RESUMO
CD4-CD8- (double-negative, DN) T cells are critical orchestrators of the cytokine network associated with the pathogenic inflammatory response in one of the deadliest cardiomyopathies known, Chagas heart disease, which is caused by Trypanosoma cruzi infection. Here, studying the distribution, activation status, and cytokine expression of memory DN T-cell subpopulations in Chagas disease patients without cardiac involvement (indeterminate form-IND) or with Chagas cardiomyopathy (CARD), we report that while IND patients displayed a higher frequency of central memory, CARD had a high frequency of effector memory DN T cells. In addition, central memory DN T cells from IND displayed a balanced cytokine profile, characterized by the concomitant expression of IFN-γ and IL-10, which was not observed in effector memory DN T cells from CARD. Supporting potential clinical relevance, we found that the frequency of central memory DN T cells was associated with indicators of better ventricular function, while the frequency of effector memory DN T cells was not. Importantly, decreasing CD1d-mediated activation of DN T cells led to an increase in IL-10 expression by effector memory DN T cells from CARD, restoring a balanced profile similar to that observed in the protective central memory DN T cells. Targeting the activation of effector memory DN T cells may emerge as a strategy to control inflammation in Chagas cardiomyopathy and potentially in other inflammatory diseases where these cells play a key role.
Assuntos
Antígenos CD4/imunologia , Antígenos CD8/imunologia , Cardiomiopatia Chagásica/imunologia , Doença de Chagas/imunologia , Células T de Memória/imunologia , Trypanosoma cruzi/imunologia , Adulto , Idoso , Animais , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Células Cultivadas , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/metabolismo , Doença de Chagas/parasitologia , Chlorocebus aethiops , Eletrocardiografia , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Masculino , Células T de Memória/metabolismo , Pessoa de Meia-Idade , Trypanosoma cruzi/fisiologia , Função Ventricular Esquerda/imunologia , Função Ventricular Esquerda/fisiologia , Células VeroRESUMO
Soluble fibrinogenlike protein 2 (sFGL2), as a novel effector of regulatory T cells (Tregs), exhibits immune regulatory activity in several inflammatory diseases. Immune activation and persistent inflammation participate in the progression of ischemic heart failure (IHF). The present study aimed to determine serum sFGL2 levels in patients with IHF and explore the relationship between sFGL2 levels and cardiac function. A total of 104 patients with IHF and 32 healthy controls were enrolled. patients with IHF were further split into subgroups according to the New York Heart Association functional classification or left ventricular ejection fraction (LVEF). Serum sFGL2 levels and peripheral Tregs frequencies were analyzed by ELISA and flow cytometry, respectively. The suppressive function of Tregs was measured by proliferation and functional suppression assays. Serum levels of sFGL2 and circulating Tregs frequencies were significantly decreased in patients with IHF compared with healthy controls. In patients with IHF, sFGL2 levels and Tregs frequencies were decreased with the deterioration of cardiac function. Tregs from patients with IHF exhibited compromised ability to suppress CD4+CD25 T cells proliferation and inflammatory cytokines secretion. Specifically, sFGL2 levels and Tregs frequencies positively correlated with LVEF, whereas negatively correlated with left ventricular enddiastolic dimension and Nterminal probrain natriuretic peptide. sFGL2 levels were positively correlated with Tregs frequencies. In conclusion, the reduction of serum sFGL2 levels are associated with the progression of IHF and sFGL2 could be used as a potential indicator for predicting disease severity.
Assuntos
Fibrinogênio/metabolismo , Insuficiência Cardíaca/sangue , Isquemia Miocárdica/sangue , Idoso , Antígenos CD4/imunologia , Feminino , Fibrinogênio/imunologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/imunologia , Curva ROC , Linfócitos T Reguladores/imunologia , Função Ventricular Esquerda/imunologiaRESUMO
After a myocardial infarction (MI), the inflammatory responses are induced and assist to repair ischaemic injury and restore tissue integrity, but excessive inflammatory processes promote abnormal cardiac remodelling and progress towards heart failure. Thus, a timely resolution of inflammation and a firmly regulated balance between regulatory and inflammatory mechanisms can be helpful. Molecular- and cellular-based approaches modulating immune response post-MI have emerged as a promising therapeutic strategy. Exosomes are essential mediators of cell-to-cell communications, which are effective in modulating immune responses and immune cells following MI, improving the repair process of infarcted myocardium and maintaining ventricular function via the crosstalk among immune cells or between immune cells and myocardial cells. The present review aimed to seek the role of immune cell-secreted exosomes in infarcted myocardium post-MI, together with mechanisms behind their repairing impact on the damaged myocardium. The exosomes we focus on are secreted by classic immune cells including macrophages, dendritic cells, regulatory T cells and CD4+ T cells; however, further research is demanded to determine the role of exosomes secreted by other immune cells, such as B cells, neutrophils and mast cells, in infarcted myocardium after MI. This knowledge can assist in the development of future therapeutic strategies, which may benefit MI patients.
Assuntos
Exossomos/imunologia , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia , Miócitos Cardíacos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/imunologiaRESUMO
Exposure to adverse factors in utero may lead to adaptive changes in cardiac structure and metabolism, which increases the risk of chronic cardiovascular disease later in life. Studies showed that the angiotensin II type 1 receptor autoantibodies (AT1-AAs) are able to cross the placenta into the circulation of pregnant rodents' embryo, which adversely affects embryogenesis. However, the effects of AT1-AA exposure on the fetal heart in utero are still unknown. In this study, we investigated whether intrauterine AT1-AA exposure has adverse effects on fetal heart structure, function and metabolism. AT1-AA-positive pregnant mouse models were successfully established by passive immunity, evidenced by increased AT1-AA content. Morphological and ultrasonic results showed that the fetal mice on embryonic day 18 (E18) of AT1-AA group have loose and disordered myocardial structure, and decreased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), compared with control groups. The myocardium of AT1-AA group fetal mice on E18 exhibited increased expression of the key molecules in the glycolytic pathway, pyruvate and lactic acid content and ATP production, suggesting that the glycolysis rate was enhanced. Furthermore, the enhanced effect of glycolysis caused by AT1-AA is mainly through the PPARß/δ pathway. These data confirmed that fetus exposure to AT1-AA in utero developed left ventricular dysfunction, myocardial structural arrangement disorders, and enhanced glycolysis on E18. Our results support AT1-AA being a potentially harmful factor for cardiovascular disease in fetal mice.
Assuntos
Autoanticorpos/toxicidade , Cardiomiopatias/etiologia , Feto/imunologia , Feto/fisiopatologia , Glicólise/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , PPAR gama/metabolismo , PPAR beta/metabolismo , Placenta/fisiologia , Gravidez , Segundo Trimestre da Gravidez , Volume Sistólico/imunologia , Função Ventricular Esquerda/imunologiaRESUMO
BACKGROUND: Cardiac injury and myocarditis have been described in adults with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children as defined by the US Centers for Disease Control and Prevention. METHODS: Over a 2-month period, contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. RESULTS: Thirty-five children were identified and included in the study. Median age at admission was 10 years (range, 2-16 years). Comorbidities were present in 28%, including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one-third; 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation. Inflammation markers were suggestive of cytokine storm (interleukin-6 median, 135 pg/mL) and macrophage activation (D-dimer median, 5284 ng/mL). Mean BNP (B-type natriuretic peptide) was elevated (5743 pg/mL). Thirty-one of 35 patients (88%) tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. All patients received intravenous immunoglobulin, with adjunctive steroid therapy used in one-third. Left ventricular function was restored in the 25 of 35 of those discharged from the intensive care unit. No patient died, and all patients treated with extracorporeal membrane oxygenation were successfully weaned. CONCLUSIONS: Children may experience an acute cardiac decompensation caused by severe inflammatory state after SARS-CoV-2 infection (multisystem inflammatory syndrome in children). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.
Assuntos
COVID-19/complicações , Insuficiência Cardíaca/virologia , Inflamação/virologia , Síndrome de Resposta Inflamatória Sistêmica/complicações , Adolescente , COVID-19/virologia , Criança , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Masculino , Estudos Retrospectivos , Volume Sistólico/fisiologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/imunologiaRESUMO
Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Ferroptose/imunologia , Transplante de Coração , Traumatismo por Reperfusão Miocárdica/imunologia , Miocárdio/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Cicloexilaminas/farmacologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Neutrófilos/patologia , Fenilenodiaminas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/imunologiaRESUMO
AIMS: The aim of the present study was to investigate the effects of successful PCI CTO on absolute myocardial blood flow (MBF) and functional recovery. METHODS AND RESULTS: Patients with a documented CTO were prospectively examined for ischaemia and viability with [15O]H2O positron emission tomography (PET) and late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR). Sixty-nine consecutive patients, in whom PCI was successful, underwent follow-up PET and CMR after approximately 12 weeks to evaluate potential improvement of MBF as well as systolic function. After PCI, stress MBF in the CTO area increased from 1.22±0.36 to 2.40±0.90 mL·min-1·g-1 (p<0.001), whilst stress MBF in the remote area also increased significantly between baseline and follow-up PET (2.58±0.68 to 2.77±0.77 mL·min-1·g-1, p=0.01). The ratio of stress MBF between CTO and remote area was 0.49±0.13 at baseline and increased to 0.87±0.24 at follow-up (p<0.001). The MBF defect size of the CTO area decreased from 5.12±1.69 to 1.91±1.75 myocardial segments after PCI (p<0.001). Left ventricular ejection fraction (LVEF) increased significantly (46.4±11.0 vs. 47.5±11.4%, p=0.01) at follow-up. CONCLUSIONS: The vast majority of CTO patients with documented ischaemia and viability showed significant improvement in stress MBF and a reduction of ischaemic burden after successful percutaneous revascularisation with only minimal effect on LVEF.
Assuntos
Oclusão Coronária/cirurgia , Intervenção Coronária Percutânea , Volume Sistólico/fisiologia , Função Ventricular Esquerda/imunologia , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Doença Crônica , Circulação Coronária/fisiologia , Oclusão Coronária/fisiopatologia , Feminino , Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Função Ventricular Esquerda/fisiologiaRESUMO
AIMS: Immunity and inflammation processes are known to be of central importance in chronic heart failure (CHF). Dendritic cells (DCs) are key players in adaptive immunity, yet their role in CHF is still unknown. The aim of this study was to investigate the circulating DCs in patients with compensated CHF. METHODS: Circulating myeloid (m) and plasmacytoid (p) DCs, as well as inflammatory cytokines interleukine (IL) 6 and IL10 were flow cytometrically analysed in peripheral blood of clinically compensated CHF patients with previously diagnosed dilated cardiomyopathy (DCM, n = 69), ischaemic cardiomyopathy (ICM, n = 49), as well as in unaffected controls (n = 51). Correlation analysis was performed between circulating DCs, cytokines and parameters of heart failure severity, such as NYHA class, the marker brain natriuretic peptide (BNP) and echocardiographic parameters of left ventricular function and dilation. RESULTS: Circulating mDCs were significantly decreased in all CHF patients, although more pronounced in DCM (0.14%, P < 0.001) than in ICM (0.18%, P = 0.043) compared to controls (0.2%). In contrast, no statistical changes were observed for pDCs. Circulating mDCs correlated with left ventricular ejection fraction (LVEF) and inversely with LV end-diastolic diameter (LVEDd) in all CHF patients. For DCM patients, an inverse correlation of mDCs with BNP was additionally observed. Circulating mDCs correlated inversely with IL6 and IL10 in all CHF patients. With the exception of IL-6 and NYHA class of DCM patients, cytokines did not significantly correlate with heart failure parameters. CONCLUSIONS: Blood mDCs are decreased in CHF patients. The reduction correlates with the severity of their HF.
Assuntos
Cardiomiopatia Dilatada/complicações , Citocinas/sangue , Células Dendríticas/imunologia , Insuficiência Cardíaca , Isquemia Miocárdica/complicações , Imunidade Adaptativa , Adulto , Idoso , Doença Crônica , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estatística como Assunto , Função Ventricular Esquerda/imunologiaRESUMO
BACKGROUND: Interleukin-1ß (IL-1ß) modulates the inflammatory response during acute myocardial infarction (AMI) and progression to ischemic cardiomyopathy. We investigated whether blockade of IL-1ß after the onset of the cardiac dysfunction prevented left ventricular (LV) adverse remodeling in a mouse model of anterior nonreperfused AMI. METHODS: Infarct size and LV systolic function were assessed by echocardiography 7 days after coronary artery ligation. Mice with large infarct size and LV ejection fraction (LVEF) <40% were randomly assigned to treatment with a monoclonal antibody directed toward IL-1ß antibody (10 mg/kg IL-1ß-AB) or with a cyclosporine directed antibody (10 mg/kg control-AB). Echocardiogram was repeated after 10 weeks, followed by assessment of contractile reserve using isoproterenol challenge and LV catheterization. RESULTS: After 10 weeks, control-AB-treated mice showed significantly increased LV end-diastolic diameter (+15%, P < 0.001) and decreased LVEF (-18%, P = 0.050). IL-1ß-AB had no significant effect on LV end-diastolic diameter (+10%, P = 0.25 vs. control-AB) but significantly prevented LVEF reduction (+7%, P = 0.031 vs. control-AB), enlargement of the right ventricle (P = 0.024), impairment in myocardial performance index (P = 0.028) and contractile reserve (P = 0.008), and increased LV end-diastolic pressure (P = 0.030). CONCLUSIONS: IL-1ß blockade using a monoclonal antibody in mice with severe LV dysfunction after AMI prevents further deterioration in LV systolic and diastolic function and restores contractile reserve.
Assuntos
Anticorpos Monoclonais/farmacologia , Interleucina-1beta/antagonistas & inibidores , Infarto do Miocárdio/terapia , Isquemia Miocárdica/terapia , Animais , Modelos Animais de Doenças , Ecocardiografia , Interleucina-1beta/imunologia , Isoproterenol/farmacologia , Masculino , Camundongos , Contração Miocárdica/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/imunologia , Índice de Gravidade de Doença , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda/imunologia , Remodelação Ventricular/imunologiaRESUMO
BACKGROUND: Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. METHODS AND RESULTS: Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c(+) green fluorescent protein-positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1ß, interleukin-18, and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6C(high) monocytes and F4/80(+) CD206(-) M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6C(low) monocytes and F4/80(+) CD206(+) M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group. CONCLUSIONS: These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.
Assuntos
Células Dendríticas/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/imunologia , Remodelação Ventricular/imunologia , Cicatrização/imunologia , Animais , Transplante de Medula Óssea , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/citologia , Fibrose , Proteínas de Fluorescência Verde/genética , Homeostase/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/mortalidade , Miocardite/imunologia , Miocardite/mortalidade , Miocardite/fisiopatologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Systemic inflammation induces a multiple organ dysfunction syndrome that contributes to morbidity and mortality in septic patients. Since increasing plasma apolipoprotein A-I (apoA-I) and HDL may reduce the complications of sepsis, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in rats undergoing cecal ligation and puncture (CLP) injury. Male Sprague-Dawley rats were randomized to undergo CLP or sham surgery. IL-6 levels were significantly elevated in plasma by 6 h after CLP surgery compared with shams. In subsequent studies, CLP rats were further subdivided to receive vehicle or 4F (10 mg/kg) by intraperitoneal injection, 6 h after sepsis induction. Sham-operated rats received saline. Echocardiographic studies showed a reduction in left ventricular end-diastolic volume, stroke volume, and cardiac output (CO) 24 h after CLP surgery. These changes were associated with reduced blood volume and left ventricular filling pressure. 4F treatment improved blood volume status, increased CO, and reduced plasma IL-6 in CLP rats. Total cholesterol (TC) and HDL were 79 +/- 5 and 61 +/- 4 mg/dl, respectively, in sham rats. TC was significantly reduced in CLP rats (54 +/- 3 mg/dl) due to a reduction in HDL (26 +/- 3 mg/dl). 4F administration to CLP rats attenuated the reduction in TC (69 +/- 4 mg/dl) and HDL (41 +/- 3 mg/dl) and prevented sepsis-induced changes in HDL protein composition. Increased plasma HDL in 4F-treated CLP rats was associated with an improvement in CO and reduced mortality. It is proposed that protective effects of 4F are related to its ability to prevent the sepsis-induced reduction in plasma HDL.
Assuntos
Apolipoproteína A-I/imunologia , Inflamação , Peptídeos/farmacologia , Sepse , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/imunologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/imunologia , Volume Sanguíneo/efeitos dos fármacos , Volume Sanguíneo/imunologia , Ecocardiografia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/mortalidade , Interleucina-6/sangue , Lipoproteínas HDL/sangue , Masculino , Mimetismo Molecular/imunologia , Peptídeos/imunologia , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/mortalidade , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/imunologiaRESUMO
BACKGROUND: Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. METHODS: Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. RESULTS: The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. CONCLUSION: These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium.
Assuntos
Apoptose/fisiologia , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Animais , Apoptose/efeitos da radiação , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Infarto do Miocárdio/imunologia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Função Ventricular Esquerda/imunologia , Remodelação Ventricular/imunologia , Remodelação Ventricular/efeitos da radiaçãoRESUMO
The objective of this study was to identify the cardiodepressant autoantibodies that could directly influence left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy (DCM), as well as to establish a simple screening method for these antibodies. Not only acute hemodynamic but also chronic prognosis improvements were reported with immunoadsorption in some patients with DCM. Various antibodies determined by immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (beta1-adrenergic [beta1-] receptors, muscarinic M2-acetylcholine [M2-] receptors, troponin I, or Na-K-ATPase) were measured in 104 patients with DCM. Cardiodepressant antibodies were also determined by ultrasonic echocardiography (UCG) of 18 day old chick embryos after adding the patients' purified immunoglobulin G, and the following clinical features were compared: age, gender, New York Heart Association class, LVEF, neurohumoral factors, arrhythmias, and other antibodies. We also checked the in vitro immunoadsorption effect against these cardiodepressant antibodies. Cardiodepressant antibodies were found in 63% of 104 patients with DCM and had no relation to other clinical parameters, except for some antibodies such as anti-beta1-receptor antibodies (81% vs. 52%, P < 0.01), anti-M2-receptor antibodies (83% vs. 48%, P < 0.01), or anti-Na-K-ATPase antibodies (85% vs. 55%, P < 0.01). However, cardiodepressant antibodies were similarly found in patients with and without antibodies against troponin I (56% vs. 64%). The LVEF of chick embryos measured by UCG in the presence of patient serum was improved after in vitro immunoadsorption. The ex vivo system using chick embryos was able to determine cardiodepressant antibodies. By multivariate analysis, antibodies against beta1- or M2-receptors was a predictor of these autoantibodies.
Assuntos
Autoanticorpos/análise , Autoanticorpos/imunologia , Cardiomiopatia Dilatada/imunologia , Idoso , Animais , Autoantígenos/imunologia , Embrião de Galinha , Ecocardiografia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hemodinâmica/imunologia , Humanos , Immunoblotting , Imunoglobulina G/imunologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Função Ventricular Esquerda/imunologiaRESUMO
Cardiac remodeling in response to pressure overload involves reorganization of the myocytes and extracellular matrix (ECM). Neurohormonal pathways have been described as effector pathways in left ventricular ECM reorganization in response to pressure overload; we now are assessing the role of the T lymphocyte in this process. Mice with defined differences in T-lymphocyte function (C57BL/6 SCID, C57BL/6 WT, and BALB/c) were treated with 50 mg/L of N(G)-nitro-l-arginine methyl ester in their drinking water for 30 days. The immune function of C57BL/6 WT mice was T-helper type 1 (TH1), BALB/c was TH2, and C57BL/6 SCID was null. The arterial blood pressure increased by 30% in all of the strains of mice. However, ventricular stiffness significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. The characterization of matrix metalloproteinase induction and activation on day 30 was associated with T-lymphocyte function. The total cardiac fibrillar collagen, percentage of fibrillar collagen cross-linking, and the activity of the cross-linking enzyme lysyl oxidase-like-3 (LOXL-3) significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. This study revealed that the LOXL-3 pathway, namely, gene expression, enzymatic activities, and LOXL-3-mediated collagen cross-linking, was associated with ventricular stiffness and incongruence with lymphocyte function. These data support the concept that the T lymphocytes may play a fundamental regulatory role in cardiac ECM composition through modulation of collagen synthesis, degradation, and cross-linking.
Assuntos
Matriz Extracelular/imunologia , Hipertensão/complicações , Linfócitos T/fisiologia , Remodelação Ventricular/imunologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Colágeno/química , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hipertensão/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Camundongos Endogâmicos C57BL/imunologia , Camundongos SCID/imunologia , NG-Nitroarginina Metil Éster/farmacologia , Especificidade da Espécie , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/imunologiaAssuntos
Hipertensão/complicações , NG-Nitroarginina Metil Éster/farmacologia , Linfócitos T/fisiologia , Remodelação Ventricular/imunologia , Animais , Hipertensão/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Especificidade da Espécie , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/imunologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
INTRODUCTION: Immune system activation and oxidative stress are involved in the pathogenesis of heart failure (HF). We aimed to test the hypothesis that upgrading from right ventricular pacing (RVp) to biventricular pacing (BiVp) can counteract these phenomena. METHODS: 28 HF patients, with BiVp were switched to RVp for one week, and then returned to BiVp. Immediately prior to, and 48 h after the return to BiVp, left ventricular (LV) systolic function was evaluated by echocardiography, and serum N-terminal pro-brain natriuretic peptide (NTproBNP), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL6), nitric oxide metabolites (NO(x)) and malondialdehyde (MDA) were assayed. RESULTS: LV systolic function significantly improved 48 h after switching from RVp to BiVp: Ao-VTI (p<0.001), SV (p<0.001) and CO (p<0.001), and mitral regurgitation significantly decreased (p=0.003). At the same time, indices of peripheral immune activation decreased: TNF-alpha (p=0.02) and IL6 (p<0.001). MDA decreased (p<0.001), whereas NO(x) increased (p=0.04). NTproBNP and CRP did not change. In addition, in "responders" (i.e. CO increase >10% during BiVp vs. RVp) NTproBNP decreased and NO(x) increased. However, during BiVp, the decreases in TNF-alpha, IL6, and MDA occurred both in responders and in non-responders and were accompanied by a reduction in mitral regurgitation. CONCLUSION: The beneficial effect of BiVp compared to RVp extends beyond improving cardiac haemodynamics and comprises a decrease in immune activation accompanied by an increase in serum NO(x) and decrease in serum MDA.
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Baixo Débito Cardíaco/imunologia , Estimulação Cardíaca Artificial/métodos , Ventrículos do Coração/inervação , Óxido Nítrico/imunologia , Marca-Passo Artificial , Função Ventricular Esquerda/imunologia , Idoso , Idoso de 80 Anos ou mais , Baixo Débito Cardíaco/fisiopatologia , Estimulação Cardíaca Artificial/efeitos adversos , Doença Crônica , Feminino , Humanos , Inflamação , Interleucina-6/imunologia , Masculino , Malondialdeído/análise , Malondialdeído/imunologia , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico , Óxido Nítrico/biossíntese , Sístole , Fator de Necrose Tumoral alfa/imunologia , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Cardiac autoantibodies may play a pathophysiological role in cardiac dysfunction of patients suffering from dilated cardiomyopathy (DCM). Immunoadsorption (IA), which removes antibodies from patients' plasma, may consequently improve cardiac function in DCM. The functional effects of DCM antibodies are only partly understood. MATERIALS AND METHODS: DCM patients (n = 10) were treated with IA by application of antibody columns directed against human immunoglobulin (Ig). IA was also performed with plasma taken from 10 healthy donors (controls). The antibodies eliminated and purified by IA were collected and dialysed. Rat hearts were isolated and perfused retrogradely via the aorta in Langendorff mode. During constant-pressure and constant-volume perfusion of the hearts, the influence of diluted antibodies on contractility, relaxation, and on coronary perfusion was analysed. RESULTS: Antibodies obtained from controls had no effect on contractility and relaxation of isolated perfused hearts during constant-pressure and constant-volume perfusion. In contrast, during constant-pressure perfusion, collected DCM antibodies caused immediate and dose-related reduction of contractility (dLVP/dtmax: dilution -1:32 = -7.1 +/- 1.1%; dilution -1:2 = -20.1 +/- 2.1%; P < 0.001) and diastolic relaxation (dLVP/dtmin: dilution -1:32 = -11.1 +/- 1.5%; dilution -1:2 = -23.9 +/- 2.2%; P < 0.001). The heart rate did not change significantly in either group. The effects of DCM antibodies on contractility and relaxation remained detectable during constant-volume perfusion. The observed reduction of contractility and diastolic relaxation was accompanied by impairment of coronary perfusion. CONCLUSION: In the rat heart, antibodies obtained from DCM patients may impair contractility and relaxation, and thereby probably also coronary perfusion.
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Autoanticorpos/imunologia , Cardiomiopatia Dilatada/imunologia , Contração Miocárdica/imunologia , Animais , Circulação Coronária/imunologia , Relação Dose-Resposta Imunológica , Humanos , Técnicas de Imunoadsorção , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Ratos , Função Ventricular Esquerda/imunologiaRESUMO
BACKGROUND: Despite improved preservation techniques, myocardial and endothelial dysfunction persists after cardiac transplantation. L-arginine has been shown to decrease endothelial injury in several models of ischemia and reperfusion. We assessed the effects of L-arginine on allograft preservation in a porcine model of cardiac transplantation. METHODS: Orthotopic cardiac transplants were performed in Yorkshire pigs. Hearts were randomly arrested with high potassium cardioplegia with or without L-arginine at a dose of 2.5 mmol/liter (LARGlow) and 5.0 mmol/liter. Donor-shed blood was collected at the time of organ harvest and intermittently perfused throughout the storage period. Coronary endothelial function was assessed at baseline and after reperfusion by measuring the change in coronary blood flow after exposure to acetylcholine or nitroglycerin. Pressure-volume relationships before and after transplant were evaluated with conductance catheter measurements. Myocardial biopsy specimens were assessed for inflammatory markers of cellular injury. RESULTS: High-dose L-arginine uniformly resulted in ischemic contracture in all hearts, and there was no return of function in any hearts after storage. The low-dose L-arginine group had a greater ability to wean off cardiopulmonary bypass and displayed improved recovery of left ventricular function. Control animals had a 26% reduction in coronary flow compared with 13% for LARGlow. LARGlow resulted in decreased release of inflammatory cytokines compared with control. CONCLUSIONS: Low-dose L-arginine preserves myocardial and endothelial function and decreases endothelial injury when it is used as a supplement to intermittent donor blood perfusion. In contrast, high-dose L-arginine resulted in severe endothelial injury and an inability to recover ventricular function after 5 hours of global ischemia.
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Transplante de Coração , Preservação de Órgãos/métodos , Perfusão/métodos , Animais , Arginina/administração & dosagem , Biomarcadores/sangue , Biópsia , Transfusão de Sangue Autóloga , Moléculas de Adesão Celular/sangue , Vasos Coronários , Endotélio Vascular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Modelos Animais , Miocárdio/patologia , Estresse Oxidativo/imunologia , Recuperação de Função Fisiológica , Suínos , Transplante Homólogo/imunologia , Doenças Vasculares/imunologia , Sistema Vasomotor/imunologia , Função Ventricular Esquerda/imunologiaRESUMO
BACKGROUND: Congestive heart failure is characterised by enhanced immune activation. Immune-mediated mechanisms may play a pathogenic role, hence the growing interest in therapeutic regimens that could modulate the immune response in heart failure. MATERIAL AND METHODS: In the present report we discuss the pathogenic role of immunological and inflammatory mediators in the pathophysiology of heart failure and discuss different treatment modalities with focus on our recent study with intravenous immunoglobulin. In that study 40 patients with symptomatic chronic heart failure and left ventricular ejection fraction (LVEF) < 40% were randomised in a double-blind fashion to receive therapy with immunoglobulin or placebo for a total period of 26 weeks. RESULTS: We found that intravenous immunoglobulin, but not placebo, shifted the cytokine balance in an anti-inflammatory direction, and that such a shift was associated with improvement in LVEF by 5 EF units. Functional capacity and haemodynamic variables also improved. INTERPRETATION: Our study supports the hypothesis that immunological variables might be of significant importance in the pathogenesis of heart failure and it suggests a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in such patients. These issues are further discussed in the present article.