RESUMEN
Patients undergoing coronary angiography after myocardial infarction (MI) often develop cardiac and renal dysfunction. We hypothesized that the apolipoprotein A-I mimetic peptide 4F (4F) would prevent those complications. Male Wistar rats were fed a high-cholesterol diet for 8 days. The rats were then anesthetized with isoflurane and randomly divided into five groups: a control group (sham-operated rats), and four groups of rats induced to MI by left coronary artery ligation, the rats in three of those groups being injected 6 h later, with the nonionic contrast agent iopamidol, 4F, and iopamidol plus 4F, respectively. At postprocedure hour 24, we performed the following experiments/tests (n = 8 rats/group): metabolic cage studies; creatinine clearance studies; analysis of creatinine, urea, sodium, potassium, triglycerides, total cholesterol, very low-, low- and high-density lipoproteins (VLDL, LDL, and HDL); immunohistochemistry; histomorphometry; Western blot analysis; and transmission electron microscopy. In another set of experiments (n = 8 rats/group), also performed at postprocedure hour 24, we measured mean arterial pressure, heart rate, heart rate variability, echocardiographic parameters, left ventricular systolic pressure, and left ventricular end-diastolic pressure. 4F protected against MI-induced increases in total cholesterol, triglycerides, and LDL; increased HDL levels; reversed autonomic and cardiac dysfunction; decreased the myocardial ischemic area; minimized renal and cardiac apoptosis; protected mitochondria; and strengthened endothelia possibly by minimizing Toll-like receptor 4 upregulation (thus restoring endothelial nitric oxide synthase protein expression) and by upregulating vascular endothelial growth factor protein expression. 4F-treated animals showed signs of cardiac neovascularization. The nitric oxide-dependent cardioprotection and renoprotection provided by 4F could have implications for post-MI treatment.
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Riñón/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Triglicéridos/metabolismo , Animales , Vasos Coronarios/metabolismo , Corazón/fisiopatología , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/metabolismoAsunto(s)
Cardiomiopatía Chagásica , Enfermedad de Chagas , Trasplante de Corazón , Miocarditis , Trypanosoma cruzi , Humanos , Miocarditis/diagnóstico , Enfermedad de Chagas/diagnóstico , Enfermedad de Chagas/parasitología , Trasplante de Corazón/efectos adversos , Biopsia , Carga de Parásitos , Cardiomiopatía Chagásica/patologíaRESUMEN
We report a 60-year-old female who underwent resection of an endometrial stromal sarcoma of the right ventricle 17 years following a hysterectomy and radiation therapy for the same tumor.
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Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Neoplasias Cardíacas/secundario , Neoplasias Cardíacas/cirugía , Ventrículos Cardíacos , Histerectomía , Sarcoma Estromático Endometrial/secundario , Sarcoma Estromático Endometrial/cirugía , Antineoplásicos/administración & dosificación , Procedimientos Quirúrgicos Cardíacos , Quimioterapia Adyuvante , Femenino , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/patología , Humanos , Letrozol , Persona de Mediana Edad , Nitrilos/administración & dosificación , Sarcoma Estromático Endometrial/diagnóstico por imagen , Sarcoma Estromático Endometrial/patología , Factores de Tiempo , Resultado del Tratamiento , Triazoles/administración & dosificaciónRESUMEN
The purpose of our work was to select phages displaying peptides capable of binding to vascular markers present in human atheroma, and validate their capacity to target the vascular markers in vitro and in low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. By peptide fingerprinting on human atherosclerotic tissues, we selected and isolated four different peptides sequences, which bind to atherosclerotic lesions and share significant similarity to known human proteins with prominent roles in atherosclerosis. The CTHRSSVVC-phage peptide displayed the strongest reactivity with human carotid atherosclerotic lesions (p < 0.05), when compared to tissues from normal carotid arteries. This peptide sequence shares similarity to a sequence present in the fifth scavenger receptor cysteine-rich (SRCR) domain of CD163, which appeared to bind to CD163, and subsequently, was internalized by macrophages. Moreover, the CTHRSSVVC-phage targets atherosclerotic lesions of a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis in vivo to High-Fat diet group versus Control group. Tetraazacyclododecane-1,4,7,10-tetraacetic acid-CTHRSSVVC peptide (DOTA-CTHRSSVVC) was synthesized and labeled with (111)InCl3 in >95% yield as determined by high performance liquid chromatography (HPLC), to validate the binding of the peptide in atherosclerotic plaque specimens. The results supported our hypothesis that CTHRSSVVC peptide has a remarkable sequence for the development of theranostics approaches in the treatment of atherosclerosis and other diseases.
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Aterosclerosis/diagnóstico , Imagen Molecular/métodos , Péptidos/metabolismo , Animales , Antígenos CD/química , Antígenos de Diferenciación Mielomonocítica/química , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Péptidos/química , Receptores de Superficie Celular/química , Receptores de LDL/deficiencia , Receptores de LDL/genéticaRESUMEN
BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of death in the first year after heart transplant (HT), but pathophysiology and histology are not completely understood. This study describes and compares morphological findings of hearts of patients with and without PGD. METHODS: We included adult patients submitted to HT in a single center who died within the first 14 days after HT and were submitted to necropsy. Clinical and histological data were recorded retrospectively. All heart slides were reviewed by a blinded pathologist. We categorized patients in two groups (PGD and non-PGD) and compared findings between them. RESULTS: Among 322 HTs, 26 patients were included. Median age was 51.5 years, 57.7% were male, 46.1% had non-ischemic cardiomyopathy, 30.8% Chagas cardiomyopathy and 23% ischemic cardiomyopathy. Eleven patients presented PGD, while 15 patients did not. PGD was severe in 72.7% of cases and moderate in 27.3%. PGD group had longer ischemic time (p=0.08), higher incidence of mechanical circulatory support (p=0.004), lower post-transplant biventricular ejection fraction (p=0.005). However, necropsy findings were similar between groups. Necrosis was detected in 80.7% of all cases (p=0.907 comparing groups), taking ≥ 10% of myocardial area in 46.1% of them, and 4 types of necrosis were found either in patients with and without PGD. CONCLUSION: Cardiac pathological findings were similar in HT patients with or without PGD who died within 14 days after the transplant and necrosis was frequent in both groups, raising the hypothesis necrosis is not the cause of cardiac dysfunction in PGD.
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Autopsia , Trasplante de Corazón , Miocardio , Disfunción Primaria del Injerto , Humanos , Trasplante de Corazón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/diagnóstico , Estudios Retrospectivos , Adulto , Miocardio/patología , AncianoRESUMEN
AIMS: Left ventricular remodelling occurs during the chronic course of aortic regurgitation (AR) and aortic stenosis (AS), leading to myocardial hypertrophy and fibrosis. Several studies have shown that extracellular volume fraction (ECV) and indexed extracellular volume (iECV) are important surrogate markers of diffuse myocardial fibrosis (MF). Postoperative data on these cardiovascular magnetic resonance (CMR) extracellular expansion parameters for either AS or AR are scarce. This study aimed to demonstrate the postoperative changes that occur in diffuse MF, and the influence of preoperative MF on the reversal of LV remodelling, in patients with AR or AS. METHODS AND RESULTS: Patients with severe AR or AS and indications for surgery were prospectively enrolled. Patients underwent pre- and postoperative CMR, and ECV and iECV were quantified. Data from 99 patients were analysed (32 with AR and 67 with AS). After surgery, the left ventricle mass index decreased in both groups (AR: 110 vs. 91 g/m2; AS: 86 vs. 68 g/m2, both P < 0.001). The late gadolinium enhancement fraction (AR: preoperative 1.9% vs. postoperative 1.7%, P = 0.575; AS: preoperative 2.4% vs. postoperative 2.4%, P = 0.615) and late gadolinium enhancement mass (AR: preoperative 3.8 g vs. postoperative 2.5 g, P = 0.635; AS: preoperative 3.4 g vs. postoperative 3.5 g, P = 0.575) remained stable in both groups. Preoperative iECV and ECV were greater in the AR group (iECV: 30 mL/m2 vs. 22 mL/m2, P = 0.001; ECV: 28.4% vs. 27.2%, P = 0.048). Indexed extracellular volume decreased after surgery in both groups (AR: 30-26.5 mL/m2, AS: 22-18.2 mL/m2, both P < 0.001); it was still greater in the AR group (AR: 26.5 mL/m2 vs. AS: 18.2 mL/m2, P < 0.001). Postoperative ECV remained stable in the AR group (preoperative 28.4% vs. postoperative 29.9%; P = 0.617) and increased in the AS group (preoperative 27.2% vs. postoperative 28.6%; P = 0.033). CONCLUSION: Patients with both AR or AS presented reduction in iECV after surgery, unfolding the reversible nature of diffuse MF. In contrast to patients with AS, those with AR developed postoperative iECV regression with stable ECV, suggesting a balanced reduction in both intracellular and extracellular myocardial components.
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Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Cardiomiopatías , Humanos , Medios de Contraste , Gadolinio , Estudios Prospectivos , Miocardio/patología , Cardiomiopatías/patología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/patología , Fibrosis , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/patología , Espectroscopía de Resonancia Magnética , Imagen por Resonancia Cinemagnética , Remodelación VentricularRESUMEN
RATIONALE: There are no reports of the systemic human pathology of the novel swine H1N1 influenza (S-OIV) infection. OBJECTIVES: The autopsy findings of 21 Brazilian patients with confirmed S-OIV infection are presented. These patients died in the winter of the southern hemisphere 2009 pandemic, with acute respiratory failure. METHODS: Lung tissue was submitted to virologic and bacteriologic analysis with real-time reverse transcriptase polymerase chain reaction and electron microscopy. Expression of toll-like receptor (TLR)-3, IFN-gamma, tumor necrosis factor-alpha, CD8(+) T cells and granzyme B(+) cells in the lungs was investigated by immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Patients were aged from 1 to 68 years (72% between 30 and 59 yr) and 12 were male. Sixteen patients had preexisting medical conditions. Diffuse alveolar damage was present in 20 individuals. In six patients, diffuse alveolar damage was associated with necrotizing bronchiolitis and in five with extensive hemorrhage. There was also a cytopathic effect in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways. There was marked expression of TLR-3 and IFN-gamma and a large number of CD8(+) T cells and granzyme B(+) cells within the lung tissue. Changes in other organs were mainly secondary to multiple organ failure. CONCLUSIONS: Autopsies have shown that the main pathological changes associated with S-OIV infection are localized to the lungs, where three distinct histological patterns can be identified. We also show evidence of ongoing pulmonary aberrant immune response. Our results reinforce the usefulness of autopsy in increasing the understanding of the novel human influenza A (H1N1) infection.
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Bronquiolitis Viral/patología , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/patología , Alveolos Pulmonares/patología , Adolescente , Anciano , Autopsia , Niño , Preescolar , Femenino , Humanos , Lactante , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Macrófagos Alveolares/inmunología , Masculino , Persona de Mediana Edad , Alveolos Pulmonares/inmunología , Adulto JovenRESUMEN
The Shwachman-Diamond syndrome is an autosomal recessive bone marrow failure syndrome with exocrine pancreatic insufficiency. Additional organ systems, such as the liver, heart and bone, may also be affected. We report a patient with a long history of cardiac failure and diagnosis of dilated cardiomyopathy with intermittent neutropenia. Periodic follow-up revealed progressive cardiac failure and pulmonary hypertension. A diagnosis of Shwachman-Diamond syndrome was made at the autopsy.
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Enfermedades de la Médula Ósea/complicaciones , Cardiomiopatía Dilatada/etiología , Insuficiencia Pancreática Exocrina/complicaciones , Lipomatosis/complicaciones , Adolescente , Resultado Fatal , Femenino , Humanos , Síndrome de Shwachman-DiamondRESUMEN
AIMS: Thoracic ascending aortic aneurysms (TAA) are characterized by elastic fibre breakdown and cystic medial degeneration within the aortic media, associated with progressive smooth muscle cell (SMC) rarefaction. The transforming growth factor (TGF)-ß/Smad2 signalling pathway is involved in this process. Because the pericellular fibrinolytic system activation is able to degrade adhesive proteins, activate matrix metalloproteinase (MMP), induce SMC disappearance and increase the bioavailability of TGF-ß, the aim was to investigate the plasminergic system in TAA. METHODS AND RESULTS: Ascending aortas [21 controls and 19 TAAs (of three different aetiologies)] were analysed. Immunohistochemistry showed accumulation of t-PA, u-PA and plasmin in TAAs, associated with residual SMCs. Overexpression of t-PA and u-PA was confirmed by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting and zymography on TAA extracts and culture medium conditioned by TAA. Plasminogen was present on the SMC surface and inside cytoplasmic vesicles, but plasminogen mRNA was undetectable in the TAA medial layer. Plasmin-antiplasmin complexes were detected in TAA-conditioned medium and activation of the fibrinolytic system was associated with increased fibronectin turnover. Fibronectin-related material was detected immunohistochemically in dense clumps around SMCs and colocalized with latent TGF-ß binding protein-1. CONCLUSIONS: The fibrinolytic pathway could play a critical role in TAA progression, via direct or indirect impact on ECM and consecutive modulation of TGF-ß bioavailability.
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Aorta/metabolismo , Aneurisma de la Aorta Torácica/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Adulto , Anciano , Aneurisma de la Aorta Torácica/genética , Western Blotting , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Proteína Smad2/genética , Proteína Smad2/metabolismo , Activador de Tejido Plasminógeno/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
BACKGROUND: Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and currently has no effective prevention and treatment. Lipid nanoparticles, termed LDE can carry chemotherapeutic agents in the circulation and concentrates them in the heart. METHODS: Twenty-eight rabbits fed a cholesterol-rich diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg/kg daily) and allocated to four groups of 7 animals treated with intravenous LDE-methotrexate (MTX; 4 mg/kg weekly), with LDE-paclitaxel (PACLI; 4 mg/kg weekly), or with LDE-PACLI (4 mg/kg weekly) and LDE-MTX (4 mg/kg weekly). A control group was treated with only weekly intravenous saline solution. Animals were euthanized 6 weeks later for morphometric, histologic, immunohistochemical, and gene expression analysis of the graft and native hearts. RESULTS: Compared with controls, grafts of rabbits treated with LDE-PACLI showed 50% reduction of coronary stenosis, and in the LDE-MTX and LDE-MTX/PACLI stenosis was approximately 18% less than in control, but this difference was not statistically significant. In the three treatment groups, macrophage infiltration was decreased. In the LDE-MTX group, gene expression of proinflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein 1, interleukin 18, vascular cellular adhesion molecule 1, and matrix metalloproteinase 12 was strongly diminished, whereas expression of antiinflammatory interleukin 10 increased. In the LDE-PACLI and LDE-PACLI/MTX groups, proinflammatory and antiinflammatory gene expressions were not consistently changed by the treatments. CONCLUSIONS: LDE-PACLI promoted strong improvement of cardiac allograft vasculopathy, but the decrease in coronary stenosis by LDE-MTX and LDE-MTX/PACLI was not significant. All three treatments decreased macrophage infiltration in the graft. These results may encourage future clinical trials to test this new therapeutic approach to coronary allograft vasculopathy.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Portadores de Fármacos , Rechazo de Injerto/prevención & control , Trasplante de Corazón/efectos adversos , Metotrexato/farmacocinética , Nanopartículas/administración & dosificación , Paclitaxel/farmacocinética , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Enfermedad de la Arteria Coronaria/etiología , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Rechazo de Injerto/genética , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/efectos de los fármacos , Inmunohistoquímica , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Inyecciones Intravenosas , Metotrexato/administración & dosificación , Miocardio/metabolismo , Paclitaxel/administración & dosificación , ARN/genética , Conejos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Whole-vessel remodeling critically determines lumen caliber in vascular (patho)physiology, and it is reportedly redox-dependent. We hypothesized that the cell-surface pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (peri/epicellular=pecPDI), which is known to support thrombosis, also regulates disease-associated vascular architecture. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling and plaque stability. In a rabbit iliac artery overdistension model, there was unusually high PDI upregulation (≈25-fold versus basal, 14 days postinjury), involving both intracellular and pecPDI. PecPDI neutralization with distinct anti-PDI antibodies did not enhance endoplasmic reticulum stress or apoptosis. In vivo pecPDI neutralization with PDI antibody-containing perivascular gel from days 12 to 14 post injury promoted 25% decrease in the maximally dilated arteriographic vascular caliber. There was corresponding whole-vessel circumference loss using optical coherence tomography without change in neointima, which indicates constrictive remodeling. This was accompanied by decreased hydrogen peroxide generation. Constrictive remodeling was corroborated by marked changes in collagen organization, that is, switching from circumferential to radial fiber orientation and to a more rigid fiber type. The cytoskeleton architecture was also disrupted; there was a loss of stress fiber coherent organization and a switch from thin to medium thickness actin fibers, all leading to impaired viscoelastic ductility. Total and PDI-associated expressions of ß1-integrin, and levels of reduced cell-surface ß1-integrin, were diminished after PDI antibody treatment, implicating ß1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream ß1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to counteract inward remodeling in vascular pathophysiology.
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Estenosis Coronaria/genética , Vasos Coronarios/patología , Proteína Disulfuro Isomerasas/genética , ARN/genética , Remodelación Vascular , Animales , Membrana Celular/metabolismo , Células Cultivadas , Estenosis Coronaria/metabolismo , Estenosis Coronaria/patología , Vasos Coronarios/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Humanos , Masculino , Fosforilación , Proteína Disulfuro Isomerasas/biosíntesis , ConejosRESUMEN
We described a case of left ventricular pseudoaneurysm associated to a severe mitral regurgitation, complicating a inferolaterodorsal acute myocardial infarction. The lesion was found in a routine echocardiogram during the in-hospital follow-up. The well-succeeded surgical strategy and the good clinical evolution of the patient were distinguished.
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Aneurisma Falso/etiología , Aneurisma Cardíaco/etiología , Insuficiencia de la Válvula Mitral/etiología , Infarto del Miocardio/complicaciones , Anciano , Aneurisma Falso/diagnóstico , Aneurisma Falso/cirugía , Femenino , Aneurisma Cardíaco/diagnóstico , Aneurisma Cardíaco/cirugía , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/cirugía , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/cirugía , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/cirugíaRESUMEN
UNLABELLED: There is scanty information concerning multiple aortic aneurysms. Thus, we verified if clinical or pathological characteristics are different in patients with multiple (two or more) aortic aneurysms in comparison with those with only one. MATERIAL AND METHODS: We selected at the necropsy files of the Heart Institute, São Paulo University School of Medicine, the last 100 cases with aortic aneurysms, comparing between the two groups: sex, age, presence of systemic arterial hypertension, diabetes, dyslipedemia, history of smoking habit, cause of the aneurysm, cause of death, and if the diagnosis was reached during life. Age was analysed by Mann-Whitney test, and the other variables by chi-square or Fisher's exact test. RESULTS: Multiple aneurysms corresponded to 14% of cases. The proportion of women among patients with multiple aneurysms was higher than among those with single aneurysm (64.3% versus 20.9%, P<.01), even if only cases with atherosclerosis were taken into consideration (women among multiple-6/10, 60.0%; among single-14/70, 20.0%; P=.01). Smoking was less reported in cases with multiple (4/14, 28.6%) than with single aneurysm (53/86, 61.6%; P=.04); considering cases with atherosclerosis, such difference decreases (40.0% of multiple versus 68.6% of single, P=.09). CONCLUSION: although atherosclerosis is present in most cases of both single and multiple aortic aneurysms, male gender and smoking, considered highly influential in such lesions, are less frequent in patients with multiple than in patients with single aneurysms. Thus mechanisms underlying multiple aortic aneurysms are probably different from those related to single, more common aneurysms.
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Aneurisma de la Aorta/etiología , Aneurisma de la Aorta/patología , Fumar/efectos adversos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Leukocyte migration is essential for the function of the immune system. Their recruitment from the vessels to the tissues involves sequential molecular interactions between leukocytes and endothelial cells (ECs). Many adhesion molecules involved in this process have already been described. However, additional molecules may be important in this interaction, and here we explore the potential role for CD100 and plexins in monocyte-EC binding. CD100 was shown to be involved in platelet-endothelial cell interaction, an important step in atherogenesis and thrombus formation. In a recent work we have described CD100 expression in monocytes and in macrophages and foam cells of human atherosclerotic plaques. In the present work, we have identified plexin B2 as a putative CD100 receptor in these cells. We have detected CD100 expression in the endothelium as well as in in vitro cultured endothelial cells. Blocking of CD100, plexin B1 and/or B2 in adhesion experiments have shown that both CD100 and plexins act as adhesion molecules involved in monocyte-endothelial cell binding. This effect may be mediated by CD100 expressed in both cell types, probably coupled to the receptors endothelial plexin B1 and monocytic plexin B2. These results can bring new insights about a possible biological activity of CD100 in monocyte adhesion and atherosclerosis, as well as a future candidate for targeting therapeutics.
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Antígenos CD/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Moléculas de Adhesión Celular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Monocitos/citología , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Animales , Antígenos CD/genética , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Adhesión Celular , Diferenciación Celular , Células Cultivadas , Células Espumosas/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Semaforinas/genéticaRESUMEN
BACKGROUND: Permanent polymers in first generation drug-eluting stent (DES) have been imputed to be a possible cause of persistent inflammation, remodeling, malapposition and late stent thrombosis. We aim to describe the in vivo experimental result of a new polymer-free DES eluting sirolimus from stent-plus-balloon (Focus np stent, Envision Scientific) compared with a bare-metal stent (BMS) (Amazonia CroCo, Minvasys) and with a biolimus A9 eluting stent (Biomatrix, Biosensors). METHODS: In 10 juvenile pigs, 23 coronary stents were implanted in the coronary arteries (8 Amazonia CroCo, 8 Focus np, and 7 Biomatrix). At 28-day follow-up, optical coherence tomography (OCT) and histology were used to evaluate neointimal hyperplasia and healing response. RESULTS: According to OCT analysis, Focus np stents had a greater lumen area and less neointimal hyperplasia response than BMS and Biomatrix had. Histomorphometry results showed less neointimal hyperplasia in Focus np than in BMS. Histology showed a higher fibrin deposition in Biomatrix stent compared to Focus np and BMS. CONCLUSIONS: The new polymer-free DES with sirolimus eluted from stent-plus-balloon demonstrated safety and reduced neointimal proliferation compared with the BMS and Biomatrix stents at 28-day follow-up in this porcine coronary model. This new polymer-free DES is promising and warrants further clinical studies.
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Vascular smooth muscle cells (VSMC) are ideal for systemic gene therapy because of their proximity to blood vessels and they have demonstrated long-term exogenous gene expression in vivo. However, the procedure generally followed to seed the transduced VSMC onto arteries denuded of endothelial cells usually induces stenosis and thrombosis, with a consequent high risk for use in humans. We demonstrate here that the vascular adventitia is a suitable place to introduce transduced VSMC and to secrete therapeutic proteins into the blood stream by a simple procedure, avoiding postoperative vascular complications. Transduced VSMC, with the retroviral vectors carrying the human growth hormone gene (hGH), were seeded into the adventitia of the rat abdominal aorta by single injection of a cell suspension. Based on the hGH and anti-hGH production in serum and on histological analysis of the removed aortas, we demonstrated hGH production over the 2-month experimental period. None of the animals used in the experiment showed stenosis, thrombosis, or other vascular or visible physiological abnormalities.
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Trasplante de Células/métodos , Endotelio Vascular/citología , Expresión Génica , Músculo Liso Vascular/trasplante , Células 3T3 , Animales , Aorta Abdominal , Células Cultivadas , ADN Complementario/genética , Endotelio Vascular/fisiología , Terapia Genética/métodos , Vectores Genéticos , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/genética , Humanos , Cinética , Ratones , Músculo Liso Vascular/citología , Regiones Promotoras Genéticas , Ratas , Ratas Wistar , Retroviridae , Secuencias Repetidas Terminales , Transfección/métodos , Zinc/farmacologíaRESUMEN
OBJECTIVE: To verify the possible role of adventitial inflammation in atherosclerotic plaque vulnerability and coronary artery remodelling. METHODS: We compared the mean numbers of lymphocytes in the adventitia and in the plaque of ruptured thrombosed and stable equi-stenotic coronary segments of 34 patients who died due to acute myocardial infarction. We also analysed adventitial microvessels, adventitial fibrosis and the external elastic membrane. RESULTS: In the adventitia, the numbers of lymphocytes and microvessels/mm2 were 69.5+/-88.3 and 60.9+/- 32.1 in culprit lesions and 16.4 +/- 21.1 and 44.3+/-16.1 in stable lesions (p<0.05); within the plaques, the mean number of lymphocytes was 24+/-40.8 in culprit lesions and 10.9+/-13.2 in stable ones (p=0.17). The mean percent area of adventitial fibrosis/cross-sectional area of the vessel was significantly lower in unstable plaques (p<0.001). The confocal images showed holes in the external elastic membrane. CONCLUSION: Unstable plaques exhibit chronic pan-arteritis, accompanied by enlargement, medial thinning, and less fibrosis than in stable lesions, which is compatible with vessel aneurysm. Adventitial inflammation may contribute significantly to atheroma instability.
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Arteritis/patología , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/patología , Endotelio Vascular/patología , Cadáver , Humanos , Recuento de Linfocitos , RoturaRESUMEN
Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions. This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks.
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Angioplastia de Balón/instrumentación , Fármacos Cardiovasculares/administración & dosificación , Catéteres , Materiales Biocompatibles Revestidos , Portadores de Fármacos , Stents Liberadores de Fármacos , Nanopartículas , Fosfolípidos/química , Sirolimus/administración & dosificación , Animales , Fármacos Cardiovasculares/sangre , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Arteria Ilíaca/lesiones , Arteria Ilíaca/metabolismo , Cinética , Masculino , Conejos , Sirolimus/sangre , Sirolimus/química , Sirolimus/farmacocinética , Porcinos , Distribución Tisular , Lesiones del Sistema Vascular/sangre , Lesiones del Sistema Vascular/patología , Lesiones del Sistema Vascular/terapiaRESUMEN
PURPOSE: Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) define neointima as the tissue encompassed between the stent and the lumen boundaries. This approach differs from the gold-standard histopathology, where neointima is traditionally calculated as the tissue between the internal elastic lamina (IEL) and the lumen. We aimed to investigate whether the neointimal assessment using IVUS and OCT-like definitions would correlate with the traditional histopathological quantification of neointima. METHODS: Histopathological analysis was obtained from a porcine model of 28-day coronary in-stent neointimal proliferation (n=13 bare stents). Traditional histopathology neointimal area (NIHPATH area) was calculated as the lumen area minus the IEL area, while the percent neointimal obstruction was defined as NIHPATH area divided by the IEL area. The IVUS/OCT-like neointima area (NIHIVUS/OCT area) was defined as the lumen area minus the stent area, while the percent neointimal obstruction was defined as NIHIVUS/OCT area divided by the stent area. RESULTS: The neointimal area as well as the percent obstruction were significantly correlated between histopathology and IVUS/OCT-like definitions (R(2)=0.89 and 0.95 respectively; P<0.01 for both). The average absolute difference between the IVUS/OCT-like and the pathology-like measurements was close to zero, however with a relatively wide dispersion (difference for neointimal area: 0.41 mm(2) [95% CI 1.72 to (-)0.90 mm(2)]; difference for percent neointimal obstruction: 2.5% [95% CI 11.5% to (-)6.5%]). CONCLUSIONS: The present findings support the use of stent area in replacement to IEL area, as in IVUS & OCT imaging protocols, for the calculation of neointimal parameters in experimental model of restenosis.
RESUMEN
BACKGROUND: Mesothelial injury is the pivot in the development of adhesions. An increase in the proliferation of mesothelial cells was verified by in vitro studies with the use of keratinocyte growth factor (KGF). This study investigated the influence of KGF associated with thermo-sterilized carboxymethyl chitosan (NOCCts) in the reduction of pericardial adhesions. METHODS: An induction model of pericardial adhesion was carried out in 24 pigs. Animals were randomly allocated to receive topical application of KGF, KGF + NOCCts, NOCCts, or saline (control). At 8 weeks, intrapericardial adhesions were evaluated and a severity score was established. The time spent to dissect the adhesions and the amount of sharp dissection used, were recorded. Histologic sections were stained with sirius red for a morphometric evaluation using a computer-assisted image analysis system. Cytokeratin AE1/AE3 immunostaining were employed to identify mesothelial cells. RESULTS: The severity score expressed in median (minimum to maximum), in relation to the control group (17 [15 to 18]), was lower in the KGF + NOCCts group (7 [6 to 9], p < 0.01) followed by the KGF group (11.5 [9 to 12], 0.01 < p < 0.05) and the NOCCts group (12 [9 to 14], p > 0.05). The dissection time was significantly lower in the KGF + NOCCts group (7.1 + or - 0.6 vs 33.9 + or - 9.2 minutes, p < 0.001). A significantly less sharp dissection was also required in the KGF + NOCCts group. In the adhesion segment, a decreased collagen proportion was found in the KGF + NOCCts group (p < 0.05). Mesothelial cells were present more extensively in groups in which KGF was delivered (p = 0.01). CONCLUSIONS: The use of KGF associated with NOCCts resulted in a synergic action that decreases postoperative pericardial adhesions in a highly significant way.