RESUMO
Importance: Catheter ablation of persistent atrial fibrillation (AF) has limited success. Procedural strategies beyond pulmonary vein isolation have failed to consistently improve results. The vein of Marshall contains innervation and AF triggers that can be ablated by retrograde ethanol infusion. Objective: To determine whether vein of Marshall ethanol infusion could improve ablation results in persistent AF when added to catheter ablation. Design, Setting, and Participants: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial was an investigator-initiated, National Institutes of Health-funded, randomized, single-blinded trial conducted in 12 centers in the United States. Patients (N = 350) with persistent AF referred for first ablation were enrolled from October 2013 through June 2018. Follow-up concluded in June 2019. Interventions: Patients were randomly assigned to catheter ablation alone (n = 158) or catheter ablation combined with vein of Marshall ethanol infusion (n = 185) in a 1:1.15 ratio to accommodate for 15% technical vein of Marshall ethanol infusion failures. Main Outcomes and Measures: The primary outcome was freedom from AF or atrial tachycardia for longer than 30 seconds after a single procedure, without antiarrhythmic drugs, at both 6 and 12 months. Outcome assessment was blinded to randomization treatment. There were 12 secondary outcomes, including AF burden, freedom from AF after multiple procedures, perimitral block, and others. Results: Of the 343 randomized patients (mean [SD] age, 66.5 [9.7] years; 261 men), 316 (92.1%) completed the trial. Vein of Marshall ethanol was successfully delivered in 155 of 185 patients. At 6 and 12 months, the proportion of patients with freedom from AF/atrial tachycardia after a single procedure was 49.2% (91/185) in the catheter ablation combined with vein of Marshall ethanol infusion group compared with 38% (60/158) in the catheter ablation alone group (difference, 11.2% [95% CI, 0.8%-21.7%]; P = .04). Of the 12 secondary outcomes, 9 were not significantly different, but AF burden (zero burden in 78.3% vs 67.9%; difference, 10.4% [95% CI, 2.9%-17.9%]; P = .01), freedom from AF after multiple procedures (65.2% vs 53.8%; difference, 11.4% [95% CI, 0.6%-22.2%]; P = .04), and success achieving perimitral block (80.6% vs 51.3%; difference, 29.3% [95% CI, 19.3%-39.3%]; P < .001) were significantly improved in vein of Marshall-treated patients. Adverse events were similar between groups. Conclusions and Relevance: Among patients with persistent AF, addition of vein of Marshall ethanol infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF or atrial tachycardia at 6 and 12 months. Further research is needed to assess longer-term efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01898221.
Assuntos
Fibrilação Atrial/terapia , Ablação por Cateter/métodos , Etanol/administração & dosagem , Veia Cava Superior , Idoso , Terapia Combinada/métodos , Feminino , Humanos , Infusões Intravenosas/efeitos adversos , Infusões Intravenosas/métodos , Estimativa de Kaplan-Meier , Masculino , Método Simples-Cego , Taquicardia/terapia , Resultado do Tratamento , Veia Cava Superior/embriologia , Veia Cava Superior/inervaçãoRESUMO
BACKGROUND: Although pulmonary vein isolation (PVI) is effective in the treatment of paroxysmal atrial fibrillation (AF), its success rates in persistent AF are suboptimal. Ablation strategies to improve outcomes including additional lesions beyond PVI have not consistently shown benefit. Recurrence as perimitral flutter (PMF) is a common form of ablation failure. The vein of Marshall (VOM) contains myocardial connections and abundant sympathetic and parasympathetic innervation implicated in the genesis and maintenance of AF, and is anatomically co-localized with the mitral isthmus, the ablation target of PMF. VOM ethanol infusion is effective in targeting these arrhythmia substrates. OBJECTIVE: To test the safety and efficacy of VOM ethanol infusion when added to PVI in patients undergoing either de novo ablation of persistent AF or after a previous ablation failure. STUDY DESIGN: VENUS-AF and MARS-AF are prospective, multicenter, randomized, controlled trials. VENUS-AF will enroll patients undergoing their first catheter ablation of persistent AF. MARS-AF will enroll patients undergoing ablation after previous ablation failure(s). Patients (nâ¯=â¯405) will be randomized to PVI alone or in combination with VOM ethanol infusion. The primary endpoints include procedural safety and freedom from AF or atrial tachycardia (AT) of more than 30 seconds on 30-day continuous event monitors at 6 and 12 months after randomization procedure (single-procedure success), off antiarrhythmic drugs. Key secondary endpoints include AF burden, freedom from AF/AT after repeat procedures and quality of life. CONCLUSIONS: The VENUS-AF and MARS-AF will determine the safety and potential rhythm control benefit of VOM ethanol infusion when added to PVI in patients with persistent AF undergoing de novo or repeat ablation, respectively.
Assuntos
Técnicas de Ablação/métodos , Fibrilação Atrial/terapia , Etanol/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Fibrilação Atrial/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Seguimentos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Veias Pulmonares , Solventes/administração & dosagem , Resultado do TratamentoRESUMO
Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.
Assuntos
Adenosina/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Idoso , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Fibrose Pulmonar/metabolismo , Remodelação VascularRESUMO
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-ß activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Hipertensão Pulmonar/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Células Cultivadas , Regulação para Baixo , Expressão Gênica , Humanos , Hipertensão Pulmonar/etiologia , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/fisiopatologia , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Isoformas de Proteínas , Interferência de RNARESUMO
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
Assuntos
Fibrose Pulmonar Idiopática/imunologia , Interleucina-6/imunologia , Macrófagos Alveolares/imunologia , Fibrose Pulmonar/imunologia , Receptores de Interleucina-6/imunologia , Transdução de Sinais/imunologia , Animais , Colágeno/imunologia , Modelos Animais de Doenças , Feminino , Fibronectinas/imunologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/terapia , Interleucina-6/genética , Pulmão/imunologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Miofibroblastos/imunologia , Miofibroblastos/patologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologiaRESUMO
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood. OBJECTIVES: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis. METHODS: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice. MEASUREMENTS AND MAIN RESULTS: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1α and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1α in the alveolar epithelium. CONCLUSIONS: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation.
Assuntos
Desoxicitidina Quinase/fisiologia , Hipóxia/complicações , Fibrose Pulmonar Idiopática/etiologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Humanos , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/enzimologia , Alvéolos Pulmonares/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/enzimologiaRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.
Assuntos
Apoptose/efeitos dos fármacos , Nucleotídeos de Desoxiadenina/metabolismo , Desoxiadenosinas/metabolismo , Desoxicitidina Quinase/metabolismo , Hipóxia/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , 2-Cloroadenosina/análogos & derivados , 2-Cloroadenosina/farmacologia , Adenosina Desaminase/deficiência , Animais , Células Cultivadas , Desoxiadenosinas/farmacologia , Humanos , Camundongos , Regulação para CimaRESUMO
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.
Assuntos
Ácido Hialurônico/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor A2B de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Idoso , Animais , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , Purinas/farmacologia , Pirazóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor A2B de Adenosina/genéticaRESUMO
Mycotic aneurysm of the superior mesenteric artery (SMA) is one of the complications associated with infective endocarditis. However, there are no previous case reports in the literature describing mycotic SMA aneurysm after left ventricular assist device (LVAD) implantation. We describe the case of a 31-year-old male diagnosed with congestive heart failure due to nonischemic dilated cardiomyopathy who underwent LVAD implantation for bridge to heart transplantation. The postoperative course was uneventful, and the patient was maintained on anticoagulation and antiplatelet therapy. There were no signs of pump failure or device-related infections. However, 7 months post-LVAD support, the patient complained of abdominal symptoms (nausea and vomiting) with low-grade fever. Computed tomography identified an aneurysmal change of the SMA (2.2 × 1.8 cm). There was no evidence of thrombus or septic vegetation inside the heart. Aneurysm and segmental small bowel resection was performed. Pathological study revealed typical findings of mycotic aneurysm with significant infiltration of inflammatory cells. The patient, however, expired due to concurrent brain hemorrhage. Postmortem study indicated no sign of pump thrombus or septic emboli inside the pump or inflow/outflow conduit. This case report presents a rare mycotic aneurysm that developed in the SMA after chronic LVAD support.
Assuntos
Aneurisma Infectado/etiologia , Insuficiência Cardíaca/cirurgia , Coração Auxiliar/efeitos adversos , Artéria Mesentérica Superior/patologia , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Aneurisma Infectado/complicações , Aneurisma Infectado/patologia , Insuficiência Cardíaca/complicações , Humanos , MasculinoRESUMO
BACKGROUND: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial demonstrated that adding vein of Marshall (VOM) ethanol infusion to catheter ablation (CA) improves ablation outcomes in persistent atrial fibrillation (AF). There was significant heterogeneity in the impact of VOM ethanol infusion on rhythm control. OBJECTIVE: The purpose of this study was to assess the association between outcomes and (1) achievement of bidirectional perimitral conduction block and (2) procedural volume. METHODS: The VENUS trial randomized patients with persistent AF (N = 343) to CA combined with VOM ethanol or CA alone. The primary outcome (freedom from AF or atrial tachycardia [AT] lasting longer than 30 seconds after a single procedure) was analyzed by 2 categories: (1) successful vs no perimitral block and (2) high- (>20 patients enrolled) vs low-volume centers. RESULTS: In patients with perimitral block, the primary outcome was reached 54.3% after VOM-CA and 37% after CA alone (P = .01). Among patients without perimitral block, freedom from AF/AT was 34.0% after VOM-CA and 37.0% after CA (P = .583). In high-volume centers, the primary outcome was reached in 56.4% after VOM-CA and 40.2% after CA (P = .01). In low-volume centers, freedom from AF/AT was 30.77% after VOM-CA and 32.61% after CA (P = .84). In patients with successful perimitral block from high-volume centers, the primary outcome was reached in 59% after VOM-CA and 39.1% after CA (P = .01). Tests for interaction were significant (P = .002 for perimitral block and P = .04 for center volume). CONCLUSION: Adding VOM ethanol infusion to CA has a greater impact on outcomes when associated with perimitral block and performed in high-volume centers. Perimitral block should be part of the VOM procedure.
Assuntos
Fibrilação Atrial/terapia , Ablação por Cateter/métodos , Etanol/administração & dosagem , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/fisiologia , Veias Pulmonares/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
Symptomatic cardiac tumors can lead to a rapid clinical deterioration and death. Prompt surgical resection is ideal in this situation as it is the only proven treatment to date. We report the radical resection of a large malignant cardiac tumor that obstructed the right ventricular outflow tract. Extensive resection precluded reconstruction and limited the ability to implant a total artificial heart; thus, 2 paracorporeal devices were implanted instead.