Assuntos
Tecido Adiposo , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Pericárdio , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tecido Adiposo/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Progressão da Doença , Tecido Adiposo Epicárdico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/farmacologia , Pericárdio/efeitos dos fármacos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/farmacologia , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêuticoAssuntos
Tecido Adiposo , Hipoglicemiantes , Liraglutida , Pericárdio , Humanos , Liraglutida/uso terapêutico , Pericárdio/efeitos dos fármacos , Pericárdio/diagnóstico por imagem , Tecido Adiposo/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco de Doenças Cardíacas , Resultado do Tratamento , Tecido Adiposo EpicárdicoRESUMO
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.
Assuntos
Tecido Adiposo , Insuficiência Cardíaca , Mediadores da Inflamação , Pericárdio , Índice de Gravidade de Doença , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Pericárdio/metabolismo , Pericárdio/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Resultado do Tratamento , Mediadores da Inflamação/metabolismo , Volume Sistólico/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Metabolômica , Biomarcadores/sangue , Tecido Adiposo EpicárdicoRESUMO
PURPOSE: This study aims to decellularized caprine pericardium tissue with varied non-ionic surfactant and anionic detergent concentrations. METHODS: Protocol A consists of 1%, 0.5%, and 0.25% (w/v) sodium dodecyl sulphate (SDS). Protocol B uses 1%, 0.5%, and 0.25% (w/v) Triton X-100. Protocol C comprised 0.5% SDS + 0.5% Triton X-100, 0.5% + 0.25%, and 0.25% SDS + 0.5% Triton X-100. RESULTS: Protocol B left a few countable cells in the pericardium tissue, but treatments A and C removed all cells. DNA quantification also demonstrated that protocol B had the most leftover DNA after decellularization. The pericardium tissue treated with an equal combination of anionic detergent and non-ionic surfactant preserves the matrix. However, changing the anionic detergent-non-ionic surfactant ratio disrupted the microstructure. Protocol A decreased pericardium tissue secant modulus (p < 0.05). Protocol B-treated pericardium tissue matched native tissue secant modulus and ultimate tensile stress. Protocol C strengthened pericardium tissue. CONCLUSION: The intact extracellular matrix and biomechanical properties like native tissues require optimal chemical doses and combinations.
Assuntos
Cabras , Octoxinol , Pericárdio , Dodecilsulfato de Sódio , Pericárdio/efeitos dos fármacos , Pericárdio/citologia , Animais , Octoxinol/farmacologia , Octoxinol/química , Dodecilsulfato de Sódio/farmacologia , Matriz Extracelular Descelularizada/química , Matriz Extracelular Descelularizada/farmacologia , Detergentes , Tensoativos/química , Tensoativos/farmacologia , DNA , Fenômenos Biomecânicos , Módulo de ElasticidadeRESUMO
NEW FINDINGS: What is the central question of this study? Can the triangular appearance of ventricular action potential, indicating proarrhythmic profile of antiarrhythmic agent, be approximated by specific changes on an electrocardiogram (ECG)? What are the main finding and its importance? The triangulation of the ventricular action potential seen when antiarrhythmic drugs induce a greater lengthening of the late repolarization compared to the initial repolarization in epicardium is closely approximated by a greater prolongation of the T wave upslope relative to the interval between the J point and the start of the T wave (the JTstart interval) on the ECG. These findings may improve the power of ECG assessments in predicting the drug-induced arrhythmia resulting from slowed phase 3 repolarization. ABSTRACT: Antiarrhythmic drugs prescribed to treat atrial fibrillation can occasionally precipitate ventricular tachyarrhythmia through a prominent slowing of the phase 3 repolarization. The latter results in the triangular shape of ventricular action potential, indicating high arrhythmic risk. However, clinically, the utility of triangulation assessments for predicting arrhythmia is limited owing to the invasive nature of the ventricular action potential recordings. This study examined whether the triangulation effect can be detected indirectly from electrocardiogram (ECG) analysis. Epicardial monophasic action potentials and the ECG were simultaneously recorded in perfused guinea-pig hearts. With antiarrhythmics (dofetilide, quinidine, procainamide and flecainide), a prolongation of the initial repolarization seen in the action potential recordings was closely approximated by lengthening of the interval between the J point and the start of the T wave (the JTstart interval) on the ECG, whereas a prolongation of the late repolarization was paralleled by widening of the T wave upslope. Dofetilide, quinidine and procainamide induced a prominent slowing of the phase 3 repolarization in epicardium, leading to triangulation of the action potential. These effects were accompanied by a greater prolongation of the T wave upslope compared to the JTstart interval. Flecainide elicited a proportional prolongation of the initial and the late ventricular repolarization, and therefore failed to induce triangulation, based on analysis of both epicardial action potential and ECG profiles. Collectively, these findings suggest that the ratio between the durations of the T wave upslope and the JTstart interval may represent the ECG metric of the ventricular action potential triangulation induced by antiarrhythmic drugs.
Assuntos
Antiarrítmicos , Arritmias Cardíacas , Potenciais de Ação , Animais , Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Eletrocardiografia , Flecainida/efeitos adversos , Cobaias , Pericárdio/efeitos dos fármacos , Pericárdio/fisiologia , Procainamida/efeitos adversos , Quinidina/efeitos adversosRESUMO
Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)-modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.
Assuntos
Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/terapia , Oxazóis/farmacologia , Pericárdio/efeitos dos fármacos , Animais , Materiais Biocompatíveis , Calcificação Fisiológica/efeitos dos fármacos , Calcinose/tratamento farmacológico , Calcinose/metabolismo , Calcinose/terapia , Linhagem Celular , Colágeno/metabolismo , Etanol/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Próteses Valvulares Cardíacas , Xenoenxertos/efeitos dos fármacos , Humanos , Masculino , Oxirredução/efeitos dos fármacos , Pericárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Células THP-1RESUMO
Triphenyl phosphate (TPHP) is an organophosphate ester-based plasticizer and flame retardant. The objective of this study was to identify the potential role of epidermal ionocytes in mediating TPHP-induced pericardial edema within zebrafish embryos. Exposure to TPHP from 24 to 72 h post fertilization (hpf) resulted in a significant increase in pericardial edema and the number of ionocytes at 72 hpf relative to time-matched embryos treated with vehicle. In addition, co-exposure of embryos to mannitol (an osmotic diuretic) blocked TPHP-induced pericardial edema and effects on ionocyte abundance. However, knockdown of ATPase1a1.4 - an abundant Na+/K+-ATPase localized to epidermal ionocytes - mitigated TPHP-induced effects on ionocyte abundance but not pericardial edema, whereas co-exposure of embryos to ouabain - a Na+/K+-ATPase inhibitor - enhanced TPHP-induced pericardial edema but not ionocyte abundance. Overall, our findings suggest that TPHP may have multiple mechanisms of toxicity leading to an increase in ionocyte abundance and pericardial edema within developing zebrafish embryos.
Assuntos
Células Epidérmicas/efeitos dos fármacos , Organofosfatos/toxicidade , Pericárdio/efeitos dos fármacos , Animais , Edema/induzido quimicamente , Embrião não Mamífero/efeitos dos fármacos , Retardadores de Chama/toxicidade , Pericárdio/embriologia , Peixe-Zebra/embriologiaRESUMO
BACKGROUND: This study reports the long-term outcomes using glutaraldehyde-treated cryopreserved homograft pericardium (CPH) in neonates, infants, children, and young adults undergoing congenital cardiac surgery. METHODS: A retrospective review was performed of all patients at a single institution (Rady Children's Hospital, San Diego, CA) who had undergone surgical implantation with CPH between 2006 and 2016. The study identified 134 consecutive patients who underwent implantation of a total of 276 patches. The baseline demographic characteristics, primary cardiac diagnosis, surgical characteristics, operative reports, and postoperative catheterization and reoperation reports were analyzed. The use of CPH was categorized by specific anatomic insertion site. RESULTS: The median age at patch implantation was 1.47 years (range, 1 day to 31.6 years). The numbers and locations of patch use were 124 for pulmonary arterial repair, 57 for repair of the aorta, 49 for septal repair, and 43 at other sites. At a median follow-up of 5.29 years, 9 patients had died (6.7%), but none of those deaths were related to CPH. Twelve patients (8.96%) underwent reoperations, and 18 patients (13.4%) underwent catheter interventions at sites of CPH implantation. The 10-year freedom from patch-induced reoperation and catheter intervention rates were 88.5% and 86.9%, respectively. Overall patch failure-free survival was 85.8% and 79.0% at 5 and 10 years, respectively. CONCLUSIONS: The use of CPH patch in the surgical correction of congenital heart disease is effective and durable, as evidenced by the low reintervention rates. These results are comparable to the early and midterm outcomes of other similarly used surgical patches.
Assuntos
Glutaral/farmacologia , Cardiopatias Congênitas/cirurgia , Pericárdio/efeitos dos fármacos , Pericárdio/transplante , Adolescente , Aloenxertos/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/métodos , Criança , Pré-Escolar , Criopreservação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Improved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies. METHODS: We present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and persistent AF (total n = 64). RNA expression levels were validated in the same and an independent cohort with qPCR. Biological processes were assessed with histological and immunohistochemical analyses. RESULTS: In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial-to-mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast-like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis, and endothelial signaling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast-like cells and extracellular matrix gene expression including enhanced tenascin-C, thrombospondins, biglycan, and versican. Morphological analyses discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signaling pathways, including cell-matrix interactions, PI3K-AKT, and Notch signaling that could regulate mesenchymal cell activation, were upregulated. CONCLUSION: Our results suggest that EMT and endothelial cell proliferation work in concert and characterize the (myo)fibroblast recruitment and ECM remodeling of AF. These processes could guide future research toward the discovery of targets for AF therapy.
Assuntos
Fibrilação Atrial/complicações , Endotélio/efeitos dos fármacos , Matriz Extracelular/fisiologia , Pericárdio/efeitos dos fármacos , Idoso , Fibrilação Atrial/fisiopatologia , Endotélio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pericárdio/metabolismoRESUMO
(1) Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) reduce adipose tissue and cardiovascular events in patients with type 2 diabetes (T2D). Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and obstructive coronary disease events in patients with T2D. (2) We performed a systematic review and meta-analysis of SGLT2-i therapy on T2D patients, reporting data on changes in EAT after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases. A random effects or fixed effects model meta-analysis was then applied. (3) Results: A total of three studies (n = 64 patients with SGLT2-i, n = 62 with standard therapy) were included in the final analysis. SGLT2 inhibitors reduced EAT (SMD: -0.82 (-1.49; -0.15); p < 0.0001). An exploratory analysis showed that HbA1c was significantly reduced with SGLT2-i use, while body mass index was not significantly reduced with this drug. (4) Conclusions: This meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with SGLT2-i treatment.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/antagonistas & inibidores , Pericárdio/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tecido Adiposo/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas/metabolismo , Humanos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pericárdio/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
Over the years, several devices have been created (and the development of many others is currently in progress) to be in permanent contact with blood: mechanical circulatory supports represent an example thereof. The hemocompatibility of these devices largely depends on the chemical composition of blood-contacting components. In the present work, an innovative material (hybrid membrane) is proposed to fabricate the inner surfaces of a pulsatile ventricular chamber: it has been obtained by coupling a synthetic polymer (e.g., commercial polycarbonate urethane) with decellularized porcine pericardium. The hemocompatibility of the innovative material has been preliminarily assessed by measuring its capacity to promote thrombin generation and induce platelet activation. Our results demonstrated the blood compatibility of the proposed hybrid membrane.
Assuntos
Plaquetas/efeitos dos fármacos , Sangue/efeitos dos fármacos , Materiais Revestidos Biocompatíveis , Membranas Artificiais , Ativação Plaquetária , Adulto , Animais , Sangue/metabolismo , Feminino , Humanos , Teste de Materiais/métodos , Pericárdio/química , Pericárdio/efeitos dos fármacos , Cimento de Policarboxilato/química , Polímeros/química , Estresse Mecânico , Propriedades de Superfície , Suínos , Trombina/química , Uretana/químicaRESUMO
ABSTRACT: Epicardial adipose tissue (EAT) dysfunction mediates chronic inflammation by regulating inflammation-related adipokines and cytokines, and it further promotes coronary artery disease (CAD) development. CD40L/CD40 is involved in multiple inflammatory pathways that contribute to various pathophysiological processes. However, the function of CD40L/CD40 in the expression and production of adipokines and cytokines in epicardial adipocytes remains unclear. The purpose of the present study was to explore the role and underlying mechanisms of CD40L/CD40 in adipokine and cytokine expression and production. We isolated adipocytes from EAT tissues of CAD and non-CAD patients. We noticed that CD40 was dramatically increased in EAT tissues of CAD patients. Loss-of-function and gain-of-function studies were performed. The results showed that CD40 silencing reduced recombinant CD40 ligand (rCD40L)-induced upregulation of plasminogen activator inhibitor-1, leptin, interleukin-6, and monocyte chemotactic protein-1 messenger RNA levels and secretion. Overexpression of CD40 displayed the opposite results. In addition, rCD40L triggered mixed lineage leukemia protein-1 (MLL1) expression both in messenger RNA and protein levels. CD40 depletion apparently blocked MLL1 expression, whereas gain of function of CD40 resulted in augmentation of MLL1 levels. Interestingly, chromatin immunoprecipitation-quantitative real-time polymerase chain reaction analysis revealed that CD40 elimination dampened histone H3 lysine 4 trimethylation enrichment at plasminogen activator inhibitor-1, leptin, interleukin-6, and monocyte chemotactic protein-1 promoter regions in the presence of rCD40L. The reverse pattern was observed upon ectopic expression of CD40. Most important, MLL1 silencing effectively reversed the promotive effects of CD40 on adipokine and cytokine secretion. Taken together, our findings suggest that CD40L/CD40 regulates adipokine and cytokine expression by H3 lysine 4 trimethylation modification in adipocytes.
Assuntos
Adipócitos/efeitos dos fármacos , Adipocinas/metabolismo , Antígenos CD40/agonistas , Ligante de CD40/farmacologia , Doença da Artéria Coronariana/metabolismo , Citocinas/metabolismo , Histonas/metabolismo , Pericárdio/efeitos dos fármacos , Adipócitos/metabolismo , Adipocinas/genética , Idoso , Antígenos CD40/genética , Antígenos CD40/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Citocinas/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Leptina/genética , Leptina/metabolismo , Masculino , Metilação , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pericárdio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas , Processamento de Proteína Pós-TraducionalRESUMO
Diabetes mellitus (DM) is a chronic and complex metabolic disorder and also an important cause of cardiovascular (CV) disease (CVD). Patients with type 2 DM (T2DM) and obesity show a greater propensity for visceral fat deposition (and excessive fat deposits elsewhere) and the link between adiposity and CVD risk is greater for visceral than for subcutaneous (SC) adipose tissue (AT). There is growing evidence that epicardial AT (EAT) and pericardial AT (PAT) play a role in the development of DM-related atherosclerosis, atrial fibrillation (AF), myocardial dysfunction, and heart failure (HF). In this review, we will highlight the importance of PAT and EAT in patients with DM. We also consider therapeutic interventions that could have a beneficial effect in terms of reducing the amount of AT and thus CV risk. EAT is biologically active and a likely determinant of CV morbidity and mortality in patients with DM, given its anatomical characteristics and proinflammatory secretory pattern. Consequently, modification of EAT/PAT may become a therapeutic target to reduce the CV burden. In patients with DM, a low calorie diet, exercise, antidiabetics and statins may change the quantity of EAT, PAT or both, alter the secretory pattern of EAT, improve the metabolic profile, and reduce inflammation. However, well-designed studies are needed to clearly define CV benefits and a therapeutic approach to EAT/PAT in patients with DM.
Assuntos
Tecido Adiposo/fisiopatologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Pericárdio/fisiopatologia , Tecido Adiposo/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exercício Físico , Humanos , Hipoglicemiantes/farmacologia , Obesidade/complicações , Obesidade/fisiopatologia , Pericárdio/efeitos dos fármacos , Fatores de RiscoRESUMO
The epicardium plays an important role in cardiomyogenesis during development, while it becomes quiescent in adult heart during homeostasis. This study investigates the efficiency of thymosin ß4 (Tß4) release with RPRHQGVM conjugated to the C-terminus of RADA16-I (RADA-RPR), the functionalized self-assembling peptide (SAP), to activate the epicardium and repairing the infarcted myocardium. Methods: The functionalized SAP was constituted with self-assembling motif, Tß4-binding site, and cell adhesive ligand. Myocardial infarction (MI) models of the transgenic mice were established by ligation of the left anterior descending coronary artery. At one week after intramyocardial injection of Tß4-conjugated SAP, the activation of the epicardium was assessed. At four weeks after implantation, the migration and differentiation of epicardium-derived cells (EPDCs) as well as angiogenesis, lymphangiogenesis and myocardial regeneration were examined. Results: We found that the designer RADA-RPR bound Tß4 and adhered to EPDCs and that Tß4 released from the functionalized SAP could effectively activate the epicardium and induce EPDCs to differentiate towards cardiovascular cells as well as lymphatic endothelial cells. Moreover, SAP-released Tß4 (SAP-Tß4) promoted proliferation of cardiomyocytes. Furthermore, angiogenesis, lymphangiogenesis and myocardial regeneration were enhanced in the MI models at 4 weeks after delivery of SAP-Tß4 along with attenuation of adverse myocardial remodeling and significantly improved cardiac function. Conclusions: These results demonstrate that sustained release of Tß4 from the functionalized SAP can activate the epicardium and effectively enhance the repair of infarcted myocardium. We believe the delivery of SAP-Tß4 may be a promising strategy for MI therapy.
Assuntos
Infarto do Miocárdio/tratamento farmacológico , Miocárdio/patologia , Peptídeos/farmacologia , Pericárdio/efeitos dos fármacos , Timosina/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Linfangiogênese/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
PURPOSE: The aim of this study was to analyze the effects of 10-minute (standard term) versus 20-minute treatment with glutaraldehyde (GA) on mechanical stability and physical strength of human pericardium in the setting of the OZAKI procedure. METHODS: Leftover pericardium (6 patients) was bisected directly after the operation, and one-half was further fixed for 10 additional minutes. Uniaxial tensile tests were performed and ultimate tensile strength (UTS), ultimate tensile strain (uts), and collagen elastic modulus were evaluated. RESULTS: Both treatments resulted in similar values of uniaxial stretching-generated elongations at rupture (10 minutes 25 ± 7 % vs. 20 minutes: 22 ± 5 %; p = 0.05), UTS (5.16 ± 2 MPa vs. 6.54 ± 3 MPa; p = 0.59), and collagen fiber stiffness (elastic modulus: 31.80 ± 15.05 MPa vs. 37.35 ± 15.78 MPa; p = 0.25). CONCLUSION: Prolongation of the fixation time of autologous pericardium has no significant effect on its mechanical stability; thus, extending the intraoperative treatment cannot be recommended.
Assuntos
Glutaral , Pericárdio , Resistência à Tração , Glutaral/farmacologia , Humanos , Pericárdio/efeitos dos fármacos , Pericárdio/fisiologia , Resistência à Tração/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Patients with univentricular hearts who require permanent pacing systems typically require placement of epicardial leads. It is frequently difficult to find a position with good thresholds due to epimyocardial fibrosis or fat. The goal of the study is to assess the progression of capture thresholds (CT), sensing parameters (P waves and R waves), and impedances (imp) of steroid eluting epicardial pacing leads in young adults who underwent Fontan conversion and a pacemaker implant. METHODS: All patients undergoing Fontan conversion in two institutions were retrospectively identified. Demographic data, congenital heart defects, pacing leads used, and pacing parameters were analyzed at implant, at 6 weeks and 12 months after implant. RESULTS: Twenty patients were identified (twelve males); mean age at conversion was 24.9 ± 5.4 years (range 18-35). Epicardial bipolar steroid eluting leads were used. The site of implant both in the atria and the ventricles varied depending on the parameters. At implant, mean atrial and ventricular impedances were 617 ± 171 Ω and 1061 ± 771 Ω, respectively, mean P wave amplitude was 2 ± 0.7 mV, and mean R wave amplitude was 12.5 ± 7.7 mV. Mean CT was 1.7 ± 0.8 V at 0.5 ms for the atrium and 2.2 ± 1.2 V at 0.5 ms for the ventricle. Ventricular CT and impedance showed an improvement within the first 12 months after implant, with four patients having a decrease in threshold of more than 2 V. CONCLUSION: In patients undergoing Fontan conversion, implant ventricular CT and impedances are frequently higher than expected but typically improve during follow-up. Acceptance of higher initial threshold values may be a potential strategy in this patient population.
OBJETIVO: Los pacientes con corazón univentricular que requieren estimulación cardíaca reciben sistemas de estimulación epicárdicos. Debido a la presencia de fibrosis o grasa epi-miocárdica es dificultoso en esta población encontrar sitios con adecuados parámetros de estimulación. El objetivo de este estudio es determinar la progresión de los umbrales de captura, los parámetros de sensado (medición de las ondas P y R) e impedancias (imp) de los catéteres epicárdicos con liberación de esteroides implantados en adultos jóvenes sometidos a cirugía de reconversión de Fontan e implante de marcapasos. MÉTODOS: Los pacientes sometidos a cirugía de reconversión de Fontan en dos instituciones fueron analizados retrospectivamente. Los datos demográficos, el tipo de cardiopatía congénita, de catéteres de estimulación y los parámetros de estimulación fueron analizados al momento del implante, a las 6 semanas y al año. RESULTADOS: Se identificaron 20 pacientes (12 de ellos de sexo masculino); la edad media al momento de la reconversión fue de 24.9 ± 5.4 años (rango 18-35). Se utilizaron catéteres epicárdicos bipolares de fijación pasiva y con liberación de esteroides en todos los casos. El sitio de implante en las aurículas y en los ventrículos fue variable de acuerdo a los parámetros. En el momento del implante las impedancias medias fueron 617 ± 171 W y 1061 ± 771 W respectivamente, la amplitud media de la onda P fue 2 ± 0.7 mV y la media de amplitud de la onda R fue de 12.5 ± 7.7 mV. Las medias de los umbrales de captura fueron 1.7 ± 0.8 V at 0.5 ms para los catéteres auriculares y 2.2 ± 1.2 V at 0.5 ms para los ventriculares. Los umbrales de captura y las impedancias ventriculares mostraron una mejoría en los 12 meses posteriores al implante, y en 4 pacientes esa mejoría en el umbral de captura ventricular fue mayor a 2 V. CONCLUSIONES: En pacientes sometidos a una cirugía de reconversión de Fontan e implante de marcapasos, los umbrales de captura e impedancias ventriculares son más elevados que los esperados, pero mejoran durante el seguimiento. La aceptación de valores más elevados puede potencialmente constituir una alternativa en esta población de pacientes.
Assuntos
Cardiopatias Congênitas , Marca-Passo Artificial , Adolescente , Adulto , Desfibriladores Implantáveis/normas , Impedância Elétrica , Eletrodos Implantados , Técnica de Fontan , Glucocorticoides/farmacologia , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/cirurgia , Humanos , Masculino , Pericárdio/efeitos dos fármacos , Pericárdio/patologia , Pericárdio/cirurgia , Estudos Retrospectivos , Taquicardia Ventricular/terapia , Resultado do Tratamento , Adulto JovemRESUMO
The environmental effects of additives have attracted increasing attention. Sodium dehydroacetate (DHA-S), as an approved preservative, is widely added in processed foods, cosmetics and personal care products. However, DHA-S has been recently reported to induce hemorrhage and coagulation aberration in rats. Yet little is known about the ecotoxicological effect and underlying mechanisms of DHA-S. Here, we utilized the advantage of zebrafish model to evaluate such effects. DHA-S induced cerebral hemorrhage, mandibular dysplasia and pericardial edema in zebrafish after 24 h exposure (48-72 hpf) at 50 mg/L. We also observed the defective heart looping and apoptosis in DHA-S-treated zebrafish through o-dianisidine and acridine orange staining. Meanwhile, DHA-S induced the deficiency of Ca2+ and vitamin D3 in zebrafish. We further demonstrated that DHA-S stimulated Ca2+ influx resulting in Ca2+-dependent mitochondrial damage in cardiomyocytes. Additionally, DHA-S inhibited glucose uptake and repressed the biosynthesis of amino acids. Finally, we identified that sodium bicarbonate could rescue zebrafish from DHA-S induced cardiovascular toxicity. Altogether, our results suggest that DHA-S is a potential risk for cardiovascular system.
Assuntos
Cálcio/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/efeitos dos fármacos , Pironas/toxicidade , Peixe-Zebra , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Hemorragia Cerebral/induzido quimicamente , Relação Dose-Resposta a Droga , Edema Cardíaco/induzido quimicamente , Coração/embriologia , Miocárdio/metabolismo , Miocárdio/patologia , Pericárdio/efeitos dos fármacos , Pericárdio/patologia , Ratos , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
ABSTRACT: Embryonic epicardial cells make an important contribution to cardiac development. However, their proliferation mechanism is still unclear. Epicardial cells from E12.5 fetal hearts were used in our study. Agrin was used to treat these cells. The expression of Aurora B, Ki67, and pH3 was measured by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. The proportion of cells in G1/S/G2 phase was determined by flow cytometry. The results showed that agrin significantly increased the expression of ki67, pH3, and Aurora B in epicardial cells. Flow cytometry results showed that agrin significantly increased the proportion of epicardial cells in S phase. However, blocking yes-associated protein significantly downregulated the levels of ki67, pH3, and Aurora B and the proportion of epicardial cells in S phase. Thus, our results suggest that agrin may promote the proliferation of epicardial cells by regulating the yes-associated protein activity. This may be useful in exploring heart development mechanisms and preventing congenital heart disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Agrina/farmacologia , Proliferação de Células/efeitos dos fármacos , Coração Fetal/efeitos dos fármacos , Pericárdio/efeitos dos fármacos , Animais , Aurora Quinase B/metabolismo , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Coração Fetal/metabolismo , Histonas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Pericárdio/metabolismo , Fosforilação , Proteínas de Sinalização YAPRESUMO
Due to its pronounced regenerative capacity, the zebrafish heart represents an advantageous model system for exploring the cellular and molecular mechanisms of cardiac regeneration. Upon injury, the epicardium, the outermost mesothelial tissue layer of vertebrate hearts, serves dual purposes in the regenerating heart as both a signaling center and a source for crucial cell types. Traditional in vivo genetic approaches to study heart regeneration can be time consuming and are not applicable to large-scale approaches and live surveillance of cellular behaviors. Here, we demonstrate ex vivo methods to culture, maintain, and study the regenerative responses of epicardial tissue in excised zebrafish hearts. Epicardial cell proliferation and migration are monitored in real time after uninjured or injured hearts are excised, washed, and cultured for up to 30 days. In addition to these techniques, we describe ex vivo genetic ablation of the epicardium, cell proliferation assays, partial ventricular explant culturing, and chemical screening.
Assuntos
Coração/crescimento & desenvolvimento , Ensaios de Triagem em Larga Escala/métodos , Metronidazol/farmacologia , Miócitos Cardíacos/citologia , Pericárdio/citologia , Regeneração , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Anti-Infecciosos/farmacologia , Movimento Celular , Proliferação de Células , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Pericárdio/efeitos dos fármacos , Peixe-ZebraRESUMO
A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a-5v) exerted neuroprotective effects on ß-amyloid (Aß)-induced PC12 cells as a potential approach for the treatment of Alzheimer's disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aß25-35-induced PC12 cells at 5 µg/mL. We found that compound 5c was non-neurotoxic at 30 µg/mL and significantly increased the viability of Aß25-35-induced PC12 cells at 1.25, 2.5 and 5 µg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3ß) and decreased the expression of nuclear factor-κB (NF-κB) in Aß25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aß25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3ß/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.