Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial.

Objective: Randomized, blinded trial of intramuscular gene transfer using plasmid vascular endothelial growth factor (VEGF) to treat diabetic polyneuropathy.

Methods: Diabetic patients with polyneuropathy were randomized to receive a VEGF-to-placebo ratio of 3:1. Three sets of injections were given at eight standardized sites adjacent to the sciatic, peroneal, and tibial nerves of one leg.

Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience.

Background: Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response.

Methods And Results: This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study.

Plasma vascular endothelial growth factor (VEGF) levels after intramuscular and intramyocardial gene transfer of VEGF-1 plasmid DNA.

The purpose of this study was to document the kinetics of vascular endothelial growth factor (VEGF) protein release into the systemic circulation after phVEGF gene transfer for therapeutic angiogenesis. VEGF plasma levels were measured by ELISA in 64 patients undergoing gene transfer of plasmid DNA: intramuscular in 34 patients with peripheral artery disease, and intramyocardial in 30 patients with coronary disease. Baseline plasma VEGF was highly variable and not normally distributed.

In vivo analysis of intramuscular gene transfer in human subjects studied by on-line ultrasound imaging.

The current study was designed to test the hypothesis that intramuscular (i.m.) injection of naked DNA leads to distribution of the injectate remote from the site of needle placement, a finding that might be expected to facilitate i.

Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia.

Objective: To investigate the effects of vascular endothelial growth factor gene therapy on ischemic neuropathy in patients with critical limb ischemia.

Design: An open-label, dose-escalating trial. Patients with angiographically proven critical leg ischemia received injections of phVEGF(165) human plasmid in the muscles of the ischemic limb.

Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects.

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs).

Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor.

Background: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The extent to which VEGF may cause tissue edema in humans has not been established.

Objective: To evaluate patients undergoing VEGF gene transfer for evidence of lower-extremity edema.

Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia.

Background: Preclinical studies have indicated that angiogenic growth factors can stimulate the development of collateral arteries, a concept called "therapeutic angiogenesis." The objectives of this phase 1 clinical trial were (1) to document the safety and feasibility of intramuscular gene transfer by use of naked plasmid DNA encoding an endothelial cell mitogen and (2) to analyze potential therapeutic benefits in patients with critical limb ischemia.

Methods And Results: Gene transfer was performed in 10 limbs of 9 patients with nonhealing ischemic ulcers (n=7/10) and/or rest pain (n=10/10) due to peripheral arterial disease.

Histopathology of in-stent restenosis in patients with peripheral artery disease.

Background: Clinical studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of in-stent restenosis. However, pathological data regarding this issue are limited. Specifically, direct evidence of proliferative activity in tissues excised from stenotic stents has not been previously reported.

Restenosis of endovascular stents from stent compression.

Objectives: We sought to determine the basis for restenosis within superficial femoral arteries (SFAs) and hemodialysis conduits treated with balloon-expandable stents.

Background: Use of stents within coronary and peripheral vessels continues to increase exponentially. The mechanism of restenosis within stents placed at various vascular sites is not well understood.

Elevated levels of basic fibroblast growth factor in patients with limb ischemia.

Basic fibroblast growth factor (bFGF), a prototypic member of a family of heparin-binding growth factors, is angiogenic both in vitro and in vivo. Increased levels and activity of bFGF have been documented in a variety of diseases, including tumors. We sought to determine whether bFGF might be similarly elevated in patients with clinical evidence of limb ischemia.

Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb.

Background: Preclinical findings suggest that intra-arterial gene transfer of a plasmid which encodes for vascular endothelial growth factor (VEGF) can improve blood supply to the ischaemic limb. We have used the method in a patient.

Methods: Our patient was the eighth in a dose-ranging series.

Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease.

The age-adjusted prevalence of peripheral arterial disease (PAD) in the U.S. population has been estimated to approach 12%.

Focal compensatory enlargement of human arteries in response to progressive atherosclerosis. In vivo documentation using intravascular ultrasound.

Background: Previous postmortem studies have demonstrated compensatory enlargement of atherosclerotic arteries in animal models and patients. Conclusions regarding these changes were drawn based on a comparison of the dimensions of diseased arteries in one group of subjects with the dimensions of normal arteries in another group. This method admits potential confounding variables, such as demographics and other disease states, which might also have an impact on arterial size.

Combined physiologic and anatomic assessment of percutaneous revascularization using a Doppler guidewire and ultrasound catheter.

Previous investigations have established the utility of intravascular ultrasound (IVUS) examination for the evaluation of arterial dimensions and qualitative changes following percutaneous revascularization. More recently, the feasibility of obtaining intravascular physiology findings before and/or after percutaneous revascularization by use of an intravascular Doppler Flowire (Cardiometrics) has been demonstrated. Accordingly, we investigated the feasibility of using this combined physiologic/anatomic approach to evaluate individuals undergoing percutaneous revascularization of stenotic or occluded coronary and peripheral arteries.

How does angioplasty work? Serial analysis of human iliac arteries using intravascular ultrasound.

Background: Previous studies regarding the mechanism by which balloon angioplasty increases luminal patency have generally used animal models or postmortem specimens from occasional fatal cases of angioplasty performed in human patients. In either case, conclusions regarding participatory mechanisms have relied exclusively on nonserial, postangioplasty histopathological examination.

Methods And Results: In the present study, intravascular ultrasound examination was performed before and after balloon angioplasty in 40 consecutive patients with iliac artery stenoses.

Human coronary and peripheral arteries: on-line three-dimensional reconstruction from two-dimensional intravascular US scans. Work in progress.

To explore the feasibility of computer-based, on-line three-dimensional reconstruction, timed manual withdrawal (pullback) recordings were obtained with two-dimensional intravascular ultrasound (US) in 42 patients who underwent percutaneous revascularization. Three-dimensional processing was performed with commercial software that stacked serially obtained intravascular US scans and created a new set of data points in four steps: interpolation, segmentation, boundary encoding, and surface rendering. In all 42 patients, satisfactory on-line three-dimensional reconstruction was accomplished.

In vivo assessment of vascular pathology resulting from laser irradiation. Analysis of 23 patients studied by directional atherectomy immediately after laser angioplasty.

Background: The pathological consequences of cardiovascular laser irradiation have been studied extensively in vitro. Previous in vivo studies of laser-induced injury have included analyses of acute and/or chronic findings in experimental animals. Little information, however, is available regarding the acute effects of laser irradiation of human vascular tissues in vivo.