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Biomedical subjects

Alberto Weber

Publications and source records attributed to Alberto Weber.

11 recordsLinked to original sources
PubMed2007

Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: taxol- and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF.

Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder.

Animals↗
PubMed2005

Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth.

BACKGROUND: Toxic neuropathies induced by cisplatin and other chemotherapeutic agents are important clinical problems because of their high incidence, their lack of effective treatment, and the fact that neuropathy represents a dose-limiting factor for these therapies. The pathogenic basis for toxic neuropathies induced by chemotherapeutic agents has not been completely elucidated. METHODS AND RESULTS: We investigated the hypothesis that experimental toxic neuropathy results from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum, and accordingly that the neuropathy could be prevented or reversed by locally administered VEGF gene transfer without augmenting tumor growth. In an animal model of cisplatin-induced neuropathy, nerve blood flow was markedly attenuated, and there was a profound reduction in the number of vasa nervorum associated with marked endothelial cell apoptosis, resulting in a severe peripheral neuropathy with focal axonal degeneration characteristic of ischemic neuropathy. After intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 in animals with an established neuropathy, vascularity and blood flow returned to levels similar to those of control rats, peripheral nerve function was restored, and histological nerve architecture was normalized. Gene therapy administered in parallel with cisplatin chemotherapy completely attenuated endothelial cell apoptosis and inhibited destruction of nerve vasculature, deterioration of nerve function, and axonal degeneration. In a rat tumor model, VEGF gene transfer administered locally did not alter tumor growth or vascularity. CONCLUSIONS: These findings implicate microvascular damage as the basis for toxic neuropathy induced by cisplatin and suggest that local angiogenic gene therapy may constitute a novel prevention or treatment for this disorder without augmenting tumor growth or vascularization.

Angiogenesis Inhibitors↗
PubMed2005

Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia.

Hyperhomocyst(e)inemia (HH) is an established independent risk factor for coronary, cerebral and peripheral vascular diseases. Recent studies have indicated that certain cardiovascular risk factors, including diabetes and hypercholesterolemia, impair expression of vascular endothelial growth factor (VEGF) and endogenous angiogenesis. In this study, we investigate the impact of moderate HH on angiogenesis and VEGF pathway in a mouse model of hindlimb ischemia. Upon induction of unilateral hindlimb ischemia, endogenous angiogenesis, expression of VEGF, and phosphorylation of the VEGF receptor Flk-1 were evaluated in mice heterozygous for a deletion of the cystathionine beta-synthase gene (CBS) and compared with those observed in CBS+/+ mice. CBS+/- mice exhibit moderate HH, as demonstrated by measuring plasma total homocyst(e)ine (tHcy) levels, which were significantly higher in these animals compared with CBS+/+ mice (4.77 +/- 0.82 vs 2.10 +/- 0.28, p < 0.01). Twenty-eight days after induction of ischemia, hindlimb blood flow was significantly reduced in CBS+/- mice compared with CBS+/+ animals (0.49 +/- 0.03, n = 12 vs 0.71 +/- 0.09, n = 10; p < 0.05). In addition, there was a significant negative correlation between plasma homocyst(e)ine levels and the laser Doppler perfusion ratio in CBS+/- mice (p = 0.0087, r = -0.7171). While VEGF expression and Flk-1 phosphorylation were not impaired in the ischemic muscles of CBS+/- mice, phosphorylation of the endothelial cell survival factor Akt was significantly inhibited by homocyst(e)ine in a dose-dependent manner in human umbilical vein endothelial cell (HUVECs) in vitro. In conclusion, our findings demonstrate that endogenous angiogenesis is inversely related to plasma levels of homocyst(e)ine in genetically engineered, heterozygous mice with moderate HH. This impairment, however, is not dependent on reduced expression of VEGF or impaired phosphorylation of its receptor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.

Animals↗
PubMed2005

Guidant Heartstring: initial experience in OPCAB surgery.

PURPOSE: The aim of this study was to evaluate the feasibility of the Heartstring hemostatic seal system for proximal anastomoses without the need for aortic side clamping in off-pump coronary artery bypass surgery . MATERIAL AND METHODS: Between May and November 2003, 50 proximal bypass anastomoses were performed with the Heartstring device in 29 consecutive patients (21 men, 8 women) with calcified aorta (assessed by transesophageal echocardiography/digital palpation). Mean patient age was 68 +/- 7 years. A mean of 1.7 anastomoses per patient was performed. Bypass patency was assessed by intraoperative flow measurements. Neurological outcome was graded in 4 severities. RESULTS: The learning curve was completed after deployment of approximately 10 devices. Crack of the seal prior to deployment occurred in 8 cases. No conversion to conventional side clamping was needed. No accidental stitching of the seal or wrapping of the suture around the seal stem occurred. Slight diffuse bleeding occurred with arterial pressure under 65 mm Hg. Bypass graft flow was 53.7 +/- 23.9 L/min. No perioperative ischemic events occurred, and there were no postoperative neurological complications. CONCLUSIONS: Proximal bypass aortic anastomoses can be performed safely without side clamping using the Heartstring hemostatic seal system. Anastomoses can be completed with no foreign material (stent) remaining.

Aged↗
PubMed2004

Umbilical cord blood derived endothelial progenitor cells for tissue engineering of vascular grafts.

BACKGROUND: A substantial limitation regarding present pediatric cardiac surgery is the lack of appropriate materials for the repair of congenital defects. To address this shortcoming, tissue engineering is a scientific field that aims at in vitro fabrication of living autologous grafts with the capacity of growth, repair, and regeneration. Here we focused on tissue engineered vascular grafts using human umbilical cord blood derived endothelial progenitor cells (EPCs), as a noninvasive cell source for pediatric applications. METHODS: EPCs were isolated from 20 ml fresh human umbilical cord blood by Ficoll gradient centrifugation and cultured in endothelial basal medium containing growth factors. After proliferation and differentiation cells were analyzed by immunohistochemistry and seeded onto three-dimensional (3D) biodegradable vascular scaffolds (porosity > 95%, n = 22). Twenty-four hours after seeding the vascular grafts were positioned into a pulse-duplicator-in vitro system and grown for 48 hours under biomimetic conditions. A second group was grown 6 days statically and an additional 6 days biomimetically. Controls were cultured statically. Analysis of the grafts included immunohistochemistry, histology, and scanning electron microscopy. RESULTS: Preseeding differentiated EPCs indicated constant endothelial phenotypes including acetylated low-density lipoprotein, cluster of differentiation 31, von Willebrand factor, and endothelial nitric oxide synthetase. Seeded EPCs established favorable cell-to-polymer attachment and proliferation into the 3D tubular scaffolds. Both conditioned and static cellular constructs demonstrated positive staining for cluster of differentiation 31, von Willebrand factor, and expression of endothelial nitric oxide synthase. CONCLUSIONS: Human umbilical cord derived EPCs indicated exceptional growth characteristics used for tissue engineering of vascular grafts. These cells demonstrated a constant endothelial phenotype and related functional features. Based on these results EPCs seem to be a promising autologous cell source with regard to cardiovascular tissue engineering, particularly for the repair of congenital defects.

Absorbable Implants↗
PubMed2004

Magnetic resonance mapping of transplanted endothelial progenitor cells for therapeutic neovascularization in ischemic heart disease.

OBJECTIVE: Intramyocardial transplantation of endothelial progenitor cells (EPCs) has been previously correlated with significant augmentation of vascularity and improvement of left ventricular function following myocardial ischemia. However, precise intramyocardial localization of the transplanted cells and the extent of in situ cell migration are unknown. We present a novel technique using magnetic resonance imaging (MRI) to localize transplanted EPCs in ischemic hearts. METHODS: CD34-positive cells were isolated from human peripheral blood by magnetic bead selection: CD34-positive cells adhere to CD34-negative antibody coated magnetic beads, while CD34-negative cells do not. All cells were labeled with fluorescent DiI-dye for histological localization. CD34-positive cells or CD34-negative cells (105, 1 x 106 and 2 x 106 cells) were transplanted into non-ischemic (n = 6) or ischemic myocardium (n = 2) of Sprague-Dawley rats. Rats were sacrificed 24 h after cell transplantation. The resected hearts were imaged ex vivo using 3 and 8.5 T magnets. Morphological correlation between the MRI findings and fluorescent microscopy for identification of retained CD34-positive cells was evaluated. RESULTS: CD34-positive cells were identified as areas of low signal intensity on T2*-weighted images within the myocardium. These areas increased in size with the gradual increase in the echo time due to susceptibility effect. The extent of the low signal intensity at a given echo time was proportional to cell dosage. No areas of low signal were identified in the CD34-negative cell transplanted hearts. Histological localization of DiI-labeled CD34-positive cells documented a direct anatomic correlation with the localization of transplanted cells on the MRI images. CONCLUSIONS: Magnetically labeled EPCs transplanted for therapeutic neovascularization in myocardial ischemia can be visualized with ex vivo MRI at high-field strengths.

Animals↗
PubMed2004

Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.

Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic or pharmacological blockade of Src preserves endothelial cell barrier function, suppressing VP and infarct volume, providing long-term improvement in cardiac function, fibrosis, and survival. To our surprise, an intravascular injection of VEGF into healthy animals, but not those deficient in Src, induced similar endothelial gaps, VP, platelet plugs, and some myocyte damage. Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection. Blockade of Src prevents disassociation of this complex with the same kinetics with which it prevents VEGF-mediated VP/edema. These findings define a molecular mechanism to account for the Src requirement in VEGF-mediated permeability and provide a basis for Src inhibition as a therapeutic option for patients with acute MI.

Animals↗
PubMed2002

Results of surgery for irreversible moderate to severe mitral valve regurgitation secondary to myocardial infarction.

OBJECTIVE: Moderate to severe irreversible mitral regurgitation secondary to myocardial infarction is an independent risk factor for reduced long-term survival. Late effects of correction of mitral incompetence concomitant with coronary artery bypass grafting (CABG) are less well known and the choice of mitral valve procedure is still debated. METHODS: From 1988 to 1998, 93 consecutive patients (mean age 63+/-9 years) were treated for moderate to severe irreversible mitral regurgitation secondary to myocardial infarction; 84 were in NYHA functional class III-IV and 19 were in cardiogenic shock. Thirty-seven patients underwent emergency surgery. Perioperative intraaortic balloon pump (IABP) was necessary in 33 patients. Follow-up ranged from 6 months to 12 years (mean 51 months+/-41). RESULTS: Mitral valve was repaired in 30 patients and replaced in 63. Replacement was preferably performed in patients with major displacement of papillary muscle and in patients with acute papillary muscle rupture. CABG (3.4 distal anastomoses) was performed in all patients and was complete in 92%. Early mortality was 15% (14/93). Multivariable analysis identified need for IABP (P=0.005) and COPD (P=0.02) as risk factors for early death. Emergency surgery had only a trend (P=0.15) for increased mortality; age, low ejection fraction, repair vs. replacement had no influence. Actuarial survival rates at 1, 5 and 10 years were 81, 65 and 56%, respectively. Late survival was similar in patients with replacement or repair (P=0.46). At last follow-up, all but one patient were in NYHA functional class I or II. CONCLUSIONS: Combined mitral valve procedure and myocardial revascularization, as complete as possible, for moderate to severe mitral regurgitation secondary to myocardial infarction achieve satisfactory early and late outcome despite the increased operative mortality. Acute papillary muscle rupture, severe restriction of the mitral valve by major displacement of the papillary muscle are better managed by valve replacement.

Adult↗
PubMed2002

Repair of postinfarction dyskinetic LV aneurysm with either linear or patch technique.

OBJECTIVES: Controversy still exists regarding the optimal surgical technique for postinfarction dyskinetic left ventricular aneurysm (LVA) repair. We compared the efficacy of two established techniques, linear vs. patch remodeling, for repair of dyskinetic LVA. PATIENTS AND METHODS: From 1989 to 1998, 95 (16 women, 79 men) consecutive patients were operated on for postinfarction dyskinetic LVA. Thirty-four patients underwent patch remodeling (R) and 61 linear (L) repair. The mean age was 61.1+/-8.5 years. Indications for surgery alone or in combination included angina in 72 patients, dyspnea in 64 and ventricular tachycardia in 41. Thirty-seven patients had a history of congestive heart failure (R 13 (38%), L 24 (39%), NS). The mean ejection fraction (EF) with aneurysm was 0.29+/-0.09 in R vs. 0.35+/-0.10 in L (P<0.04), whereas the mean EF without aneurysm was 0.43+/-0.11 in R vs. 0.46+/-0.08 in L (P=0.3). Seventy-one aneurysms were anterior (R 30 (88%), L 41 (68%), P<0.05). Concomitant coronary artery bypass grafting was performed in 84 patients (R 29 (85%), L 55 (90%), NS). Follow-up ranged from 1 to 12 years (mean 5.6+/-3.4 years, median 6.1 years). RESULTS: Early mortality was 8% (n=8) (R 4, L 4, NS). Survival at 1, 5 and 10 years was 88, 73, and 44%, respectively. It did not differ significantly between R (1 and 5 year survival 85, 66%) and L (90, 76%, P=0.58). Preoperative risk factors for mortality were history of congestive heart failure (1 and 5 year survival 81 and 57% vs. 90 and 78%, respectively, hazard ratio (HR)=1.95, P<0.05), non-anterior localization of the aneurysm (86 and 49% vs. 86 and 77%, HR=2.06, P<0.05), history of thromboembolic events (57 and 19% vs. 89 and 74%, HR=3.27, P<0.05), and left ventricular EF (HR=0.97 per %, P=0.05). At late follow-up the mean functional class was 1.8+/-0.6 in long-term survivors (preoperative 2.9+/-0.9, P<0.001) with no difference between the groups. CONCLUSIONS: The technique of repair of postinfarction dyskinetic LVA should be adapted in each patient to the cavity size and extent of the scarring process into the septum and subvalvular mitral apparatus. Applying these considerations to the choice of the technique of repair, both techniques achieved satisfactory results with respect to perioperative mortality, late functional status and survival.

Aged↗
PubMed2002

Surgical management of acute mitral valve regurgitation due to post-infarction papillary muscle rupture.

BACKGROUND AND AIM OF THE STUDY: Acute myocardial infarction associated with mitral papillary muscle rupture and cardiogenic shock carries a high mortality. Data relating to early and late survival after emergency mitral valve surgery and concomitant complete coronary artery revascularization in this patient population were analyzed. METHODS: Between January 1988 and December 1998, 21 consecutive patients (mean age 62+/-9.7 years) underwent emergency coronary and concomitant mitral valve surgery for acute myocardial infarction and mitral papillary muscle rupture associated with cardiogenic shock. Mitral valve replacement was performed in 19 patients (90%), and mitral valve repair in two (10%). An average of 2.2 distal anastomoses per patient was performed. Revascularization was complete in 19 patients (90%). Preoperatively, intra-aortic balloon pumping was used in 11 patients (52%), and two (10%) had salvage surgery when arriving at the operating room under cardiopulmonary resuscitation. Early and late follow up was complete; mean follow up was 5+/-3 years (range: 16 months to 12 years). RESULTS: Thirty-day mortality was 19% (4/21), with two cardiac-related early deaths (10%). Early morbidity included perioperative stroke in 6% (1/17), myocardial infarction in 6% (1/17), and need for hemodialysis in 18% (3/17). There were three late deaths; one was cardiac-related. Actuarial survival at one, five and 10 years was 81, 68 and 56%, respectively. All survivors were in NYHA class I or II. CONCLUSION: Emergency surgery for acute post-infarction mitral papillary muscle rupture is justified, even as a salvage procedure. Concomitant mitral valve surgery and complete coronary artery revascularization achieve acceptable survival rates and satisfactory functional results.

Acute Disease↗