RESUMEN
BACKGROUND: Microsomal prostaglandin E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E(2) biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges(-/-) mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges(+/+) mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow-derived leukocytes in the recovery of LV function after coronary ligation. METHODS AND RESULTS: Cardiac structure and function in Ptges(+/+) mice with Ptges(+/+) bone marrow (BM(+/+)) and Ptges(+/+) mice with Ptges(-/-) BM (BM(-/-)) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography-tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM(-/-) mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM(+/+) mice. BM(-/-) mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM(+/+) mice. Levels of prostaglandin E(2) were higher in the infarct and viable myocardium of BM(-/-) mice than in BM(+/+) mice. CONCLUSIONS: Lack of mPGES-1 in bone marrow-derived leukocytes negatively regulates COX-1 expression, prostaglandin E(2) biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction.
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Oxidorreductasas Intramoleculares/metabolismo , Microsomas/enzimología , Células Mieloides/enzimología , Infarto del Miocardio/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Animales , Presión Sanguínea/fisiología , Células de la Médula Ósea/enzimología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Diástole/fisiología , Modelos Animales de Enfermedad , Oxidorreductasas Intramoleculares/genética , Leucocitos/enzimología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Miocarditis/genética , Miocarditis/metabolismo , Miocarditis/mortalidad , Prostaglandina-E Sintasas , Sístole/fisiología , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/mortalidad , Remodelación Ventricular/fisiologíaRESUMEN
Stem cells exhibit long-term self-renewal by asymmetric division and multipotent differentiation. During embryonic development, cell fate is determined with predictable orientation, differentiation, and partitioning to form the organism. This includes the formation of a hemangioblast from which 2 derivative cell clusters commit to either a hematopoietic or an endothelial lineage. Frequently, it is not clear whether tissue resident stem cells in the adult originate from the bone marrow. Here, we show that blast colony-forming cells exhibiting bilineage (hematopoietic and vascular) potential and long-term self-renewal originate from the uterus in the mouse. This is the first in vitro and in vivo evidence of an adult hemangioblast retained from development in the uterus. Our findings offer new understanding of uterine cell renewal and turnover and may provide insights and opportunities for the study of stem cell maintenance.
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Hemangioblastos/citología , Hematopoyesis , Útero/citología , Animales , Linaje de la Célula , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Femenino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Bicuspid aortic valve is associated with aortic aneurysm formation that may extend beyond the ascending aorta. METHODS: Between 1979 and 1997, 143 bicuspid aortic valve patients had aortic valve operations with replacement of an aneurysmal ascending aorta: 93 (65%) underwent full root replacement and 50 (35%) underwent separate valve and graft replacement. Distal aortic anastomosis was open in 42 patients (29%) and closed in 101 (71%). Late survival and complications were compared by surgical technique. RESULTS: Patients undergoing full root replacement tended to be younger (mean age 46 +/- 16 vs 59 +/- 13, p < 0.001) and presented with more aortic insufficiency (80% vs 35%, p < 0.001). Three (2.1%) hospital deaths occurred. Event-free survival was 82% (95% confidence interval, 75% to 88%) at 10 years and 41% (95% confidence interval, 11% to 71%) at 20 years. At a median follow-up of 11.5 years, the incidence of new aneurysms and late aortic complications were not significantly different among the procedure groups. Age at the time of operation was the only predictor of late survival (hazard ratio, 1.07; p = 0.007). CONCLUSIONS: Aortic root replacement with distal aortic reconstruction can be achieved with very low operative mortality and excellent long-term outcomes in patients with bicuspid aortic valve and dilated ascending aorta. The type of surgical procedure done in the aortic root and in the distal ascending aorta does not influence late survival, subsequent operation, or aortic complications. This is likely influenced by our patient-specific strategy when replacing the aortic root and distal ascending aorta.
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Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/cirugía , Válvula Aórtica/anomalías , Válvula Aórtica/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Cell therapy has received much attention for its potential to regenerate ischemic organs, but initial clinical trials in aged patients did not replicate the dramatic benefits recorded in preclinical studies with young animals. This study was designed to improve our understanding of age-related changes in the response to ischemic injury and the regenerative capacity of implanted cells in the context of cell therapy for older recipients. METHODS AND RESULTS: Restoration of regional perfusion after hind limb femoral artery ligation was impaired (P < .05) in old (vs young) rats, reflecting approximately 50% reductions in circulating endothelial progenitor cells and the release of vascular endothelial growth factor/basic fibroblast growth factor. Bone marrow stromal cells from young or old donors implanted into the ischemic hind limbs of young or old rats restored regional perfusion. Specifically, we documented significantly greater (P < .05) angiogenic potential in young (vs old) donor cells when recipient age was controlled and greater (P < .05) regenerative responses in young (vs old) recipients when donor cell age was controlled. Contributing to these differences were significantly greater survival in young (vs old) donor cells (in vitro and after implantation) and about 2-fold more production of vascular endothelial growth factor/basic fibroblast growth factor and mobilization of endogenous endothelial progenitor cells in young (vs old) rats in response to ischemia. CONCLUSIONS: The outcome of cell therapy in older recipients is determined by a combination of age effects on the donor cells and on the recipients' endogenous responses. Donor cell age and recipient age are equally important contributors to the outcome of cell therapy; thus, novel biointerventions will need to target both components of the process.
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Envejecimiento , Trasplante de Médula Ósea , Células Endoteliales/trasplante , Isquemia/cirugía , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , Trasplante de Células Madre , Factores de Edad , Animales , Movimiento Celular , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Femenino , Arteria Femoral/cirugía , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Miembro Posterior , Isquemia/metabolismo , Isquemia/patología , Isquemia/fisiopatología , Flujometría por Láser-Doppler , Ligadura , Músculo Esquelético/patología , Ratas , Ratas Endogámicas Lew , Flujo Sanguíneo Regional , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVES: This study evaluated the capacity of ultrasound-targeted microbubble destruction (UTMD) to deliver angiogenic genes, improve perfusion, and recruit progenitor cells after a myocardial infarction (MI) in mice. BACKGROUND: Angiogenic gene therapy after an MI may become a clinically relevant approach to improve the engraftment of implanted cells if targeted delivery can be accomplished noninvasively. The UTMD technique uses myocardial contrast echocardiography to target plasmid gene delivery to the myocardium and features low toxicity, limited immunogenicity, and the potential for repeated application. METHODS: Empty plasmids (control group) or those containing genes for vascular endothelial growth factor (VEGF), stem cell factor (SCF), or green fluorescent protein (to visualize gene delivery) were incubated with perflutren lipid microbubbles. The microbubble-deoxyribonucleic acid mixture was injected intravenously into C57BL/6 mice at 7 days after coronary artery ligation (MI). The UTMD technique facilitated transgene release into the myocardium. Twenty-one days after MI, myocardial perfusion and function were assessed by contrast echocardiography. Protein expression was quantified by Western blot and enzyme-linked immunosorbent assay. Flow cytometry quantified progenitor cell recruitment to the heart. Blood vessel density was evaluated immunohistochemically. RESULTS: Green fluorescent protein expression in the infarcted myocardium demonstrated gene delivery. Myocardial VEGF and SCF levels increased significantly in the respective groups (p < 0.05). The physiologic impact of VEGF and SCF gene delivery was confirmed by increased myocardial recruitment of VEGF receptor 2- and SCF receptor (c-kit)-expressing cells, respectively (p < 0.05). Consequently, capillary and arteriolar density (Factor VIII and alpha-smooth muscle actin staining), myocardial perfusion, and cardiac function were all enhanced (p < 0.01 relative to control group) in recipients of VEGF or SCF. CONCLUSIONS: Noninvasive UTMD successfully delivered VEGF and SCF genes into the infarcted heart, increased vascular density, and improved myocardial perfusion and ventricular function. The UTMD technique may be an ideal method for noninvasive, repeated gene delivery after an MI.
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Circulación Coronaria , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Infarto del Miocardio/terapia , Miocardio/metabolismo , Neovascularización Fisiológica , Factor de Células Madre/biosíntesis , Ultrasonido , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Animales , Medios de Contraste/administración & dosificación , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Fluorocarburos/administración & dosificación , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Humanos , Infusiones Intravenosas , Ratones , Ratones Endogámicos C57BL , Microburbujas , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/patología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Recuperación de la Función , Factor de Células Madre/genética , Células Madre/metabolismo , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Función Ventricular IzquierdaRESUMEN
In recent years, the differentiation of bone marrow cells (BMCs) into myocytes has been extensively investigated, but the findings remain inconclusive. The purpose of this study was to determine the conditions necessary to induce myogenic differentiation in short-term cultures of adult BMCs, and to identify the BMC subpopulation responsible for this phenomenon. We report that high-density cultures of murine hematopoietic BMCs gave rise to spontaneous beating cell clusters in the presence of vascular endothelial and fibroblast growth factors. These clusters originated from c-kit(pos) cells. The formation of the clusters could be completely blocked by adding a c-kit/tyrosine kinase inhibitor, Gleevec (imatinib mesylate; Novartis International, Basel, Switzerland, http://www.novartis.com), to the culture. Cluster formation was also blunted in BMCs from c-kit-deficient (Kit(W)/Kit(W-v)) mice. Clustered cells expressed cardiomyocyte-specific transcription factor genes Gata-4 and Nkx2.5, sarcomeric proteins beta-MHC and MLC-2v, and ANF and connexin-43. Immunostaining revealed alpha-sarcomeric actinin expression in more than 90% of clustered cells. Under electron microscopy, the clustered cells exhibited a sarcomeric myofiber arrangement and z-bands. This study defines the microenvironment required to achieve a reproducible in vitro model of beating, myogenic cell clusters. This model could be used to examine the mechanisms responsible for the postnatal myogenic differentiation of BMCs. Our results identify c-kit(pos) bone marrow hematopoietic cells as the source of the myogenic clusters.
Asunto(s)
Células de la Médula Ósea/citología , Células Madre Hematopoyéticas/citología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Adulto , Animales , Benzamidas , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Diferenciación Celular/fisiología , Linaje de la Célula , Movimiento Celular/fisiología , Células Cultivadas , Factor 2 de Crecimiento de Fibroblastos/farmacología , Expresión Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Mesilato de Imatinib , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica , Microscopía de Contraste de Fase , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
OBJECTIVES: Cell therapy improved cardiac function after a myocardial infarction in several preclinical studies; however, the functional benefits were limited in the initial clinical trials, perhaps because of inadequate cell engraftment. We used noninvasive molecular imaging to compare the distribution and myocardial retention of cells implanted by using clinical delivery routes. METHODS: Bone marrow stromal cells isolated from male rats and transfected with a firefly luciferase reporter gene were injected by using 3 increasingly invasive techniques (ie, intravenous, intra-aortic, and intramyocardial) into female rats 3 or 28 days after coronary ligation. Whole-body bioluminescence imaging was performed 2, 24, and 48 hours later; implanted cells were quantified at 48 hours in explanted organs by means of bioluminescence and real-time polymerase chain reaction. RESULTS: Variations in cell distribution among groups were profound, with nearly complete trapping of the injected cells in the lungs after intravenous delivery. Cell delivery into the aortic root (with the distal aorta occluded) produced minimal cell retention in the heart. Direct intramyocardial injection facilitated the best early targeting of the cells (P < .05 vs intravenous and intra-aortic injection). Rapid signal loss over 48 hours indicated very poor cell survival in all 3 groups, although implanted cell retention was greater in mature compared with acute infarcts. CONCLUSIONS: This is the first study to correlate live cell imaging with quantitative genetic and histologic techniques. Noninvasive molecular imaging tracked delivered cells and will permit the evaluation of new and improved delivery platforms designed to increase cell homing, retention, and engraftment.
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Trasplante de Médula Ósea/métodos , Inyecciones/métodos , Luciferasas de Luciérnaga/análisis , Mediciones Luminiscentes , Infarto del Miocardio/terapia , Análisis de Varianza , Animales , Movimiento Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Inmunohistoquímica , Inyecciones Intralesiones , Inyecciones Intravenosas , Masculino , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/terapia , Probabilidad , Distribución Aleatoria , Ratas , Ratas Endogámicas Lew , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Medición de Riesgo , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
OBJECTIVE: Cell-based gene therapy can enhance the effects of cell transplantation by temporally and spatially regulating the release of the gene product. The purpose of this study was to evaluate transient matrix metalloproteinase inhibition by implanting cells genetically modified to overexpress a natural tissue inhibitor of matrix metalloproteinases (tissue inhibitor of matrix metalloproteinase-3) into the hearts of mutant (tissue inhibitor of matrix metalloproteinase-3-deficient) mice that exhibit an exaggerated response to myocardial infarction. Following a myocardial infarction, tissue inhibitor of matrix metalloproteinase-3-deficient mice undergo accelerated cardiac dilatation and matrix disruption due to uninhibited matrix metalloproteinase activity. This preliminary proof of concept study assessed the potential for cell-based gene therapy to reduce matrix remodeling in the remote myocardium and facilitate functional recovery. METHODS: Anesthetized tissue inhibitor of matrix metalloproteinase-3-deficient mice were subjected to coronary ligation followed by intramyocardial injection of vector-transfected bone marrow stromal cells, bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3, or medium. Functional, morphologic, histologic, and biochemical studies were performed 0, 3, 7, and 28 days later. RESULTS: Bone marrow stromal cells and bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 significantly decreased scar expansion and ventricular dilatation 28 days after coronary ligation and increased regional capillary density to day 7. Only bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 reduced early matrix metalloproteinase activities and tumor necrosis factor alpha levels relative to medium injection. Bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 were also more effective than bone marrow stromal cells in preventing progressive cardiac dysfunction, preserving remote myocardial collagen content and structure, and reducing border zone apoptosis for at least 28 days after implantation. CONCLUSIONS: Tissue inhibitor of matrix metalloproteinase-3 overexpression enhanced the effects of bone marrow stromal cells transplanted early after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3-deficient mice by contributing regulated matrix metalloproteinase inhibition to preserve matrix collagen and improve functional recovery.
Asunto(s)
Infarto del Miocardio/fisiopatología , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Remodelación Ventricular/fisiología , Proteínas ADAM/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Colágeno/análisis , Modelos Animales de Enfermedad , Terapia Genética , Metaloproteinasa 2 de la Matriz/análisis , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Miocardio/química , Células del Estroma/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/análisis , Factor de Necrosis Tumoral alfa/análisis , Remodelación Ventricular/efectos de los fármacosRESUMEN
The mechanisms for the beneficial impact of bone marrow cell (BMC) therapy after myocardial infarction (MI) are ill defined. We hypothesized that the implanted cells improve function by attenuating post-MI inflammation and repair. In mice, 3 x 10(5) fresh BMCs were implanted immediately after coronary ligation. Cardiac function was evaluated over time. Inflammatory cytokines and cells were measured, and their impacts on the (myo)fibroblastic repair response, angiogenesis, and scar formation were determined. All differences below had P values of <0.05. BMC implantation reduced the decline in fractional shortening and ventricular dilation. Invasive hemodynamics confirmed a difference in systolic function at day 7 and diastolic function at day 28 favoring the BMC group. Interestingly, BMC implantation caused a 1.6-fold increase in the number of macrophages infiltrating the infarct but did not affect neutrophils. This increase was associated with a 1.9-fold higher myocardial TNF-alpha level. The heightened inflammatory response was associated with a 1.4-fold induction of transforming growth factor-beta and a 1.3-fold induction of basic fibroblast growth factor. These changes resulted in a 1.6-fold increase in alpha-smooth muscle actin and a 1.9-fold increase in total discoidin domain receptor 2-expressing cells in the BMC group. These two markers are expressed by cardiac (myo)fibroblasts. Capillary density in the border zone increased 2.0-fold. Consistent with a more robust repair-mediated scar "contracture," the final scar size was 0.7-fold smaller in the BMC group. In conclusion, after MI, BMC therapy induced a more robust inflammatory response that improved the "priming" of the (myo)fibroblast repair phase. Enhancing this response may further improve the beneficial impact of cellular therapy.
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Trasplante de Médula Ósea/efectos adversos , Corazón/fisiología , Miocarditis/etiología , Animales , Presión Sanguínea/fisiología , Volumen Sanguíneo/fisiología , Proliferación Celular , Vasos Coronarios/fisiología , Citocinas/metabolismo , Femenino , Fibroblastos/fisiología , Citometría de Flujo , Pruebas de Función Cardíaca , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismoRESUMEN
BACKGROUND: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes suggests that their beneficial effects on cardiac function after a myocardial infarction are mediated by paracrine effects. We evaluated the roles of these factors in the preservation of matrix architecture (in the infarct and remote regions) by varying the timing (postmyocardial infarction) and delivery site of the implanted cells. METHODS AND RESULTS: Skeletal myoblasts (5x10(6)) or control media were injected into the infarct or noninfarcted myocardium at 5 or 30 days after coronary artery ligation in rats. Function was assessed by echocardiography before transplantation and 14 and 30 days thereafter and with a Millar catheter at 30 days after transplantation. Ventricular geometry, remote fibrillar collagen architecture, and changes in the matrix metalloproteinase-TIMP system were evaluated. Myoblast implantation in both sites and at both times preserved matrix architecture (length and width of collagen fibers) in the remote myocardium (in association with some decreases in remote myocardial matrix metalloprotease activity), improved global cardiac function, and attenuated the progressive increase in end diastolic volume (P<0.05 for all measures compared with medium controls). Cells delivered into the infarct region preserved scar thickness; cells delivered into the noninfarcted myocardium preserved wall thickness. CONCLUSIONS: Regardless of whether the cells were injected into the infarct or the noninfarcted myocardium early after an myocardial infarction or later, skeletal myoblasts improved cardiac function by preventing ventricular dilation and preserving matrix architecture in the remote region, likely mediated by paracrine effects.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Mioblastos Esqueléticos/trasplante , Infarto del Miocardio/cirugía , Animales , Células Cultivadas , Colágeno/ultraestructura , Vasos Coronarios , Ecocardiografía , Femenino , Corazón/fisiopatología , Inyecciones , Ligadura , Metaloproteinasas de la Matriz/metabolismo , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/enzimología , Miocardio/ultraestructura , Ratas , Ratas Endogámicas Lew , Volumen Sistólico , Factores de Tiempo , Función Ventricular , Remodelación VentricularRESUMEN
OBJECTIVES: Bicuspid aortic valves are associated with a poorly characterized connective tissue disorder that predisposes to aortic catastrophes. Because no criterion exists dictating the appropriate extent of aortic resection in aneurysmal disease of the bicuspid aortic valve, we studied the patterns of aortic dilation in this population. METHODS: Sixty-four patients with bicuspid aortic valves who underwent computed tomographic or magnetic resonance angiography and echocardiography were retrospectively identified between January 2002 and March 2006. Orthonormal 2-dimensional or 3-dimensional aortic diameters were measured at 10 levels. Agglomerative hierarchic clustering with centered correlation distance measurements and complete linkage analysis was used to detect distinct patterns of aortic dilatation. RESULTS: Mean aortic diameter was 28.1 +/- 0.7 mm at the annulus and 21.7 +/- 0.4 mm at the diaphragmatic hiatus. The aorta was largest in the tubular ascending aorta (45.9 +/- 1.0 mm). Compared with the descending aorta, the transverse aortic arch was also dilated (P < .01). Cluster analysis showed 4 patterns of aortic dilatation: cluster I, aortic root alone (n = 8, 13%); cluster II, tubular ascending aorta alone (n = 9, 14%); cluster III, tubular portion and transverse arch (n = 18, 28%); and, cluster IV, aortic root and tubular portion with tapering across the transverse arch (n = 29, 45%). CONCLUSION: Distinct patterns of aortic dilatation in patients with bicuspid aortic valves call for an individualized degree of aortic replacement to minimize late aortic complications and reoperation. Patients in clusters III and IV should have transverse arch replacement (plus concomitant root replacement in cluster IV). Patients in cluster I should undergo complete aortic root replacement, whereas in patients in cluster II supracommissural ascending aortic grafting is adequate.
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Aneurisma de la Aorta/fisiopatología , Válvula Aórtica/patología , Enfermedades de las Válvulas Cardíacas/fisiopatología , Adolescente , Adulto , Anciano , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/diagnóstico , Femenino , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE(2) biosynthetic pathway. We caused acute MI in Ptges(+/+) and Ptges(-/-) mice to define the role of mPGES-1 in cardiac ischemic injury. METHODS AND RESULTS: Twenty-eight days after MI, Ptges(-/-) mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges(+/+) mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges(-/-) than Ptges(+/+) mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges(-/-) mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and alpha- and beta-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges(-/-) than Ptges(+/+) mice after MI. Ptges(+/+) mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges(-/-) mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE(2) but not PGD(2), thromboxane A(2), PGI(2), or PGF(2alpha) are higher in the infarct and LV remote from the infarct after MI in Ptges(+/+) than Ptges(-/-) mice. CONCLUSIONS: In Ptges(+/+) mice, mPGES-1 in inflammatory cells catalyzes PGE(2) biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.
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Eliminación de Gen , Oxidorreductasas Intramoleculares/deficiencia , Oxidorreductasas Intramoleculares/genética , Microsomas/enzimología , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Remodelación Ventricular/genética , Animales , Oxidorreductasas Intramoleculares/fisiología , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Infarto del Miocardio/genética , Prostaglandina-E Sintasas , Remodelación Ventricular/fisiologíaRESUMEN
INTRODUCTION: Murphy Roth Large (MRL) mice have a remarkable regenerative capacity. A recent report demonstrated rapid cardiac healing in these mice following cryogenically induced right ventricular injury, suggesting the potential for new regenerative therapies to restore cardiac function in mammals. We therefore evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice in response to a clinically relevant left ventricular coronary ligation. METHODS: Female MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation. Cardiac function was evaluated by echocardiography at Days 0, 5, 15, and 60. At Day 96, invasive hemodynamics were assessed by pressure-volume loops using a Millar catheter. Hearts were perfusion fixed for histomorphometric analysis at Days 5, 15, and 96. Some hearts were fresh frozen at Days 5 and 15 for immunohistochemical analysis and digital quantitation of blood vessel density (CD31) and cellular proliferation (Ki67). RESULTS: MRL mice healed ear punch wounds (89% reduction in area) more extensively than C57BL/6 mice (28% reduction in area) but did not differ functionally from C57BL/6 animals before or after coronary ligation. In addition, blood vessel density and cell proliferation were similar between the two strains. CONCLUSIONS: Although MRL mice rapidly healed ear injury, they did not exhibit regeneration of the left ventricle or enhanced functional improvement in response to coronary ligation. The prospect of cardiac regeneration after myocardial infarction will require further studies designed to elucidate the possible mechanisms of functional restoration.
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Infarto del Miocardio/fisiopatología , Miocardio/patología , Regeneración , Función Ventricular Izquierda , Cicatrización de Heridas , Animales , Proliferación Celular , Vasos Coronarios/cirugía , Modelos Animales de Enfermedad , Femenino , Ligadura , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Miocitos Cardíacos/patología , Neovascularización Fisiológica , Recuperación de la Función , Factores de TiempoRESUMEN
Cardiovascular disease is the number-one cause of mortality in the developed world. The aim of this study is to define the mechanisms by which bone marrow progenitor cells are mobilized in response to cardiac ischemic injury. We used a closed-chest model of murine cardiac infarction/reperfusion, which segregated the surgical thoracotomy from the induction of cardiac infarction, so that we could study isolated fluctuations in cytokines without the confounding impact of surgery. We show here that bone marrow activation of the c-kit tyrosine kinase receptor in response to released soluble KitL is necessary for bone marrow progenitor cell mobilization after ischemic cardiac injury. We also show that release of KitL and c-kit activation require the activity of matrix metalloproteinase-9 within the bone marrow compartment. Finally, we demonstrate that mice with c-kit dysfunction develop cardiac failure after myocardial infarction and that bone marrow transplantation rescues the failing cardiac phenotype. In light of the ongoing trials of progenitor cell therapy for heart disease, our study outlines the endogenous repair mechanisms that are invoked after cardiac injury. Amplification of this pathway may aid in restoration of cardiac function after myocardial infarction.
Asunto(s)
Médula Ósea/enzimología , Infarto del Miocardio/enzimología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Células Madre/fisiología , Animales , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/citología , Activación Enzimática , Femenino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/sangre , Proteínas Proto-Oncogénicas c-kit/genética , ARN Mensajero/biosíntesis , Factor de Células Madre/sangre , Factor de Células Madre/metabolismo , Células Madre/citología , Regulación hacia ArribaRESUMEN
BACKGROUND: Diabetic cardiomyopathy is a common cause of heart failure in diabetic patients, but current treatments do not directly improve ventricular function. Cell transplantation can prevent cardiac dilatation after injury, and may also prevent congestive heart failure in diabetic cardiomyopathy. AIM: This study evaluated the functional effects of smooth muscle cells (SMCs) implanted into the myocardium of insulin- and non insulin-treated diabetic rats. METHODS: Four weeks after streptozotocin infusion, adult Wistar rats were implanted with BrdU-labelled SMCs or culture media (N=12/group). Six rats in each group were also treated with insulin. Echocardiograms were performed at 0, 4 and 8 weeks after streptozotocin injection, and histology and heart function were evaluated at 4 weeks after implantation. RESULTS: Blood glucose levels decreased after insulin treatment. Among cell-injected rats, histology indicated that those that did not receive insulin retained fewer surviving BrdU+ SMCs, and a smaller volume of myocardial tissue positive for alpha-smooth muscle actin. Cardiac function was preserved in the insulin-treated groups relative to those that did not receive insulin. Among insulin-treated rats, the cell-injected group functioned better than the media-injected group. CONCLUSIONS: Diabetic cardiomyopathy is partially treatable with insulin; however, a combination of SMC transplantation and insulin treatment produced the best functional result. Cell transplantation may prevent the progression of diabetic cardiomyopathy in patients whose glucose levels are controlled with insulin.
Asunto(s)
Cardiomiopatías/terapia , Diabetes Mellitus Experimental/complicaciones , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Miocitos del Músculo Liso/trasplante , Animales , Aorta/citología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Cardiomiopatías/etiología , Terapia Combinada/métodos , Diabetes Mellitus Experimental/sangre , Supervivencia de Injerto/efectos de los fármacos , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3(-/-)). The coronary artery was ligated in timp-3(-/-) and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure-volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3(-/-) than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3(-/-) mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-alpha levels were significantly greater in timp-3(-/-) than in WT mice at different times after ligation. By histological evaluation, timp-3(-/-) mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium.
Asunto(s)
Infarto del Miocardio/enzimología , Inhibidor Tisular de Metaloproteinasa-3/deficiencia , Remodelación Ventricular/fisiología , Animales , Apoptosis , Vasos Sanguíneos/enzimología , Vasos Sanguíneos/patología , Volumen Cardíaco , Proliferación Celular , Ecocardiografía , Colágenos Fibrilares/metabolismo , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/fisiopatología , Miocardio/enzimología , Miocardio/patología , Presión , Análisis de Supervivencia , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Función Ventricular IzquierdaRESUMEN
PURPOSE OF REVIEW: Techniques of aortic root replacement have been developed that preserve the native aortic valve. These techniques avoid anticoagulation in patients who would otherwise receive a composite valve graft with a mechanical valve. RECENT FINDINGS: Longer-term data on the longevity of the main two techniques of aortic valve-sparing operations, the root remodeling and the valve reimplantation technique, are now becoming available. Root remodeling appears to have acceptable outcomes in patients without annuloaortic ectasia or Marfan syndrome. In such patients, the aortic valve reimplantation technique provides superior longevity because it provides external support for the aortic annulus and prevents ongoing dilatation. SUMMARY: Although aortic valve-sparing operations are being performed more frequently, particularly in younger patient populations, these procedures have not been adopted in the current guidelines. The excellent long-term outcomes of such procedures should facilitate their widespread adoption.
Asunto(s)
Aorta/cirugía , Aneurisma de la Aorta/cirugía , Válvula Aórtica/cirugía , Procedimientos Quirúrgicos Vasculares/métodos , HumanosRESUMEN
BACKGROUND: We hypothesized that c-kit receptor function in the bone marrow is important for facilitating healing, leading to efficient cardiac repair after myocardial infarction (MI). METHODS AND RESULTS: We used Kit(W)/Kit(W-v) c-kit mutant mice and their wild-type littermates to assess the importance of c-kit function in cardiac remodeling after coronary ligation. We found that mutant mice developed 1.6-fold greater ventricular dilation (P=0.008) attributable to a 1.3-fold greater infarct expansion by day 14 after MI (P=0.01). The number of proliferating smooth muscle alpha-actin expressing cells was 1.8-fold lower in mutant mice at day 3 (P<0.01), resulting in a 1.6 to 1.8-fold reduction in total regional nonvascular smooth muscle alpha-actin expressing cells by both microscopy and flow cytometry (P<0.001 for both). This decrease was accompanied by a 1.4-fold reduction in the number of CD31 expressing blood vessels (P<0.05). Prior transplantation of wild-type bone marrow cells into mutant mice rescued the efficient establishment of vessel-rich repair tissue by inducing a 1.5-fold increase in nonvascular smooth muscle alpha-actin expressing cells and CD31 expressing blood vessels (P<0.05 for both). The increased recruitment of cells into the infarct region in the chimeric mice was associated with reduced infarct expansion (P<0.03) compared to wild-type levels. CONCLUSIONS: Bone marrow c-kit function critically impacts the myofibroblast repair response in infarcted hearts. Interventions that increase the infiltration of c-kit+ cells to the infarcted heart may potentiate this endogenous repair response, prevent infarct expansion, and improve the recovery of cardiac function after MI.