166 research outputs found
A novel technique to assess flow-mediated vasodilation**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
406-2 Stem cell factor plays a critical role in neointimal formation by bone marrow derived progenitor cells
Vascular endothelial growth factor transgene expression in cell-transplanted hearts
AbstractObjectiveWe 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.MethodsLewis 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.ResultsVascular 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.ConclusionsTransplantation 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
Cell transplantation preserves matrix homeostasis: A novel paracrine mechanism
ObjectivesCell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation.MethodsSmooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (14C-proline uptake).ResultsLeft ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% ± 42% of CON, P = .02; TIMP-3, 118% ± 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% ± 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% ± 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation.ConclusionsThese data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis
a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma
Background Despite novel therapeutic agents, most multiple myeloma (MM)
patients eventually relapse. Two large phase III trials have shown
significantly improved response rates (RR) of lenalidomide/dexamethasone
compared with placebo/dexamethasone in relapsed MM (RMM) patients. These
results have led to the approval of lenalidomide for RMM patients and
lenalidomide/dexamethasone has since become a widely accepted second-line
treatment. Furthermore, in RMM patients consolidation with high-dose
chemotherapy plus autologous stem cell transplantation has been shown to
significantly increase progression free survival (PFS) as compared to
cyclophosphamide in a phase III trial. The randomized prospective ReLApsE
trial is designed to evaluate PFS after lenalidomide/dexamethasone induction,
high-dose chemotherapy consolidation plus autologous stem cell transplantation
and lenalidomide maintenance compared with the well-established
lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is
a randomized, open, multicenter phase III trial in a planned study population
of 282 RMM patients. All patients receive three lenalidomide/dexamethasone
cycles and - in absence of available stem cells from earlier harvesting -
undergo peripheral blood stem cell mobilization and harvesting. Subsequently,
patients in arm A continue on consecutive lenalidomide/dexamethasone cycles,
patients in arm B undergo high dose chemotherapy plus autologous stem cell
transplantation followed by lenalidomide maintenance until discontinuation
criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B)
and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after
autologous stem cell transplantation (arm B) and every 3 months thereafter
(arm A + B). After finishing the study treatment, patients are followed up for
survival and subsequent myeloma therapies. The expected trial duration is 6.25
years from first patient in to last patient out. The primary endpoint is PFS,
secondary endpoints include overall survival (OS), RR, time to best response
and the influence of early versus late salvage high dose chemotherapy plus
autologous stem cell transplantation on OS. Discussion This phase III trial is
designed to evaluate whether high dose chemotherapy plus autologous stem cell
transplantation and lenalidomide maintenance after lenalidomide/dexamethasone
induction improves PFS compared with the well-established continued
lenalidomide/dexamethasone regimen in RMM patients. Trial registration:
ISRCTN16345835 (date of registration 2010-08-24)
Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma
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