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Biomedical subjects

Elazer R Edelman

Publications and source records attributed to Elazer R Edelman.

At least 37 records · Page 2Linked to original sources
PubMed2004

Embolic protection with filtering or occlusion balloons during saphenous vein graft stenting retrieves identical volumes and sizes of particulate debris.

BACKGROUND: Distal embolization of plaque particulate liberated during stenting may cause periprocedural complications. The number, size, and volume of debris released during stenting, however, have not been quantified, rendering embolic protection approaches empiric. We used a novel method of microparticle size assessment to measure volume and characterize individual sizes of particles captured by the PercuSurge GuardWire balloon or a vascular filter during saphenous vein graft stenting. METHODS AND RESULTS: Braided nitinol filters (average distal pore size 100 microns) were used in 47 saphenous vein grafts in 44 patients. The PercuSurge GuardWire was used in 17 saphenous vein grafts in 16 patients. Particulate debris was subjected to microparticle size analysis (RapidVue, Beckman Coulter). All samples contained particulate debris. For both filter and GuardWire populations, most particles were <100 microm in longest dimension (87% and 90% of particles, respectively), and the distribution of particle sizes was identical. Total embolic load per lesion for both filters and GuardWire aspirates was also similar: median embolic load per filter was 16 mm3 (range 2 to 84 mm3). Median embolic load per GuardWire was also 16 mm3 (range 7 to 42 mm3). Histopathologic analysis demonstrated that most samples contained plaque elements and platelet-rich thrombus. CONCLUSIONS: During saphenous vein graft interventions, particulate retrieved with a vascular filtering device or an occlusion balloon was similar in amount and character. This supports the notion that unless soluble mediators play an important role in adverse acute clinical events after stenting, the clinical efficacy of filtering devices may be equal to that of occlusion devices.

Alloys↗
PubMed2004

Resonance energy transfer for assessing the molecular integrity of proteins for local delivery.

It remains unclear whether the limitations to the therapeutic potential of angiogenic growth factors stem from pharmacokinetic concerns related to inadequate delivery or from a reduced sensitivity of target tissues. Here, we report a novel method using resonance energy transfer to assess the molecular integrity of proteins after local delivery. As an example, we labeled fibroblast growth factor-2 with a fluorescent donor and nonfluorescent acceptor pair, tetramethylrhodamine and QSY-7, and demonstrate in an ex vivo bovine carotid artery model that this growth factor is not limited by proteolytic constraints imposed by the tissue. Our data indicate that FGF-2 is unlikely to be degraded within the arterial wall and suggest that pharmacokinetic limitations alone cannot fully explain the muted response seen thus far in therapeutic angiogenesis. In general, resonance energy transfer may serve as a novel approach to assess the molecular integrity of protein-based therapies in local delivery.

Animals↗
PubMed2004

Dynamic flow alterations dictate leukocyte adhesion and response to endovascular interventions.

Although arterial bifurcations are frequent sites for obstructive atherosclerotic lesions, the optimal approach to these lesions remains unresolved. Benchtop models of arterial bifurcations were analyzed for flow disturbances known to correlate with vascular disease. These models possess an adaptable geometry capable of simulating the course of arterial disease and the effects of arterial interventions. Chronic in vivo studies evaluated the effect of flow disturbances on the pattern of neointimal hyperplasia. Acute in vivo studies helped propose a mechanism that bridges the early mechanical stimulus and the late tissue effect. Side-branch (SB) dilation adversely affected flow patterns in the main branch (MB) and, as a result, the long-term MB patency of stents implanted in pig arteries. Critical to this effect is chronic MB remodeling that seems to compensate for an occluded SB. Acute leukocyte recruitment was directly influenced by the changes in flow patterns, suggesting a link between flow disturbance on the one hand and leukocyte recruitment and intimal hyperplasia on the other. It is often impossible to simultaneously maximize the total cross-sectional area of both branches and to minimize flow disturbance in the MB. The apparent trade-off between these two clinically desirable goals may explain many of the common failure modes of bifurcation stenting.

Animals↗
PubMed2003

Liposomal alendronate inhibits systemic innate immunity and reduces in-stent neointimal hyperplasia in rabbits.

BACKGROUND: Innate immunity is of major importance in vascular repair. The present study evaluated whether systemic and transient depletion of monocytes and macrophages with liposome-encapsulated bisphosphonates inhibits experimental in-stent neointimal formation. METHODS AND RESULTS: Rabbits fed on a hypercholesterolemic diet underwent bilateral iliac artery balloon denudation and stent deployment. Liposomal alendronate (3 or 6 mg/kg) was given concurrently with stenting. Monocyte counts were reduced by >90% 24 to 48 hours after a single injection of liposomal alendronate, returning to basal levels at 6 days. This treatment significantly reduced intimal area at 28 days, from 3.88+/-0.93 to 2.08+/-0.58 and 2.16+/-0.62 mm2. Lumen area was increased from 2.87+/-0.44 to 3.57+/-0.65 and 3.45+/-0.58 mm2, and arterial stenosis was reduced from 58+/-11% to 37+/-8% and 38+/-7% in controls, rabbits treated with 3 mg/kg, and rabbits treated with 6 mg/kg, respectively (mean+/-SD, n=8 rabbits/group, P<0.01 for all 3 parameters). No drug-related adverse effects were observed. Reduction in neointimal formation was associated with reduced arterial macrophage infiltration and proliferation at 6 days and with an equal reduction in intimal macrophage and smooth muscle cell content at 28 days after injury. Conversely, drug regimens ineffective in reducing monocyte levels did not inhibit neointimal formation. CONCLUSIONS: Systemic transient depletion of monocytes and macrophages, by a single liposomal bisphosphonates injection concurrent with injury, reduces in-stent neointimal formation and arterial stenosis in hypercholesterolemic rabbits.

Alendronate↗
PubMed2003

Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.

BACKGROUND: C-reactive protein (CRP), an acute-phase reactant long considered merely an innocent bystander in the inflammatory process, is now recognized as a powerful predictor of cardiovascular events. Emerging in vitro evidence suggests that CRP may have direct proinflammatory and prothrombotic effects on monocytes and endothelial cells. To determine whether CRP directly modulates vascular cell function in vivo, we subjected wild-type mice, which do not express CRP, and human CRP-transgenic (CRPtg) mice to 2 models of arterial injury. METHODS AND RESULTS: Baseline serum CRP levels in CRPtg mice were 18+/-6 mg/L. CRP levels were undetectable in wild-type mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 75% of CRPtg arteries (6 of 8) compared with 17% (2 of 12) in wild-type mice (P<0.05). In a model of arterial photochemical injury, clot formation time was shortened in CRPtg mice; mean time to occlusion was 33+/-19 minutes compared with 59+/-19 minutes in wild-type mice (n=10; P<0.05). CONCLUSIONS: Arterial injury in CRPtg mice results in an expedited and higher rate of thrombotic occlusion. This is the first report of a prothrombotic phenotype directly attributable to the presence of human CRP in vivo. Investigation of the inflammatory-thrombotic axis in CRPtg mice may elucidate the prothrombotic actions of CRP in unstable arterial diseases and may pave the way for novel therapeutic interventions for preventing cardiovascular events.

Animals↗
PubMed2003

Tissue engineering therapy for cardiovascular disease.

The present treatments for the loss or failure of cardiovascular function include organ transplantation, surgical reconstruction, mechanical or synthetic devices, or the administration of metabolic products. Although routinely used, these treatments are not without constraints and complications. The emerging and interdisciplinary field of tissue engineering has evolved to provide solutions to tissue creation and repair. Tissue engineering applies the principles of engineering, material science, and biology toward the development of biological substitutes that restore, maintain, or improve tissue function. Progress has been made in engineering the various components of the cardiovascular system, including blood vessels, heart valves, and cardiac muscle. Many pivotal studies have been performed in recent years that may support the move toward the widespread application of tissue-engineered therapy for cardiovascular diseases. The studies discussed include endothelial cell seeding of vascular grafts, tissue-engineered vascular conduits, generation of heart valve leaflets, cardiomyoplasty, genetic manipulation, and in vitro conditions for optimizing tissue-engineered cardiovascular constructs.

Animals↗
PubMed2003

A structural model that explains the effects of hyperglycemia on collagenolysis.

Prior investigations into the effects hyperglycemia on collagen degradation have yielded conflicting results. We present a new formalism for understanding the biochemistry of collagenolysis and the effects of hyperglycemia on collagen degradation. The analysis is based on an understanding of environments that affect the conformational stability of collagen. We suggest that collagen can exist in two distinct conformational states-a native state and a vulnerable state. Vulnerable collagen corresponds to a non-native conformation where partially unfolded regions near collagenase cleavage sites enable collagenases to efficiently degrade collagen. Theoretical calculations on collagen-like model peptides suggest that relatively short periods of hyperglycemia can alter the equilibrium distribution of states to favor vulnerable states of collagen. These data provide new insights into the mechanism of collagenolysis and resolve apparently discrepant experimental data on the effects of hyperglycemia on collagen degradation.

Animals↗
PubMed2003

Impact of transport and drug properties on the local pharmacology of drug-eluting stents.

Drugs released from stents are driven by physiological transport forces, principally solvent-driven flow (convection) and random molecular agitation (diffusion). The relative strength of these two forces determines drug penetration and distribution in the arterial wall. Drug physicochemical factors can induce critical modulations to the primary distribution, both transiently and at steady state. Hydrophobic interactions and nonspecific binding, for example, can both result in tissue drug concentrations severalfold above administered concentration. Drug interaction with native proteins may also interfere with drug transfer at the stent-artery interface. These transport forces and tissue interactions can induce local drug concentrations even at steady state to vary by one or more orders of magnitude over the span of a few cells. To account for significant local variations in drug concentrations following stent-based delivery, rational design of vascular delivery systems requires consideration of drug distribution and tissue interactions on a local, continuum basis. Continuum analysis adapts traditional pharmacokinetics to the local environment by supplementing discrete global parameters of drug content with continuous local values of concentration, transport and binding. The interplay of these parameters with local flux conditions and drug and tissue properties defines the local drug distribution in space and over time. This type of analysis may well become increasingly relevant given the trend toward stent-based drug therapy in cardiovascular care.

Angioplasty, Balloon↗
PubMed2003

Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries.

Radiolabeled drug-eluting stents have been proposed recently as a novel method to potentially reduce restenosis in coronary arteries. A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue. However, the relatively low proportion of drugs transferred to the arterial wall (<2%-5% typically) raises questions about the degree to which radiolabeled drugs eluted from the stent can contribute to the total radiation dose delivered to tissues. A three-dimensional diffusion-convection transport model is used to model the transport of a hydrophilic drug released from the surface of a stent to the arterial media. Large drug concentration gradients are observed near the stent struts giving rise to a nonuniform radiation activity distribution for the drug in the tissues as a function of time. A voxel-based kernel convolution method is used to calculate the radiation dose rate resulting from this activity build-up in the arterial wall based on the medical internal radiation dose formalism. Measured residence time for the P-32 ODN in the arterial wall and at the stent surface obtained from animal studies are used to normalize the results in terms of absolute dose to tissue. The results indicate that radiation due to drug eluted from the stent contributes only a small fraction of the total radiation delivered to the arterial wall, the main contribution coming from the activity that remains embedded in the stent coating. For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions, the activity build-up in the arterial wall contributes only a small fraction to the total dose delivered by the P-32 ODN stent. For these compounds, it is concluded that radiolabeled drug-eluting stent will not likely improve the performance of radioactive stents for the treatment of restenosis. Also, variability in the delivery efficacy of drug delivery devices makes accurate dosimetry difficult and the drug washout in the systemic circulatory system may yield an unnecessary activity build-up and dose to healthy organs.

Arteries↗
PubMed2003

Leukocyte recruitment and expression of chemokines following different forms of vascular injury.

UNLABELLED: Inflammation plays a central role in restenosis following coronary intervention. Recent human and animal data suggest important differences between the inflammatory responses to simple balloon angioplasty compared with stent implantation. To investigate the mechanisms of these differences, New Zealand white rabbits underwent bilateral iliac artery balloon denudation. Half received intravascular stents. Arteries were harvested at three, seven and 14 days for immunohistochemistry, and 4 hours, 8 hours and 14 days for chemokine mRNA analysis. Leukocyte content was quantified utilizing immunohistochemistry (RPN357, monoclonal antibody (mAb) against rabbit neutrophil; RAM-11, mAb against rabbit macrophage). We analyzed the mRNA levels of the chemokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) through semi-quantitative polymerase chain reaction. We demonstrated the spatial pattern of MCP-1 mRNA levels through in situ mRNA hybridization. In balloon-injured arteries, leukocyte recruitment was confined to early neutrophil infiltration. IL-8 and MCP-1 mRNA levels peaked within hours and were undetectable at 14 days. In contrast, in stented arteries, early neutrophil recruitment was followed by prolonged macrophage accumulation. IL-8 and MCP-1 mRNA levels peaked within hours but were still detectable 14 days post injury. CONCLUSIONS: In contrast to balloon injury, stent-induced injury results in sustained chemokine expression and leukocyte recruitment. These data may have important implications for antirestenotic strategies.

Angioplasty, Balloon↗
PubMed2002

Phosphorylation-induced conformational changes in a mitogen-activated protein kinase substrate. Implications for tyrosine hydroxylase activation.

Mitogen-activated protein (MAP) kinase-mediated phosphorylation of specific residues in tyrosine hydroxylase leads to an increase in enzyme activity. However, the mechanism whereby phosphorylation affects enzyme turnover is not well understood. We used a combination of fluorescence resonance energy transfer (FRET) measurements and molecular dynamics simulations to explore the conformational free energy landscape of a 10-residue MAP kinase substrate found near the N terminus of the enzyme. This region is believed to be part of an autoregulatory sequence that overlies the active site of the enzyme. FRET was used to measure the effect of phosphorylation on the ensemble of peptide conformations, and molecular dynamics simulations generated free energy profiles for both the unphosphorylated and phosphorylated peptides. We demonstrate how FRET transfer efficiencies can be calculated from molecular dynamics simulations. For both the unphosphorylated and phosphorylated peptides, the calculated FRET efficiencies are in excellent agreement with the experimentally determined values. Moreover, the FRET measurements and molecular simulations suggest that phosphorylation causes the peptide backbone to change direction and fold into a compact structure relative to the unphosphorylated state. These results are consistent with a model of enzyme activation where phosphorylation of the MAP kinase substrate causes the N-terminal region to adopt a compact structure away from the active site. The methods we employ provide a general framework for analyzing the accessible conformational states of peptides and small molecules. Therefore, they are expected to be applicable to a variety of different systems.

Animals↗
PubMed2002

Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits.

BACKGROUND: Emerging data indicate that the inflammatory response after mechanical arterial injury correlates with the severity of neointimal hyperplasia in animal models and postangioplasty restenosis in humans. The present study was designed to examine whether a nonspecific stimulation of the innate immune system, induced in close temporal proximity to the vascular injury, would modulate the results of the procedure. Methods and Results- Rabbits subjected to iliac artery balloon injury (balloon denudation with or without stent deployment) were injected twice with a bacterial lipopolysaccharide (LPS) (500 ng/rabbit) before and after surgery. The dose was chosen to be sufficient to induce systemic inflammation but not septic shock. A systemic marker of inflammation (serum interleukin-1beta levels measured by ELISA) and monocytic stimulation (CD14 levels on monocytes measured by flow cytometry) were increased after LPS administration. Arterial macrophage infiltration at 7 days after injury was 1.7+/-1.2% of total cells in controls and 4.2+/-1.8% in LPS-treated rabbits (n=4, P<0.05). Morphometric analysis of the injured arteries 4 weeks after injury revealed significantly increased luminal stenosis (38+/-4.2% versus 23+/-2.6, mean+/- SEM; n=8, P<0.05) and neointima-to-media ratio (1.26+/-0.21 versus 0.66+/- 0.09, P<0.05) in LPS-treated animals compared with controls. This effect was abolished by anti-CD14 Ab administration. Serum interleukin-1beta levels and monocyte CD14 expression were significantly increased in correlation with the severity of intimal hyperplasia. LPS treatment increased neointimal area after stenting from 0.57+/-0.07 to 0.77+/- 0.1 mm(2) and stenosis from 9+/-1% to 13+/-1.7% (n=5, P< 0.05). CONCLUSIONS: Nonspecific systemic stimulation of the innate immune system concurrently with arterial vascular injury facilitates neointimal formation, and conditions associated with increased inflammation may increase restenosis.

Angioplasty, Balloon↗
PubMed2002

Arterial ultrastructure influences transport of locally delivered drugs.

An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.

Animals↗
PubMed2002

Effect of pre-adsorbed proteins on attachment, proliferation, and function of endothelial cells.

As certain proteins control cell adhesion, it has been hoped that cell transplantation and tissue engineering could be augmented by pre-adsorption of specific proteins to biological or synthetic surfaces. The questions that remain, however, are whether such proteins can affect cell production as well as adhesion, and if so, whether in a protein-specific manner. We examined the adhesion and the biochemical secretion of bovine aortic endothelial cells (BAEC) on tissue culture polystyrene (TCPS) discs coated with fibronectin (Fn), laminin (Ln), or gelatin. The three coating proteins nonspecifically promote sub-confluent and post-confluent endothelial cell production of total protein up to 2.5-fold of the reference value. Total soluble glycosaminoglycan (GAG) production slightly increased with the different coatings only at low cell density. In contrast, Ln and Fn, not gelatin, drastically enhanced post-confluent BAEC production of prostaglandin (PGI2). However, antibody-blockage of the alpha5 integrin, constituent of the Fn receptor in BAEC, appeared to inhibit the upregulation of PGI2 production observed on Fn-coated surfaces. The results indicate that the cell adhesion mediators used as coating agents dictate cell biological production as well as adhesion and proliferation.

Adsorption↗
PubMed2002

Low background, pulsatile, in vitro flow circuit for modeling coronary implant thrombosis.

We have developed an in vitro method for creating pulsatile flows to mimic coronary type flow patterns on a beat-to-beat basis. The flow is created by accelerating fluid loops about an axis, inducing relative wall motion. Using this technique, a variety of oscillating flow patterns can be generated and modulated. Such flow generation offers the potential to monitor sensitive, flow-dependent, biological parameters like thrombosis while minimizing background disturbances from pump action and circuit effects. We examined this potential by measuring the loop occlusion time for loops stented with stainless steel 7-9 NIR stents and stentless control loops.

Adult↗