RESUMEN
A 77-year-old man, who had been under medical treatment for myasthenia gravis without thymoma, was diagnosed with aortic arch aneurysm. He underwent total aortic arch replacement and total resection of the thymus through median sternotomy. His symptoms relating to myasthenia gravis dramatically disappeared after the surgery. The serum anti-acetyl chorine receptor antibody decreased from 2.7 to 0.7 nmol/l (N<0.2) with the reduction of oral predonisolone from 12.5 to 5 mg/day at 4 years after the surgery. The concomitant operations significantly improved his quality of life.
Asunto(s)
Aneurisma de la Aorta Torácica/cirugía , Miastenia Gravis/cirugía , Anciano , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Humanos , Masculino , Miastenia Gravis/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
A 59-year-old male who had undergone mitral valve replacement with the Starr-Edwards ball valve Model 6120 (S-E ball valve) 45 years ago was admitted to our hospital for hemolytic anemia and heart failure. Echocardiography revealed that there was no valve dysfunction but paravalvular leakage between the annulus of P2 and the sewing ring of the Starr-Edwards ball valve. He underwent mitral valve replacement. The S-E ball valve was successfully replaced with bileaflet mechanical valve. The explanted S-E ball valve was free from signs of structural valve degeneration. This case shows one of the longest durability of the S-E ball valve in mitral position in the world.
Asunto(s)
Insuficiencia Cardíaca/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Remoción de Dispositivos , Enfermedades de las Válvulas Cardíacas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Válvula Mitral/cirugía , Diseño de Prótesis , Reoperación , Factores de TiempoRESUMEN
A 42-year-old woman was admitted with chest pain. Coronary angiography did not reveal any significant stenosis, but left ventriculography showed akinesis and ballooning of the apex with a hyperkinetic basal segment indicating Takotsubo cardiomyopathy. Cerebral embolism occurred after one and a half years because of a left ventricular thrombus. The apical akinesis had worsened to a left ventricular aneurysm (maximum diameter 43 mm). The left ventricle was reconstructed to avoid repeated thrombus formation and cerebral infarction despite anticoagulant therapy. A pathological assessment revealed a fibrotic myocardium, but the cause of the cardiac aneurysm remained unknown. Although the outcome of Takotsubo cardiomyopathy is relatively good, careful observation and appropriate treatment are needed considering the possibility of aggravation.
Asunto(s)
Aneurisma Cardíaco/cirugía , Ventrículos Cardíacos/cirugía , Cardiomiopatía de Takotsubo/cirugía , Disfunción Ventricular Izquierda/cirugía , Adulto , Anuloplastia de la Válvula Cardíaca , Femenino , Aneurisma Cardíaco/etiología , Humanos , Cardiomiopatía de Takotsubo/complicaciones , Disfunción Ventricular Izquierda/etiologíaRESUMEN
A 61-year-old male had undergone coronary artery bypass grafting (CABG) using a saphenous vein. Postoperative angiography represented an ascending aortic pseudoaneurysm derived from the proximal anastomotic site of the saphenous vein graft( SVG) which was connected to the obtuse marginal branch and left posterior descending branch sequentially. We performed the closure of tear and the plication of pseudoaneurysmal wall through median sternotomy on the 56th postoperative day. A 7mm length longitudinal tear in the ascending aorta close to the proximal anastomotic site of the SVG was observed. This tear was considered to be caused by the intimal injury during the anastomosis of SVG to ascending aorta. Aortic pseudoaneurysm formation close to the proximal anastomotic site of SVG is a rare and potentially lethal complication requiring urgent operation. Postoperative angiography or enhanced 3 dimensional computed tomography after CABG should be performed before hospital discharge.
Asunto(s)
Aneurisma Falso/cirugía , Aneurisma de la Aorta/cirugía , Puente de Arteria Coronaria , Aneurisma Falso/etiología , Aneurisma de la Aorta/etiología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Vena Safena/cirugíaRESUMEN
Infected aneurysm (IA) of the anterior interosseal artery (AIA), the first branch of the ulnar artery, is an infrequent but serious complication of infectious endocarditis (IE). We report a successful case of excision of IA arising from AIA. In this case, the IA expanded and adhered to the ulnar artery, resulting in occlusion of the ulnar artery. Reconstruction of the ulnar artery was not needed by the preoperative evaluation and the intraoperative occlusion testing. We discuss surgical treatment of IA following IE in upper extremities.
Asunto(s)
Aneurisma Infectado/cirugía , Arteriopatías Oclusivas/etiología , Endocarditis Bacteriana/complicaciones , Arteria Cubital , Extremidad Superior/irrigación sanguínea , Procedimientos Quirúrgicos Vasculares , Anciano , Aneurisma Infectado/diagnóstico por imagen , Aneurisma Infectado/microbiología , Antibacterianos/uso terapéutico , Arteriopatías Oclusivas/diagnóstico por imagen , Constricción Patológica , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Enterococcus/aislamiento & purificación , Humanos , Ligadura , Masculino , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Arteria Cubital/diagnóstico por imagenRESUMEN
BACKGROUND: In order to reduce the risk of cerebral embolism during aortic replacement through a left thoracotomy, we performed ascending or arch aortic cannulation (AAC) as well as early extracorporeal perfusion (EEP) under deep hypothermic circulatory arrest (DHCA). In this study we examined the effectiveness of these modifications in preventing cerebral embolism after distal arch replacement. METHODS: Between January 2006 and March 2010, 40 patients underwent distal arch replacement through a left thoracotomy, using 2 pieces of an artificial graft. In all patients, AAC, EEP, and the open technique for aortic anastomosis were performed under DHCA. The AAC resulted in the proximal aortic perfusion from the proximal site of the diseased aorta. The EEP was induced by aortic distal perfusion from the side branch of a distal graft. After completion of the proximal anastomosis under EEP and DHCA, anastomosis between the proximal and distal grafts was made during rewarming. Neurologic deficit in the brain and spinal cord, as well as early surgical results, were clinically evaluated. RESULTS: There was no permanent neurologic deficit after the surgery in the operative survivors. No patient had a stroke (0%). Temporary paraplegia and paraparesis occurred in 1 and 2 patients, respectively (7.7%); all 3 patients were able to walk prior to their discharge from hospital. Mortality in this series was 5.0% (2 of 40 patients); the cause of death was rupture of an esophageal ulcer and cardiogenic shock possibly due to myocardial infarction. CONCLUSIONS: The AAC and EEP, in addition to deep hypothermia and DHCA, minimized the risk of cerebral embolism after distal arch aortic replacement by the left lateral approach.
Asunto(s)
Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/cirugía , Embolia Intracraneal/prevención & control , Toracotomía/métodos , Anciano , Anastomosis Quirúrgica/métodos , Prótesis Vascular , Cateterismo , Paro Circulatorio Inducido por Hipotermia Profunda , Femenino , Humanos , Embolia Intracraneal/etiología , Masculino , Toracotomía/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: This study examined effects of diabetes mellitus (DM) on cellular proliferation associated with vascular endothelial growth factor (VEGF) signaling in endothelial progenitor cells (EPCs) and evaluated protein expression involved in cellular proliferation and proapoptotic signaling in chronically ischemic myocardium. METHODS: Insulin-dependent DM was induced in yucatan miniswine with alloxan. Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Seven weeks after ameroid constrictor, perfusion of ischemic territory was measured by isotope-labeled microspheres, and ischemic myocardium was harvested. Bone marrow (BM) samples were harvested from iliac bone and mononuclear cells (MNCs) were cryopreserved. EPCs were isolated from cryopreserved MNCs in control (n = 6) and DM swine (n = 6). EPC proliferation was assessed. RESULTS: EPC proliferation was decreased in DM as compared to control (1.02 ± 0.09, 0.40 ± 0.04, p < 0.01). VEGF-induced EPC proliferation was impaired in DM as compared to control (p < 0.01). Expression of ERK protein, an activator of VEGF-induced cell proliferation, was decreased. AKT activation, an inhibitor of apoptosis, was decreased, while Bad, an activator of proapoptotic signaling, was elevated in the ischemic myocardium from DM. Collateral dependent perfusion was impaired in DM. CONCLUSION: Impaired VEGF-induced proliferation response in EPC as well as an increase in negative myocardial protein expression for cell proliferation and proapoptotic signaling via VEGF could be a therapeutic target to enhance the effects of proangiogenesis therapies in DM and other chronic illnesses.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Isquemia Miocárdica/cirugía , Células Madre/metabolismo , Factores de Crecimiento Endotelial Vascular/farmacología , Aloxano , Animales , Western Blotting , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular , Trasplante de Células/métodos , Células Cultivadas , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Insulina/farmacología , Distribución Aleatoria , Valores de Referencia , Estadísticas no Paramétricas , Células Madre/citología , Porcinos , Porcinos Enanos , Factores de Crecimiento Endotelial Vascular/metabolismoAsunto(s)
Aorta/lesiones , Hilos Ortopédicos/efectos adversos , Migración de Cuerpo Extraño/etiología , Tórax en Embudo/cirugía , Procedimientos Ortopédicos/efectos adversos , Heridas Penetrantes/etiología , Adulto , Aorta/cirugía , Aortografía/métodos , Implantación de Prótesis Vascular , Remoción de Dispositivos , Falla de Equipo , Migración de Cuerpo Extraño/diagnóstico por imagen , Migración de Cuerpo Extraño/cirugía , Humanos , Masculino , Procedimientos Ortopédicos/instrumentación , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Heridas Penetrantes/diagnóstico por imagen , Heridas Penetrantes/cirugíaRESUMEN
OBJECTIVE: Impaired endothelium-independent vasodilation is a known consequence of types 1 and 2 diabetes, and the mechanism of impaired vasodilation is not well understood. The following study investigated the effects of types 1 and 2 diabetes in endothelial-independent vasodilation associated with coronary vascular smooth muscle (VSM) relaxation and contractile signaling mechanisms. MATERIALS AND METHODS: Type 1 diabetes was induced in Yucatan miniswine via alloxan injection and treated with or without insulin (DM and IDM). Nondiabetic swine served as controls (ND). Expression and/or phosphorylation of determinants of VSM relaxation and contraction signaling were examined in coronary arteries and microvessels. Coronary microvessel relaxation was assessed by using sodium nitroprusside (SNP). In addition, SNP-induced vasodilation and myosin light-chain (MLC) phosphorylation was determined in coronary microvessels isolated from ND and type 2 diabetic human atrial appendage. RESULTS: Diabetic impairment in SNP-induced relaxation was completely normalized by insulin. Soluble guanylate cyclase (sGC) VSM expression decreased in both DM and IDM groups and did not correlate with vasorelaxation. Phosphorylation of MLC and myosin phosphatase increased in the DM group and MLC phosphorylation strongly correlated with impaired VSM relaxation (r=0.670, P<0.01). Coronary microvessels from type 2 diabetic human patients exhibited similarly impaired vasodilation and enhanced VSM MLC phosphorylation. CONCLUSIONS: Impaired vasodilation in type 1 diabetes correlates with enhanced VSM MLC phosphorylation. In addition, enhanced VSM MLC phosphorylation is associated with impaired vasodilation in type 2 diabetes in humans.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Músculo Liso Vascular/metabolismo , Cadenas Ligeras de Miosina/metabolismo , Vasodilatación , Aloxano/toxicidad , Animales , Vasos Coronarios/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/farmacología , Microvasos/metabolismo , Contracción Muscular/efectos de los fármacos , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Fosforilación/efectos de los fármacos , Porcinos , Porcinos Enanos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND/AIM: Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue. METHODS: Dietary induction of hypercholesterolemia was performed over 20 weeks in Yucatan swine with treated animals receiving atorvastatin 3 mg/kg/day. Chronic myocardial ischemia was induced via surgical placement of an ameroid constrictor ring around the proximal circumflex artery at age 20 weeks, followed by tissue harvest at age 27 weeks. Myocardial levels of protein, lipid, and DNA biomarkers of oxidative stress, serum levels of 8-isoprostane, nitric oxide (NO) dependent, and independent coronary microvascular reactivity, as well as isotope-labeled microsphere myocardial perfusion analysis and histologic analysis for endothelial cell density was performed. RESULTS: Atorvastatin treatment was associated with elevated levels of myocardial protein oxidation and lipid peroxidation. Conversely, serum oxidant stress biomarkers were not elevated. Atorvastatin treatment improved nitric oxide dependent and independent microvascular reactivity, and was associated with decreased perfusion in the ischemic myocardial territory. CONCLUSION: Treatment with atorvastatin was associated with increased levels of myocardial tissue protein and lipid oxidative stress biomarkers and a reduced functional endogenous angiogenic response, but improved coronary microvascular reactivity. Increased oxidative stress in tissues may play a role in the reduced angiogenic response seen with atorvastatin treatment in other studies.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Isquemia Miocárdica/complicaciones , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Pirroles/uso terapéutico , Adenosina Difosfato/farmacología , Animales , Atorvastatina , Colesterol/sangre , Circulación Coronaria , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , ADN/metabolismo , Dinoprost/análogos & derivados , Dinoprost/sangre , Dinoprost/farmacología , Endotelio Vascular/patología , Femenino , Hipercolesterolemia/complicaciones , Hipercolesterolemia/metabolismo , Técnicas In Vitro , Peroxidación de Lípido , Masculino , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Oxidación-Reducción , Proteínas/metabolismo , Porcinos , Porcinos Enanos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: This study examined ex vivo expansion of bone marrow-derived endothelial progenitor cell (EPC) from cryopreserved bone marrow-derived mononuclear cells, and evaluated proliferation and migration function of the cryopreserved EPC (Cryo-EPC). METHODS: Bone marrow samples were taken from swine iliac bone (n = 6). Isolated bone marrow-derived mononuclear cells were cultured or cryopreserved at -80 degrees C for 2 to 3 months. After cell culture for 4 days, attached cells, EPCs with or without cryopreservation, were collected. Direct fluorescent staining by acetylated low-density lipoprotein, isolectin B4, and 4',6-diamidino-2-phenylindole were performed to confirm the attached cells as EPC. Endothelial progenitor cell proliferation by vascular endothelial growth factor was evaluated by the tetrazolium method. Endothelial progenitor cell migration in response to stromal-derived factor-1alpha was also evaluated by using a Boyden chamber assay. RESULTS: The percentage of cells positively stained by direct fluorescent staining by acetylated low-density lipoprotein and isolectin B4 was similar between fresh and Cryo-EPC (EPC = 96.0 +/- 0.42 versus Cryo-EPC = 95.2 +/- 1.2; p = 0.21). Vascular endothelial growth factor increased proliferation activity in fresh and Cryo-EPC (p < 0.01). Stromal-derived factor-1alpha increased migration activity in fresh and Cryo-EPC (p < 0.01). There was no difference in proliferation and migration activity between fresh and Cryo-EPC. CONCLUSIONS: Ex vivo expansion by cell culture was a useful method for collection of bone marrow-derived EPC from cryopreserved mononuclear cells. Proliferation and migration function of EPC is preserved after cryopreservation.
Asunto(s)
Células de la Médula Ósea , Criopreservación , Células Endoteliales/fisiología , Trasplante de Células Madre/tendencias , Células Madre/fisiología , Animales , Movimiento Celular/fisiología , Proliferación Celular , Células Cultivadas , Células Endoteliales/citología , Predicción , Modelos Animales , Sensibilidad y Especificidad , Células Madre/citología , Porcinos , Porcinos EnanosRESUMEN
OBJECTIVE: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine. METHODS: Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated. RESULTS: Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% +/- 3% vs 70% +/- 7%, ATOR vs NORM at 10(-10) mol/L, P = .05) and fibroblast growth factor-2 (35% +/- 3% vs 57% +/- 5%, ATOR vs NORM at 10(-10) mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (-0.29 +/- 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% +/- 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% +/- 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups. CONCLUSIONS: Atorvastatin supplementation is associated with impaired growth factor-mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Isquemia Miocárdica/fisiopatología , Neovascularización Fisiológica/efectos de los fármacos , Pirroles/farmacología , Animales , Atorvastatina , Colesterol/sangre , Circulación Colateral/efectos de los fármacos , Femenino , Técnicas In Vitro , Masculino , Microcirculación/efectos de los fármacos , PorcinosRESUMEN
OBJECTIVE: Growth factor and cell-based angiogenesis are attractive therapeutic options for diabetic patients with end-stage coronary disease. Reduced collateral vessel formation observed in diabetes is associated with increased expression of anti-angiogenic proteins, angiostatin and endostatin. The aim of this study was to determine the effects of insulin treatment on the diabetic angiogenic response to chronic myocardial ischemia. METHODS: Yucatan miniswine were treated with alloxan (pancreatic beta-cell specific toxin, 150 mg/kg) and divided into two groups. In the diabetic group (DM, n = 8), blood glucose levels were kept greater than 250 mg/dL, and in the insulin-treated group (IDM, n = 6), intramuscular insulin was administered daily to keep blood glucose less than 150 mg/dL. A third group of age-matched swine served as nondiabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex artery ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using microspheres. Microvascular function, capillary density, and myocardial expression of anti-angiogenic mediators were evaluated. RESULTS: Diabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate and substance P, which were reversed in insulin-treated animals. Collateral-dependent perfusion in the ischemic circumflex territory, which was profoundly reduced in diabetic animals (-0.18 +/- 0.02 vs +0.23 +/- 0.07 mL . min(-1) . g(-1); P < .001), improved significantly with insulin treatment (0.12 +/- 0.05 mL . min(-1) . g(-1); P < .01). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.3- and 3.6-fold increase in diabetic animals respectively (both P < .01 vs ND), was markedly reduced in insulin-treated animals (2.3- and 1.8-fold vs ND; both P < .01). CONCLUSIONS: Insulin treatment successfully reversed diabetic coronary endothelial dysfunction and significantly improved the endogenous angiogenic response. These pro-angiogenic effects may be mediated through downregulation of anti-angiogenic mediators. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetic patients.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Angiopatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Inhibidores de la Angiogénesis , Animales , Enfermedad Crónica , Circulación Colateral/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Angiopatías Diabéticas/complicaciones , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Técnicas In Vitro , Insulina/uso terapéutico , Masculino , Microcirculación/efectos de los fármacos , Isquemia Miocárdica/etiología , Isquemia Miocárdica/fisiopatología , PorcinosRESUMEN
OBJECTIVES: Cardiac surgery using cardioplegia and cardiopulmonary bypass subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function. Research in animal and cell models demonstrates that acute myocardial ischemia/reperfusion injury causes phosphorylation of heat shock protein 27 and alphaB-crystallin. Phosphorylation of heat shock protein 27 and alphaB-crystallin is implicated in the regulation of both beneficial and detrimental responses to ischemic injury. The phosphorylation status of these proteins in human myocardium after ischemic insults associated with cardioplegia and cardiopulmonary bypass is unknown. METHODS: Right atrial appendage and chest wall skeletal muscle samples were collected from patients before and after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass-induced changes in phosphorylation and localization of heat shock protein 27 and alphaB-crystallin were determined using immunoblot and confocal microscopy with total and phospho-specific antibodies. RESULTS: Cardioplegia and cardiopulmonary bypass increased the phosphorylation of heat shock protein 27 on serine 15, 78, and 82, and alphaB-crystallin on serine 59 and 45, but not serine 19. The majority of heat shock protein 27 and alphaB-crystallin localized to I-bands of cardiac myofilaments and shifted to a detergent insoluble fraction after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass-induced phosphorylation of specific heat shock protein 27 and alphaB-crystallin residues were associated with additional subcellular locations. Increases in phosphorylation of heat shock protein 27 and alphaB-crystallin were negatively correlated with cardiac function after surgery. CONCLUSION: Cardiac surgery using cardioplegia and cardiopulmonary bypass is associated with phosphorylation and myofilament translocation of heat shock protein 27 and alphaB-crystallin in human myocardium. Phosphorylation of specific heat shock protein 27 and alphaB-crystallin serine residues is associated with distinct localization. Understanding the human myocardial small heat shock protein response may have significant implications for surgical myocardial protection.
Asunto(s)
Puente Cardiopulmonar/efectos adversos , Paro Cardíaco Inducido/efectos adversos , Proteínas de Choque Térmico/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Cadena B de alfa-Cristalina/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patología , Electroforesis en Gel de Poliacrilamida , Humanos , Immunoblotting , Microscopía Confocal , Microscopía Fluorescente , Daño por Reperfusión Miocárdica/etiología , Miocardio/patología , FosforilaciónRESUMEN
OBJECTIVES: Neurologic injury after cardiac surgery, often manifested as neurocognitive decline, is a common postoperative complication without clear cause. We studied acute variations in gene-expression profiles of patients with neurocognitive decline (NCD group) compared with those without neurocognitive decline (NORM group) after cardiopulmonary bypass. METHODS: Forty-two patients undergoing coronary artery bypass grafting, valve procedures, or both by using cardiopulmonary bypass were administered a validated neurocognitive battery preoperatively and postoperatively at day 4. Neurocognitive decline was defined as 1 standard deviation from baseline on 25% or greater of tasks. Whole-blood mRNA was isolated preoperatively and at 6 hours after surgical intervention for fold-change calculation. Relative gene expression in the NCD versus the NORM group was assessed by using Affymetrix GeneChip U133 Plus 2.0 (>40,000 genes) from mRNA samples collected. Differential expression, clustering, gene ontology, and canonical pathway analysis were performed. Validation of microarray gene expression was performed with SYBR Green real-time polymerase chain reaction. RESULTS: Patients with neurocognitive decline (17/42 [40.5%] patients) were associated with a significantly different gene-expression response compared with that of healthy patients. Compared with preoperative samples, 6-hour samples had 531 upregulated and 670 downregulated genes uniquely in the NCD group compared with 2214 upregulated and 558 downregulated genes uniquely in the NORM group (P < .001; lower confidence bound, > or =1.2). Compared with patients in the NORM group, patients with neurocognitive decline had significantly different gene-expression pathways involving inflammation (including FAS, IL2RB, and CD59), antigen presentation (including HLA-DQ1, TAP1, and TAP2), and cellular adhesion (including ICAM2, ICAM3, and CAD7) among others. CONCLUSIONS: Patients with neurocognitive decline have inherently different genetic responses to cardiopulmonary bypass compared with those of patients without neurocognitive decline Genetic variations in inflammatory, cell adhesion, and apoptotic pathways might be important contributors to the pathophysiology of neurologic injury after cardiopulmonary bypass and could become a target for prevention and risk stratification.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/efectos adversos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Expresión Génica , Anciano , Puente Cardiopulmonar , Distribución de Chi-Cuadrado , Trastornos del Conocimiento/diagnóstico , Femenino , Humanos , Masculino , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: New-onset postoperative atrial fibrillation (PAF) continues to be among the most common complications after cardiac surgery, leading to significant morbidity and cost. We studied the role of oxidative stress on patients after cardiopulmonary bypass. METHODS: Patients undergoing coronary artery bypass grafting or valve procedures who exhibited new-onset PAF (n = 11) and those who remained in sinus rhythm (n = 13) were prospectively matched based on preoperative, intraoperative, and postoperative characteristics. Postoperative atrial fibrillation was assessed by electrocardiogram and must have required initiation of antiarrhythmic therapy or anticoagulation. Right atrial and skeletal muscle samples were harvested before and after cardiopulmonary bypass for oxidative protein immunostaining (Oxyblot assay). Serum samples were collected preoperatively and postoperatively at 6 hours and day 4 for microarray assessment of gene expression and to quantify total peroxide levels. RESULTS: Patients with PAF had significantly more elevation in total peroxide levels in serum compared with patients in sinus rhythm at 6 hours (5.83 +/- 1.9 versus 2.02 +/- 0.2 fold, respectively; p = 0.039) but not at day 4 (3.81 +/- 1.2 versus 2.17 +/- 0.5 fold, respectively; p = 0.188). Patients with PAF also had significantly more myocardial oxidation compared with patients in sinus rhythm at 6 hours (4.19 +/- 1.4 versus 0.94 +/- 0.3 fold, respectively; p = 0.021). Increased serum peroxide levels in patients who exhibited PAF correlated with elevated myocardial protein oxidation but not peripheral muscle oxidation. Gene expression analysis revealed a differential genomic response in patients with new-onset PAF (more oxidation) compared with patients in sinus rhythm (more reduction). CONCLUSIONS: Patients who exhibit PAF after cardiac surgery have significantly increased acute oxidative stress, which translates into increased myocardial oxidation. Also, patients with PAF have a differential oxidative genomic response after cardiopulmonary bypass that may predispose them to oxidative stress.
Asunto(s)
Fibrilación Atrial/etiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Peroxidación de Lípido/fisiología , Estrés Oxidativo/fisiología , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/mortalidad , Procedimientos Quirúrgicos Cardíacos/métodos , Estudios de Casos y Controles , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/métodos , Femenino , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Medición de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. METHODS AND RESULTS: Diabetes was induced in male Yucatan miniswine using a pancreatic beta-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173+/-14 versus 234+/-23 cells/hpf, P=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4+/-0.9-fold increase, P<0.001), and endostatin (2.9+/-0.4-fold increase, P=0.03) were significantly elevated in the diabetic myocardium. CONCLUSIONS: Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Isquemia Miocárdica/fisiopatología , Neovascularización Patológica/fisiopatología , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Masculino , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Porcinos , Porcinos Enanos , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) can lead to dysfunction in the coronary and skeletal microcirculation leading to impaired tissue perfusion. alpha-Adrenergic signaling pathways acting on these microcirculatory beds are thought to involve protein kinase C (PKC). We investigate here the role of the conventional PKCs in microvascular function in the setting of CP/CPB. METHODS: Atrial and skeletal muscle was harvested from 30 patients undergoing cardiac surgery before and after CP/CPB. Microvessels were used for Western blotting and immunofluorescent staining against conventional PKCs. Microvascular constriction was assessed in pre- and post-CP/CPB samples in response to alpha-adrenergic stimulation with phenylephrine, with and without a PKC-alpha inhibitor or PKC-alpha activator. PKC activity was assessed in isolated microvessels. RESULTS: Western blotting and immunostaining demonstrated only PKC-alpha in coronary and skeletal microvessels. CP/CPB diminished contractile responses to phenylephrine in coronary and skeletal samples. Inhibition of PKC-alpha reduced phenylephrine induced vasoconstriction in coronary and skeletal microvessels, whereas activation of PKC-alpha-augmented phenylephrine induced responses. PKC activity was decreased in coronary microvessels and to an even greater degree in skeletal microvessels after CP/CPB. CONCLUSIONS: PKC-alpha is the predominant conventional PKC present in the human coronary and skeletal microcirculation. It likely plays a key role in alpha-adrenergic signaling in microvessels and in the vasomotor dysfunction after CP/CPB.
Asunto(s)
Capilares/enzimología , Circulación Coronaria/fisiología , Músculo Esquelético/irrigación sanguínea , Proteína Quinasa C-alfa/metabolismo , Anciano , Western Blotting , Activación Enzimática/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Microcirculación/fisiología , Persona de Mediana Edad , Miocardio , Proteína Quinasa C/metabolismo , Proteína Quinasa C beta , Vasoconstricción/fisiologíaRESUMEN
BACKGROUND: Arteriovenous grafts often fail due to stenosis caused by venous anastomotic intimal hyperplasia (IH) and vascular smooth muscle cell (VSMC) proliferation. We examined the effects of inhaled carbon monoxide (CO), a product of heme-oxygenase-1 degradation of heme, on IH in a porcine arteriovenous graft model. MATERIALS AND METHODS: Eighteen Yorkshire pigs were divided into three groups (N = 6/group): (1) CO 100 ppm preoperatively for 1 h; (2) CO 250 ppm preoperatively for 1 h and intraoperatively; and (3) air-treated controls. Animals underwent end-to-side placement of polytetrafluoroethylene grafts connecting the common femoral artery and vein in both groins. Intimal thickness of the venous anastomosis at 30 days was measured blinded. The effect of CO on pig VSMC proliferation was studied in cell culture using [(3)H]thymidine incorporation. RESULTS: Pigs in the group receiving CO 250 ppm showed significantly less IH compared to animals in the group receiving 100 ppm and the air-treated group (267.5 +/- 21.4, 824 +/- 145.8, and 914.8 +/- 133.7 pixels, respectively, P < 0.0001). This effect was not observed when comparing the 100 ppm group to the air-treated group. COHb levels were significantly elevated in the 100 ppm and 250 ppm compared to air-treated pigs (5.8 +/- 0.47, 13.2 +/- 1.0 versus 2.3 +/- 0.11%, respectively, P < 0.001). Oxygen saturation, respiratory rate, and hemodynamics were not significantly different between the groups. CO induced VSMC growth arrest compared to air in vitro (11.9 +/- 4 versus 20.3 +/- 5 10(3) counts/min/well, P < 0.01). CONCLUSION: A single exposure to a low concentration of inhaled CO (250 ppm) confers protection against intimal proliferation of VSMCs when given perioperatively in a clinically relevant model of arteriovenous grafts. These data are the first to suggest, in a clinically relevant model, the potential role for CO in clinical applications.
Asunto(s)
Antimetabolitos/farmacología , Prótesis Vascular , Monóxido de Carbono/farmacología , Oclusión de Injerto Vascular/tratamiento farmacológico , Oclusión de Injerto Vascular/prevención & control , Administración por Inhalación , Animales , Implantación de Prótesis Vascular , División Celular/efectos de los fármacos , Células Cultivadas , Arteria Femoral , Vena Femoral , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Politetrafluoroetileno , Sus scrofa , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patologíaRESUMEN
OBJECTIVES: The disappointing results of myocardial angiogenic therapy have been attributed, in part, to endothelial dysfunction present in patients with coronary disease. Statins have established proendothelial properties but seem to have dose-dependent effects on angiogenesis. We investigated the functional and molecular effects of high-dose atorvastatin on vascular endothelial growth factor-induced myocardial angiogenesis in hypercholesterolemic swine. METHODS: Yucatan miniswine (20-30 kg) were fed either a normal (ND group, n = 8) or high-cholesterol diet, with (HC-ATOR group, n = 8) or without (HC group, n = 8) atorvastatin (3 mg x kg(-1) x d(-1)), for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery, followed 3 weeks later by perivascular vascular endothelial growth factor administration (2 microg over 4 weeks) with a sustained release osmotic pump. Microvessel relaxation responses, myocardial perfusion, and myocardial expression of angiogenic mediators were assessed 4 weeks later. RESULTS: Hypercholesterolemic swine demonstrated impaired microvessel relaxation to vascular endothelial growth factor (P < .01 vs ND group) and adenosine diphosphate (P < .001 vs ND group), which was normalized in the HC-ATOR group. After perivascular vascular endothelial growth factor administration, collateral-dependent myocardial perfusion was significantly increased in the ND group but decreased in both the HC and HC-ATOR groups (both P < .01 vs the ND group). The animals in the HC-ATOR group demonstrated increased myocardial expression of the antiangiogenic protein endostatin and increased Akt phosphorylation without significant changes in Akt and endothelial nitric oxide synthase expression. CONCLUSIONS: Atorvastatin treatment reverses hypercholesterolemia-induced endothelial dysfunction without appreciable improvements in collateral-dependent myocardial perfusion in response to vascular endothelial growth factor treatment. Increased myocardial endostatin expression and chronic Akt activation, associated with atorvastatin therapy, might account for the lack of improvement in the angiogenic response to vascular endothelial growth factor therapy.