RESUMEN
Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.
Asunto(s)
Inductores de la Angiogénesis/farmacología , Eritropoyetina/farmacología , Infarto del Miocardio/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Factor de Crecimiento de Hepatocito/sangre , Humanos , Inmunohistoquímica , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Neovascularización Fisiológica/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/farmacología , Recuperación de la Función , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Somatomedinas/genética , Volumen Sistólico , Sus scrofa , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Función Ventricular IzquierdaRESUMEN
Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n=8) or vehicle (n=5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (P<0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (P<0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (P<0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (P<0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (P<0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs.
Asunto(s)
Trasplante de Médula Ósea/métodos , Corazón/fisiopatología , Células Madre Multipotentes/trasplante , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/cirugía , Neovascularización Fisiológica , Células del Estroma/trasplante , Animales , Diferenciación Celular , Enfermedad Crónica , Vasos Coronarios , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Fibrosis , Infusiones Intravenosas , Células Madre Multipotentes/metabolismo , Células Madre Multipotentes/patología , Infarto del Miocardio/complicaciones , Isquemia Miocárdica/etiología , Isquemia Miocárdica/patología , Miocardio/patología , Fenotipo , Células del Estroma/metabolismo , Células del Estroma/patología , Porcinos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVES: This study was conducted to examine the relationship between provoked coronary spasm and clinical course in patients with acute myocardial infarction (AMI). BACKGROUND: Coronary spasm has a pathogenetic role in the occurrence of AMI and progressive atherosclerosis. There is no report that focused on the prognostic significance of provoked coronary spasm in AMI patients. METHODS: Our group investigated 240 consecutive patients who underwent spasm-provocation tests using acetylcholine after AMI. Coronary spasm was defined as a transient total or subtotal occlusion of the luminal diameter. The patients were divided into 2 groups (positive group: n = 174, negative group: n = 66). RESULTS: The clinical courses of the 2 groups were compared at long-term follow up (mean, 43 months). Major adverse cardiac events (death, acute coronary syndrome, or revascularization) occurred in 82 patients (47.1%) in the positive group and 18 patients (27.3%) in the negative group (p = 0.0055). The frequency of major adverse cardiac event-free survival was significantly lower in the positive group than in the negative group (p = 0.0018). Provoked coronary spasm was a significant independent predictor of poor prognosis. CONCLUSIONS: Provoked coronary spasm predicts adverse outcome in AMI patients.
Asunto(s)
Vasoespasmo Coronario/fisiopatología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Acetilcolina , Síndrome Coronario Agudo/etiología , Anciano , Angina de Pecho/etiología , Angioplastia Coronaria con Balón , Vasoespasmo Coronario/inducido químicamente , Vasoespasmo Coronario/complicaciones , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVE: Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may improve cardiac function after acute myocardial infarction (AMI) by accelerating angiogenesis or cardiomyogenesis, but negative results and side effect of G-CSF have also been reported. However, no previous studies have used large animal models of ischemia/reperfusion to investigate the effect and side effect of G-CSF after AMI. METHODS: The diagonal branch of the left anterior descending coronary artery of swine was balloon-occluded for 1 h and then reperfused. The animals of the G-CSF group were injected with G-CSF subcutaneously (5.0 microg/kg/day) for 6 days after MI and then sacrificed after 4 weeks. The control group received the same volume of saline. RESULTS: There were no differences between the groups in the rate of thrombotic obstruction or progression of stenosis lesion in coronary angiography. The ejection fraction and end-diastolic volume in the G-CSF group were not significantly improved over the control values. The fibrotic area was significantly smaller in the G-CSF group than in the controls (P<0.05), and the numbers of vessels counted in anti-von Willebrand factor and anti-alpha-smooth muscle actin-stained sections were significantly larger (P<0.005 and P<0.05, respectively). The expression of collagen III mRNA was significantly lower in the G-CSF group than in the control in the infarct (P<0.0005) and border areas (P<0.005), and TGF-beta mRNA was significantly lower in the G-CSF group in the border area (P<0.05). CONCLUSIONS: G-CSF could modify the healing process after AMI by accelerating angiogenesis in a swine ischemia/reperfusion model. At the dose administered, however, G-CSF did not seem to improve the global cardiac function.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Infarto del Miocardio/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Animales , Oclusión con Balón , Biomarcadores/sangre , Angiografía Coronaria , Fibrosis/prevención & control , Técnicas para Inmunoenzimas , Masculino , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Reperfusión Miocárdica/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , PorcinosRESUMEN
OBJECTIVE: Significant Q-wave is sometimes invisible in the patients with triple vessel disease (TVD) even though TVD is a serious coronary heart disease. We offer the preliminary method to analyze the time-frequency profile of QRS in TVD patients. METHODS: Electrocardiograms (ECG) band-pass filtered through 50 to 300Hz were recorded from the persons without heart diseases (Normal group; n=24), the patients with single vessel disease (SVD group; n=12) and TVD (TVD group; n=12) and saved into PC. For each subject, the time-frequency powers of ECG (lead II) were calculated by the continuous wavelet transform (CWT) with 40 frequency bands. They were integrated during QRS to get the integrated time-frequency powers (ITFP) for all the frequency bands. RESULTS: The ITFP at lower frequency range (90 Hz or less) were smaller in SVD and TVD groups, compared with normal group. The ITFP at higher frequency range (120 to 350 Hz) were larger in patients with recurrent heart failure due to TVD. The increase in ITFP at wider frequency bands was seen with and without significant Q waves. CONCLUSION: The present results that the increase in higher frequency power in TVD with recurrent heart failure may indicate the severity of myocardial damage, regardless of significant Q-wave.