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Biomedical subjects

Richard D Weisel

Publications and source records attributed to Richard D Weisel.

At least 19 recordsLinked to original sources
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

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

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

Cell transplantation to improve ventricular function in the failing heart.

Current therapies for congestive heart failure are limited in efficacy or in applicability. Cardiac cell transplantation offers a novel therapeutic approach to improve heart function. Although significant progress has been made over the past decade in the development of cell transplantation, only recently have investigators studied the changes in ventricular function following cell transplantation. This review article describes the latest research developments, evaluates recent studies of ventricular function after cell transplantation, and discusses the future directions of cell transplantation as a new therapy to 'repair broken hearts'.

Animals↗
PubMed2003

Restoration and regeneration of failing myocardium with cell transplantation and tissue engineering.

Cell transplantation and the creation of bioengineered cardiovascular tissues are novel biologic approaches to restore and regenerate failing myocardium. These rapidly evolving therapies may complement and enhance other mechanical and surgical interventions for patients with congestive heart failure, providing cardiac surgeons with a wider range of treatments for patients at risk of congestive heart failure. Proof-of-concept studies have been performed in several experimental animal models of human cardiovascular disease, such as myocardial infarction and dilated cardiomyopathy. Although the exact mechanisms are unclear, cell transplantation restores cardiac function and limits ventricular dilatation. Clinical cell transplantation has been performed in a limited number of patients with encouraging preliminary results. In contrast, bioengineered muscle grafting is largely experimental but offers the promise of myocardial regeneration by replacing irreversibly damaged myocardium with healthy autologous tissue to facilitate more extensive ventricular remodeling surgery.

Animals↗
PubMed2003

Caveolin: a key target for modulating nitric oxide availability in health and disease.

The endothelial layer is a key component of the cardiovascular system. Recent evidence indicates that strategies aimed at preserving the endothelium may have important implications in the battle against cardiovascular disease. Nitric oxide remains the critical factor determinant of endothelial function. Understanding the regulatory components involved in nitric oxide production may elucidate novel targets for improving compromised vascular function. The caveolae/caveolin system has recently become of interest due to its ability to regulate endothelial nitric oxide synthase activity. The caveolae/caveolin system is a multifaceted structure in the plasma membrane, which plays an integral role in cellular signaling. Recognizing the potential of this specialized domain may provide the fundamental knowledge to target the endothelium in disease.

Animals↗
PubMed2003

Optimal conditions for heart cell cryopreservation for transplantation.

Cultured myocyte transplantation into an infarcted myocardium has been shown to improve contractile function. Cryopreservation of cultured muscle cells or heart tissue will be important for the technology to be practical. This study, using fetal cardiomyocytes, evaluated the optimal conditions for muscle cell cryopreservation. Study 1: Fetal rat cardiomyocytes were isolated and cultured. The freshly isolated and passage 1, 2, 3 and 4 cells were cryopreserved in a solution containing 70% IMDM, 20% FBS and 10% DMSO and stored in -196 degrees C for 1, 2, 4, 8, 12 and 24 weeks. The cells were thawed and cultured. Cell number and contractility were evaluated at 0, 2, 4, 6, 8 and 10 days of culture. Study 2: Rat myocardium was cryopreserved in sizes of 0.2, 2 and 6 mm3 for 1 week. The tissue was thawed and cells were isolated. Cell growth and contractility were evaluated. (1) Cardiomyocytes grew and contracted after cryopreservation. Storage time did not affect cell survival rate, beating cell numbers and beating rates. Increasing cell passage prior to cryopreservation decreased the percentage of beating cells. (2) Cells isolated from cryopreserved tissue grew in vitro and contracted normally. Cell yield decreased with increased cryopreserved tissue size. Fetal rat cardiomyocytes survived and functioned after in vitro cryopreservation. Viable cells can be isolated from cryopreserved myocardium and cultured. Cryopreservation of small pieces of myocardium is preferred for maximal cell yields.

Animals↗
PubMed2002

Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3.

In the failing heart, an imbalance in matrix metalloproteinases (MMPs) and their biological regulators, the tissue inhibitors of MMPs (TIMPs), may result in cardiac dilatation from matrix degradation. We hypothesized that a reduction of myocardial TIMP-3 is associated with adverse matrix remodeling in both human and experimental heart failure. Cardiomyopathic hamsters at age 15 wk (normal), 25 wk (compensated stage), and 35 wk (overt failure) were compared with age-matched normal controls. MMP activity (gelatinase bioassay) was increased in cardiomyopathic hearts (P = 0.03) and peaked during the transition to overt heart failure. TIMP-3 content (immunoblot) was decreased compared with normal controls (74 +/- 5% at 25 wk, 69 +/- 10% at 35 wk; P = 0.001) and its reduction was associated with increased MMP activity (r = -0.6; P = 0.004). TIMP-1 increased progressively (P = 0.001), whereas TIMP-2, TIMP-4, and MMP protein levels were unchanged. Myocardial collagen (hydroxyproline content) increased with time during the progression to end-stage cardiac failure (P < 0.0001). Collagen synthesis ([(14)C]proline uptake) was elevated in cardiomyopathy at 15 and 25 wk (P < 0.05). The collagen cross-linking ratio (insoluble:soluble collagen) was reduced (P = 0.003) as the left ventricle dilated. By confocal microscopy restricted to viable myocardium, collagen content was reduced (P = 0.04) with fragmentation (P < 0.0001) and thinning (P = 0.003) of perimysial collagen fibers. Similarly, patients with end-stage congestive heart failure (n = 7) compared with nonfailing controls (n = 2) had elevated gelatinase MMP activity (P = 0.02) associated with isolated reductions in TIMP-3 (55 +/- 5% of normal; P = 0.003). Reductions of TIMP-3 parallel adverse matrix remodeling in the cardiomyopathic hamster and the failing human heart. TIMP-3 may contribute to the regulation of myocardial remodeling and its reduction may promote a transition from compensated to end-stage congestive heart failure.

Animals↗
PubMed2002

Mechanical stretch regimen enhances the formation of bioengineered autologous cardiac muscle grafts.

BACKGROUND: Surgical repair of congenital and acquired cardiac defects may be enhanced by the use of autologous bioengineered muscle grafts. These tissue-engineered constructs are not optimal in their formation and function. We hypothesized that a mechanical stretch regimen applied to human heart cells that were seeded on a three-dimensional gelatin scaffold (Gelfoam) would improve tissue formation and enhance graft strength. METHODS AND RESULTS: Heart cells from children undergoing repair of Tetralogy of Fallot were isolated and cultured. Heart cells were seeded on gelatin-matrix scaffolds (Gelfoam) and subjected to cyclical mechanical stress (n=7) using the Bio-Stretch Apparatus (80 cycles/minute for 14 days). Control scaffolds (n=7) were maintained under identical conditions but without cyclical stretch. Cell counting, histology, and computerized image analysis determined cell proliferation and their spatial distribution within the tissue-engineered grafts. Collagen matrix formation and organization was determined with polarized light and laser confocal microscopy. Uniaxial tensile testing assessed tissue-engineered graft function. Human heart cells proliferated within the gelatin scaffold. Remarkably, grafts that were subjected to cyclical stretch demonstrated increased cell proliferation and a marked improvement of cell distribution. Collagen matrix formation and organization was enhanced by mechanical stretch. Both maximal tensile strength and resistance to stretch were improved by cyclical mechanical stretch. CONCLUSION: The cyclical mechanical stretch regimen enhanced the formation of a three-dimensional tissue-engineered cardiac graft by improving the proliferation and distribution of seeded human heart cells and by stimulating organized matrix formation resulting in an order of magnitude increase in the mechanical strength of the graft.

Absorbable Implants↗
PubMed2002

Optimal biomaterial for creation of autologous cardiac grafts.

BACKGROUND: The optimal cardiac graft for the repair of congenital heart defects will be composed of autologous cells and will grow with the child. The biodegradable material should permit rapid cellular growth and delayed degradation with minimal inflammation. We compared a new material, epsilon-caprolactone-co-L-lactide sponge reinforced with knitted poly-L-lactide fabric (PCLA), to gelatin (GEL) and polyglycolic acid (PGA), which are previously evaluated materials. METHODS: Syngenic rat aortic smooth muscle cells (SMCs, 2x10(6)) were seeded onto GEL, PGA, and PCLA patches and cultured (n=11 per group). The DNA content in each patch was measured at 1, 2, and 3 weeks after seeding. Histological examination was performed 2 weeks after seeding. Cell-seeded patches were employed to replace a surgically created defect in the right ventricular outflow tract (RVOT) of rats (n=5 per group). Histology was studied at 8 weeks following implantation. RESULTS: In vitro studies showed that the DNA content increased significantly (P<0.05) in all patches between 1 and 3 weeks after seeding. Histology and staining SMCs for anti-alpha-smooth muscle actin (alphaSMA) revealed better growth of cells in the interstices of the grafts with GEL and PCLA than the PGA graft. In vivo studies demonstrated that seeded SMCs survived at least 8 weeks after the patch implantation in all groups. PCLA scaffolds were replaced by more cells with larger alphaSMA-positive areas and by more extracellular matrix with larger elastin-positive areas than with GEL and PGA. The patch did not thin and expanded significantly. The GEL and PGA patches thinned and expanded. All grafts had complete endothelialization on the endocardial surface. CONCLUSIONS: SMC-seeded biodegradable materials can be employed to repair the RVOT. The novel PCLA patches permitted better cellular penetration in vitro and did not thin or dilate in vivo and did not produce an inflammatory response. The cell-seeded PCLA patch may permit the construction of an autologous patch to repair congenital heart defects.

Absorbable Implants↗
PubMed2002

Combined procedure of surgical repair and cell transplantation for left ventricular aneurysm: an experimental study.

BACKGROUND: This study was designed to investigate the efficacy of the combined procedure of left ventricular (LV) repair and fetal cardiomyocyte transplantation (CM-TX) in a rat myocardial infarction model. METHODS AND RESULTS: A moderate-sized LV aneurysm was created by proximal ligation of the left coronary artery in 47 Lewis rats. Four weeks later, they were underwent another operation and received culture medium injection (n=10; group I), fetal CM-TX (n=10; group II), purse-string LV repair with culture medium injection (n=14; group III), or LV repair with fetal CM-TX (n=13; group IV). They were echocardiographically followed-up during the subsequent 4 weeks, and cardiac catheterization was performed in the final week. In the late period, LV dimension in group IV was smaller than that in group III (end-diastolic dimension, 0.92+/-0.02 versus 1.01+/-0.03 cm, P=0.0090; end-systolic dimension, 0.62+/-0.02 versus 0.74+/-0.04 cm, P=0.0093; at the fourth week), although they initially showed similar decreases in both groups. At the final week, end-systolic elastance was higher in group IV than in groups I, II, or III (0.61+/-0.10 versus 0.19+/-0.03, 0.30+/-0.09, 0.33+/-0.07 mm Hg/ micro L, P=0.0002, 0.0037, and 0.0042, respectively). CONCLUSIONS: Fetal CM-TX exerted preventive effects against late LV dilation and dysfunction after LV repair in the rat model. The results suggest that repair surgery combined with fetal CM-TX may enhance the surgical benefits for patients with LV aneurysm in the long term.

Animals↗