Search PubMed⌕ Search

Biomedical subjects

Richard D Weisel

Publications and source records attributed to Richard D Weisel.

At least 55 records · Page 3Linked to original sources
PubMed2004

Vascular endothelial growth factor transgene expression in cell-transplanted hearts.

OBJECTIVE: We evaluated the effect of transplanted cell type, time, and region of the heart on transgene expression to determine the potential of combined gene and cell delivery for myocardial repair. METHODS: Lewis rats underwent myocardial cryoinjury 3 weeks before transplantation with heart cells (a mixed culture of cardiomyocytes, smooth muscle cells, endothelial cells and fibroblasts, n = 13), vascular endothelial growth factor-transfected heart cells (n = 13), skeletal myoblasts (n = 13), vascular endothelial growth factor-transfected skeletal myoblasts (n = 13), or medium (control, n = 12). Vascular endothelial growth factor expression in the scar, border zone, and normal myocardium was evaluated at 3 days and at 1, 2, and 4 weeks by means of quantitative polymerase chain reaction. Transplanted cells and vascular endothelial growth factor protein were identified immunohistologically on myocardial sections. RESULTS: Vascular endothelial growth factor levels were very low in control scars but increased transiently after medium injection. Transplantation with heart cells and skeletal myoblasts significantly increased vascular endothelial growth factor expression in the scar and border zone. Transplantation of vascular endothelial growth factor-transfected heart cells and vascular endothelial growth factor-transfected skeletal myoblasts further augmented vascular endothelial growth factor expression, resulting in 4- to 5-fold greater expression of vascular endothelial growth factor in the scar at 1 week. Peak vascular endothelial growth factor expression was greater and earlier in vascular endothelial growth factor-transfected heart cells than in vascular endothelial growth factor-transfected skeletal myoblasts. Vascular endothelial growth factor was primarily expressed by the transplanted cells. Some of the transplanted heart cells and vascular endothelial growth factor-transfected heart cells were identified in the endothelial layer of blood vessels in the scar. CONCLUSIONS: Transplantation of heart cells and skeletal myoblasts induces vascular endothelial growth factor expression in myocardial scars and is greatly augmented by prior transfection with a vascular endothelial growth factor transgene. Vascular endothelial growth factor expression is limited to the scar and border zone for 4 weeks. Both heart cells and skeletal myoblasts may be excellent delivery vehicles for cell-based myocardial gene therapy.

Animals↗
PubMed2004

Prevention and management of deep sternal wound infection.

Deep sternal wound infection (DSWI) is an uncommon but serious complication of median sternotomy in cardiac surgery, associated with significant mortality and morbidity. We performed a retrospective review of 30,102 consecutive cardiac surgical patients operated on at our institution from 1990 to 2003 and found an incidence of DSWI of 0.77%. The in-hospital mortality rate was 6.9% for DSWI patients versus 2.8% for patients without DSWI (P = 0.0002). Multivariable predictors for development of DSWI were old age, diabetes, previous stroke or TIA, and congestive heart failure. The use of bilateral internal thoracic artery (BITA) grafts increased the risk of DSWI in patients undergoing coronary artery bypass surgery, particularly in those with congestive heart failure alone or with diabetes. Skeletonization of BITA grafts resulted in a lower risk of DSWI, comparable to nondiabetic patients (1.3% versus 1.6%, P = 0.8). Patients with DSWI were treated with either sternal debridement and primary closure or sternectomy with myocutaneous flap reconstruction, resulting in a 6-month freedom from adverse event rate of 76% in both groups.

Cardiac Surgical Procedures↗
PubMed2004

Tissue-engineered grafts matured in the right ventricular outflow tract.

Autologous smooth muscle cell (SMC)-seeded biodegradable scaffolds could be a suitable material to repair some pediatric right ventricular outflow tract (RVOT) cardiac anomalies. Adult syngenic Lewis rat SMCs (2 x 10(6)) were seeded onto a new biodegradable copolymer sponge made of epsilon-caprolactone-co-L-lactide reinforced with poly-L-lactide fabric (PCLA). Two weeks after seeding, the patch was used to repair a surgically created RVOT defect in an adult rat. At 8 weeks after implantation the spongy copolymer component was biodegraded, and SM tissue and extracellular matrices containing elastin fibers were present in the scaffolds. By 22 weeks more fibroblasts and collagen were present (p < 0.05). The number of capillaries in the grafts also increased (p < 0.001) between 8 and 22 weeks. The fibrous poly-L-lactide component of the PCLA scaffold remained. The 22-week grafts maintained their thickness and surface area in the RVOT. The SMCs prior to implantation were in a synthetic phenotype and developed in vivo into a more contractile phenotype. By 8 weeks the patches were endothelialized on their endocardial surfaces. Future work to increase the SM tissue and elastin content in the patch will be necessary before implantation into a pediatric large-animal model is tested.

Absorbable Implants↗
PubMed2003

Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts.

BACKGROUND: Recurrent ventricular dilatation can occur after surgical repair of a left ventricular (LV) aneurysm. Use of an autologous bioengineered muscle graft to replace resected scar tissue may prevent recurrent dilatation and improve cardiac function. METHODS: Vascular smooth muscle cells (SMCs, 5 x 10(6) cells) from rat aortas were seeded onto synthetic PCLA (sponge polymer of epsilon-caprolactone-co-L-lactide reinforced with knitted poly-L-lactide fabric) patches and cultured for 2 weeks to allow tissue formation. Syngenic rats underwent proximal left coronary artery ligation to create a transmural myocardial scar. Four weeks after coronary ligation, cell-seeded patches (n=15) or unseeded patches (n=12) were used for a modified endoventricular circular patch plasty (EVCPP) repair of the infarct area. Ligated controls (n=14) and nonligated normal rats (n=10) had sham surgeries without EVCPP. Cardiac function was assessed by echocardiography and isolated Langendorff heart perfusion. Graft histology and morphology was also assessed. RESULTS: After 8 weeks in vivo, seeded patches were thicker (P<0.05) and smaller in area (P<0.003) than unseeded patches. Only seeded patches had prominent elastic tissue formation (P<0.001) in association with SMCs. LV systolic function by echocardiography was improved in the seeded group compared with both unseeded (P<0.002) and control groups (P<0.0001). LV volumes in both patch repair groups were comparable but were significantly smaller (P<0.05) than controls. LV distensibility tended toward improvement in the seeded group as compared with unseeded hearts, but the difference did not achieve statistical significance (P=0.06). CONCLUSIONS: Surgical repair with muscle-cell seeded grafts reduced abnormal chamber distensibility and improved LV function after myocardial infarction as compared with unseeded grafts. Bioengineered muscle grafts may be superior to synthetic materials for the surgical repair of LV scar.

Animals↗
PubMed2003

Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction.

BACKGROUND: Adipocyte-derived hormones may represent a mechanism linking insulin resistance to cardiovascular disease. In the present study, we evaluated the direct effects of resistin, a novel adipocyte-derived hormone, on endothelial activation. METHODS AND RESULTS: Endothelial cells (ECs) were incubated with human recombinant resistin (10 to 100 ng/ML, 24 hours), and endothelin-1 (ET-1) release, ET-1 mRNA expression, and nitric oxide (NO) production were assessed. Transient transfection assays were used to evaluate the effects of resistin on transcription of human ET-1 gene promoter. Furthermore, the effects of resistin on AP-1-mutated ET-1 promoter were evaluated. The effects of resistin on expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) were studied in addition to CD40 receptor, CD40 ligand-induced MCP-1 expression, and tumor necrosis factor receptor-associated factor-3 (TRAF3), an inhibitor of CD40 signaling. Incubation of ECs with resistin resulted in an increase in ET-1 release and ET-1 mRNA expression, with no change in NO production. Whereas treatment with resistin resulted in an increase in ET-1 promoter activity, the AP-1-mutated promoter was inactive after resistin stimulation. Additionally, resistin-treated cells showed increased expression of VCAM-1 and MCP-1, with concomitant reductions in TRAF-3 expression. Resistin did not alter CD40 receptor expression; however, increased CD40 ligand induced MCP-1 production. CONCLUSIONS: The novel adipokine resistin exerts direct effects to promote EC activation by promoting ET-1 release, in part by inducing ET-1 promoter activity via the AP-1 site. Furthermore, resistin upregulates adhesion molecules and chemokines and downregulates TRAF-3, an inhibitor of CD40 ligand signaling. In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome.

Adipocytes↗
PubMed2003

C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle.

BACKGROUND: Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of angiotensin type 1 receptor (AT1-R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT1-R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the angiotensin receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model. METHODS AND RESULTS: The effects of human recombinant CRP (0 to 100 microg/mL) on AT1-R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT1-R binding was assessed with 125I-labeled angiotensin II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [3H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II-induced ROS production were evaluated by 2',7'-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT1-R mRNA and protein expression and increased AT1-R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT1-R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan. CONCLUSIONS: CRP, at concentrations known to predict cardiovascular events, upregulates AT1-R-mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.

Angioplasty, Balloon↗
PubMed2003

C-reactive protein activates the nuclear factor-kappaB signal transduction pathway in saphenous vein endothelial cells: implications for atherosclerosis and restenosis.

OBJECTIVES: Elevated levels of C-reactive protein are one of the strongest prognostic factors in atherosclerosis. In addition to predicting vascular disease, C-reactive protein may directly facilitate the development of a proinflammatory and proatherosclerotic phenotype. Recent studies have demonstrated marked up-regulation of various adhesion molecules and inflammatory responses in endothelial cells subjected to C-reactive protein. The nuclear factor-kappaB signal transduction is known to play a key role in the expression of these proatherogenic entities. This study examines the direct effects of C-reactive protein on nuclear factor-kappaB activation and related mechanisms in saphenous vein endothelial cells. METHODS: The activation of nuclear factor-kappaB was determined by confocal microscopy assessing the nuclear localization of nuclear factor-kappaB in endothelial cells incubated with C-reactive protein (50 microg/mL) for 30 minutes and 3 hours. Cells not incubated with C-reactive protein were used as negative controls, and cells incubated with tumor necrosis factor-alpha (10 ng/mL) for 15 minutes were used as positive controls in all studies. The degradation of IkappaB-alpha and IkappaB-beta was assessed by Western blotting of the cell lysates obtained from cells incubated with human recombinant C-reactive protein (50 microg/mL) for 15 minutes, 30 minutes, and 1 hour. RESULTS: Nuclear factor-kappaB nuclear translocation in endothelial cells increased significantly after 30 minutes of incubation with C-reactive protein (P <.01). Nuclear localization of nuclear factor-kappaB returned to baseline levels after 3 hours of incubation with C-reactive protein. Incubation with C-reactive protein resulted in degradation of IkappaB-alpha that was maximal at 30 minutes (P <.05). C-reactive protein showed no significant effect on IkappaB-beta degradation. CONCLUSIONS: These data demonstrate, for the first time, that C-reactive protein activates the nuclear factor-kappaB signal transduction pathway in endothelial cells. Degradation of IkappaB-alpha, but not IkappaB-beta, seems to be the major pathway leading to nuclear factor-kappaB nuclear translocation and activation induced by C-reactive protein. These data support the concept that C-reactive protein, at concentrations known to predict diverse vascular insults, directly facilitates a proinflammatory and proatherosclerotic phenotype through activation of nuclear factor-kappaB. These data have important implications for saphenous vein atherosclerosis in patients with elevated C-reactive protein levels.

Arteriosclerosis↗
PubMed2003

Beneficial effect of autologous cell transplantation on infarcted heart function: comparison between bone marrow stromal cells and heart cells.

BACKGROUND: Cell transplantation may restore function after myocardial infarction, but the optimal cell type remains controversial. We compared autologous bone marrow stromal cells (BMCs) with autologous heart cells (HCs) in a porcine myocardial infarction model. METHODS: Yorkshire pigs underwent coil occlusion of the left anterior descending artery. Bone marrow stromal cells were obtained from sternal marrow and HCs were obtained by left ventricular biopsy, then cultured for 4 weeks. Four weeks after infarction, a 99mTc-sestamibi single-photon emission tomography (99mTc-MIBI SPECT) scan was performed and the pigs were then transplanted with BMCs (n = 7), HCs (n = 7), or culture medium (n = 14). Four weeks after transplantation, 99mTc-MIBI SPECT scanning was repeated to evaluate regional perfusion. Pressure-volume loops were constructed from micromanometer and conductance catheter data to evaluate left ventricular function. Hearts were evaluated histologically. RESULTS: Bone marrow stromal cells and HCs engrafted within the infarct and assumed a myocyte morphology. SPECT MIBI scans showed increased perfusion in the infarct in cell-transplanted pigs, while perfusion decreased in the control pigs. Heart cell transplantation improved preload-recruitable stroke work and HC and BMC transplantation both shifted the end-systolic pressure-volume relation to the left. Both BMCs and HCs prevented thinning and expansion of the infarct region, and some BMCs differentiated into endothelial cells in newly formed blood vessels perfusing the infarct. CONCLUSIONS: Both BMCs and HCs engrafted in the infarct region and improved let ventricular function by preventing infarct thinning. Bone marrow stromal cells demonstrated greater plasticity in vivo, and may offer a practical alternative to HC transplantation to restore function and perfusion after a myocardial infarction.

Animals↗
PubMed2003

Cardiac cell transplantation: closer to bedside.

The current treatment for heart failure is inadequate for a large number of patients who do not qualify for heart transplantation or innovative surgical therapy. Cellular augmentation of damaged myocardium has been actively investigated in the past decade. Cells best suited for the task are skeletal myoblasts and bone morrow mesenchymal stem cells. Both cell types are autologous, abundant, and easy to harvest. The focus of early human trials will be to establish the safety of an effective cellular dose. Trials conducted with an inadequate cellular dose may discredit cell therapy because of lack of effect but, more importantly, may provide a false sense of safety because of a lack of adverse events secondary to a small inoculating dose.

Animals↗
PubMed2003

Cell transplantation to prevent heart failure: a comparison of cell types.

BACKGROUND: Autologous cell transplantation may restore viable muscle after a myocardial infarction. We compared the effect of three cell types or an angiotensin-converting enzyme (ACE) inhibitor on preservation of ventricular function after cardiac injury. METHODS: A uniform transmural myocardial scar was created in adult rats by cryoinjury. Three weeks later the rats were randomly assigned to one of four blinded treatments: transplantation with 5 x 10(6) aortic smooth muscle cells (SMC, n = 12), ventricular heart cells (VHC, n = 13), skeletal muscle cells (SKC, n = 13) or culture medium alone (control, n = 11). The ACE inhibitor group (n = 8) received enalapril (1.0 mg/kg per day), also beginning 3 weeks after cryoinjury. Five and 12 weeks after transplantation, left ventricle (LV) function was assessed in a Langendorff apparatus, and histologic and immunohistological evaluation of the LV scars was performed. RESULTS: At 5 weeks, greater scar elastin content and better LV function was noted with cell transplantation or ACE inhibitor therapy compared with control rats (p < 0.05). Twelve weeks after transplantation, cell-transplanted rats still had greater elastin content and better LV function than control rats, although elastin content and LV function had declined in ACE inhibitor-treated animals to levels below those observed in control rats (p < 0.05). CONCLUSIONS: Transplantation of SMC, VHC, and SKC preserved ventricular function equivalent to the effects of an ACE inhibitor. Muscle cell transplantation, but not ACE inhibitor therapy, continues to be effective later after cryoinjury. No differences were detected between the muscle cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Hyperglycemia potentiates the proatherogenic effects of C-reactive protein: reversal with rosiglitazone.

Accumulating evidence suggests that C-reactive protein (CRP), at concentrations known to predict diverse vascular insults, directly promotes endothelial cell activation, uncovering a proatherosclerotic and proinflammatory phenotype. In the present study, we hypothesized that (a). hyperglycemia would serve to exaggerate the proatherogenic effects of CRP and (b). the PPARgamma agonist, rosiglitazone would attenuate this effect. Human saphenous vein endothelial cells were studied under the following conditions (n= 10 per group): control, human recombinant CRP (25 microg/ml, 24 h), hyperglycemia (25 mM, 24 h) and hyperglycemia + CRP. In each case, the effects of co-incubation with rosiglitazone (1 microM) were evaluated. Nitric oxide and endothelin-1 release from endothelial cells was quantified, in addition to the expression of adhesion molecules and monocyte chemoattractant chemokine (MCP-1). Incubation of endothelial cells with CRP increased endothelin-1 production, and upregulated adhesion molecule and MCP-1 expression. These proatherogenic effects of CRP were potentiated in the presence of hyperglycemia. CRP also decreased endothelial nitric oxide release, and this effect remained unchanged by hyperglycemia. Importantly, the PPARgamma agonist, rosiglitazone, attenuated the proatherogenic effects of CRP under both basal and hyperglycemic conditions. The direct proatherogenic actions of CRP are exaggerated in the hyperglycemic milieu, and attenuated by rosiglitazone. Elevated CRP levels in patients with diabetes may serve to uncover a severe proatherogenic phenotype.

Arteriosclerosis↗
PubMed2003

Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation.

BACKGROUND: Patients with bicuspid aortic valve malformations are at an increased risk of aortic dilatation, aneurysm formation, and dissection. Vascular tissues with deficient fibrillin-1 microfibrils release matrix metalloproteinases, enzymes that weaken the vessel wall by degrading elastic matrix components. In bicuspid aortic valve disease a deficiency of fibrillin-1 and increased matrix metalloproteinase matrix degradation might result in aortic degeneration and dilatation. METHODS: Samples of the pulmonary artery and aorta were obtained from surgical patients with bicuspid aortic valves (n = 21) and tricuspid aortic valves (n = 16). RESULTS: Fibrillin-1 content was reduced in bicuspid aortic valve aortas compared with that seen in tricuspid aortic valve aortas (P =.001), whereas the associated matrix components, elastin and collagen, were unchanged (P =.51 and P =.21). Reductions of aortic fibrillin-1 content were independent of valve function and patient age. Compared with tricuspid aortic valve aorta, matrix metalloproteinase 2 activity was increased more than 2-fold in bicuspid aortic valve aortas (P =.04) and correlated positively with aortic diameter (r = 0.74, P =.05). Matrix metalloproteinase 9 activity was not significantly different. Fibrillin-1 content was also reduced in the pulmonary arteries of patients with bicuspid aortic valves (P =.06), suggesting a systemic deficiency of fibrillin-1. Promatrix metalloproteinase 2 was increased (P =.04), reflecting an increased production of matrix metalloproteinase 2 in these fibrillin-1-deficient tissues, whereas active matrix metalloproteinase 2 and matrix metalloproteinase 9 species were unchanged, and correspondingly, the pulmonary arteries were not dilated. CONCLUSIONS: Deficient fibrillin-1 content in the vasculature of patients with bicuspid aortic valves might trigger matrix metalloproteinase production, leading to matrix disruption and dilatation. This process of vascular matrix remodeling in patients with bicuspid aortic valves offers novel therapeutic targets to prevent the aortic degeneration and dilatation characteristic of this disease.

Adult↗