree), myocardial viability and ventricular remodeling in patients who had suffered a recent ST-segment elevation acute myocardial infarction (STEMI). One hundred patients with STEMI who underwent successful revascularization of the culprit lesion in the first 12 hours after the onset of symptoms will be enrolled in the study. The level of systemic inflammation will be evaluated based on the serum biomarker levels (hs-CRP, matrix metalloproteinases, interleukin-6) in the acute phase of the myocardial infarction (MI) and at 1 month. Pan-coronary plaque vulnerability will be assessed based on serum biomarkers known to be associated with increased plaque vulnerability (V-CAM or I-CAM) and at 1 month after infarction, based on computed tomographic angiography analysis of vulnerability features of all coronary plaques. Myocardial viability and remodeling will be assessed based on 3D speckle tracking echocardiography associated with dobutamine infusion and LGE-CMR associated with post-processing imaging methods. The study population will be categorized in 2 subgroups: subgroup 1 - subjects with STEMI and increased inflammatory response at 7 days after the acute event (hs-CRP ≥ 3 mg/dl), and subgroup 2 - subjects with STEMI and no increased inflammatory response at 7 days (hs-CRP < 3 mg/dl). Study outcomes will consist in the rate of post-infarction heart failure development and the major adverse events (MACE) rate. CONCLUSION: VIABILITY is the first prospective study designed to evaluate the influence of infarct-related inflammatory response on several major determinants of post-infarction outcomes, such as coronary plaque vulnerability, myocardial viability, and ventricular remodeling.


Assuntos
Doença da Artéria Coronariana/imunologia , Inflamação/imunologia , Placa Aterosclerótica/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Remodelação Ventricular/imunologia , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Humanos , Inflamação/sangue , Inflamação/diagnóstico por imagem , Placa Aterosclerótica/sangue , Placa Aterosclerótica/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
3.
Heart Vessels ; 34(4): 557-563, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30315494

RESUMO

A higher rate of bioresorbable vascular scaffold (BVS) thrombosis has been observed after device implantation compared to implantation of permanent metallic stents in recently published studies. The mechanism of BVS thrombosis is currently under debate. To assess whether the immune-inflammatory response after BVS implantation is a potential trigger of BVS thrombosis. The PRAGUE-19 study was an academic study that enrolled consecutive patients with ST-segment elevation myocardial infarction (STEMI) with the intention to implant a BVS. A laboratory sub-study included 49 patients with an implanted BVS (of which 38 underwent the complete 2-year follow-up) and 52 patients having an implanted permanent metallic stent as the control group (of which 30 underwent the complete 2-year follow-up). Samples for inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] were taken before BVS or stent implantation, on days 1 and 2 after device implantation and at 1 month and 2 years for a clinical control. The primary combined clinical endpoint of the sub-study (death, reinfarction or target vessel revascularization) occurred in 4.08% of the BVS group and 7.69% of the control group (p = 0.442) during the 2-year follow-up period, with overall mortality of 2.04% in the BVS group and 1.92% in the control group (p = 0.966). Definite BVS thrombosis occurred in one patient in the subacute phase; there was no late or very late thrombosis. Two definite stent thromboses were observed in the control group: one in the subacute phase and the other in the late phase. Baseline inflammatory marker levels did not differ between the groups. Lower levels of IL-6 and hs-CRP were observed in the BVS group compared to the control group (12.02 ± 5.94 vs. 15.21 ± 5.33 pg/ml; p < 0.01; 3952.9 ± 1704.75 ng/ml vs. 4507.49 ± 1190.01 ng/ml; p = 0.037, respectively) on days 1 and 2 (12.01 ± 6.31 vs. 13.85 ± 6.01 pg/ml; p = 0.089; 4447.92 ± 1325.31 ng/ml vs. 4637.03 ± 1290.99 ng/ml; p = 0.255, respectively). No differences in IL-6 or hs-CRP were observed after 1 month or 2 years in the clinical control. Levels of TNF-α did not differ between the groups in the early period after BVS or metallic stent implantation, nor during follow-up. The immune-inflammatory response is lower during the early phase after BVS implantation compared to that after metallic stent implantation, but the responses did not differ in the long term.


Assuntos
Implantes Absorvíveis , Stents Farmacológicos , Everolimo/farmacologia , Imunidade Inata , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Tecidos Suporte , Adulto , Idoso , Angiografia Coronária , Citocinas/metabolismo , Feminino , Seguimentos , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/instrumentação , Desenho de Prótese , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Fatores de Tempo
4.
J Cardiovasc Transl Res ; 11(1): 22-32, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29313268

RESUMO

It remains unclear if the developmental trajectories of a specific inflammatory biomarker during the acute phase of ST-elevation myocardial infarction (STEMI) provide outcome prediction. By applying latent class growth modeling (LCGM), we identified three distinctive trajectories of CD14++CD16+ monocytes using serial flow cytometry assays from day 1 to day 7 of symptom onset in 96 de novo STEMI patients underwent primary percutaneous coronary intervention. Membership in the high-hump-shaped trajectory (16.8%) independently predicted adverse cardiovascular outcomes during a median follow-up of 2.5 years. Moreover, inclusion of CD14++CD16+ monocyte trajectories significantly improved area under the curve (AUC) when added to left ventricular ejection fraction-based prediction model (ΔAUC = 0.093, P = 0.013). Therefore, CD14++CD16+ monocyte trajectories during STEMI hospitalization are a novel risk factor for post-STEMI adverse outcomes. These results provide the first proof-of-principle evidence in support of the risk stratification role of LCGM-based longitudinal modeling of specific inflammatory markers during acute STEMI.


Assuntos
Hospitalização , Mediadores da Inflamação/imunologia , Monócitos/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/imunologia , Humanos , Mediadores da Inflamação/sangue , Receptores de Lipopolissacarídeos/sangue , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Intervenção Coronária Percutânea , Receptores de IgG/sangue , Receptores de IgG/imunologia , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Fatores de Tempo , Resultado do Tratamento
5.
Trials ; 18(1): 601, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258572

RESUMO

BACKGROUND: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. DISCUSSION: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014.


Assuntos
Anti-Inflamatórios/administração & dosagem , Linfócitos B/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Mediadores da Inflamação/sangue , Inibidores da Agregação de Plaquetas/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Terapia Trombolítica , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Anti-Inflamatórios/efeitos adversos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores/sangue , Brasil , Protocolos Clínicos , Clopidogrel , Angiografia Coronária , Quimioterapia Combinada , ELISPOT , Ezetimiba/administração & dosagem , Feminino , Citometria de Fluxo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Metabolômica , Inibidores da Agregação de Plaquetas/efeitos adversos , Proteômica , Projetos de Pesquisa , Rosuvastatina Cálcica/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Sinvastatina/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Terapia Trombolítica/efeitos adversos , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
6.
Circ Res ; 121(8): 930-940, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851810

RESUMO

RATIONALE: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. OBJECTIVE: We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. METHODS AND RESULTS: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, Mertk(CR) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCIILOCCR2- (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-ß. Mertk deficiency compromised the accumulation of MHCIILO phagocytes, and this was rescued in Mertk(CR) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. CONCLUSIONS: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCIILO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.


Assuntos
Macrófagos/enzimologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/enzimologia , Animais , Apoptose , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade Inata , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/enzimologia , Monócitos/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/imunologia , Miocárdio/patologia , Fagocitose , Fenótipo , Proteólise , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/imunologia , Receptores CCR2/genética , Receptores CCR2/imunologia , Receptores CCR2/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Transdução de Sinais , Fatores de Tempo , c-Mer Tirosina Quinase
7.
Am J Physiol Heart Circ Physiol ; 312(2): H265-H274, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864235

RESUMO

L5-LDL, the most electronegative LDL associated with major cardiovascular risks, significantly rises in patients with ST-segment elevation myocardial infarction (STEMI). The inflammatory nature of atherosclerotic vascular diseases has prompted us to investigate whether L5-LDL induces the production of inflammatory cytokines, especially vascular ischemia-related interleukin (IL)-1ß, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1ß were higher in the STEMI patients than in the controls (P < 0.05). In THP-1-derived human macrophages, L5-LDL significantly increased the levels of both IL-1ß and cleaved caspase-1, indicating the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes by L5-LDL. Knockdown of NLRP3 and its adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) resulted in decreased L5-LDL-induced IL-1ß. Furthermore, knock down of the lectin-type oxidized LDL receptor (LOX-1) in THP-1 cells attenuated L5-LDL-induced activation of NF-κB and caspase-1, leading to subsequent inhibition of IL-1ß in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1ß in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1ß production in macrophages by activation of NF-κB and caspase-1 through the LOX-1-dependent pathway. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1ß in STEMI, and identifies L5-LDL as a novel therapeutic target in acute myocardial infarction. NEW & NOTEWORTHY: This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1ß in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1ß in macrophages. The results showed that L5-LDL induced activation of caspase-1 and NF-κB through the lectin-type oxidized LDL receptor (LOX-1)-dependent pathway, leading to the production of IL-1ß.


Assuntos
Interleucina-1beta/imunologia , Lipoproteínas LDL/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Receptores Depuradores Classe E/imunologia , Western Blotting , Proteínas Adaptadoras de Sinalização CARD , Caspase 1/imunologia , Linhagem Celular , Proteínas do Citoesqueleto/genética , Técnicas de Silenciamento de Genes , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Humanos , Inflamassomos/imunologia , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos Mononucleares , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Interferência de RNA , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Receptores Depuradores Classe E/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Iran J Allergy Asthma Immunol ; 15(4): 257-263, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27921405

RESUMO

The important role of reperfusion therapies in the treatment of acute myocardial infarction is well documented. However, reperfusion therapies can initiate inflammatory response and may damage the myocardium. The purpose of current study was to compare the effects of percutaneous coronary intervention and thrombolytic therapy on inflammatory markers in the setting of ST elevation myocardial infarction (STEMI). Eighty three patients with STEMI were enrolled in this study. 40 patients underwent percutaneous coronary intervention (PCI), and 43 patients received streptokinase (1.5 million IU) as a main medical reperfusion therapy. Monocyte expression of Toll-like receptor 4 (TLR4),  serum levels of TNF-α and IL-1ß, red cell distribution width (RDW) and C- reactive protein (CRP) were compared between groups at admission time, two hours and four hours after termination of treatment. p<0.05 was considered as statistically significant for all tests. Compared to baseline, both treatments increased monocyte expression of TLR4, serum levels of cytokines and CRP. Compared to PCI, medical reperfusion therapy significantly raised both monocyte expression of TLR4 (39.8±4.7 % vs 49.1±3.6 %, p<0.01), and serum levels of TNF-α (13.2±3.7 pg/ml vs 25.1±2.6pg/mlp<0.05). No effect was seen on RDW levels. Moreover, medical reperfusion therapy caused significant rise in CRP levels (p<0.01). The present study demonstrates that thrombolytic therapy is associated with higher inflammatory responses compared to PCI. Our findings suggest that thrombolytic therapy may increase the likelihood of detrimental effects of reperfusion therapy on the myocardium.


Assuntos
Mediadores da Inflamação/sangue , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Estreptoquinase/administração & dosagem , Terapia Trombolítica , Regulação para Cima , Idoso , Feminino , Humanos , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia
10.
Eur Heart J Acute Cardiovasc Care ; 5(4): 382-95, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25681486

RESUMO

After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression.


Assuntos
Biomarcadores/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Quimiocinas/sangue , Citocinas/sangue , Humanos , Contagem de Leucócitos , Prognóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Remodelação Ventricular
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