RESUMEN
BACKGROUND: Pulmonary injury is a major complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Lung injury after BPA can be exacerbated by a high mean pulmonary arterial pressure (PAP). Although oxygen inhalation is expected to lower mean PAP in patients with CTEPH, no relevant investigation has been conducted. METHODS: Consecutive patients with CTEPH who underwent BPA were enrolled in this study. We evaluated the hemodynamics using right heart catheterization while breathing ambient air and with administration of 5 L/min oxygen for 10 min. RESULTS: This study included 52 consecutive patients with CTEPH, of whom 23 (44%) were treated with specific pulmonary vasodilators. Exposure to oxygen was well tolerated. Oxygen administration significantly decreased mean PAP by 3.8 ± 3.2 mmHg (p<0.001) and pulmonary vascular resistance by 0.8 ± 1.8 Wood units (p<0.001). Moreover, the ratio of pulmonary vascular resistance to systemic vascular resistance was significantly reduced by 13.5% (p<0.001). Multivariate regression analysis identified baseline mean PAP (ß = -0.427, p = 0.006) as the only significant predictor of decreased mean PAP under oxygen administration. No significant difference in oxygen effect on mean PAP was found between patients with and without vasodilators. CONCLUSIONS: In patients with CTEPH, 5 L/min supplemental oxygen inhalation could decrease mean PAP significantly by selective pulmonary artery dilatation, regardless of the usage of vasodilators, and thus could be helpful to maximize the safety of BPA. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry (No.: UMIN000026882); URL: https://www.umin.ac.jp/ctr/index.htm.
Asunto(s)
Angioplastia de Balón , Hipertensión Pulmonar , Embolia Pulmonar , Angioplastia de Balón/efectos adversos , Enfermedad Crónica , Dilatación , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Oxígeno , Arteria Pulmonar , Embolia Pulmonar/terapiaRESUMEN
BACKGROUND: The fibroblast growth factor (FGF) system plays a critical role in the maintenance of vascular integrity via enhancing the stability of VE-cadherin at adherens junctions. However, the precise molecular mechanism is not well understood. In the present study, we aimed to investigate the detailed mechanism of FGF regulation of VE-cadherin function that leads to endothelial junction stabilization. METHODS AND FINDINGS: In vitro studies demonstrated that the loss of FGF signaling disrupts the VE-cadherin-catenin complex at adherens junctions by increasing tyrosine phosphorylation levels of VE-cadherin. Among protein tyrosine phosphatases (PTPs) known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation. Increased endothelial permeability caused by FGF signaling inhibition was rescued by SHP2 overexpression, indicating the critical role of SHP2 in the maintenance of endothelial junction integrity. CONCLUSIONS: These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability.
Asunto(s)
Uniones Adherentes/metabolismo , Antígenos CD/metabolismo , Cadherinas/metabolismo , Células Endoteliales/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Transducción de Señal/fisiología , Animales , Permeabilidad Capilar , Bovinos , Células Cultivadas , Células Endoteliales/citología , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , FosforilaciónRESUMEN
BACKGROUND: The previous OLIVUS trial reported a positive role in achieving a lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent (ARB), for stable angina pectoris (SAP) patients requiring percutaneous coronary intervention (PCI). However, the benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear. Thus, we examined the 4-year clinical outcomes from OLIVUS according to treatment strategy with olmesartan. METHODS: Serial volumetric IVUS examinations (baseline and 14 months) were performed in 247 patients with hypertension and SAP. When these patients underwent PCI for culprit lesions, IVUS was performed in their non-culprit vessels. Patients were randomly assigned to receive 20-40mg of olmesartan or control, and treated with a combination of ß-blockers, calcium channel blockers, glycemic control agents and/or statins per physician's guidance. Four-year clinical outcomes and annual progression rate of atherosclerosis, assessed by serial IVUS, were compared with major adverse cardio- and cerebrovascular events (MACCE). RESULTS: Cumulative event-free survival was significantly higher in the olmesartan group than in the control group (p=0.04; log-rank test). By adjusting for validated prognosticators, olmesartan administration was identified as a good predictor of MACCE (p=0.041). On the other hand, patients with adverse events (n=31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p<0.001). CONCLUSIONS: Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio- and cerebrovascular events in this study cohort.
Asunto(s)
Angioplastia Coronaria con Balón , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Imidazoles/uso terapéutico , Tetrazoles/uso terapéutico , Ultrasonografía Intervencional , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/mortalidad , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Trastornos Cerebrovasculares/etiología , Distribución de Chi-Cuadrado , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/mortalidad , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Cardiopatías/etiología , Humanos , Imidazoles/efectos adversos , Japón , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Tetrazoles/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/fisiología , Activación Enzimática , Factores de Crecimiento de Fibroblastos/genética , Miembro Posterior/irrigación sanguínea , Miembro Posterior/patología , Humanos , Isquemia/metabolismo , Isquemia/patología , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neovascularización Fisiológica/fisiología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismo , Transducción de Señal/fisiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type- nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.
Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Cateninas/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Uniones Adherentes/metabolismo , Animales , Western Blotting , Permeabilidad Capilar/fisiología , Adhesión Celular/fisiología , Línea Celular , Movimiento Celular/fisiología , Células Cultivadas , Células Endoteliales/citología , Endotelio Vascular/citología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Inmunoprecipitación , Fosforilación , Interferencia de ARN , Ratas , Transducción de Señal , Venas Umbilicales/citología , Venas Umbilicales/metabolismo , Catenina deltaRESUMEN
OBJECTIVES: The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis. BACKGROUND: Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents. METHODS: A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [<50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV. RESULTS: Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6 % for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p < 0.05 for all). CONCLUSIONS: These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imidazoles/uso terapéutico , Tetrazoles/uso terapéutico , Ultrasonografía Intervencional/métodos , Anciano , Angina de Pecho/diagnóstico por imagen , Angina de Pecho/tratamiento farmacológico , Angina de Pecho/mortalidad , Angioplastia Coronaria con Balón , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Presión Sanguínea/efectos de los fármacos , Angiografía Coronaria , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/tratamiento farmacológico , Estudios Prospectivos , Tasa de Supervivencia , Tetrazoles/efectos adversosRESUMEN
BACKGROUND: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to have a role in inflammation. We examined the serum level of activin A in patients with acute myocardial infarction (AMI) undergoing successful primary percutaneous coronary intervention (PCI). METHODS: The subjects were 30 AMI patients, 20 stable angina pectoris (AP) patients and 20 normal subjects. The serum levels of activin A in AMI patients were measured before PCI and on days 1, 2, 7, and 14. RESULTS: Activin A levels before PCI in AMI patients (557+/-255 pg/ml) showed a significantly higher value than those in AP patients (364+/-159 pg/ml) and control subjects (316+/-144 pg/ml). Increased serum activin A level before PCI was decreased on day 2, and then gradually re-elevated on days 7 and 14. The serum activin A level before PCI was correlated with log-transformed peak creatine kinase (CK) as a surrogate of infarct size (r=0.48, p=0.008). Stepwise multiple regression analysis demonstrated that the serum activin A level before PCI was an independent predictor of peak CK. CONCLUSIONS: The serum activin A level, increased in AMI, was positively correlated with peak CK and CK-MB levels which are measures of infarction size.
Asunto(s)
Activinas/sangre , Infarto del Miocardio/diagnóstico , Anciano , Angina de Pecho/diagnóstico , Angioplastia Coronaria con Balón , Creatina Quinasa/sangre , Forma MB de la Creatina-Quinasa/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Infarto del Miocardio/cirugía , Análisis de RegresiónRESUMEN
AIM: Pulse wave velocity has been used as an index of aortic stiffness. Recently, the cardio-ankle vascular index (CAVI), which reflects the stiffness of the aorta independently of blood pressure, has been developed. In this study, we analyzed the relationship between CAVI and left ventricular (LV) diastolic dysfunction. METHODS: A total of 119 patients were referred for echocardiography to evaluate ventricular function. Patients with reduced systolic function were excluded. Patients were divided on the basis of normal or reduced LV diastolic function determined by echocardiography. CAVI was measured using an automatic waveform analyzer. RESULTS: CAVI was significantly higher in patients with reduced LV diastolic function than those with normal LV diastolic function (9.0+/-1.1 and 8.5+/-1.1, p=0.009). Multiple linear regression analysis revealed that CAVI was independently associated with the ratio of peak early diastolic velocity to peak atrial diastolic velocity and left atrial diameter. When patients were classified on the basis of CAVI quartiles, multiple logistic regression analysis demonstrated that the highest quartile of CAVI showed an increased odds ratio for the presence of LV diastolic dysfunction. CONCLUSION: The present study revealed that an increased CAVI was independently associated with LV diastolic dysfunction in patients with preserved systolic function.
Asunto(s)
Aorta/fisiopatología , Resistencia Vascular , Disfunción Ventricular Izquierda/diagnóstico , Anciano , Índice Tobillo Braquial , Diástole , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad RelativaRESUMEN
BACKGROUND: Adenosine has been available for use in myocardial perfusion single-photon emission computed tomography (SPECT) in Japan since 2005. The purpose of this study was to evaluate the safety of and tolerance to thallium-201 myocardial perfusion SPECT with intravenous adenosine infusion in Japanese patients with suspected coronary artery disease. METHODS AND RESULTS: Two hundred and six consecutive patients who underwent an adenosine infusion (120 mug . kg(-1) . min(-1)) SPECT at Sumitomo Besshi Hospital (Niihama, Japan) were investigated. The effects of adenosine infusion were monitored for each patient. A coronary angiography was performed in 81 patients. Adenosine infusion significantly decreased blood pressure and increased heart rate. Adverse reactions were observed in 161 patients (78.2%). Most reactions were transient, disappearing soon after the termination of adenosine infusion. No serious adverse reactions, such as acute myocardial infarction or death, occurred. Adenosine infusion was terminated in 3 patients (1.5%) because of near syncope or sustained 2:1 atrioventricular block. Electrocardiographic changes occurred in 15 patients (7.3%). Self-assessed scoring after SPECT showed that the patients were very tolerant (74.6% of 177 patients) of adenosine infusion myocardial SPECT. The sensitivity and specificity were 75.0% and 69.7%, respectively. CONCLUSIONS: Adenosine infusion myocardial SPECT is safe and well tolerated in the Japanese population, despite the frequent occurrence of minor adverse reactions.
Asunto(s)
Adenosina/farmacología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Radioisótopos de Talio , Tomografía Computarizada de Emisión de Fotón Único , Adenosina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Bloqueo Atrioventricular/inducido químicamente , Bloqueo Atrioventricular/diagnóstico por imagen , Bloqueo Atrioventricular/fisiopatología , Presión Sanguínea/efectos de los fármacos , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/fisiopatología , Electrocardiografía , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Japón , Masculino , Persona de Mediana Edad , Radiografía , Síncope/inducido químicamente , Síncope/diagnóstico por imagen , Síncope/fisiopatología , Radioisótopos de Talio/efectos adversosRESUMEN
We describe a case presenting with facial and hypoglossal nerve paresis due to cortical cerebral infarction. A 54-year-old man visited our hospital complaining of sudden episode of dysarthria and facial paresis. Neurological findings revealed tongue deviation to the left and left facial paresis with forehead wrinkling while neither limb paralysis nor sensory impairment was observed. Head CT performed on day 3 after onset revealed a cortical infarction in the right prefrontal gyrus. Symptoms gradually improved with medical management. This patient had isolated facial and hypoglossal nerve paresis without other neurological symptoms. Patients with mild paresis of cranial nerves should be diagnosed carefully, because their paresis could be supranuclear type.