RESUMEN
INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data on longitudinal studies about early and late onset cardiotoxicity in this group of patients is scarce. The objective of the present study was to assess predictors of early and late onset cardiotoxicity in patients with breast cancer treated with A. METHODS: 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) to treat breast cancer were included in this prospective study. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years after the beginning of CHT. Clinical data, systolic and diastolic echo parameters and cardiac biomarkers including high sensitivity Troponin T (TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Heart-type fatty acid binding protein (H-FABP) were assessed. RESULTS: Mean doxorubicin dose was 243 mg/m2. Mean follow-up was 51.8 ± 8.2 months. At one-year incidence of anthracycline related-cardiotoxicity (AR-CT) was 4% and at the end of follow-up was 18% (15 patients asymptomatic left ventricular systolic dysfunction, 1 patients heart failure and 2 patients a sudden cardiac death). Forty-nine patients developed diastolic dysfunction (DD) during first year. In the univariate analysis DD during first year was the only parameter associated with AR-CT (Table 1). In the logistic regression model DD was independently related with the development of AR-CT, with an odds ratio value of 7.5 (95% CI 1.59-35.3). CONCLUSIONS: Incidence of late-onset cardiotoxicity is high but mostly subclinical. Diastolic dysfunction early after chemotherapy is a strong predictor of anthracycline cardiotoxicity.
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Neoplasias de la Mama , Cardiomiopatías , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Cardiotoxicidad/diagnóstico , Cardiotoxicidad/epidemiología , Cardiotoxicidad/etiología , Antraciclinas/efectos adversos , Estudios Prospectivos , Incidencia , Antibióticos Antineoplásicos/efectos adversos , Péptido Natriurético Encefálico , BiomarcadoresRESUMEN
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.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Hipertensión Pulmonar/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Macrófagos Alveolares/metabolismo , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Células Cultivadas , Regulación hacia Abajo , Expresión Génica , Humanos , Hipertensión Pulmonar/etiología , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/fisiopatología , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/metabolismo , Isoformas de Proteínas , Interferencia de ARNRESUMEN
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.
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Adenosina/metabolismo , Hipertensión Pulmonar/metabolismo , Hipoxia/metabolismo , Anciano , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Fibrosis Pulmonar/metabolismo , Remodelación VascularRESUMEN
INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. METHODS: This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. RESULTS: At the end of follow-up (median: 12 months, interquartile range: 11.1-12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04-1.36), and age: 1.12 (95% CI: 1.03-1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. CONCLUSION: Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI and age were independently associated with DD following anthracycline chemotherapy.
Asunto(s)
Antraciclinas/efectos adversos , Neoplasias de la Mama/complicaciones , Cardiomiopatías/etiología , Diástole/fisiología , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Estudios de Cohortes , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Estudios Prospectivos , UltrasonografíaRESUMEN
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.
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Desoxicitidina Quinasa/fisiología , Hipoxia/complicaciones , Fibrosis Pulmonar Idiopática/etiología , Animales , Línea Celular , Proliferación Celular/fisiología , Humanos , Hipoxia/enzimología , Hipoxia/fisiopatología , Fibrosis Pulmonar Idiopática/enzimología , Fibrosis Pulmonar Idiopática/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alveolos Pulmonares/enzimología , Alveolos Pulmonares/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Mucosa Respiratoria/enzimologíaRESUMEN
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.
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Fibrosis Pulmonar Idiopática/inmunología , Interleucina-6/inmunología , Macrófagos Alveolares/inmunología , Fibrosis Pulmonar/inmunología , Receptores de Interleucina-6/inmunología , Transducción de Señal/inmunología , Animales , Colágeno/inmunología , Modelos Animales de Enfermedad , Femenino , Fibronectinas/inmunología , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/mortalidad , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/terapia , Interleucina-6/genética , Pulmón/inmunología , Pulmón/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Miofibroblastos/inmunología , Miofibroblastos/patología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patologíaRESUMEN
Bleeding can occur as a sequela to cardiac surgery. Surgical products-such as conventional sutures and clips, and somewhat less conventional sealants-have been developed to prevent this event. Among these, CoSeal is a sealant used at our institution; here we report the cases of 2 patients in whom CoSeal was used successfully as either a supplement or an alternative to suture repair. This sealant was found to be useful in attaining hemostasis both in high-pressure ventricular repair and in the rupture of a friable coronary sinus adjacent to vital structures (in this instance, a left circumflex coronary artery).
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Pérdida de Sangre Quirúrgica/prevención & control , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Cardiopatías/cirugía , Hemostasis Quirúrgica/métodos , Polietilenglicoles/administración & dosificación , Femenino , Cardiopatías/complicaciones , Cardiopatías/diagnóstico , Cardiopatías/fisiopatología , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
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.
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Ácido Hialurónico/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptor de Adenosina A2B/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Anciano , Animales , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/patología , Pulmón/irrigación sanguínea , Pulmón/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/patología , Purinas/farmacología , Pirazoles/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Adenosina A2B/genéticaRESUMEN
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.
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Apoptosis/efectos de los fármacos , Nucleótidos de Desoxiadenina/metabolismo , Desoxiadenosinas/metabolismo , Desoxicitidina Quinasa/metabolismo , Hipoxia/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , 2-Cloroadenosina/análogos & derivados , 2-Cloroadenosina/farmacología , Adenosina Desaminasa/deficiencia , Animales , Células Cultivadas , Desoxiadenosinas/farmacología , Humanos , Ratones , Regulación hacia ArribaRESUMEN
BACKGROUND: Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS: Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS: In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS: Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation.
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Aorta/cirugía , Atrios Cardíacos/cirugía , Neoplasias Cardíacas/cirugía , Paraganglioma Extraadrenal/cirugía , Adulto , Aorta/patología , Angiografía Coronaria , Estudios de Seguimiento , Atrios Cardíacos/patología , Neoplasias Cardíacas/irrigación sanguínea , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patología , Humanos , Masculino , Neoplasia Residual/irrigación sanguínea , Neoplasia Residual/diagnóstico , Neoplasia Residual/patología , Neoplasia Residual/cirugía , Paraganglioma Extraadrenal/irrigación sanguínea , Paraganglioma Extraadrenal/diagnóstico , Paraganglioma Extraadrenal/patología , Reoperación , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
The aortic root is often affected by aneurysmal degeneration of the ascending aorta or dissection. It is important for the clinician to be familiar with current guidelines and recommendations for detection, monitoring, and intervention of the aneurysmal aortic root. Timely surgical referral to an experienced aortic center allows for close monitoring and possible intervention that may preserve the aortic valve in appropriate cases and avoid disastrous complications such as aortic dissection, rupture, or death. Patients with bicuspid aortic valve syndrome or connective tissue disorders (e.g. Marfan syndrome) are particularly at risk and should be followed aggressively. Whenever possible, attempts should be made to preserve or repair the aortic valve using valve-sparing aortic root replacement techniques. This article provides an overview of recent advances in management of the aortic root, including guidelines for surgical intervention, technical procedures, and outcomes.