Syed Razvi

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. She was aged 71 with an ischaemic right leg. We administered 2,000 micrograms human plasmid phVEGF165 that was applied to the hydrogel polymer coating of an angioplasty balloon. By inflating the balloon, plasmid DNA was transferred to the distal popliteal artery. FINDINGS Digital subtraction angiography 4 weeks after gene therapy showed an increase in collateral vessels at the knee, mid-tibial, and ankle levels, which persisted at a 12-week view. Intra-arterial doppler-flow studies showed increased resting and maximum flows (by 82% and 72%, respectively). Three spider angiomas developed on the right foot/ankle about a week after gene transfer; one lesion was excised and revealed proliferative endothelium, the other two regressed. The patient developed oedema in her right leg, which was treated successfully. INTERPRETATION Administration of endothelial cell mitogens promotes angiogenesis in patients with limb ischaemia.

Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results.

PURPOSE Thromboangiitis obliterans (TAO), or Buergers disease, a distinct form of vascular occlusive disease that afflicts the peripheral arteries of young smokers, is often characterized by an inexorable downhill course even in patients who discontinue smoking once a stage of critical limb ischemia associated with ulceration or gangrene is reached. As part of a phase I clinical trial to document the safety and efficacy of intramuscular gene transfer of naked plasmid DNA-encoding vascular endothelial growth factor (phVEGF165) in the treatment of critical limb ischemia, we treated TAO in 6 patients. METHODS Seven limbs in 6 patients (3 men, 3 women; mean age, 33 years; range, 33 to 51 years) who satisfied the criteria for TAO and had signs or symptoms of critical limb ischemia were treated twice, 4 weeks apart, with 2 or 4 mg of phVEGF165, which was administered by direct intramuscular injection at 4 arbitrarily selected sites in the ischemic limb. The gene expression was documented by enzyme-linked immunosorbent assay that was performed on peripheral blood samples. RESULTS The ulcers that were nonhealing for more than 1 month healed completely in 3 of 5 limbs after the intramuscular phVEGF165 gene therapy. Nocturnal rest pain was relieved in the remaining 2 patients, although both continue to have claudication. The evidence of the improved perfusion to the distal ischemic limb included an increase of more than 0.1 in the ankle brachial index in 3 limbs, an improved flow shown with magnetic resonance imaging in 7 of the 7 limbs, and newly visible collateral vessels shown with serial contrast angiography in 7 of the 7 limbs. The adverse consequences of the phVEGF165 gene transfer were limited to transient ankle or calf edema in 3 of the 7 limbs. Two patients with advanced distal forefoot gangrene ultimately required below-knee amputation despite the evidence of improved perfusion. A histologic section disclosed the classic pathologic findings of TAO. CONCLUSION Therapeutic angiogenesis with phVEGF165 gene transfer, if instituted before the development of forefoot gangrene, may provide a novel therapy for patients with advanced Buergers disease that is unresponsive to standard medical or surgical treatment methods.

Three-dimensional reconstruction of human coronary and peripheral arteries from images recorded during two-dimensional intravascular ultrasound examination

Background Intravascular ultrasound provides high-resolution images of vascular lumen, plaque, and subjacent structures in the vessel wall; current instrumentation, however, limits the operator to viewing a single, tomographic, two-dimensional image at any one time. Comparative analysis of serial two-dimensional images requires repeated review of the video playback recorded during the two-dimensional examination, followed by a “minds eye” type of imagined reconstruction. Methods and Results Computer-based, automated three-dimensional reconstruction was used to generate a tangible format with which to assess and compare a “stacked” series of two-dimensional images. Three-dimensional representations were prepared from sequential images obtained during intravascular ultrasound examination in 52 patients, 50 of whom were studied before and/or after percutaneous revascularization. Conventional two-dimensional ultrasound images were acquired by means of a systematic, timed pullback of the ultrasound catheter through the respective vascular segments. Images were then assembled in automated fashion to create a three-dimensional depiction of the vessel lumen and wall. Computer-enhanced three-dimensional reconstructions were generated in both sagittal and cylindrical formats. The sagittal format resulted in a longitudinal profile similar to that obtained during angiographic examination; in contrast to angiography, however, the. sagittal reconstruction offered 360° of limitless orthogonal views of the plaque and arterial wall as well as the vascular lumen. The cylindrical format yielded a composite view of a given vascular segment, and a hemisected version of the cylindrical reconstruction enabled en face inspection of the reconstructed luminal surface. Sagittal reconstructions facilitated analysis of dissections and plaque fractures resulting from percutaneous revascularization, and the hemisected cylindrical reconstructions enhanced analysis of endovascular prostheses. Conclusions This preliminary experience demonstrates that computer-based three-dimen-sional reconstruction may further augment the use of intravascular ultrasound in assessing vascular pathology and guiding interventional therapy.

Combination balloon-ultrasound imaging catheter for percutaneous transluminal angioplasty. Validation of imaging, analysis of recoil, and identification of plaque fracture.

BackgroundWe investigated the hypothesis that an ultrasound transducer positioned within an angioplasty balloon could be used to perform quantitative assessment of arterial dimensions before and after percutaneous transluminal angioplasty (PTA) and to identify certain mechanical alterations consequent to PTA, including vascular wall recoil and the initiation of plaquefractures. Methods and ResultsA combination balloon-ultrasound imaging catheter (BUIC) that houses a 20-MHz ultrasound transducer within and halfway between the proximal and distal ends of an angioplasty balloon was used to perform PTA in 10 patients with peripheral vascular disease. Each PTA site was also evaluated before and after PTA by standard (nonballoon) intravascular ultrasound (IVUS) technique. In eight patients in whom satisfactory images were recorded with the BUIC before PTA, luminal cross-sectional area (XSA) of stenotic sites (0.10 ± 0.01 cm2) did not differ significantly from measurements of XSA by IVUS (0.09 ± 0.01 cm2, p=NS). Likewise, minimum luminal diameter (Dmin) measured by BUIC (0.34 ± 0.02 cm) was similar to that measured by IVUS (0.33 ± 0.01 cm, p=NS). In nine patients in whom satisfactory images were recorded with the BUIC after PTA, XSA measured by BUIC (0.29 ± 0.03 cm2) did not differ significantly from XSA measured by IVUS (0.30 ± 0.03 cm2, p=NS). Dmin measured by BUIC after PTA (0.57 ± 0.02 cm) was also similar to D.,. measured by IVUS (0.57 ± 0.03 cm, p=NS). After PTA, XSA and Dmin measured immediately after deflation were significantly less than balloon XSA and diameter at full inflation, indicating significant elastic recoil of the dilated site. For the nine patients in whom post-PTA images were satisfactory for quantitative analysis, including four patients in whom recoil was 39%o, 46%, 50%, and 61%, percent recoil measured 28.6 ± 7.2%. Finally, plaque fractures were identified on-line in six of 10 patients (60%); in each case, initiation of plaque fracture was observed at inflation pressures of 2 atm or less. Conclsions. The results of this preliminary human investigation indicate that an ultrasound transducer positioned within an angioplasty balloon can be used to perform quantitative and qualitative analyses of lumen-plaque-wall alterations immediately preceding, during, and immediately after PTA in patients with peripheral vascular disease.

Real-time three-dimensional reconstruction of intravascular ultrasound images of iliac arteries.

Abstract Intravascular ultrasound (IU) imaging provides detailed tomographic images of the vascular wall and lumen.1–3 One liability of this novel imaging modality, however, is the inability to view a given vascular segment in a composite format; detailed cross-sectional images are thus provided at the expense of a longitudinal perspective. The circumferential nature of a postangioplasty dissection may be well demonstrated by IU, for example, but the full longitudinal extent may not be readily apparent, even after repeated review of the videotaped images recorded over the length of the involved segment. Computer-based 3-dimensional (3-D) reconstruction (R) from serially recorded IU images offers a potential solution to this problem. By creating a longitudinal display of the entire vascular segment, 3-DR offers a composite format for presentation of detailed IU data, facilitating comparison of selected cross-sectional ullages with those that are proximal and distal. Previous studies from our laboratory have outlined the concepts, technique and instrumentation used for 3-DR, and demonstrated the feasibility and potential use of 3-DR.4–6 Whereas off-line analysis of such 3-DRs has provided insight into mechanisms of recanalization, to be clinically useful during interventional procedures, 3-D image generation must be rapid, if not instantaneous. We report here the use of real-time 3-DR from IU images recorded during percutaneous iliac artery revascularization in 2 patients.

Noninvasive assessment of peripheral vascular disease by color flow Doppler/two-dimensional ultrasound

Abstract The development, in 1985, of phased array scanning in a linear format 1 established the potential for acquiring high quality color flow Doppler (CFD) maps of the vasculature in the lower extremities. Subsequently, however, little information has been published 2,3 describing examination of the peripheral arteries by CFD, whether in linear, sector or anular format. Accordingly, the present study was undertaken to evaluate the utility of CFD in combination with 2-dimensional ultrasound (2DU) for the assessment of peripheral vascular disease.

Prospective investigation of a subcutaneous, implantable central venous access device for therapeutic plasma exchange in adults with neurological disorders

Standard alternatives to antecubital access for long‐term therapeutic plasma exchange, including percutaneous polyurethane or tunneled silicone catheters, are associated with complications and inconvenience for the patient. We have investigated the Bard CathLink® 20, a subcutaneously implantable central venous access device, as an alternative for outpatient plasma exchange. The CathLink® 20 consists of a funnel‐shaped titanium port connected to a soft polyurethane‐derived catheter and is accessed percutaneously using an 18‐gauge catheter‐over‐needle Angiocath®. Six patients with paraproteinemic polyneuropathies underwent 64 outpatient plasma exchanges using the CathLink® 20 for access, 31 using 2 CathLink® 20s (draw and return), 20 using a single CathLink® 20 as the draw site and 13 using a single CathLink® 20 as the return site. Mean (± SD) plasma removed was 3,680 ± 551 ml in 115.2 ± 25.3 min. Apheresis personnel were able to access the ports in 1.23 ± 0.6 attempts per port per procedure. Six of 70 planned procedures were aborted: 3 because of failure of an antecubital access site and 3 because of catheter occlusion resolved using a thrombolytic agent. Whole blood flow rate was approximately 54 ml/min, and plasma flow rate was about 32 ml/min for 135 min. Access pressures were stable at −150 to −200 torr (P = 0.1395). Return line pressures varied between 90 and 130 torr (P = 0.0147). No patient required hospitalization during the study. Though not optimized for apheresis, the CathLink® 20 provides a reasonable option for chronic apheresis patients who lack adequate peripheral venous access. J. Clin. Apheresis 17:1–6, 2002.