RESUMO
IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.
Assuntos
Imunidade Adaptativa , Tecido Adiposo , Imunidade Inata , Pericárdio , Humanos , Pericárdio/imunologia , Pericárdio/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Tecido Adiposo/imunologia , Idoso , Adulto , Linfócitos/imunologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Transcriptoma , Tecido Adiposo EpicárdicoRESUMO
AIM: Constrictive pericarditis (CP) is characterised by scarring fibrosis and a loss of pericardial elasticity, which causes heart failure. IgG4 (immunoglobulin G4)-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterised by the infiltration of IgG4-immunopositive plasmacytes and high serum IgG4 levels that frequently shape tumorous lesions. Although pericardial involvement of IgG4-RD is rare, with indications of CP, pericardial effusion and irregular masses, the clinical and pathological features remain unclear. In this study, we examined the relationship between CP and IgG4-RD. METHODS: Among 35 thick-walled CP cases (histologically pericardial thickening ≥2 mm), eight cases were aetiology identified. Using the diagnostic criteria for IgG4-RD, 11 cases were classified as IgG4-CP, whereas the remainder were considered true idiopathic CP (16 cases) and the clinical pathological features were evaluated. RESULTS: Compared with the other groups, the IgG4-CP group was more common in men and associated with low-grade fever and massive pericardial effusion with frequent recurrence. Deaths resulting from heart failure occurred in a few cases of the IgG4-CP group, but not in other groups. An increase in C-reactive protein and a high positivity rate of anti-nuclear antibodies frequently occurred in the IgG4-CP group. Histologically, the IgG4-CP group included lymphoid follicle, eosinophil infiltration and few calcifications. CONCLUSIONS: Pericardial IgG4-RD occurs not only as nodular lesions, but also as thick-walled CP, and accounts for approximately 40% of thick-walled CP cases of unknown cause. The predominant clinical characteristic was refractory and recurrent pericardial effusion. Recognising IgG4-RD as a cause of CP is important to initiate appropriate therapy.
Assuntos
Doença Relacionada a Imunoglobulina G4 , Imunoglobulina G , Derrame Pericárdico , Pericardite Constritiva , Humanos , Pericardite Constritiva/patologia , Pericardite Constritiva/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Doença Relacionada a Imunoglobulina G4/patologia , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/complicações , Idoso , Imunoglobulina G/sangue , Adulto , Derrame Pericárdico/patologia , Derrame Pericárdico/imunologia , Derrame Pericárdico/etiologia , Idoso de 80 Anos ou mais , Pericárdio/patologia , Pericárdio/imunologia , Biomarcadores/sangue , Biomarcadores/análise , Recidiva , Estudos Retrospectivos , Fibrose , BiópsiaRESUMO
The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.
Assuntos
Microambiente Celular , Coração , Multiômica , Miocárdio , Humanos , Comunicação Celular , Fibroblastos/citologia , Ácido Glutâmico/metabolismo , Coração/anatomia & histologia , Coração/inervação , Canais Iônicos/metabolismo , Miocárdio/citologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Neuroglia/citologia , Pericárdio/citologia , Pericárdio/imunologia , Plasmócitos/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Nó Sinoatrial/anatomia & histologia , Nó Sinoatrial/citologia , Nó Sinoatrial/fisiologia , Sistema de Condução Cardíaco/anatomia & histologia , Sistema de Condução Cardíaco/citologia , Sistema de Condução Cardíaco/metabolismoRESUMO
A 62-year-old man with metastatic hepatocellular carcinoma presented with ST elevation myocardial infarction had received one dose of nivolumab 3 weeks prior. Cardiac catheterisation was negative for obstructive coronary artery disease. He was transferred to the cardiac intensive care unit due to ventricular arrhythmias and markedly elevated troponin T levels. Transthoracic echocardiogram showed severely depressed left ventricular ejection fraction of 18% (normal 55%-70%) with mid and apical ballooning consistent with takotsubo syndrome (TTS). Intravenous glucocorticoids were administered due to suspicion for superimposed myocarditis. Cardiac MRI 3 days later showed mid-myocardial and subepicardial delayed enhancement in the inferior and lateral walls as well as apex indicative of myopericarditis. He clinically improved on steroids and was discharged with outpatient follow-up. This case highlights major cardiac complications that may arise with immune checkpoint inhibitor therapy. In addition, it emphasises the importance of assessing for concomitant myocarditis even when initial imaging suggests TTS.
Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Miocardite/diagnóstico , Pericardite/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Cardiomiopatia de Takotsubo/diagnóstico , Administração Intravenosa , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Ecocardiografia , Eletrocardiografia , Glucocorticoides/administração & dosagem , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocardite/induzido quimicamente , Miocardite/tratamento farmacológico , Miocardite/imunologia , Nivolumabe/efeitos adversos , Pericardite/induzido quimicamente , Pericardite/tratamento farmacológico , Pericardite/imunologia , Pericárdio/diagnóstico por imagem , Pericárdio/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/induzido quimicamente , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Cardiomiopatia de Takotsubo/induzido quimicamente , Cardiomiopatia de Takotsubo/tratamento farmacológico , Cardiomiopatia de Takotsubo/imunologiaAssuntos
Tecido Adiposo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pericárdio , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pericárdio/efeitos dos fármacos , Pericárdio/imunologiaRESUMO
Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared with controls without CAD. Cardiac surgery patients with (n = 13) or without CAD (n = 13) were consented, and samples of EAT and subcutaneous adipose tissue (SAT) were obtained. Transcriptomic analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential expression was defined as a 1.5-fold change (ANOVA P < 0.05). Six hundred ninety-three genes were differentially expressed between SAT and EAT in controls and 805 in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. Quantitative reverse transcription PCR confirmed that there was no difference in expression of CCL2, CCR2, TNF-α, IL-6, IL-8, and PAI1 between groups. Immunohistochemistry showed more macrophages in EAT than SAT, but there was no difference in their number or activation state between groups. In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD. We conclude that the specific adipose tissue depot, rather than CAD status, is responsible for the majority of differential gene expression.
Assuntos
Doença da Artéria Coronariana/imunologia , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/patologia , Pericárdio/patologia , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/cirurgia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Pericárdio/imunologia , Pericárdio/cirurgia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismoRESUMO
Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6+ macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6+ macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium.
Assuntos
Fibrose/prevenção & controle , Fator de Transcrição GATA6/metabolismo , Coração/fisiologia , Macrófagos/imunologia , Infarto do Miocárdio/imunologia , Miocárdio/patologia , Pericárdio/imunologia , Animais , Movimento Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Remodelação VentricularRESUMO
Tissue-resident macrophages require specific milieus for the maintenance of defining gene-expression programs. Expression of the transcription factor GATA6 is required for the homeostasis, function and localization of peritoneal cavity-resident macrophages. Gata6 expression is maintained in a non-cell autonomous manner and is elicited by the vitamin A metabolite, retinoic acid. Here, we found that the GATA6 transcriptional program is a common feature of macrophages residing in all visceral body cavities. Retinoic acid-dependent and -independent hallmark genes of GATA6+ macrophages were induced by mesothelial and fibroblastic stromal cells that express the transcription factor Wilms' Tumor 1 (WT1), which drives the expression of two rate-limiting enzymes in retinol metabolism. Depletion of Wt1+ stromal cells reduced the frequency of GATA6+ macrophages in the peritoneal, pleural and pericardial cavities. Thus, Wt1+ mesothelial and fibroblastic stromal cells constitute essential niche components supporting the tissue-specifying transcriptional landscape and homeostasis of cavity-resident macrophages.
Assuntos
Fator de Transcrição GATA6/metabolismo , Macrófagos/fisiologia , Pericárdio/imunologia , Cavidade Peritoneal/fisiologia , Cavidade Pleural/imunologia , Proteínas Repressoras/metabolismo , Células Estromais/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Fator de Transcrição GATA6/genética , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Repressoras/genética , Tretinoína/metabolismo , Proteínas WT1RESUMO
Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n = 12) and without (non-T2DM, n = 17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6 ± 0.7 vs. 5.8 ± 0.2 mmol/l, p < 0.001) and glycated hemoglobin (52.0 ± 3.4 vs. 36.9 ± 1.0 mmol/mol, p < 0.001) and tended to have more pronounced inflammation (hsCRP: 9.8 ± 3.1 vs. 5.1 ± 1.9 mg/ml, p = 0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57 ± 0.65 vs. 4.45 ± 1.56% for T2DM vs. non-T2DM, p = 0.041) with a similar, albeit insignificant, trend in EAT (0.996 ± 0.33 vs. 2.46 ± 0.78% for T2DM vs. non-T2DM, p = 0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5 ± 2.0 vs. 4.6 ± 1.9% of DC cells, p = 0.005) and EAT (29.1 ± 8.7 vs. 8.4 ± 2.4% of DC, p = 0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1 ± 8.7 vs. 13.5 ± 2.0% of DC, p = 0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.
Assuntos
Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Tecido Adiposo/imunologia , Idoso , Doença da Artéria Coronariana/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/imunologia , Pericárdio/imunologia , Pericárdio/metabolismo , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismoRESUMO
Multiple reports of uncoupling protein 1 (UCP1) expression have established its presence in human epicardial adipose tissue (eAT). Its functional relevance to eAT, however, remains largely unknown. In a recent study, we reported that adrenergic stimulation of eAT was associated with downregulation of secreted proteins involved in oxidative stress-related and immune-related pathways. Here, we explored the UCP1-associated features of human eAT using next-generation deep sequencing. Paired biopsies of eAT, mediastinal adipose tissue (mAT), and subcutaneous adipose tissue (sAT) obtained from cardiac surgery patients, with specific criteria of high and low expression of UCP1 in eAT, were subjected to RNA sequencing. Although eAT exhibited a depot-specific upregulation in the immune-related pathways relative to mAT and sAT, high UCP1 expression in eAT was specifically associated with differential gene expression that functionally corresponded with downregulation in the production of reactive oxygen species and immune responses, including T cell homeostasis. Our data indicate that UCP1 and adaptive immunity share a reciprocal relationship at the whole-transcriptome level, thereby supporting a plausible role for UCP1 in maintaining tissue homeostasis in human eAT.
Assuntos
Tecido Adiposo/imunologia , Doenças Cardiovasculares/imunologia , Obesidade/imunologia , Pericárdio/imunologia , Proteína Desacopladora 1/metabolismo , Imunidade Adaptativa , Tecido Adiposo/patologia , Idoso , Biópsia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/cirurgia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mediastino/patologia , Obesidade/complicações , Obesidade/patologia , Pericárdio/patologia , Análise de Sequência de RNA , Proteína Desacopladora 1/imunologia , Regulação para CimaRESUMO
The adult heart contains macrophages derived from both embryonic and adult bone marrow (BM)-derived precursors. This population diversity prompted us to explore how distinct macrophage subsets localize within the heart, and their relative contributions in cardiac disease. In this study, using the reciprocal expression of Lyve-1 and Ccr2 to distinguish macrophages with distinct origins, we show that, in the steady state, both embryonic (Lyvepos) and BM-derived (Ccr2pos) macrophages populate the major vessels of the heart in mice and humans. However, cardiac macrophage populations are markedly perturbed by inflammation. In a mouse model of Kawasaki disease, BM-derived macrophages preferentially increase during acute cardiac inflammation and selectively accumulate around major cardiac vessels. The accumulation of BM-derived macrophages coincides with the loss of their embryonic counterparts and is an initiating, essential step in the emergence of subsequent cardiac vasculitis in this experimental model. Finally, we demonstrate that the accumulation of Ccr2pos macrophages (and the development of vasculitis) occurs in close proximity to a population of Ccr2 chemokine ligand-producing epicardial cells, suggesting that the epicardium may be involved in localizing inflammation to cardiac vessels. Collectively, our findings identify the perivascular accumulation of BM-derived macrophages as pivotal in the pathogenesis of cardiac vasculitis and provide evidence about the mechanisms governing their recruitment to the heart.
Assuntos
Células-Tronco Embrionárias/citologia , Macrófagos/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Miocardite/imunologia , Miocárdio/imunologia , Pericárdio/imunologia , Vasculite/imunologia , Animais , Movimento Celular , Proliferação de Células , Vasos Coronários/patologia , Modelos Animais de Doenças , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Receptores CCR2/metabolismoRESUMO
Immunocompetent cells including lymphocytes play a key role in the development of adipose tissue inflammation and obesity-related cardiovascular complications. The aim of the study was to explore the relationship between epicardial adipose tissue lymphocytes and coronary artery disease (CAD). To this end, we studied the content and phenotype of lymphocytes in peripheral blood, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT) in subjects with and without CAD undergoing elective cardiac surgery. Eleven subjects without CAD (non-CAD group) and 22 age-, BMI-, and HbA1C-matched individuals with CAD were included into the study. Blood, SAT, and EAT samples were obtained at the beginning of surgery. Lymphocyte populations were quantified as % of CD45+ cells using flow cytometry. Subjects with CAD had a higher total lymphocyte amount in EAT compared with SAT (32.24 ± 7.45 vs. 11.22 ± 1.34%, p = 0.025) with a similar trend observed in non-CAD subjects (29.68 ± 7.61 vs. 10.13 ± 2.01%, p = 0.067). T (CD3+) cells were increased (75.33 ± 2.18 vs. 65.24 ± 4.49%, p = 0.032) and CD3- cells decreased (21.17 ± 2.26 vs. 31.64 ± 4.40%, p = 0.028) in EAT of CAD relative to the non-CAD group. In both groups, EAT showed an elevated percentage of B cells (5.22 ± 2.43 vs. 0.96 ± 0.21%, p = 0.039 for CAD and 12.49 ± 5.83 vs. 1.16 ± 0.19%, p = 0.016 for non-CAD) and reduced natural killer (NK) cells (5.96 ± 1.32 vs. 13.22 ± 2.10%, p = 0.012 for CAD and 5.32 ± 1.97 vs. 13.81 ± 2.72%, p = 0.022 for non-CAD) relative to SAT. In conclusion, epicardial adipose tissue in subjects with CAD shows an increased amount of T lymphocytes relative to non-CAD individuals as well as a higher number of total and B lymphocytes and reduced NK cells as compared with corresponding SAT. These changes could contribute to the development of local inflammation and coronary atherosclerosis.
Assuntos
Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Pericárdio/metabolismo , Linfócitos T/metabolismo , Tecido Adiposo/imunologia , Idoso , Linfócitos B , Doença da Artéria Coronariana/imunologia , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pericárdio/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Linfócitos T/imunologiaRESUMO
BACKGROUND: Oxidized low-density lipoproteins and scavenger receptors (SRs) play an important role in the formation and development of atherosclerotic plaques. However, little is known about their presence in epicardial adipose tissue (EAT). The objective of the study was to evaluate the mRNA expression of different SRs in EAT of patients with ischemic heart disease (IHD), stratifying by diabetes status and its association with clinical and biochemical variables. METHODS: We analyzed the mRNA expression of SRs (LOX-1, MSR1, CXCL16, CD36 and CL-P1) and macrophage markers (CD68, CD11c and CD206) in EAT from 45 patients with IHD (23 with type 2 diabetes mellitus (T2DM) and 22 without T2DM) and 23 controls without IHD or T2DM. RESULTS: LOX-1, CL-P1, CD68 and CD11c mRNA expression were significantly higher in diabetic patients with IHD when compared with those without T2DM and control patients. MSR1, CXCL16, CD36 and CD206 showed no significant differences. In IHD patients, LOX-1 (OR 2.9; 95% CI 1.6-6.7; P = 0.019) and CD68 mRNA expression (OR 1.7; 95% CI 0.98-4.5; P = 0.049) were identified as independent risk factors associated with T2DM. Glucose and glycated hemoglobin were also shown to be risk factors. CONCLUSIONS: SRs mRNA expression is found in EAT. LOX-1 and CD68 and were higher in IHD patients with T2DM and were identified as a cardiovascular risk factor of T2DM. This study suggests the importance of EAT in coronary atherosclerosis among patients with T2DM.
Assuntos
Tecido Adiposo , Diabetes Mellitus Tipo 2 , Macrófagos/fisiologia , Isquemia Miocárdica , Pericárdio/imunologia , Pericárdio/metabolismo , Receptores Depuradores/genética , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Idoso , Estudos de Casos e Controles , Movimento Celular , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/imunologia , Cardiomiopatias Diabéticas/metabolismo , Feminino , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Isquemia Miocárdica/genética , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/metabolismo , Receptores Depuradores/metabolismo , Regulação para Cima/genéticaRESUMO
BACKGROUND: Glutaraldehyde cross-linked bioprosthetic heart valves might fail due to progressive degradation and calcification. METHODS: In this study, we developed a new BHVs preparation strategy named as "HPA/TRA/FMN" that utilized 3,4-hydroxyphenylpropionic acid (HPA)/tyramine (TRA) conjugated pericardium and riboflavin 5'-monophosphate (FMN) initiated photo-cross-linking method. HPA/TRA-pericardium conjugation would provide extra phenol groups for FMN initiated photo-cross-linking. RESULTS: The feeding ratio of riboflavin 5'-monophosphate was optimized. The collagenase and elastase enzymatic degradation in vitro, biomechanics, calcification, elastin stability in vivo, and macrophage marker CD68 were characterized. We demonstrated that riboflavin photo-cross-linked pericardiums had great collagen and elastin stability, improved mechanical properties, better resistance for calcification, and less CD68 positive macrophages in rat subdermal implantation study. CONCLUSIONS: This new riboflavin photo-cross-linking strategy would be a promising method to make BHVs which have better elastin stability, less calcification, and reduced inflammatory response.
Assuntos
Calcinose/imunologia , Reagentes de Ligações Cruzadas , Próteses Valvulares Cardíacas , Riboflavina/imunologia , Animais , Bioprótese , Glutaral/imunologia , Pericárdio/imunologia , Transplante Heterólogo/métodosRESUMO
Although mast cell distribution has been described in both human and canine hearts, cardiac mast cells in mice have yet to be categorically localized. We therefore sought to describe mast cell distribution within the mouse heart and characterize their dependence on the Microphthalmia-associated transcription factor (Mitf). Cardiac mast cells were visualized using Toluidine Blue and avidin staining, and their distribution within the heart described. Cardiac mast cells were most prevalent in the epicardium (50%) or myocardium (45%). Less frequently, mast cells were noted in the endocardium (5%). Within the myocardium, 31% of the mast cells had perivascular location. By studying two different Mitf mutant strains, Mitfmi-vga9 and MitfMi-wh, we demonstrated that these mutations led to near-complete deficiency of cardiac mast cells. Accordingly, expression of the mMCP-4 and mMCP-5 genes was lost and chymase enzyme activity was severely reduced. Additionally, hearts from mice heterozygous for these Mitf mutations contained significantly fewer mast cells compared to wild-type mice. Our results demonstrated that the distribution of cardiac mast cells in mice is different from humans and dogs. Cardiac mast cells are dependent on Mitf expression, with loss-of-function mutation in the Mitf gene leading to near-complete lack of cardiac mast cells. Loss of a single Mitf allele is sufficient for relative mast cell deficiency.
Assuntos
Regulação da Expressão Gênica/imunologia , Mastócitos/imunologia , Fator de Transcrição Associado à Microftalmia/imunologia , Miocárdio/imunologia , Pericárdio/imunologia , Animais , Cães , Humanos , Mastócitos/citologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição Associado à Microftalmia/genética , Proteínas Quimioatraentes de Monócitos/genética , Proteínas Quimioatraentes de Monócitos/imunologia , Mutação , Serina Endopeptidases/genética , Serina Endopeptidases/imunologiaRESUMO
PURPOSE: This case-control retrospective discovery study is to identify antigenic bovine pericardium (BP) proteins that stimulate graft-specific humoral immune response in patients implanted with glutaraldehyde fixed bovine pericardial (GFBP) heart valves. EXPERIMENTAL DESIGN: Banked serum is collected from age- and sex-matched patients who received either a GFBP or mechanical heart valve replacement. Serum IgG is isolated and used to generate poly-polyclonal antibody affinity chromatography columns from each patient. Native and deglycosylated BP protein extracts are separately added to individual patient affinity chromatography columns, with unbound proteins washed through the column. Proteins captured in the affinity chromatography columns are submitted for proteomic identification. Differences between GFBP and mechanical heart valve replacement recipients are analyzed with Gaussian linearized modeling. RESULTS: Carbohydrate antigens overwhelm protein capture in the column, requiring BP protein deglycosylation prior to affinity chromatography. Nineteen BP protein antigens, which stimulated graft-specific IgG production, are identified in patients who received GFBP valve replacements. Identified antigens are significantly over-represented for calcium-binding proteins. CONCLUSIONS AND CLINICAL RELEVANCE: Patients implanted with GFBP valves develop a graft-specific humoral immune response toward BP protein antigens, with 19 specific antigens identified in this work. The molecular functions of over-represented antigens, specifically calcium-binding proteins, may aid in understanding the underlying factors that contribute to structural valve deterioration.
Assuntos
Antígenos , Bioprótese , Próteses Valvulares Cardíacas , Imunidade Humoral , Imunoglobulina G , Pericárdio/imunologia , Proteômica , Animais , Antígenos/sangue , Antígenos/imunologia , Bovinos , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pericárdio/química , Estudos RetrospectivosRESUMO
Pericardial membrane derived from bovine heart tissues is a promising source of material for use in tissue-engineering applications. However, tissue processing is required for its use in humans due to the presence of animal antigens. Therefore, the purpose of this study was to evaluate the structural integrity and biocompatibility of the bovine pericardium (BP) after a soft decellularization process with a 0.1% sodium dodecyl sulfate (SDS) solution, with the aim to remove xenoantigens and preserve extracellular matrix (ECM) bioactivity. The decellularization process promoted a mean reduction of 77% of the amount of DNA in the samples in which cell nuclei staining was undetectable. The ECM content was maintained as mostly preserved after decellularization as well as its biomechanical properties. In addition, the decellularization protocol has proven to be efficient in removing the xenoantigen alpha-gal, which is responsible for immune rejection. The decellularized BP was noncytotoxic in vitro and allowed human adipose-derived stem cell (hASC) adhesion. Finally, after 7 days in culture, the tissue scaffold became repopulated by hASCs, and after 30 days, the ECM protein pro-collagen I was seen in the scaffold. Together, these characteristics indicated that soft BP decellularization with 0.1% SDS solution allows the acquirement of a bioactive scaffold suitable for cell repopulation and potentially useful for regenerative medicine.
Assuntos
Matriz Extracelular/imunologia , Pericárdio/imunologia , Engenharia Tecidual , Alicerces Teciduais , Animais , Bovinos , Matriz Extracelular/metabolismo , Humanos , Dodecilsulfato de Sódio/metabolismo , Engenharia Tecidual/métodos , Transplante Heterólogo/métodosRESUMO
BACKGROUND: Pericardial tissue from various animal species is utilized for the production of the bioprosthetic heart valves (BHV) used clinically. Experimental data show that the eventual breakdown of BHV is partly due to immunological interactions with carbohydrate tissue antigens. To understand these processes, we have examined the glycolipid-based carbohydrate antigens in naïve porcine, bovine, and equine pericardia. EXPERIMENTAL: Total non-acid and acid glycosphingolipid fractions were isolated from porcine, bovine, and equine pericardia, and individual glycolipid compounds were characterized by thin-layer chromatography, mass spectrometry, and binding of monoclonal antibodies, lectins and bacteria in chromatogram binding assays. RESULTS: The non-acid glycolipid fractions from all species contained glycosphingolipids based on the globo- and neolacto-series, including pentaglycosylceramides with terminal Galα3 determinants. Terminal blood group A and H (O) structures based on type 2 core chains were present in porcine pericardium, while the Forssman pentaosylceramide was found in equine pericardium. All acid glycolipid fractions contained sulfatide and several gangliosides with both N-acetyl- and N-glycolyl-neuraminic acid as terminal saccharide chain determinants. CONCLUSION: Several carbohydrate antigens which are potential targets for the human immune system have been identified in the animal pericardial tissues used for the production of BHV. Which of these antigens are left in the tissues after industrial BHV production processes, as well as their potential role in eventual BHV degradation, remains to be elucidated.
Assuntos
Anticorpos Monoclonais/imunologia , Glicoesfingolipídeos/metabolismo , Valvas Cardíacas/imunologia , Valvas Cardíacas/patologia , Pericárdio/imunologia , Animais , Bioprótese/parasitologia , Bovinos , Próteses Valvulares Cardíacas , Cavalos , Humanos , Ácidos Neuramínicos/farmacologia , Suínos , Transplante Heterólogo/métodosRESUMO
BACKGROUND: Self-expandable percutaneous pulmonary valve implantation (PPVI) for native right ventricular outflow tract lesions is still in the clinical trial phase. The aim of this study is to present the result of feasibility study of a novel self-expandable knitted nitinol wire stent mounted with a treated trileaflet α-Gal-free porcine pericardial valve for PPVI. METHODS AND RESULTS: A feasibility study using Pulsta valve (TaeWoong Medical Co, Gyeonggi-do, South Korea) was designed for patients with severe pulmonary regurgitation in the native right ventricular outflow tract, and 6-month follow-up outcomes were reviewed. Ten tetralogy of Fallot patients were enrolled. Before PPVI, severe pulmonary regurgitation (mean pulmonary regurgitation fraction, 45.5%±7.2%; range, 34.9%-56%) and enlarged right ventricular volume (mean indexed right ventricular end-diastolic volume, 176.7±14.3 mL/m2; range, 158.9-205.9 mL/m2) were present. The median age at PPVI was 21.7±6.5 years (range, 13-36 years). Five patients were successfully implanted with 28 mm and the other 5 with 26 mm valves loaded on the 18F delivery cable. No significant periprocedural complications were noted in any patient. At the 6-month follow-up, indexed right ventricular end-diastolic volume was dramatically decreased to 126.3±20.3 mL/m2 (range, 99-164.2 mL/m2), and the mean value of peak instantaneous pressure gradient between the right ventricle and the pulmonary artery decreased from 6.8±3.5 mm Hg (range, 2-12 mm Hg) before PPVI to 5.7±6.7 mm Hg (range, 2-12 mm Hg) without significant pulmonary regurgitation. There was no adverse event associated with the valve. CONCLUSIONS: A feasibility study of the Pulsta valve for native right ventricular outflow tract lesions was completed successfully with planned Pulsta valve implantation and demonstrated good short-term effectiveness without serious adverse events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02555319.