FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2044294583> ?p ?o ?g. }

• W2044294583 endingPage "2692" @default.
• W2044294583 startingPage "2687" @default.
• W2044294583 abstract "HomeCirculationVol. 91, No. 11Arterial Gene Therapy for Therapeutic Angiogenesis in Patients With Peripheral Artery Disease Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBArterial Gene Therapy for Therapeutic Angiogenesis in Patients With Peripheral Artery Disease Jeffrey M. Isner, Kenneth Walsh, James Symes, Ann Pieczek, Satoshi Takeshita, Jason Lowry, Susan Rossow, Kenneth Rosenfield, Lawrence Weir, Edi Brogi and Robert Schainfeld Jeffrey M. IsnerJeffrey M. Isner From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Kenneth WalshKenneth Walsh From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , James SymesJames Symes From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Ann PieczekAnn Pieczek From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Satoshi TakeshitaSatoshi Takeshita From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Jason LowryJason Lowry From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Susan RossowSusan Rossow From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Kenneth RosenfieldKenneth Rosenfield From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Lawrence WeirLawrence Weir From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author , Edi BrogiEdi Brogi From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author and Robert SchainfeldRobert Schainfeld From St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Search for more papers by this author Originally published1 Jun 1995https://doi.org/10.1161/01.CIR.91.11.2687Circulation. 1995;91:2687–2692Background Peripheral Artery Disease: Primary Pharmacological Therapy Is Ineffective for Patients With Critical Limb Ischemia The prognosis for patients with chronic critical leg ischemia, ie, rest pain and/or established lesions that jeopardize the integrity of the lower limbs, is often poor. Psychological testing of such patients has typically disclosed quality-of-life indexes similar to those of patients with cancer in critical or even terminal phases of their illness.1 It has been estimated that in toto,2 150 000 patients per year require lower-limb amputations for ischemic disease in the United States. Their prognosis after amputation is even worse3 : the perioperative mortality for below-knee amputation in most series is 5% to 10% and for above-knee amputation 15% to 20%. Even when they survive, nearly 40% will have died within 2 years of their first major amputation; a major amputation is required in 30% of cases; and full mobility is achieved in only 50% of below-knee and 25% of above-knee amputees. These grim statistics are compounded by the lack of efficacious drug therapy. As concluded in the Consensus Document of the European Working Group on Critical Leg Ischemia,3 “. . .there presently is inadequate evidence from published studies to support the routine use of primary pharmacological treatment in patients with critical leg ischemia. . . .” Evidence for the utility of medical therapy in the treatment of claudication is no better.45 Consequently, the need for alternative treatment strategies in such patients is compelling. Therapeutic Angiogenesis Is a Novel Strategy for the Treatment of Critical Limb Ischemia The therapeutic implications of angiogenic growth factors were identified by the pioneering work of Folkman6 and other workers more than two decades ago. Beginning a little more than a decade ago,7 a series of polypeptide growth factors were purified, sequenced, and demonstrated to be responsible for natural as well as pathological angiogenesis. More recent investigations have established the feasibility of using recombinant formulations of such angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia. This novel strategy for the treatment of vascular insufficiency has been called therapeutic angiogenesis. The angiogenic growth factors first used for this purpose comprised members of the fibroblast growth factor (FGF) family. Baffour et al8 administered basic FGF (bFGF) in daily doses of 1 or 3 μg IM to rabbits with acute hindlimb ischemia; at the completion of 14 days of treatment, angiography and necropsy measurement of capillary density showed evidence of augmented collateral vessels in the lower limb compared with controls. Pu et al9 used acidic FGF (aFGF) to treat rabbits in which the acute effects of surgically induced hindlimb ischemia were allowed to subside for 10 days before a 10-day course of daily 4-mg IM injection was begun; at the completion of 30 days of follow-up, both angiographic and hemodynamic evidence of collateral development was superior to ischemic controls treated with IM saline. Yanagisawa-Miwa et al10 likewise demonstrated the feasibility of bFGF for salvage of infarcted myocardium, but in this case, growth factor was administered intra-arterially at the time of coronary occlusion, followed 6 hours later by a second intra-arterial bolus. More recently, administration of bFGF was shown to increase collateral flow11 as well as improve myocardial function12 in animal models of chronic myocardial ischemia. We used a rabbit model of hindlimb ischemia13 to investigate the therapeutic potential of a 45-kD dimeric glycoprotein, vascular endothelial growth factor (VEGF), isolated initially as a heparin-binding factor secreted from bovine pituitary folliculostellate cells.14 VEGF was also purified independently as a tumor-secreted factor that induced vascular permeability by the Miles assay1516 ; thus its alternate designation, vascular permeability factor. Two features distinguish VEGF from other heparin-binding, angiogenic growth factors. First, the NH2 terminus of VEGF is preceded by a typical signal sequence; therefore, unlike bFGF, VEGF can be secreted by intact cells.17 Second, its high-affinity binding sites, shown to include the tyrosine kinase receptors Flt118 and Flk1/KDR,1920 are present on endothelial cells but not other cell types; consequently, the mitogenic effects of VEGF—in contrast to aFGF and bFGF, both of which are known to be mitogenic for smooth muscle cells2122 and fibroblasts as well as endothelial cells—are limited to endothelial cells.1423We considered the fact that the VEGF gene encodes a secretory signal sequence that might be exploited as part of a strategy designed to accomplish therapeutic angiogenesis by arterial gene transfer. We had previously used the plasmid pXGH5 encoding the gene for human growth hormone, a secreted protein, to transfect rabbit aortic rings in vitro24 and rabbit ear arteries in vivo25 and obtained physiological levels of human growth hormone, even though immunohistochemical examination of the transfected tissue disclosed evidence of successful transfection in <1% of cells in the transfected arterial segment. Thus, gene products that are secreted may have profound biological effects, even when the number of transduced cells remains low. In contrast, for genes such as bFGF that do not encode a secretory signal sequence, transfection of a much larger cell population might be required for that intracellular gene product to express its biological effects. We therefore applied 400 μg of phVEGF165, encoding the 165–amino acid isoform of VEGF, to the hydrogel polymer outside coating of an angioplasty balloon2627 and delivered the balloon catheter percutaneously to the iliac artery of rabbits in which the femoral artery had been excised to cause hindlimb ischemia. Site-specific transfection of phVEGF165 was confirmed by analysis of the transfected internal iliac arteries using reverse transcriptase–polymerase chain reaction (RT-PCR) and then sequencing the RT-PCR product. Augmented development of collateral vessels was documented by serial angiograms in vivo and increased capillary density at necropsy. Consequent amelioration of the hemodynamic deficit in the ischemic limb was documented by improvement in the calf blood pressure ratio (ischemic to normal limb) to 0.70±0.08 in the VEGF-transfected group versus 0.50±0.18 in controls (P<.05). These findings28 thus established the principle that site-specific arterial gene transfer can be used to achieve physiologically meaningful therapeutic modulation of vascular disorders, including therapeutic angiogenesis. Despite similarly encouraging results achieved in our laboratory with administration of the recombinant protein in the same animal model,29303132 we believe that transferring the gene encoding that protein (ie, gene therapy) is preferable, for two reasons. First, the feasibility of a clinical trial of recombinant VEGF protein is currently limited by the lack of approved or available quantities of human-quality grade recombinant protein. Principally because of the extraordinary cost of scaling up from research grade to human-quality recombinant protein and the associated uncertainty regarding reimbursement for recombinant protein therapies in the future, no for-profit company, to the best of our knowledge, is currently planning a clinical trial of recombinant protein therapy with VEGF. Second is the potential requirement to maintain an optimally high and local concentration over time. In the case of therapeutic angiogenesis, for example, it may be preferable to deliver a lower dose over a period of several days or more from an actively expressing transgene in the circulation of the ischemic limb, rather than a single or multiple bolus doses of systemically recirculating recombinant protein. It is conceivable, although as yet unproven, that such continuous, local production of VEGF resulting from the transgene may be preferable, from the standpoints of both safety and bioactivity, to a single, larger dose of the recombinant protein administered by any (intra-arterial, intravenous, intramuscular) route. Experimental Design Objectives Primary Objective The primary objective of this investigation is to document the safety of the phVEGF165 arterial gene therapy for therapeutic angiogenesis. Secondary Objectives The secondary objectives are (1) to determine the bioactivity of arterial gene therapy using phVEGF165 to relieve rest pain and/or heal ischemic ulcers of the lower extremities in patients with peripheral artery disease and (2) to determine the anatomic and physiological extent of collateral artery development in patients receiving phVEGF165 arterial gene therapy. Selection of Patients Patients will be selected for this protocol if they have rest pain and/or nonhealing ischemic ulcers and are not satisfactory candidates for nonsurgical or surgical revascularization. The lack of available medical therapy for patients with critical limb ischemia implies that many of these patients may face amputation of a portion of their limb as the sole therapeutic option. The potential for achieving limb salvage in a selected group of patients with no alternative therapeutic option suggests to us that these patients represent good candidates for arterial gene therapy as outlined below. Patients will be considered to be “not satisfactory” candidates for nonsurgical revascularization (and therefore appropriate candidates for arterial gene therapy) if the lesions that require revascularization to restore pulsatile flow to the foot are classified as category 4 according to the Society of Cardiovascular and Interventional Radiology classification.33With regard to surgical revascularization, no such uniform, standardized classification system intended to define a patient’s operative candidacy is available to draw on. Accordingly, we prefer to define patients who are satisfactory candidates for surgery, since there is typically more consensus regarding this characterization. Patients will therefore be considered to be satisfactory candidates for surgery if selective, digital-subtraction angiographic examination successfully identifies acceptable distal runoff, including angiographic evidence of at least one lower limb vessel that is of sufficient caliber and distal reconstitution to serve as a recipient graft site; if preoperative clinical assessment discloses no comorbid illness that would make the patient an unacceptably high risk for reconstructive surgery; and, in the event that surgical reconstruction requires distal bypass, if a sufficient length of autologous vein required to serve as the bypass conduit is available. Thus, patients will be considered candidates for the current gene therapy protocol if they do not satisfy these criteria or if a reconstructive procedure (at the same level) has already been attempted and failed. The consequences of peripheral artery disease in the patient subset we have selected to study are sufficiently predictable to allow meaningful assessment of the results of gene therapy. Rest pain has an unrelenting course; ie, once the diagnosis has been established, it will not resolve spontaneously. For rest pain, a minimum of 4 weeks of dependence on narcotics will be required for patient selection. For nonhealing ulcers, patients will be included only if a minimum of 4 weeks of conservative measures has failed to improve the appearance of the ulcer. Published and/or clinical experience would suggest that spontaneous improvement in either rest pain and/or an ischemic ulcer following this duration of conservative therapy is unlikely.34We will recruit a total of 22 patients for this study; these patients will receive escalating doses of phVEGF165 according to a schedule that will allow us to progressively achieve the primary objective—documentation of the safety of phVEGF165 arterial gene therapy. As indicated below, the two initial patients will each receive 100 μg of the plasmid DNA, while the next two patients will each receive 300 μg. Provided that this proves safe, we then propose to treat subsequent groups of six patients each with escalating doses of 1000, 2000, and 4000 μg, respectively. In addition to documenting the safety of each incremental dose, a series of noninvasive and invasive tests designed to achieve the secondary objectives of this protocol—determination of bioactivity, including evidence of angiogenesis—will be performed as well. While consideration has been given to the issue of a control group, the requirement for catheter manipulation in patients with marginal limb perfusion and extensive atherosclerosis mitigates against this option. For the patient undergoing gene transfer, we believe the risks associated with catheterization are offset by the potential relief from unremitting rest pain or healing of refractory ulcers; for the patient undergoing a sham transfection, the small risk is not offset by any potential benefit. The physician is thus placed in the uncomfortable position of persuading a patient and that patient’s physician and family that the patient should undergo the inconvenience, discomfort, and small risk of an intervention from which the patient will derive no conceivable benefit. Inclusion Criteria Both men and women ≥40 years old are eligible. Patients must not be pregnant; if child-bearing capabilities are preserved, patients must agree to use barrier contraception for 3 months after gene transfer. Symptoms include rest pain typical of arterial insufficiency, with or without established ischemic ulcers (see below). A minimum of 4 weeks of rest pain with dependence on narcotics with no improvement will be required. Signs include nonhealing lesions of the lower extremities due to arterial insufficiency. A minimum of 4 weeks of conservative therapy without evidence of significant healing will be required. Noninvasive findings will be as follows. (1) Resting ankle-brachial index in the affected limb must be <0.6 on two consecutive examinations performed at least 1 week apart. For patients with noncompressible ankle arteries (due to calcific deposits with or without associated diabetes), the great toe index must be <0.6. (2) Rest pain and/or ischemic ulcers may preclude exercise testing (graded-load protocol35 ) in most patients. Each patient, however, will be asked to exercise; if the patient is unable to do so, this will be noted. The ability to successfully complete any portion of any exercise protocol after treatment will be evaluated in the event that rest pain is eliminated and/or ulcerations healed. Diagnostic angiography must demonstrate occlusion in the affected limb of one or more of the following: the iliac, superficial femoral, popliteal, and/or one or more infrapopliteal arteries. The site of occlusion and associated anatomic findings must be such that selective arterial transfection is technically feasible. Patients will be included only if they agree to and are judged appropriate to discontinue concomitant prostaglandin therapy and/or therapy with vasodilators, dextran, hetastarch, pentoxifylline, l-carnitine, and/or hyperbaric oxygen. Patients may continue to receive aspirin and coumarin, provided that these therapies have been used by the patient for a minimum of 6 months before entry into the study. Exclusion Criteria Exclusion criteria include (1) aortic or lower-extremity arterial surgery, angioplasty, or lumbar sympathectomy within 2 months; (2) radiographic and radioisotopic evidence of concomitant osteomyelitis in the ischemic extremity; (3) any concomitant disease process with a life expectancy of <1 year or sufficiently severe as to compromise clinical follow-up examinations; (4) significant history of alcohol or drug abuse within the past 3 months; (5) previous or current history of neoplasm; (6) clinically significant abnormality in liver function or other laboratory tests, including prostate-specific antigen and carcinoembryonic antigen, and/or signs by chest radiograph, abdominal CT scan, mammography in the case of women or prostate examination in the case of men of malignant neoplasm; (7) clinical evidence of type I diabetes mellitus, diabetic retinopathy, and/or other ophthalmologic complications of diabetes; (8) patients who are pregnant or refuse to use barrier contraception; and (9) refusal or inability to give informed consent. Construction of Plasmid Plasmid Structure The cDNA to be used in this protocol encodes the 165–amino acid isoform of VEGF and has been described previously.1736The plasmid into which the VEGF cDNA has been inserted, phVEGF165, is a simple eukaryotic expression plasmid that uses the 763–base-pair cytomegalovirus (CMV) promoter/enhancer to drive VEGF expression. This promoter/enhancer has been used to express reporter genes in a variety of cell types and can be considered to be constitutive. Downstream from the VEGF cDNA is the SV40 polyadenylation sequence. Also included in this plasmid is a fragment containing the SV40 origin of replication that includes the 72-bp repeat, but this sequence is not functionally relevant (for autonomous replication) in the absence of SV40 T antigen. These fragments occur in the pUC118 vector, which includes an Escherichia coli origin of replication and the β-lactamase gene for ampicillin resistance. To confirm plasmid identity, the entire phVEGF165 sequence (5651 bp) was determined (designated VEGF V1-V2) by use of 24 sequencing primers. This determined sequence was compared with the deduced sequence (designated 1. VEGF). The structure of the double-stranded DNA was determined by the cycle sequencing method using fluorescent dideoxy terminator nucleotides with an Applied Biosystem 373A automated sequencer. Sequences were analyzed on Macintosh Quadra computers with MacVector and Sequence Navigator software. The quality control for this sequencing analysis consists of parallel sequence analyses of Bluescript and M13 controls. Our sequencing found three regions that were missing from the predicted sequence: (1) −4 bp (of a repeat) at the junction of the SV40 early polyA and origin sequences; (2) −35 bp within the M13 region; and (3) −14 bp at the junction between M13 and pUC. Outside these regions, there was >98.2% sequence homology between the determined and predicted sequences. Vectors No vectors will be used to deliver the above-described plasmid. Instead, the plasmid will be applied to the hydrogel polymer coating of a standard angioplasty balloon, as was the case in our preclinical animal testing.2628 The catheter and method used for this delivery mode are also described in detail below. Plasmid Preparation The plasmid DNA will be prepared at the time of gene transfer in the St Elizabeth’s Medical Center’s human gene therapy laboratory. DNA will be prepared from cultures of phVEGF165-transformed E. coli by the Qiagen method according to the directions of the manufacturer (Qiagen, Inc). Briefly, cultures will be grown from master glycerol stock in 500 mL of LB medium with 100 μg/mL ampicillin. Cells will be harvested at a density of 1.0 to 1.5 absorbance at 600 nm (A600) U/mL and prepared with a Qiagen-tip 2500. After elution from the Qiagen column, the plasmid DNA will be precipitated with alcohol, dried on a Speed Vac, and stored in vials, reconstituted in sterile saline. We anticipate yields of 1.5 to 2.5 mg of plasmid DNA. These plasmid batches will be pooled before further analyses and, ultimately, administration to patients. The sealed vials containing aliquots of the plasmid DNA pool will be stored in a dedicated storage freezer/refrigerator in the human gene therapy laboratory. Approximately 1 hour before delivery, plasmid solution will be divided into aliquots in individual sterile vials mixed under sterile conditions as follows: 0.1 mL of plasmid DNA (5 mg/mL) is diluted to 250 μL with sterile water at room temperature. Approximately 15 minutes before delivery, vials of plasmid will be brought to the special procedures laboratory and, under sterile conditions, applied by pipette to the hydrogel polymer coating of the inflated angioplasty balloon, after which the balloon will be allowed to air-dry. Stages of Treatment Pretreatment Studies The Table provides a schedule of pre–gene transfer studies. Treatment Gene transfer itself will be performed percutaneously in a fashion identical to that used for the preclinical animal studies. If the profunda is the intended site of gene transfer, then a retrograde, wire-guided approach from the contralateral common femoral artery will be used, according to standard techniques, to advance the angioplasty catheter/sheath to the site of gene transfer under fluoroscopic guidance. Once positioned, the sheath will be withdrawn and the balloon inflated for 5 minutes at nominal inflation pressures, after which the balloon will be deflated, drawn back into the sheath, and removed. An angiogram will then be recorded to document the anatomy and collateral circulation at the time of gene transfer and to confirm that no vessel trauma has occurred. If the distal superficial femoral artery or popliteal arteries represent the site of gene transfer, the approach will be antegrade and ipsilateral but otherwise identical. Posttreatment Studies See the Table for a schedule of post–gene transfer studies. Criteria for Response The primary clinical end points that will be used to measure the response to therapy in this study will be abolition of rest pain and/or healing of the ischemic ulcer. With regard to the secondary objective of this study, noninvasive and invasive studies are intended to provide comprehensive data regarding both the clinical response of the ischemic limb and anatomic and functional evidence of collateral vessel development. Potential Side Effects 1. VEGF is known to be made by transformed cells of certain tumors, presumably to develop a blood supply that will allow the tumor to grow further. Although an extensive examination will be performed to exclude the possibility of a previously unrecognized neoplasm, a microscopic growth could be present that might be missed by the battery of screening tests. It is therefore theoretically possible that VEGF resulting from gene transfer could promote the development of a tumor that is currently too small to be recognized. It should be noted, however, that previous laboratory studies have established that VEGF expression, although sufficient to promote a growth process, did not lead to malignant proliferation or to metastasis,37 a finding in agreement with the notion that stimulation of angiogenesis is necessary but not sufficient for malignant growth.382. It is also theoretically possible that VEGF may aggravate deteriorating eyesight due to diabetes mellitus.39 The risk of this complication will presumably be reduced by exclusion of patients with type I diabetes and/or an ophthalmologic examination that discloses evidence of diabetic eye changes. Potential Risks of Gene Transfer Even though we have attempted to minimize the risks associated with gene transfer by eliminating the need for any viral, liposomal, or other vectors, it is recognized that theoretical risks of gene transfer remain. Previous studies suggest that intravenous administration of DNA in the absence of the viral vectors does not elicit an autoimmune response.40 This empirical experience is consistent with the observation that double-stranded DNA is minimally antigenic because the bases are in essence “shielded” from immunologic surveillance by the double helices.41 Administration of supercoiled double-stranded DNA is thus unlikely to elicit an immunologic response. DNA that is subsequently denatured is likely to be removed by the reticuloendothelial system. It is further worth noting that recent studies suggest that histones may account for a significant proportion of the antigenicity associated with DNA42 ; in the case of plasmids generated from E. coli, however, histones are absent from the recombinant DNA, thus further reducing the likelihood of an immunologic response.This article is an abridged version of a protocol approved by the Food and Drug Administration, the Recombinant DNA Advisory Committee of the National Institutes of Health, and the principal investigator, co–principal investigator, and coinvestigators. Table 1. Schedule of Examinations for Year 1 Pre– and Post–Gene Transfer Pre–Gene Transfer (≤4 Weeks Before Gene Transfer)Post–Gene TransferWeekMonth1234567891011124567891011121. HistoryXXXXXXXXXXXXXXXXXXXXXX2. Physical examinationXXXXXXXXXXXXXXXXXXXXXX3. Complete blood count (hemoglobin, hematocrit, leukocytes, platelets)XXXXXXX4. Clinical chemistry profile1XXXXXXX5. Carcinoembryonic antigen, prostate-specific antigenXXXXXXX6. Urine analysis2XXXXXXX7. Stool hemoccultXXXXXXX8. Chest radiographXXXX9. Chest and abdominal CTXXXX10. Head magnetic resonance imagingX11. Sigmoidoscopy and prostate examinationX12. Ankle-brachial index/great toe index/peripheral vascular resistanceXXXXXXXXXXXXXXXXXXXXXX13. Magnetic resonance angiographyXXXXXXXXXXXXXX14. Duplex color/flow DopplerXXXXXXXXXXXXXX15. TcPo2XXXXXXX16. Spiral CTXXXXXXX17. Diagnostic angiographyXXXXX18. Quality of life questionnaireXXXXXXXXXXXXXXXXXXXXXX19. Ophthalmologic examination3XXXCT indicates computed tomographic scan. 1Includes Westergren sedimentation rate, serum electrolytes (sodium, potassium, chloride, bicarbonate), blood urea nitrogen, creatinine, glucose, uric acid, total protein, albumin, calcium, phosphate, total bilirubin, conjugated bilirubin, AST, ALT, alkaline phosphatase, LDH. 2Includes qualitative protein, blood, glucose, ketones, pH, microscopic examination. 3Includes funduscopic photography.The authors gratefully acknowledge the assistance of Mickey Neely in the preparation of the manuscript, and Dr Joachim Schorr (Qiagen GmbH, Hilden, Germany) for helpful discussions and aid in determining plasmid quality. FootnotesCorrespondence to Jeffrey M. Isner, MD, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA 02135. E-mail [email protected] References 1 Albers M, Fratezi AC, DeLuccia N. Assessment of quality of life of patients with severe ischemia as a result of infrainguinal arterial occlusive disease. J Vasc Surg.1992; 16:54-59. CrossrefMedlineGoogle Scholar2 Dormandy JA, Thomas PRS. What is the natural history of a critically ischemic patient with and without his leg? In: Greenhalgh RM, Jamieson CW, Nicolaides AN, eds. Limb Salvage and Amputation for Vascular Disease. Philadelphia, Pa: WB Saunders Co; 1988:11-26. Google Scholar3 European Working Group on Critical Leg Ischemia. Second European consensus document on chronic critical leg ischemia. Circulation. 1991;84(suppl IV):IV-1-IV-26. Google Scholar4 Isner JM, Rosenfield K. Redefining the treatment of peripheral artery disease: role of percutaneous revascularization. Circulation.1993; 88:1534-1557. CrossrefMedlineGoogle Scholar5 Pentecost MJ, Criqui MH, Dorros G, Goldstone J, Johnston KW, Martin EC, Ring EJ, Spies JB. Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels: a statement for health professionals from a special writing group of the Councils on Cardiovascul" @default.
• W2044294583 created "2016-06-24" @default.
• W2044294583 creator A5004293329 @default.
• W2044294583 creator A5015395296 @default.
• W2044294583 creator A5016268322 @default.
• W2044294583 creator A5021569532 @default.
• W2044294583 creator A5027226502 @default.
• W2044294583 creator A5049563925 @default.
• W2044294583 creator A5052536397 @default.
• W2044294583 creator A5058992043 @default.
• W2044294583 creator A5060967318 @default.
• W2044294583 creator A5080183722 @default.
• W2044294583 creator A5090591361 @default.
• W2044294583 date "1995-06-01" @default.
• W2044294583 modified "2023-09-23" @default.
• W2044294583 title "Arterial Gene Therapy for Therapeutic Angiogenesis in Patients With Peripheral Artery Disease" @default.
• W2044294583 cites W1537712767 @default.
• W2044294583 cites W1917066306 @default.
• W2044294583 cites W1978139448 @default.
• W2044294583 cites W1981612052 @default.
• W2044294583 cites W1983763042 @default.
• W2044294583 cites W1988173254 @default.
• W2044294583 cites W1999171451 @default.
• W2044294583 cites W2003598961 @default.
• W2044294583 cites W2007277878 @default.
• W2044294583 cites W2017627019 @default.
• W2044294583 cites W2040458308 @default.
• W2044294583 cites W2043863730 @default.
• W2044294583 cites W2049827480 @default.
• W2044294583 cites W2061230824 @default.
• W2044294583 cites W2062719651 @default.
• W2044294583 cites W2064823979 @default.
• W2044294583 cites W2081580391 @default.
• W2044294583 cites W2084506573 @default.
• W2044294583 cites W2092077170 @default.
• W2044294583 cites W2114696647 @default.
• W2044294583 cites W2133762215 @default.
• W2044294583 cites W2134582008 @default.
• W2044294583 cites W2137893922 @default.
• W2044294583 cites W2157885004 @default.
• W2044294583 cites W2162249561 @default.
• W2044294583 cites W4245635197 @default.
• W2044294583 cites W4245693946 @default.
• W2044294583 cites W61632934 @default.
• W2044294583 cites W70271102 @default.
• W2044294583 doi "https://doi.org/10.1161/01.cir.91.11.2687" @default.
• W2044294583 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/7538919" @default.
• W2044294583 hasPublicationYear "1995" @default.
• W2044294583 type Work @default.
• W2044294583 sameAs 2044294583 @default.
• W2044294583 citedByCount "186" @default.
• W2044294583 countsByYear W20442945832012 @default.
• W2044294583 countsByYear W20442945832013 @default.
• W2044294583 countsByYear W20442945832015 @default.
• W2044294583 countsByYear W20442945832017 @default.
• W2044294583 countsByYear W20442945832019 @default.
• W2044294583 countsByYear W20442945832020 @default.
• W2044294583 countsByYear W20442945832021 @default.
• W2044294583 countsByYear W20442945832023 @default.
• W2044294583 crossrefType "journal-article" @default.
• W2044294583 hasAuthorship W2044294583A5004293329 @default.
• W2044294583 hasAuthorship W2044294583A5015395296 @default.
• W2044294583 hasAuthorship W2044294583A5016268322 @default.
• W2044294583 hasAuthorship W2044294583A5021569532 @default.
• W2044294583 hasAuthorship W2044294583A5027226502 @default.
• W2044294583 hasAuthorship W2044294583A5049563925 @default.
• W2044294583 hasAuthorship W2044294583A5052536397 @default.
• W2044294583 hasAuthorship W2044294583A5058992043 @default.
• W2044294583 hasAuthorship W2044294583A5060967318 @default.
• W2044294583 hasAuthorship W2044294583A5080183722 @default.
• W2044294583 hasAuthorship W2044294583A5090591361 @default.
• W2044294583 hasConcept C104317684 @default.
• W2044294583 hasConcept C111599444 @default.
• W2044294583 hasConcept C126322002 @default.
• W2044294583 hasConcept C164705383 @default.
• W2044294583 hasConcept C185592680 @default.
• W2044294583 hasConcept C2777466421 @default.
• W2044294583 hasConcept C2778213512 @default.
• W2044294583 hasConcept C2778271429 @default.
• W2044294583 hasConcept C2779134260 @default.
• W2044294583 hasConcept C2780394083 @default.
• W2044294583 hasConcept C2781188250 @default.
• W2044294583 hasConcept C3018348675 @default.
• W2044294583 hasConcept C46762472 @default.
• W2044294583 hasConcept C55493867 @default.
• W2044294583 hasConcept C71924100 @default.
• W2044294583 hasConceptScore W2044294583C104317684 @default.
• W2044294583 hasConceptScore W2044294583C111599444 @default.
• W2044294583 hasConceptScore W2044294583C126322002 @default.
• W2044294583 hasConceptScore W2044294583C164705383 @default.
• W2044294583 hasConceptScore W2044294583C185592680 @default.
• W2044294583 hasConceptScore W2044294583C2777466421 @default.
• W2044294583 hasConceptScore W2044294583C2778213512 @default.
• W2044294583 hasConceptScore W2044294583C2778271429 @default.
• W2044294583 hasConceptScore W2044294583C2779134260 @default.
• W2044294583 hasConceptScore W2044294583C2780394083 @default.
• W2044294583 hasConceptScore W2044294583C2781188250 @default.
• W2044294583 hasConceptScore W2044294583C3018348675 @default.

• next