RESUMEN
BACKGROUND: Nur77 is an orphan nuclear receptor expressed in human atheroma. In vascular cells in vitro, Nur77 expression is induced by pro-inflammatory factors, such as oxidized LDL (oxLDL). METHODS: We analyze the role of Nur77 in the oxLDL-induced differentiation of macrophages into dendritic cells (DC). The murine RAW264.7 macrophage cell line was stably transfected with expression plasmids encoding either GFP or GFP fusions with either full-length Nur77 (GFP-Nur77), Nur77 lacking the DNA binding domain (GFP-Nur77-ΔDBD) or Nur77 lacking the transactivation domain (GFP-Nur77-ΔTAD). RESULTS: GFP-Nur77 overexpression significantly suppressed the effect of oxLDL treatment on DC morphologic changes, expression of DC maturation markers, endocytic activity, allogeneic activation of T cell proliferation, and the activity and secretion of pro-inflammatory cytokines. Analysis of GFP-Nur77-ΔTAD and GFP-Nur77-ΔDBD indicated that the Nur77 DNA binding and transactivation domains were both required for this effect. GFP-Nur77-ΔDBD consistently had the opposite effect to GFP-Nur77, increasing DC-type differentiation in all assays. Interestingly, GFP-Nur77-ΔDBD protein was cytosolic, whereas GFP-Nur77 and GFP-Nur77-ΔTAD were both nuclear. CONCLUSIONS: These data show that GFP-Nur77 inhibited differentiation of oxLDL-treated macrophages into DC. The effects of Nur77 on the macrophage phenotype may involve changes in its subcellular distribution.
Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Lipoproteínas LDL/inmunología , Macrófagos/inmunología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/inmunología , Animales , Línea Celular , Células Dendríticas/patología , Humanos , Lipoproteínas LDL/genética , Macrófagos/patología , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/inmunología , Placa Aterosclerótica/patologíaRESUMEN
OBJECTIVE: The development of a murine model of spontaneous atherosclerotic plaque rupture with luminal thrombus. METHODS AND RESULTS: Combined partial ligation of the left renal artery and left common carotid artery in 8-week-old apolipoprotein E-deficient mice induced endogenous renovascular hypertension and local low oscillatory shear stress in the left common carotid artery. After 8 weeks, a fresh left common carotid artery lumen thrombus associated with severe plaque burden was found in 50% (10/20) of the mice. Histological analyses indicated that all left common carotid artery lesions had vulnerable features, and 50% (5/10) of the mice showed plaque rupture with a lumen thrombus. Multiple layers with layering discontinuity and intraplaque hemorrhages were found in 80% (8/10) of the mice. Further experiments showed that both increased blood pressure, and angiotensin-II contributed to plaque progression and vulnerability. Decreased intimal collagen associated with increased collagenase activity and matrix metalloproteinase expression also resulted in plaque disruption. CONCLUSIONS: We demonstrate a murine model of spontaneous plaque rupture with a high incidence of luminal thrombus. The model not only nicely recapitulates the pathophysiological processes of human plaque rupture but it is also simple, fast, and highly efficient to generate.
Asunto(s)
Apolipoproteínas E/deficiencia , Enfermedades de las Arterias Carótidas/fisiopatología , Hemorragia/fisiopatología , Hipertensión Renovascular/fisiopatología , Placa Aterosclerótica/fisiopatología , Estrés Mecánico , Angiotensina II/metabolismo , Animales , Apolipoproteínas E/genética , Presión Sanguínea/fisiología , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/genética , Arteria Carótida Común/patología , Arteria Carótida Común/fisiopatología , Colágeno/metabolismo , Colagenasas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hemorragia/epidemiología , Incidencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/patologíaRESUMEN
Dendritic cells (DCs) are the most potent professional antigen-presenting cells and are involved in the initiation and progression of atherosclerosis. Recent data suggest that mature macrophages differentiate into dendritic-like cells when exposed to oxidized low-density lipoprotein (oxLDL). The purpose of the present study was to determine the effect of atorvastatin on the differentiation of macrophages to DCs and the molecular mechanisms of this transition. Mouse macrophage-like RAW264.7 cell was differentiated into a dendritic-like phenotype by incubation with oxLDL in the absence or presence of atorvastatin. The results showed that atorvastatin suppressed DC-like morphologic changes in vitro as assessed by decreased expression of DC maturation markers (CD83, CD11c, CD86, major histocompatibility complex class II, and CD1d). Atorvastatin also inhibited other oxLDL-induced functional changes including endocytic activity, ability to induce T cell proliferation, and cytokine secretion. Western blot analysis showed that oxLDL treatment of RAW264.7 cells induced phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, blocking p38 MAPK with SB203580 significantly downregulated the expression of DC maturation markers, accompanied by decreased cytokine secretion. The findings of the present work demonstrate that that atorvastatin suppresses the oxLDL-induced DC-like differentiation of RAW264.7 cells by inactivating the p38 MAPK signaling pathway.
Asunto(s)
Células Dendríticas/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteínas LDL/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Pirroles/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Atorvastatina , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Células Dendríticas/citología , Células Dendríticas/metabolismo , Regulación hacia Abajo , Lipoproteínas LDL/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Transducción de Señal , Factores de TiempoRESUMEN
Most patients with acute ST-elevation myocardial infarction (STEMI) cannot receive timely primary percutaneous coronary intervention (PCI) because of lack of facilities or delays in patient transfer or catheterization team mobilization. In these patients, early routine post-thrombolysis PCI might be a reasonable, useful strategy. This study investigated feasibility and safety of early PCI after successful half-dose alteplase reperfusion in a Chinese population. Patients with STEMI received half-dose alteplase if expected time delay to PCI was ≥90 min. Patients who reached clinical criteria of successful thrombolysis reperfusion were recommended to undergo diagnostic angiography within 3-24 h after thrombolysis. Patients with residual stenosis ≥70% in the infarct-related artery underwent PCI, regardless of flow or patency status. Epicardial arterial flow was assessed using thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count (CTFC). Myocardial perfusion was assessed using myocardial blush grade (MBG) and TIMI myocardial perfusion frame count (TMPFC). Forty-nine patients were enrolled and underwent diagnostic angiography 3-11.3 h (median 6.5 h) after thrombolysis. Forty-six patients underwent PCI. No procedure-related complications occurred, except two patients who had no reflow after PCI. Twenty-two (47.8%) patients had TIMI grade 3 flow before PCI and 33 (71.7%) after PCI. CTFC was significantly improved after PCI (48.5 ± 32.1 vs. 37.9 ± 25.6, P = 0.01). MBG and TMPFC exhibited a similar improving trend after PCI, and the best myocardial perfusion tended to be achieved 3-12 h after lysis. During the 30-day follow-up, there were two deaths. The composite end point of death, cardiogenic shock, heart failure, reinfarction, and recurrent ischemia occurred in four patients. TIMI minor bleeding occurred in four patients. No TIMI major bleeding and stroke occurred. Early routine PCI after half-dose alteplase thrombolysis in Chinese population appears feasible. A larger clinical trial should be designed to further elucidate its efficacy and safety. Early PCI after thrombolysis in STEMI: The EARLY-PCI pilot feasibility study, ChiCTR-TNC-11001363.
Asunto(s)
Angioplastia Coronaria con Balón/métodos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/terapia , Terapia Trombolítica/métodos , Anciano , China/epidemiología , Estudios de Factibilidad , Femenino , Heparina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
BACKGROUND: Myocardial tissue-level perfusion failure is associated with adverse outcomes following ST-elevation myocardial infarction (STEMI) despite successful epicardial recanalization. We have developed a new quantitative index-thrombolysis in myocardial infarction (TIMI) myocardial perfusion frame count (TMPFC)--for assessing myocardial tissue level perfusion. However, factors affecting this novel index of myocardial perfusion are currently unknown. METHODS: A total of 255 consecutive STEMI patients undergoing primary angioplasty were enrolled. Myocardial tissue level perfusion was assessed by TMPFC, which measures the filling and clearance of contrast in the myocardium using cine-angiographic frame counting. We differentiate three groups with two cut off values for TMPFC: a TMPFC of 90 frames was the upper boundary of the 95% confidence interval (CI) for the TMPFC observed in normal arteries, and a TMPFC of 130 was the 75th percentile of TMPFC. RESULTS: STEMI patients with TMPFC > 130 frames (68 patients, 26.7%) had higher clinical and angiographic risk factor profiles as well as a higher 30-day MACE rate compared with those with TMPFC ≤ 90 frames and those with TMPFC > 90 and ≤ 130 frames. Multivariable analysis identified that the independent predictors of TMPFC > 130 frames were age ≥ 75 years (OR 2.08, 95%CI 1.21 to 3.58, P = 0.007), diabetes (OR 1.37, 95%CI 1.01 to 1.86, P = 0.042), Killip class ≥ 2 (OR 1.52, 95%CI 1.05 to 2.21, P = 0.027), and prolonged pain-to-balloon time (OR 1.73, 95%CI 1.07 to 2.79, P = 0.013). TMPFC > 130 frames was identified as the strongest independent predictor of 30-day major adverse cardiac event (MACE) (OR 2.77, 95%CI 1.21 to 6.31, P = 0.008), along with age ≥ 75 years (OR 2.19, 95%CI 1.11 to 4.33, P = 0.016), female gender (OR 1.67, 95%CI 1.03 to 2.70, P = 0.038), and Killip class ≥ 2 (OR 1.83, 95%CI 1.07 to 3.14, P = 0.021). CONCLUSIONS: STEMI patients with poor myocardial perfusion assessed by TMPFC had higher risk factor profiles. Advanced age, diabetes, higher Killip class, and longer ischemia time were independent predictors of impaired TMPFC after primary percutaneous coronary intervention. These results emphasize that particular attention should be paid on myocardial microvascular reperfusion in STEMI patients with these risk factors.
Asunto(s)
Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/terapia , Anciano , Angioplastia Coronaria con Balón , Angiografía Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Reperfusión Miocárdica , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
OBJECTIVES: We sought to develop a new quantitative method to evaluate the degree of myocardial perfusion. BACKGROUND: Currently available methods for assessing myocardial perfusion, both TIMI myocardial perfusion grading (TMPG) and myocardial blush grading (MBG), are subjective. METHODS: TIMI Myocardial Perfusion Frame Count (TMPFC), an objective method that measures the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting, was developed to quantify myocardial perfusion. Myocardial perfusion of 45 normal coronary arteries in 15 patients, and 137 culprit arteries in 137 patients immediately after primary angioplasty, was successfully assessed with TMPFC. RESULTS: The mean TMPFC in the normal arteries was 83.47 +/- 17.96 frames (95% CI: 78.07 frames Asunto(s)
Angioplastia Coronaria con Balón
, Cineangiografía
, Angiografía Coronaria
, Circulación Coronaria
, Infarto del Miocardio/diagnóstico por imagen
, Infarto del Miocardio/terapia
, Imagen de Perfusión Miocárdica/métodos
, Anciano
, Angioplastia Coronaria con Balón/efectos adversos
, Bases de Datos como Asunto
, Electrocardiografía
, Femenino
, Humanos
, Masculino
, Persona de Mediana Edad
, Infarto del Miocardio/fisiopatología
, Variaciones Dependientes del Observador
, Valor Predictivo de las Pruebas
, Estudios Prospectivos
, Recurrencia
, Reproducibilidad de los Resultados
, Medición de Riesgo
, Factores de Riesgo
, Factores de Tiempo
, Resultado del Tratamiento
RESUMEN
OBJECTIVE: To evaluate the prognostic value of plasma brain natriuretic peptide (BNP) and C-reactive protein (CRP) in patients with acute coronary syndromes (ACS) underwent percutaneous coronary intervention (PCI). METHODS: Patients with ACS underwent PCI in our hospital from December 2004 to September 2005 were included in this study. Plasma BNP (n = 189) and CRP (n = 141) were measured at a median of (34.2 +/- 16.3) hours from symptom onset, total mortality and the risk for major adverse cardiac events (MACE, including death, recurrent MI, recurrent angina, heart failure, readmission for any reason) at 30 days and at 3 months was analyzed. RESULTS: Patients were divided into 4 groups according to their BNP levels (BNP
Asunto(s)
Síndrome Coronario Agudo/diagnóstico , Proteína C-Reactiva/metabolismo , Péptido Natriurético Encefálico/sangre , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/terapia , Adulto , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , PronósticoRESUMEN
OBJECTIVE: The aim of this study was to evaluate the value of sixteen-detector row computed tomography angiography (CTA) for the assessment of coronary artery bypass graft (CABG). METHODS: Sixty-two consecutive patients undergoing coronary artery bypass grafting were recruited. Among them, 6 patients were excluded from the study due to unfavorable control of heart rate. A total of 56 patients with 152 coronary artery bypass grafts (internal mammary artery, n = 48; saphenous venous grafts, n = 104) were examined by computed tomography angiography (CTA) with sixteen-detector row CT and by conventional invasive coronary angiography (CAG). All CT procedures were performed with retrospective electrocardiogram gating method. The patients' mean heart rate was 58 +/- 6 beats/minute. 120 ml of Visipaque 320 were continuously injected with the rate of 4.0 ml/sec during the procedure. The patency and the stenosis of coronary artery bypass grafts were evaluated by two experienced readers. RESULTS: All the coronary artery bypass grafts were visualized by CTA, and all the proximal bypass anastomoses and 71% of the distal bypass anastomoses were also visualized by CTA. Furthermore, 29 occlusions and 13 significant stenoses of coronary artery bypass grafts were detected by CTA. The comparison of the results between CTA and CAG showed that among all the 42 occluded and stenosed coronary artery bypass grafts detected by CTA, 34 were confirmed by CAG; among all the 110 normal coronary artery bypass grafts detected by CTA, 108 were confirmed by CAG. There were 8 false positive and 2 false negative findings, resulting in a sensitivity of 94%, a specificity of 95%, a positive predictive value of 86%, and a negative predictive value of 99%. CONCLUSION: Sixteen-detector row CTA technology may provide a reliable visualization and higher diagnostic accuracy of coronary artery bypass grafts lesions. This technique can be used as a noninvasive procedure for the diagnosis of suspected coronary artery bypass grafts dysfunction.