RESUMO
Despite early reperfusion, patients with ST segment elevation myocardial infarction (STEMI) may present large myocardial necrosis and significant impairment of ventricular function. The present study aimed to evaluate the role of subtypes of B lymphocytes and related cytokines in the infarcted mass and left ventricular ejection fraction obtained by cardiac magnetic resonance imaging performed after 30 days of STEMI. This prospective study included 120 subjects with STEMI submitted to pharmacoinvasive strategy. Blood samples were collected in subjects in the first (D1) and 30th (D30) days post STEMI. The amount of CD11b+ B1 lymphocytes (cells/ml) at D1 were related to the infarcted mass (rho = 0.43; P=0.033), measured by cardiac MRI at D30. These B1 cells were associated with CD4+ T lymphocytes at D1 and D30, while B2 classic lymphocytes at day 30 were related to left ventricular ejection fraction (LVEF). Higher titers of circulating IL-4 and IL-10 were observed at D30 versus D1 (P=0.013 and P<0.001, respectively). Titers of IL-6 at D1 were associated with infarcted mass (rho = 0.41, P<0.001) and inversely related to LVEF (rho = -0.38, P<0.001). After multiple linear regression analysis, high-sensitivity troponin T and IL-6 collected at day 1 were independent predictors of infarcted mass and, at day 30, only HDL-C. Regarding LVEF, high-sensitivity troponin T and high-sensitivity C-reactive protein were independent predictors at day 1, and B2 classic lymphocytes, at day 30. In subjects with STEMI, despite early reperfusion, the amount of infarcted mass and ventricular performance were related to inflammatory responses triggered by circulating B lymphocytes.
Assuntos
Linfócitos B/imunologia , Infarto do Miocárdio/imunologia , Adulto , Antígenos CD/imunologia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-4/sangue , Imageamento por Ressonância Magnética , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Sensibilidade e Especificidade , Troponina T/sangueRESUMO
Interleukin- (IL-) 17 is increased in acute myocardial infarction (AMI) and plays a key role in inflammatory diseases through its involvement in the activation of leukocytes. Here, we describe for the first time the effect of IL-17 in the migration and activation of monocyte subsets in patients during ST-segment elevation myocardial infarction (STEMI) and post-STEMI. We analyzed the circulating levels of IL-17 in patient plasma. A gradual increase in IL-17 was found in STEMI and post-STEMI patients. Additionally, IL-17 had a powerful effect on the recruitment of CD14++CD16+/CD14+CD16++ monocytes derived from patients post-STEMI compared with the monocytes from patients with STEMI, suggesting that IL-17 recruits monocytes with inflammatory activity post-STEMI. Furthermore, IL-17 increased the expression of TLR4 on CD14 + CD16 - and CD14++CD16+/CD14+CD16++ monocytes post-STEMI and might enhance the response to danger-associated molecular patterns post-STEMI. Moreover, IL-17 induced secretion of IL-6 from CD14++CD16- and CD14++CD16+/CD14+CD16++ monocytes both in STEMI and in post-STEMI, which indicates that IL-17 has an effect on the secretion of proinflammatory cytokines from monocytes during STEMI and post-STEMI. Overall, we demonstrate that in STEMI and post-STEMI, IL-17 is increased and induces the migration and activation of monocyte subsets, possibly contributing to the inflammatory response through TLR4 and IL-6 secretion.
Assuntos
Endotélio Vascular/metabolismo , Interleucina-17/metabolismo , Monócitos/imunologia , Infarto do Miocárdio/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletrocardiografia , Endotélio Vascular/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de IgG/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In this sense, some studies are investigating pharmacological therapies using acetylcholinesterase inhibitors, such as pyridostigmine bromide (PYR), aiming to increase parasympathetic tone after MI. Here we hypothesized that the use of PYR before the MI might bring an additional positive effect to the autonomic function, and consequently, in the inflammatory response and cardiac function. The present study aimed to evaluate left ventricular function, baroreflex sensitivity, autonomic modulation, and inflammatory profile in PYR-treated rats previously to MI. METHODS: Male Wistar rats (250-300 g) were treated for 60 days with PYR. After treatment, they were submitted to the MI. After the MI, the autonomic and ventricular function were evaluated, as well as the systemic, left ventricle, and adipose tissue inflammatory profile. RESULTS: PYR, performed before MI, prevented HR increase, systolic function impairment, baroreflex sensitivity drop, as well as pulse interval variance, RMSSD, blood pressure and parasympathetic modulation reduction in treated rats compared to untreated rats. Also, this positive functional changes may have been a result of the reduced inflammatory parameters in the left ventricle (IFN-γ, IL-6, and IL-1ß), as well as increased IL-10 expression and IL-10/TNF-α ratio in treated animals before MI. CONCLUSION: Prior treatment with PYR prevents impairment of the autonomic nervous system after MI, which may be associated with the attenuated expression of inflammatory factors and heart dysfunction.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Brometo de Piridostigmina/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Brometo de Piridostigmina/farmacologia , Ratos , Ratos WistarRESUMO
Among the different cardiovascular disease complications, atherosclerosis-induced myocardial infarction (MI) is the major contributor of heart failure (HF) and loss of life. This review presents short- and long-term features of post-MI in human hearts and animal models. It is known that the heart does not regenerate, and thus loss of cardiac cells after an MI event is permanent. In survivors of a heart attack, multiple neurohumoral adjustments as well as simultaneous remodeling in both infarcted and noninfarcted regions of the heart help sustain pump function post-MI. In the early phase, migration of inflammatory cells to the infarcted area helps repair and remove the cell debris, while apoptosis results in the elimination of damaged cardiomyocytes, and there is an increase in the antioxidant response to protect the survived myocardium against oxidative stress (OS) injury. However, in the late phase, it appears that there is a relative increase in OS and activation of the innate inflammatory response in cardiomyocytes without any obvious inflammatory cells. In this late stage in survivors of MI, a progressive slow activation of these processes leads to apoptosis, fibrosis, cardiac dysfunction, and HF. Thus, this second phase of an increase in OS, innate inflammatory response, and apoptosis results in wall thinning, dilatation, and consequently HF. It is important to note that this inflammatory response appears to be innate to cardiomyocytes. Blunting of this innate immune cardiomyocyte response may offer new hope for the management of HF.
Assuntos
Insuficiência Cardíaca/imunologia , Imunidade Inata , Infarto do Miocárdio/imunologia , Animais , Apoptose , Insuficiência Cardíaca/etiologia , Humanos , Infarto do Miocárdio/etiologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Estresse OxidativoRESUMO
The occlusion of a coronary artery by a thrombus generated on a ruptured atherosclerotic plaque has been pursued in the last decades as a determining event for the clinical outcome after myocardial infarction (MI). Yet, MI causes a cell death wave front, which triggers an inflammatory response to clear cellular debris, and which in excess can double the myocardial lesion and influence the clinical prognosis in the short and long term. Accordingly, proper, timely regulated inflammatory response has now been considered a second pivotal player in cardiac recovery after MI justifying the search for pharmacological strategies to modulate inflammatory effectors. This chapter reviews the key events and the main effectors of inflammation after myocardial ischemic insult, as well as the contribution of this phenomenon to the progression of atherosclerosis.
Assuntos
Inflamação/complicações , Infarto do Miocárdio/complicações , Miocárdio/patologia , Animais , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologiaAssuntos
Síndrome Antifosfolipídica , Reestenose Coronária , Infarto do Miocárdio , Intervenção Coronária Percutânea , Stents , Adulto , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/epidemiologia , Síndrome Antifosfolipídica/imunologia , Estudos de Casos e Controles , Reestenose Coronária/diagnóstico , Reestenose Coronária/epidemiologia , Reestenose Coronária/imunologia , Feminino , Seguimentos , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/terapia , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/estatística & dados numéricos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/métodos , Fatores de Risco , TempoRESUMO
BACKGROUND: Heart failure represents an important public health issue due to its high costs and growing incidence worldwide. Evidence showing the regenerative potential of postmitotic heart tissue has suggested the existence of endogenous cardiac stem cells in adult hearts. Cardiosphere-derived cells (CDC) constitute a candidate pool of such cardiac stem cells. Previous studies using acute myocardial infarction (MI) models in rodents demonstrated an improvement in cardiac function after cell therapy with CDC. We evaluated the therapeutic potential of CDC 60 days after MI in a rat model. METHODS: CDC were obtained from human discarded myocardial tissue and rat hearts by enzymatic digestion with collagenase II. At 10-15 days after isolation, small, round, phase-bright cells (PBCs) appeared on top of the adherent fibroblast-like cells. The PBCs were collected and placed on a nonadherent plate for 2 days, where they formed cardiospheres which were then transferred to adherent plates, giving rise to CDC. These CDC were characterized by flow cytometry. Wistar rats were submitted to MI through permanent occlusion of the anterior descending coronary artery. After 60 days, they were immunosuppressed with cyclosporine A during 10 days. On the third day, infarcted animals were treated with 5 × 105 human CDC (hCDC) or placebo through intramyocardial injection guided by echocardiogram. Another group of animals was treated with rat CDC (rCDC) without immunosuppression. hCDC and rCDC were stably transduced with a viral construct expressing luciferase under control of a constitutive promoter. CDC were then used in a bioluminescence assay. Functional parameters were evaluated by echocardiogram 90 and 120 days after MI and by Langendorff at 120 days. RESULTS: CDC had a predominantly mesenchymal phenotype. Cell tracking by bioluminescence demonstrated over 85% decrease in signal at 5-7 days after cell therapy. Cardiac function evaluation by echocardiography showed no differences in ejection fraction, end-diastolic volume, or end-systolic volume between groups receiving human cells, rat cells, or placebo. Hemodynamic analyses and infarct area quantification confirmed that there was no improvement in cardiac remodeling after cell therapy with CDC. CONCLUSION: Our study challenges the effectiveness of CDC in post-ischemic heart failure.
Assuntos
Oclusão Coronária/terapia , Hospedeiro Imunocomprometido , Infarto do Miocárdio/terapia , Esferoides Celulares/transplante , Animais , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/imunologia , Oclusão Coronária/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Ciclosporina/administração & dosagem , Modelos Animais de Doenças , Ecocardiografia , Testes de Função Cardíaca , Humanos , Injeções Intralesionais , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Wistar , Esferoides Celulares/citologia , Esferoides Celulares/fisiologia , Células-Tronco/citologia , Células-Tronco/fisiologia , Falha de TratamentoRESUMO
We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats.
Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Neurônios Colinérgicos/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Macrófagos/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/imunologia , Brometo de Piridostigmina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Fenótipo , Ratos Endogâmicos WKY , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.
El objetivo fue sistematizar las evidencias disponibles sobre la pertinencia de utilizar la evaluación económica para la incorporación/exclusión de tecnología en enfermedades raras. Se realizó una revisión sistemática de la literatura en MEDLINE vía PubMed, CRD, LILACS, SciELO y Google Académico (literatura gris). Los estudios de evaluación económica se originan de la Economía del Bienestar, en la que los individuos maximizan sus utilidades, basándose en la eficiencia de asignación. No existe un criterio ampliamente aceptado para examinar las utilidades, a fin de dar más peso a los individuos con mayores necesidades. Generalmente, los estudios no equilibran asimétricamente las utilidades, todas son consideradas iguales, lo que en Brasil es también un principio constitucional. Los sistemas de salud han ratificado el uso de la evaluación económica como la principal herramienta para ayudar en la toma de decisiones. Sin embargo, este abordaje no excluye el uso de otras metodologías complementarias a los estudios de coste-efectividad, como la técnica de compensación personal o la regla del rescate.
O objetivo deste estudo foi analisar as evidências disponíveis sobre a adequação do uso de avaliação econômica sobre incorporação/exclusão de tecnologias para doenças raras. Foi realizada uma revisão estruturada da literatura, nas bases MEDLINE, via PubMed, CRD, LILACS, SciELO e Google Acadêmico (literatura cinzenta). Os estudos de avaliação econômica têm origem na Economia do Bem-Estar, na qual os indivíduos maximizam suas utilidades, fundamentando-se na eficiência alocativa. Não há um critério amplamente aceito para ponderar as utilidades esperadas, no sentido de dar mais peso aos indivíduos com maiores necessidades em saúde. Geralmente não se ponderam assimetricamente as utilidades; todas são tratadas de forma igualitária, que, no caso brasileiro, também é um princípio constitucional. Os sistemas de saúde têm ratificado o uso de avaliação econômica como principal instrumento para auxiliar na tomada de decisão. No entanto, essa postura não exclui o uso de outras metodologias complementares aos estudos de custo-efetividade, como Person Trade-Off e regra de resgate.
Assuntos
Animais , Humanos , Camundongos , Aterosclerose/enzimologia , Aterosclerose/patologia , Células Espumosas/enzimologia , Metaloproteinases da Matriz/metabolismo , Ruptura Aórtica/etiologia , Ruptura Aórtica/prevenção & controle , Aterosclerose/complicações , Aterosclerose/imunologia , Células Espumosas/patologia , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos , Modelos Imunológicos , Metaloproteinases da Matriz/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miócitos de Músculo Liso/patologia , Inibidores Teciduais de Metaloproteinases/imunologia , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
The aim of this study was to evaluate the effects of exercise training (ET, 50-70% of VO2 max, 5 days/week) and detraining (DT) on inflammatory and metabolic profile after myocardial infarction (MI) in rats. Male Wistar rats were divided into control (C, n = 8), sedentary infarcted (SI, n = 9), trained infarcted (TI, n = 10; 3 months of ET), and detrained infarcted (DI, n = 11; 2 months of ET + 1 month of DT). After ET and DT protocols, ventricular function and inflammation, cardiovascular autonomic modulation (spectral analysis), and adipose tissue inflammation and lipolytic pathway were evaluated. ET after MI improved cardiac and vascular autonomic modulation, and these benefits were correlated with reduced inflammatory cytokines on the heart and adipose tissue. These positive changes were sustained even after 1 month of detraining. No expressive changes were observed in oxidative stress and lipolytic pathway in experimental groups. In conclusion, our results strongly suggest that the autonomic improvement promoted by ET, and maintained even after the detraining period, was associated with reduced inflammatory profile in the left ventricle and adipose tissue of rats subjected to MI. These data encourage enhancing cardiovascular autonomic function as a therapeutic strategy for the treatment of inflammatory process triggered by MI.