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Purpose: Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation in persistent AF (persAF), and cryoballoon PVI emerged as an initial ablation strategy. Symptomatic atrial arrhythmia recurrence following successful PVI in persAF is observed more frequently than in paroxysmal AF. Predictors for arrhythmia recurrence following cryoballoon PVI for persAF are not well described, and the role of left atrial appendage (LAA) anatomy is uncertain. Methods: Patients with symptomatic persAF and pre-procedural cardiac computed tomography angiography (CCTA) images undergoing initial second-generation cryoballoon (CBG2) were enrolled. Left atrial (LA), pulmonary vein (PV) and LAA anatomical data were assessed. Clinical outcome and predictors for atrial arrhythmia recurrence were evaluated by univariate and multivariate regression analysis. Results: From May 2012 to September 2016, 488 consecutive persAF patients underwent CBG2-PVI. CCTA with sufficient quality for measurements was available in 196 (60.4%) patients. Mean age was 65.7 ± 9.5 years. Freedom from arrhythmia was 58.2% after a median follow-up of 19 (13; 29) months. No major complications occurred. Independent predictors for arrhythmia recurrence were LAA volume (HR 1.082; 95% CI, 1.032 to 1.134; p = 0.001) and mitral regurgitation ≥ grade 2 (HR, 2.49; 95% CI 1.207 to 5.126; p = 0.013). LA volumes ≥110.35â ml [sensitivity: 0.81, specificity: 0.40, area under the curve (AUC) = 0.62] and LAA volumes ≥9.75â ml (sensitivity: 0.56, specificity 0.70, AUC = 0.64) were associated with recurrence. LAA-morphology, classified as chicken-wing (21.9%), windsock (52.6%), cactus (10.2%) and cauliflower (15.3%), did not predict outcome (log-rank, p = 0.832). Conclusion: LAA volume and mitral regurgitation were independent predictors for arrhythmia recurrence following cryoballoon ablation in persAF. LA volume was less predictive and correlated with LAA volume. LAA morphology did not predict the clinical outcome. To improve outcomes in persAF ablation, further studies should focus on treatment strategies for persAF patients with large LAA and mitral regurgitation.
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BACKGROUND: We aimed to compare patient characteristics and outcome of patients who had either undergone pulmonary vein isolation (PVI) or AV-node ablation (AVN) to control AF-related symptoms. METHODS: From the German Ablation Registry, we analyzed data of 4444 patients (95%) who had undergone PVI and 234 patients (5%) with AVN. RESULTS: AVN patients were on average 10 years older than PVI patients (71 ± 10 vs. 61 ± 10 years, p < 0.001) with 33% aged > 75 years. AVN patients had significantly more cardiovascular comorbidities (diabetes 21% vs. 8%, renal insufficiency 24% vs. 3%, underlying heart disease 80% vs. 36%, severely reduced left ventricular function 28% vs. 1%, all p < 0.001). Significantly more PVI patients had paroxysmal AF (63% vs. 18%, p < 0.001), and more AVN patients had long-standing persistent AF (44% vs. 7%, p < 0.001). At 1-year follow-up, mortality in the AVN group was much higher (Kaplan-Meier estimates 9.8% vs. 0.5%). 20% of PVI patients had undergone another ablation vs. 3% AVN patients (p < 0.001). Symptomatic improvement was equally achieved in about 80%. Re-hospitalization for cardiovascular reasons occurred significantly more often in PVI vs. AVN patients (31% vs. 18%, p < 0.001). CONCLUSION: In the large German Ablation Registry, AVN ablation was performed much less frequently than PVI for symptomatic treatment of AF and typically in older patients with more comorbidity. Symptomatic improvement was similar in both groups. Hospitalizations for cardiovascular reasons were lower in AVN patients despite older age and more cardiovascular comorbidities. 20% of PVI patients had undergone at least one re-ablation.
Assuntos
Fibrilação Atrial/cirurgia , Nó Atrioventricular/cirurgia , Ablação por Cateter/métodos , Frequência Cardíaca/fisiologia , Satisfação do Paciente , Veias Pulmonares/cirurgia , Sistema de Registros , Idoso , Fibrilação Atrial/mortalidade , Fibrilação Atrial/fisiopatologia , Nó Atrioventricular/fisiopatologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do TratamentoRESUMO
The p38 mitogen-activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding. The PK-PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.
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Both cardiac computed tomography (CT) and interventional electrophysiology (EP) have evolved considerably in recent years. Technical improvements in CT have significantly reduced the radiation dose in cardiac applications. This imaging technology plays an important role in preprocedural planning and guidance of the procedures in many EP centers worldwide. Furthermore, CT is the imaging modality of choice to diagnose relevant complications in ablation of atrial fibrillation, e.g. pulmonary vein stenosis or atrioesophageal fistula. In anatomically driven ablation procedures, such as balloon-based procedures in atrial fibrillation, detailed analysis of the relevant cardiac structures is absolutely crucial not only to reduce radiation exposure and procedure times but also to improve ablation success and to reduce the occurrence of complications. Current software applications enable 3-dimensional reconstruction of cardiac images and the integration into electroanatomical navigation systems. This article reviews the available evidence in this field and highlights recent developments in image guidance for ablation of atrial fibrillation.
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Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Mapeamento Potencial de Superfície Corporal/métodos , Procedimentos Cirúrgicos Cardiovasculares/métodos , Técnica de Subtração , Cirurgia Assistida por Computador/métodos , Humanos , Imageamento Tridimensional/métodos , Radiografia , SoftwareAssuntos
Fibrilação Atrial/terapia , Antiarrítmicos/efeitos adversos , Antiarrítmicos/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/etiologia , Ablação por Cateter/métodos , Ensaios Clínicos como Assunto , Seguimentos , Átrios do Coração/cirurgia , Humanos , Próteses e Implantes , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Resultado do Tratamento , Vitamina K/antagonistas & inibidoresRESUMO
Encouraging results of ablation therapy in patients with paroxysmal atrial fibrillation (AF) have prompted changes in professional practice guidelines. The most recent European guidelines have suggested that ablation might be offered as first-line therapy in selected patients. Cryoballoon ablation is a promising technology in interventional AF therapy. Two different sizes of the cryoballoon are currently available: a smaller (23 mm) and a larger (28 mm) balloon relative to the ostial diameter of the pulmonary veins. New tools, the circular mapping catheter and the use of intracardiac echocardiography, provide important periprocedural information. A meta-analysis of previous studies revealed outcome data with an AF-free survival rate of 72.83% at the 1-year follow-up in paroxysmal AF patients undergoing cryoballoon ablation. The most frequent, but reversible complication is phrenic nerve palsy with reported incidences up to 10%. All efforts must be taken to overcome this limitation, since the overall major complication rate tends to be lower in cryoballoon compared to radiofrequency ablation. In persistent AF, reported results in cryoballoon ablation had a limited success rate below 50% after a single procedure. A double balloon approach using both cryoballoon sizes might overcome some of the limitations in persistent AF. Prospective data and randomized studies are required. This article outlines the current status of cryoballoon technology in AF ablation therapy.
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Fibrilação Atrial/cirurgia , Cateterismo/tendências , Criocirurgia/métodos , Criocirurgia/tendências , Previsões , Humanos , Resultado do TratamentoRESUMO
This multicentre study aimed at evaluating the reliability (reproducibility) and relevance (predictivity) of a new commercially available human corneal epithelial (HCE) model (SkinEthic Laboratories, Nice, France) to assess acute ocular irritation. A prevalidation approach (protocol optimisation, transfer and performance) was followed and at each of the four participating laboratories, 20 coded reference chemicals, covering the whole range of irritancy, were tested. The compounds were applied topically to the HCE cultures and the level of cytotoxicity (tissue viability and histological analysis) was determined. Once a standardised protocol was established, a high level of reproducibility between the laboratories was observed. In order to assess the capability of the HCE model to discriminate between irritants (I) and non-irritants (NI), a classification prediction model (PM) was defined based on a viability cut-off value of 60%. The obtained in vitro classifications were compared with different in vivo classifications (e.g. Globally Harmonised System) which were calculated from individual rabbit data described in the ECETOC data bank. Although an overall concordance of 80% was obtained (sensitivity = 100% and specificity = 56%), the predictivity of the HCE model substantially increased when other sources of in vivo and in vitro data were taken into account.
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Córnea/efeitos dos fármacos , Irritantes/toxicidade , Testes de Toxicidade Aguda/métodos , Olho , Humanos , Técnicas In Vitro , Compostos Orgânicos/toxicidade , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
Cardiovascular disease is rare in premenopausal women compared to men. The authors investigate sex hormone-induced endothelin-1 (ET-1) release and the involvement of classic sex hormone receptors as well as the ability of sigma-1/cocaine receptors to respond to sex hormones. ET-1 release was measured in the supernatant of endothelial cells after treatment with beta-estradiol, progesterone, testosterone, or combined with their antagonists, and with the sigma-1 receptor ligand ditolylguanidine (DTG), or haloperidol, a sigma-1 receptor antagonist. Binding assays were performed using 2.5 x 10(-8) M [3H]DTG. Female sex hormones decreased ET-1 release whereas testosterone increased it, sex hormone antagonists only slightly attenuated or had no effect on the respective hormone's effect. DTG totally blocked the female sex hormone-induced inhibition on ET-1 release, whereas testosterone-induced stimulation was not affected. However, haloperidol blocked both. [3H]DTG binding was displaced by beta -estradiol but not by testosterone. DTG-binding sites account for 513 +/- 114 per cell, KD 8.79 nM. These data suggest that besides classic steroid hormone receptors, sigma-1/cocaine receptors mediate the effects of female sex hormones on ET-1 release, an up to now unknown signalling pathway. Results also suggest that female and male sex hormones may bind to different sites on sigma-1 receptors, exerting opposite pharmacological effects.
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Proteínas de Transporte/fisiologia , Células Endoteliais/efeitos dos fármacos , Endotelina-1/metabolismo , Estradiol/farmacologia , Receptores de Droga/fisiologia , Receptores de Esteroides/fisiologia , Receptores sigma/fisiologia , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Células Endoteliais/metabolismo , Feminino , Humanos , Progesterona/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Receptores sigma/efeitos dos fármacos , Suínos , Testosterona/farmacologiaRESUMO
Major histocompatibility complex (MHC) class I-restricted alphabeta T cells express the CD8alphabeta heterodimer, which acts as a MHC class I-specific co-receptor. Rats are so far the only species with frequent expression of the CD8alphabeta by MHC-unrestricted gammadelta T cells. This study compares CD8alphabeta expression by splenic rat alphabeta and gammadelta T cells and reveals a lineage-specific difference in the control of CD8beta expression. After activation in vitro, many gammadelta T cells, but not alphabeta T cells, persistently down-modulate the expression of CD8beta, but not CD8alpha, at the RNA level. Down-regulation occurred after stimulation with T-cell receptor (TCR)-specific monoclonal antibody (mAb) and interleukin-2 (IL-2) or CD28-mediated costimulation, and after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Functional differences between modulating and non-modulating cells were not found with respect to interferon-gamma (IFN-gamma) production and cytolytic activity. The modulation could be indicative for a fundamental difference between alphabeta and gammadelta T cells and also limits the use of CD8beta as a stable marker of gammadelta T-cell subsets. Possibly, CD8beta modulation provides a mechanism to escape over-stimulation by (auto-)antigens by increasing the threshold of TCR-mediated activation in gammadelta T cells.
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Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Receptores de Antígenos de Linfócitos T gama-delta/análise , Animais , Antígenos CD8/genética , Técnicas de Cultura de Células , Citotoxicidade Imunológica , Regulação para Baixo/imunologia , Feminino , Interferon gama/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/imunologiaRESUMO
The coincidence of hyperthyroidism and thyroid carcinoma seldom occurs. Only few reports on functionally metastases of thyroid carcinoma have been published. We report a 59-year-old man who underwent subtotal thyroidectomy for toxic nodular goiter. Histological examination revealed a follicular thyroid carcinoma. After thyroidectomy and cervical lymphadenectomy the patient developed a strong hyperthyreosis. Scintigraphy showed strong radioiodine uptake in the sacrum. De-bulking resection of the metastasis followed by high-dose radioiodine treatment was performed. After radioiodine therapy the patient became euthyroid. Treatment of hyperthyreosis in metastatic thyroid cancer requires a multimodal therapeutic concept.
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Adenocarcinoma Folicular/secundário , Hipertireoidismo/cirurgia , Sacro/cirurgia , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Glândula Tireoide/cirurgia , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/radioterapia , Adenocarcinoma Folicular/cirurgia , Terapia Combinada , Diagnóstico por Imagem , Humanos , Hipertireoidismo/patologia , Hipertireoidismo/radioterapia , Radioisótopos do Iodo/uso terapêutico , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Sacro/patologia , Sacro/efeitos da radiação , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/cirurgia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , TireoidectomiaRESUMO
BACKGROUND: Systemic sclerosis (SSc) is a generalized disorder of the interstitial tissues and vasculature with distinct abnormalities in three systems, immune and autoimmune, vascular and microvascular, and mesenchymal extracellular matrix (ECM), that lead to exuberant fibrosis. The aim of this study was to compare the number of blood vessel profiles in the marginal gingiva between SSc patients and patients with periodontitis but without SSc by using biopsies. METHODS: Marginal gingiva and gingival papilla were obtained from 13 scleroderma patients and 8 patients with periodontitis after routine tooth extraction and gingival curettage. On the histological sections, immunohistochemical investigations were performed using the avidin-biotin complex method (ABC) and the monoclonal antibody CD 31/Clone JC70A (platelet endothelial cell adhesion molecule-1). Blood vessels were identified by light microscopy (original magnification x400) and counted within 0.3615 mm2. Medians of blood vessel profiles were compared by Mann-Whitney U-test. RESULTS: There is no statistical difference between the median of blood vessel profiles in the marginal gingiva of SSc patients as compared to the median of blood vessel profiles in the marginal gingiva of patients with periodontitis (P = 0.665). We did not discover avascular areas in the subepithelial connective tissue. DISCUSSION: The pathological changes in the microvasculature in the dermis of SSc patients are not transferable to the marginal periodont, as intraindividual histological examinations of dermis and oral mucosa in relation to the degree of the disease are not available yet.
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Periodonto/irrigação sanguínea , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Escleroderma Sistêmico/patologia , Adulto , Idoso , Índice de Placa Dentária , Matriz Extracelular/patologia , Feminino , Gengiva/irrigação sanguínea , Humanos , Masculino , Microcirculação/patologia , Pessoa de Meia-Idade , Índice PeriodontalRESUMO
In accordance with their lack of MHC restriction, most mouse and human gamma delta T cells express neither the CD4 nor CD8(alpha beta) coreceptor. In striking contrast, up to 80% of splenic rat gamma delta T cells express the CD8alpha beta isoform of CD8, which for the alpha beta T cell subset serves as a marker for MHC class I-restricted cells. We compared CD8 on alpha beta and gamma delta T cells with regard to co-stimulatory function and correlation of CD8 expression with TCRDV usage and CDR3delta length. In both subsets, CD8 acted as a co-stimulatory molecule in vitro and was found to bind the kinase lck efficiently. No differences between the CDR3delta length spectra of CD8+ and CD8- gamma delta T cells or between unselected thymic and peripheral gamma delta T cells were found. As seen in man and mice, CDR3delta were rather long, a structural feature which can be expected to interfere with an alpha beta TCR-like mode of MHC class I binding. In summary, CD8 expressed by rat gamma delta T cells is a molecule with the potential to act as a coreceptor, but its expression gives no indication for antigen recognition analogous to that of MHC class I-restricted alpha beta T cells.