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Biomedical subjects

E R Edelman

Publications and source records attributed to E R Edelman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon-injured arteries.

Macrophages are abundant after stent-induced arterial injury. Inhibition of macrophage recruitment blocks neointimal growth in this model. In contrast, after superficial injury from balloon endothelial denudation, macrophages are sparse. However, many anti-inflammatory therapies remain effective against neointimal growth after balloon injury. To investigate further the role of leukocytes after injury, 41 New Zealand White rabbits underwent iliac artery balloon denudation. In 18, subcutaneous pumps were placed to deliver intravenous heparin (0.3 mg/kg per hour). Arteries were harvested at 6 hours and at 3, 7, and 14 days. In 8 animals, either M1/70 (a monoclonal antibody [mAb] against adhesion molecule Mac-1) or a nonspecific IgG was given (5 mg/kg IV bolus and then 1 mg/kg SC QOD), and arteries were harvested at 6 hours and 3 days. Computer-aided morphometry was performed as was immunohistochemistry to assess smooth muscle cell (SMC) proliferation (bromodeoxyuridine-positive cells), neutrophil content (RPN357, mAb against rabbit neutrophil/thymocyte), and macrophage content (RAM-11, mAb against rabbit macrophage). Heparin inhibited neointimal growth at 7 and 14 days (64% and 32.5% reduction, respectively; P:<0.05). Neutrophils were observed in the media early after balloon injury, and heparin and M1/70 inhibited this infiltration (82% and 83% reduction, respectively; P:<0.05 each) with a coincident inhibition of medial SMC proliferation at 3 days (49% and 84% reduction, respectively; P:<0.05 each). Macrophages were absent at all time points. Neutrophil, but not macrophage, infiltration occurs early after endothelial denudation. Inhibition of this process is associated with a reduction in medial SMC proliferation. These data suggest a central role for neutrophils in restenosis and help to explain prior reports of an inhibitory effect of anti-inflammatory therapies on neointimal growth after balloon injury.

Angioplasty, Balloon↗
PubMed2000

Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty.

Inflammation plays an essential role in the initiation and progression of atherosclerosis, but its role in vascular repair after mechanical arterial injury (i.e., percutaneous transluminal coronary angioplasty, PTCA) is unknown. In animal models of vascular injury, leukocytes are recruited as a precursor to intimal thickening. Furthermore, markers of leukocyte activation - in particular, increased expression of the beta2-integrin Mac-1 (alphaMbeta2, or CD11b/CD18), which is responsible for firm leukocyte adhesion to platelets and fibrinogen on denuded vessels - predict restenosis after PTCA. To determine whether Mac-1-mediated leukocyte recruitment is causally related to neointimal formation, we subjected mice lacking Mac-1 to a novel form of mechanical carotid artery dilation and complete endothelial denudation. We now report that the selective absence of Mac-1 impairs transplatelet leukocyte migration into the vessel wall, reducing leukocyte accumulation over time. Diminished medial leukocyte accumulation was accompanied by markedly reduced neointimal thickening after vascular injury. These data establish a role for inflammation in neointimal thickening and suggest that leukocyte recruitment to mechanically injured arteries may prevent restenosis.

Angioplasty, Balloon↗
PubMed2000

Local drug delivery: an emerging approach in the treatment of restenosis.

Very limited success has been demonstrated with systemic pharmacological treatment to reduce the incidence of restenosis following angioplasty in patients. The lack of success of many of the pharmacotherapeutic agents in reducing the restenosis rates post-angioplasty and following stent implementation is believed to arise from inadequate concentrations of the agents at the lesion site. This has led to the development of various local delivery devices that would ideally deliver and retain adequate amounts of drug to the vessel wall for sufficient periods of time to ensure a therapeutic effect without inducing further injury or compromising blood flow. Local dosing would avoid systemic toxicity, and the use of modified balloon catheters or coated stents might enable percutaneous approaches.

Angioplasty, Balloon, Coronary↗
PubMed1999

Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial.

BACKGROUND: Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 microg of bFGF (n=8), 100 microg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0+/-6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-microg bFGF group had angina, whereas all patients in the 100-microg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7+/-3.7% to 23.8+/-5.7%, P=0.06), no significant change in the 10-microg bFGF group, and significant improvement in the 100-microg bFGF group (19.2+/-5.0% to 9.1+/-5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-microg bFGF group (10.7+/-3.9% to 3. 7+/-6.3%, P=0.06). CONCLUSIONS: This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.

Alginates↗
PubMed1999

Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo.

Drug activity is often studied in well controlled and characterized cellular environments in vitro. However, the biology of cells in culture is only a part of the tissue behavior in vivo. Quantitative studies of the dose response to drugs in vivo have been limited by the inability to reliably determine or predict the concentrations achieved in tissues. We developed a method to study the dose response of injured arteries to exogenous heparin in vivo by providing steady and predictable arterial levels of drug. Controlled-release devices were fabricated to direct heparin uniformly and at a steady rate to the adventitial surface of balloon-injured rat carotid arteries. We predicted the distribution of heparin throughout the arterial wall by using computational simulations of intravascular drug binding and transport, and we correlated these concentrations with the biologic response of the tissues. This allowed the estimation of the arterial concentration of heparin required to maximally inhibit intimal hyperplasia after injury in vivo, 0.3 mg/ml. This estimation of the required concentration of drug seen by a specific tissue is independent of the route of administration and holds for all forms of drug release. In this way we may now be able to evaluate the potential of widely disparate forms of drug release and to finally create some rigorous criteria by which to guide the development of particular delivery strategies for local diseases.

Animals↗
PubMed1999

Balloon-artery interactions during stent placement: a finite element analysis approach to pressure, compliance, and stent design as contributors to vascular injury.

Endovascular stents expand the arterial lumen more than balloon angioplasty and reduce rates of restenosis after coronary angioplasty in selected patients. Understanding the factors involved in vascular injury imposed during stent deployment may allow optimization of stent design and stent-placement protocols so as to limit vascular injury and perhaps reduce restenosis. Addressing the hypothesis that a previously undescribed mechanism of vascular injury during stent deployment is balloon-artery interaction, we have used finite element analysis to model how balloon-artery contact stress and area depend on stent-strut geometry, balloon compliance, and inflation pressure. We also examined superficial injury during deployment of stents of varied design in vivo and in a phantom model ex vivo to show that balloon-induced damage can be modulated by altering stent design. Our results show that higher inflation pressures, wider stent-strut openings, and more compliant balloon materials cause markedly larger surface-contact areas and contact stresses between stent struts. Appreciating that the contact stress and contact area are functions of placement pressure, stent geometry, and balloon compliance may help direct development of novel stent designs and stent-deployment protocols so as to minimize vascular injury during stenting and perhaps to optimize long-term outcomes.

Animals↗
PubMed1999

Endothelial implants inhibit intimal hyperplasia after porcine angioplasty.

The perivascular implantation of tissue-engineered endothelial cells around injured arteries offers an opportunity to study fundamental vascular physiology as well as restore and improve tissue function. Cell source is an important issue because the ability to implant either xenogeneic or allogeneic cells would greatly enhance the clinical applications of tissue-engineered grafts. We investigated the biological and immunological responses to endothelial cell xenografts and allografts in pigs 4 weeks after angioplasty of the carotid arteries. Porcine or bovine aortic endothelial cells were cultured within Gelfoam matrices and implanted in the perivascular space of 42 injured arteries. Both porcine and bovine endothelial cell grafts reduced the restenosis index compared with control by 54% and 46%, respectively. Perivascular heparin release devices, formulated to release heparin at twice the rate of release of heparan sulfate proteoglycan from endothelial cell implants, produced no significant reduction in the restenosis index. Endothelial cell implants also reduced occlusive thrombosis compared with control and heparin release devices. Host immune responses to endothelial implants were investigated by immunohistochemical examination of explanted devices and by immunocytochemistry of serum samples. The bovine cell grafts displayed infiltration of leukocytes, consisting primarily of lymphocytes, and caused an increase in antibodies detected in serum samples. Reduced cellular infiltration and no humoral response were detected in animals that received allografts. Despite the difference in immune response, the biological effects of xenografts or allografts did not differ significantly.

Angioplasty↗
PubMed1999

Measuring arterial strain induced by endovascular stents.

Endovascular stents are expandable, fenestrated tubes that are threaded in their collapsed state through an artery to a site of occlusion, plastically enlarged and left as permanent implants to scaffold the artery open. The stent induces large-scale vascular strains that are difficult to measure in vivo and yet can be critical determinants of stent-vessel biology. A method is developed to measure the strain tensor developed on the surface of an artery as a stent is expanded in vivo. Arterial sections are marked with reference points and imaged as the stent is expanded. An axially symmetric parametric model of the artery is determined for each expansion time-point, and these reference points are back-projected onto this surface. The back-projected reference points are grouped and analysed to determine the circumferential, axial and torsional strain tensor components in each arterial subsection. The method is characterised in vitro using bovine artery segments and a latex phantom, and is then tested on rabbits to demonstrate its feasibility in vivo. In vitro experiments on stented bovine arteries show typical post-stenting strains of 0.60, -0.26, and 0.08 mm mm-1 in the circumferential, axial and torsional directions, respectively, sampled every 1 mm along the length of the stented region. Phantom experiments characterise the RMS error of system measurements as 0.1 mm mm-1. The system is shown capable of measuring strains of straight, accessible vessels in the presence of respiratory/cardiac motion and visual glare in vivo.

Animals↗
PubMed1999

Measurement of drug distribution in vascular tissue using quantitative fluorescence microscopy.

Quantitative tools to assess vascular macromolecular distributions have been limited by low signal-to-noise ratios, reduced spatial resolution, postexperimental motion artifact, and the inability to provide multidimensional drug distribution profiles. Fluorescence microscopy offers the potential of identifying exogenous compounds within intact tissue by reducing autofluorescence, the process by which endogenous compounds emit energy at the same wavelength as fluorescent labels. A new technique combining fluorescence microscopy with digital postprocessing has been developed to address these limitations and is now described in detail. As a demonstration, histologic cross-sections of calf carotid arteries that had been loaded endovascularly with FITC-Dextran (20 kD) ex vivo were imaged at two different locations of the electromagnetic spectrum, one exciting only autofluorescent structures and the other exciting both autofluorescent elements and exogenous fluorescent labels. The former image was used to estimate the autofluorescence in the latter. Subtraction of the estimated autofluorescence resulted in an autofluorescence-corrected image. A standard curve, constructed from arteries that were incubated until equilibrium in different bulk phase concentrations of FITC-Dextran, was used to convert fluorescent intensities to tissue concentrations. This resulted in a concentration map with spatial resolution superior to many of the previous methods used to quantify macromolecular distributions. The transvascular concentration profiles measured by quantitative fluorescence microscopy compared favorably with those generated from the proven en face serial sectioning technique, validating the former. In addition, the fluorescence method demonstrated markedly increased spatial resolution. This new technique may well prove to be a valuable tool for elucidating the mechanisms of macromolecular transport, and for the rational design of drug delivery systems.

Blood Vessels↗
PubMed1998

A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits.

Leukocytes are recruited early and abundantly to experimentally injured vessels, in direct proportion to cell proliferation and intimal growth. Activated circulating leukocytes and Mac-1 (CD11b/CD18, alphaMbeta2) expression are markers of restenosis risk in patients undergoing angioplasty. As angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition, we hypothesized that Mac-1-dependent adhesion to fibrin(ogen) is an important determinant of leukocyte recruitment and function, which may in turn promote intimal growth. To study this hypothesis we administered M1/70, an anti-CD11b blocking mAb, to rabbits (1 mg/kg i.v.) immediately before, and every 48 hr for 3, 6, or 14 days after, iliac artery balloon denudation or deeper stent-induced injury. M1/70, which bound to isolated rabbit monocytes and dose-dependently inhibited Mac-1-mediated fibrinogen binding in vitro, reduced leukocyte recruitment more than 2-fold 3, 6, and 14 days after injury. Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 (intimal area after balloon injury, 0.12 +/- 0.09 mm2, compared with 0.32 +/- 0.08 mm2 in vehicle-treated controls, P < 0.01, and 0.38 +/- 0.08 mm2 in IgG-treated controls, P < 0.005; intimal area after stent injury, 0. 56 +/- 0.16 mm2, compared with 0.84 +/- 0.13 mm2 in vehicle-treated controls, P < 0.05, and 0.90 +/- 0.15 mm2 in IgG-treated controls, P < 0.02). Mac-1 blockade reduces experimental neointimal thickening, suggesting that leukocyte recruitment to and infiltration of injured arteries may be a valid target for preventing intimal hyperplasia.

Angioplasty, Balloon↗
PubMed1998

Pathobiologic responses to stenting.

As the interventions available to treat obstructive coronary artery disease become increasingly complex, our understanding of the vascular response to these interventions requires greater sophistication. Molecular and cellular biologic tools have now propelled us into another phase of work with vascular devices. Initially, studies of endovascular implants such as stents focused on developing models of vascular injury. With these models, we could then examine the designs of individual stents and connect structure with performance. Now we are entering a third phase in which stent manufacturers are looking to science to dictate stent design.

Angioplasty, Balloon, Coronary↗
PubMed1998

Effects of amide and amine plasma-treated ePTFE vascular grafts on endothelial cell lining in an artificial circulatory system.

We sought to examine whether surface modification of expanded polytetrafluoroethylene (ePTFE) vascular grafts might extend graft patency without modifying the graft structure. Amide and amine plasma (butylamine) were applied to graft surfaces using radio frequency glow discharge. Surface analyses by Fourier transform infrared spectroscopy-attenuated total reflectance, X-ray photoelectron spectroscopy, and dynamic contact angle measurements revealed the presence of nitrogen-containing functional groups on the plasma modified graft surfaces, along with an increased surface hydrophilicity. Bovine aortic endothelial cells were seeded on amide and amine plasma coated ePTFE vascular grafts and placed inside an artificial circulatory system under well-defined flow conditions. The seeded endothelial cells were exposed to either constant or pulsatile flow condition for 5 days. Their corresponding maximum wall shear stresses were 1 dyn/cm2 under constant flow and 65, 108, and 259 dyn/cm2 under various pulsatile flows. Plasma modified ePTFE vascular grafts enhanced the endothelial cell lining under constant and pulsatile flow conditions. Fluorescence nuclear staining, scanning electron microscopy, and histological staining indicated the formation of an endothelial cell monolayer on the plasma coated graft surfaces.

Amides↗
PubMed1998

Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results.

BACKGROUND: Patients not amenable to complete myocardial revascularization by conventional methods present a difficult clinical problem. Here we present the early results and technical considerations of the administration of basic fibroblast growth factor for the induction of collateral growth using heparin-alginate slow-release devices in patients undergoing coronary artery bypass grafting. METHODS: Eight patients were enrolled. Patients were candidates if they had at least one graftable obstructed coronary artery and at least one major arterial distribution not amenable to revascularization, a serum creatinine level less than 3 mg/dL, ejection fraction greater than 0.20, and estimated operative mortality of less than 25%. During conventional coronary artery bypass grafting, 10 heparin-alginate devices, each containing either 1 microg or 10 microg of basic fibroblast growth factor, were implanted in the epicardial fat in multiple regions of the unrevascularizable territory and also in the distal distribution of a grafted or patent artery. RESULTS: There was no mortality and no evidence of renal, hematologic, or hepatic toxicity during follow-up. Three months after the operation, all patients remain free of angina. Seven patients were examined with stress perfusion scans. Three patients had clear enhancement of perfusion to the unrevascularized myocardium, 1 patient had a new fixed defect, and 3 had minimal overall change but had evidence of new small, fixed perfusion defects. Seven patients had improved or similar myocardial contractile function (ejection fraction at 3-month follow-up = 0.53 +/- 0.22 versus 0.47 +/- 0.14 preoperatively). One patient suffered a perioperative myocardial infarction in the area of basic fibroblast growth factor administration. CONCLUSIONS: This preliminary study demonstrates the safety and technical feasibility of therapeutic angiogenesis with basic fibroblast growth factor delivered by heparin-alginate slow-release devices. Further studies examining the safety, clinical efficacy, and long-term results are ongoing.

Aged↗
PubMed1998

The biologic effects of growth factor-toxin conjugates in models of vascular injury depend on dose, mode of delivery, and animal species.

Toxin-conjugates, complexes designed from the fusion of tissue toxins and pathology-specific ligands, offer the potential for targeted cytotoxic therapy. Some have postulated that the recurrent failure of these conjugates to exhibit benefit in animal models of vascular injury arose because the timing and frequency of conjugate delivery were insufficient to meet the demands of the arterial wall. Previous data suggest that increasingly frequent dosing would lead to superior inhibition of intimal hyperplasia. We now report on the biological effects of the controlled release of a recombinant conjugate of basic fibroblast growth factor (bFGF) and the plant toxin saporin (SAP), bFGF-SAP. Alginate/heparin-Sepharose microspheres and films were designed as drug carriers to control release the bFGF-SAP conjugate or bFGF alone in small doses. When bFGF-SAP-incorporated microspheres or films were implanted adjacent to balloon angioplastied porcine carotid arteries, the controlled release of bFGF-SAP over the four-week study stimulated rather than inhibited hyperplasia. When these same devices were used in cell culture, unexpected findings were produced. bFGF-SAP reduced in vitro bovine vascular smooth muscle cell growth at high concentrations (1-10 microgram/mL) but increased smooth muscle cell growth at lower concentrations (up to 1 microgram/mL). Microsphere controlled-released bFGF-SAP ( approximately 60 ng/mL over 4 days) stimulated the growth of smooth muscle cells more than any of the tested bolus applications of the conjugate. These data provide cause to reconsider our acceptance of controlled release technology as the answer to all forms of drug delivery problems, and to apply more rigorous means of matching the kinetics of drug delivery to the kinetics of the vascular response to injury.

Angioplasty↗
PubMed1998

Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia.

A number of heparin-binding growth factors, including basic (bFGF) and acidic (aFGF) fibroblast growth factors have been shown to promote angiogenesis in vivo. In this study, we employed a sustained-release polymer extravascular delivery system to evaluate the angiogenic efficacy of a novel form of genetically modified aFGF in the setting of chronic myocardial ischemia. Fifteen Yorkshire pigs subjected to Ameroid occluder placement on the left circumflex (LCX) artery were treated with perivascularly administered aFGF in ethylene vinyl acetate (EVAc) polymer (10 micrograms, n = 7) or EVAc alone (controls, n = 8). Seven to nine weeks later, after coronary angiography to document Ameroid-induced coronary occlusion, all animals underwent studies of coronary flow and global and regional left ventricular function. Microsphere-determined coronary flow in the Ameroid-compromised territory was significantly increased in aFGF-treated compared with control animals, and this improvement in perfusion was maintained during ventricular pacing. Left ventricular function studies demonstrated improved global and regional function in aFGF-treated animals. We conclude that local perivascular delivery of genetically modified aFGF results in significant improvement in myocardial flow and regional and global left ventricular function.

Animals↗