Gene therapy for peripheral arterial disease

Introduction: Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI.

Areas covered: This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed.

Expert opinion: To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects.     

Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial

Despite advances in revascularization techniques, limb salvage and relief of pain cannot be achieved in many diabetic patients with diffuse peripheral vascular disease. Our objective was to determine the effect of intramuscular administration of phVEGF165 (vascular endothelial growth factor gene-carrying plasmid) on critical limb ischemia (CLI) compared with placebo (0.9% NaCl). A double-blind, placebo-controlled study was performed in 54 adult diabetic patients with CLI. The primary end point was the amputation rate at 100 days. Secondary end points were a 15% increase in pressure indices (ankle-to-brachial index and toe-to-brachial index), clinical improvement (skin, pain, and Quality of Life score), and safety. In patients (n=27) treated with placebo versus phVEGF165-treated patients (n=27) the following results were found: 6 amputations versus 3 (p=not significant [NS]); hemodynamic improvement in 1 versus 7 (p=0.05); improvement in skin ulcers, 0 versus 7 (p=0.01); decrease in pain, 2 versus 5 (p=NS); and overall, 3 versus 14 responding patients (p=0.003). No grade 3 or 4 adverse effects were seen in these patients. We conclude that this small, randomized gene therapy study failed to meet the primary objective of significant amputation reduction. However, significant and meaningful improvement was found in patients treated with a VEGF165-containing plasmid. There were no substantial adverse events.     

Gene therapy for peripheral arterial diseases

Therapeutic angiogenesis using angiogenic growth factor is expected to be a new treatment for with patients with critical limb ischemia. The first human clinical trial treating peripheral vascular disease was started in 1994 using vascular endothelial growth factor (VEGF). To date, other potent angiogenic growth factors, such as fibroblast growth factor(FGF) or hepatocyte growth factor(HGF), have been also estimated in clinical trials for peripheral arterial disease. Several results from phase 1 or 2 trials using VEGF, FGF and HGF gene were encouraging. Phase 3 trials are now ongoing and their results are expected.     

Angiogenic gene therapy strategies for the treatment of cardiovascular disease

Coronary artery disease (CAD) and peripheral vascular disease (PVD) are significant medical problems worldwide, and arguably the biggest medical problems in the developed world. Although substantial progress has been made in prevention as well as in the treatment of these diseases, particularly of CAD, there are a large number of patients, who despite maximal medical treatment, have substantial symptomatology, and who are not candidates for mechanical revascularization. Therapeutic angiogenesis represents a novel, conceptually appealing, treatment option for these patients. Consequently, there are several different products in clinical trials, looking at various angiogenic growth factors. A number of small, mostly open-labeled phase I or phase I/II studies have been conducted with adeno- and plasmid-based vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) gene constructs in CAD and PVD. Although these studies have provided intriguing indications that new vessel formation is possible, and that these new vessels could be functional, these studies have been too small to allow conclusions to be drawn about potential efficacy. A number of proof-of-concept studies are presently underway or planned with four different constructs Ad(GV)VEGF121.10 (BioByPass; GenVec Inc), ph-VEGF (St Elizabeth's Medical Center of Boston Inc), Ad5-FGF4 (Collateral Therapeutics Inc/Schering Inc) and NV1FGF (Aventis Pharma AG/Aventis Gencell), and should, upon completion, provide a better indication as to the potential therapeutic role of these treatment modalities in the armamentarium against atherosclerotic disease. This exciting new field is reviewed, with special emphasis on clinical trials.     

Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease

The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.     

Statins and secondary prevention of coronary heart disease

A mini-review (Griffiths, 2002) of double-blind randomized controlled trials (RCTs) was undertaken to assess the long-term effect of lipid lowering treatments (statins versus placebo) in secondary prevention of myocardial infarction (MI). The population sample was adult patients with a history of MI, documented coronary heart disease or coronary artery disease. The Cochrane Library and the database Medline were searched and three RCTs appeared to possess all of the stipulated inclusion and exclusion criteria. The trials all compared statins against a placebo; one trial was of simvastatin--the Scandinavian Simvastatin Survival Study (1994)--and the other two were of pravastatin--the Cholesterol and Recurrent Events Trial (CARE) (Sacks et al, 1996) and Long Term Intervention with Pravastatin Ischaemic Disease (LIPID) (Anon, 1998). The trials demonstrated that statins had a clear and consistent effect in significantly reducing the risk of MI. Overall an approximate decline of 30% in MI was produced from the three trials.     

Efficacy of low-density lipoprotein apheresis in arteriosclerosis obliterans of the lower extremities: two cases with marked alleviation of clinical symptoms

We have recognized marked effectiveness for intermittent claudication with low-density lipoprotein (LDL) apheresis in two cases of arteriosclerosis obliterans (ASO). The Case 1 was a 73-year-old man with intermittent claudication of both lower extremities (Fontaine class II), digital subtraction angiography (DSA) revealed complete obstruction of the left common iliac artery, formation of a collateral to the peripheral portion of the left common iliac artery, and diffuse stenosis of the peripheral portion of the right common iliac artery. Ten sessions of LDL apheresis (LDL-A) improved the walking distance from 100 m before to 600 m after LDL-A treatment. The Case 2 was a 61-year-old man with intermittent claudication of the left lower extremity (walking distance: 200 m) began at 59 years. DSA revealed diffuse stenosis of the peripheral portion of the left popliteal artery. Ten sessions of LDL-A improved the walking distance from 200 m before to 800 m after LDL-A. At one month after the end of LDL-A treatment, DSA revealed formation of collateral to the peripheral portion of the left popliteal artery. Our findings suggest that LDL-A combined with drug treatment is safe and useful for the treatment of ASO, especially walking distance improved with short term treatment.     

Hepatocyte growth factor as potential cardiovascular therapy

Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates the growth, motility and morphogenesis of various types of cells, and is also a member of the angiogenic growth factors. Hepatocyte growth factor is secreted by vascular endothelial cells and smooth muscle cells, and the hepatocyte growth factor receptor, c-met, was also observed in these vascular cells. Treatment of human aortic endothelial cells with recombinant hepatocyte growth factor resulted in a significant increase in cell proliferation, accompanied by mitogen-activated protein kinase and Akt/protein kinase B phosphorylation. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to augment collateral artery development has been proposed. As preclinical study of gene therapy using hepatocyte growth factor to treat peripheral arterial disease, naked hepatocyte growth factor plasmid was intramuscularly injected into the ischemic hind limb of rabbits in order to evaluate its angiogenic activity. Intramuscular injection of hepatocyte growth factor plasmid once on day 10 following surgery, produced significant augmentation of collateral vessel development in the ischemic limb on day 30. In the clinical setting, the authors further investigated the safety and efficacy of hepatocyte growth factor plasmid DNA in patients with critical limb ischemia, in a prospective open-labeled trial. Intramuscular injection of naked plasmid DNA was performed in the ischemic limbs of six patients with critical limb ischemia with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. In the efficacy evaluation, a reduction of pain scale of more than 1 cm on a visual analog pain scale was observed in five out of six patients. An increase in ankle pressure index of more than 0.1 was observed in five out of five patients. The long diameter of eight out of 11 ischemic ulcers in four patients was reduced by more than 25%. Intramuscular injection of naked hepatocyte growth factor plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Although the present data were obtained to demonstrate safety in a Phase I/early Phase II trial, the initial clinical outcome with hepatocyte growth factor gene transfer seems to indicate its usefulness as sole therapy for critical limb ischemia. Randomized placebo-controlled clinical trials of alternative dosing regimens of gene therapy will be required to define the efficiency of this therapy.     

VEGF gene transfer for diabetic neuropathy

Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory defects involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the patient. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic patients. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic patients, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetics, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascularity and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive overexpression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two objectives: 1. Objective #1: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes and associated macrovascular disease involving the lower extremities. 2. Objective #2: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes without macrovascular disease involving the lower extremities. The protocol outlined in this Investigational New Drug Application has been designed as a Phase I/II, single-site, dose escalating, double-blind, placebo controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities. Diabetic males or females > 21 years old with sensory neuropathy with or without macrovascular disease will be eligible. A total of 192 patients will be recruited into two arms of the study (each arm consisting of 96 patients) over a period of 4 years (the fifth year will be limited to follow-up examinations). The 96 patients in each of the two arms of the study will comprise 3 cohorts, each consisting of 32 patients. Within each of these cohorts, patients will be randomized to receive phVEGF165 or placebo based upon a 3:1 randomization ratio. Thus, at the completion of the study, 24 patients will have each received a given dose (1, 2, or 4 mg phVEGF165) and 24 patients will have received placebo. Doses will be employed in a serial dose-escalating fashion. The entire volume of the study drug will be divided and delivered in 8 intramuscular injections administered into the foot, calf muscle, or distal thigh muscle of the affected extremity. Following the initial set of injections, repeat treatment with an identical dose will be provided 2 and 4 weeks after initial treatment.     

Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P < 0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.     

Hepatocyte growth factor as potential cardiovascular therapy

Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates the growth, motility and morphogenesis of various types of cells, and is also a member of the angiogenic growth factors. Hepatocyte growth factor is secreted by vascular endothelial cells and smooth muscle cells, and the hepatocyte growth factor receptor, c-met, was also observed in these vascular cells. Treatment of human aortic endothelial cells with recombinant hepatocyte growth factor resulted in a significant increase in cell proliferation, accompanied by mitogen-activated protein kinase and Akt/protein kinase B phosphorylation. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to augment collateral artery development has been proposed. As preclinical study of gene therapy using hepatocyte growth factor to treat peripheral arterial disease, naked hepatocyte growth factor plasmid was intramuscularly injected into the ischemic hind limb of rabbits in order to evaluate its angiogenic activity. Intramuscular injection of hepatocyte growth factor plasmid once on day 10 following surgery, produced significant augmentation of collateral vessel development in the ischemic limb on day 30. In the clinical setting, the authors further investigated the safety and efficacy of hepatocyte growth factor plasmid DNA in patients with critical limb ischemia, in a prospective open-labeled trial. Intramuscular injection of naked plasmid DNA was performed in the ischemic limbs of six patients with critical limb ischemia with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. In the efficacy evaluation, a reduction of pain scale of more than 1 cm on a visual analog pain scale was observed in five out of six patients. An increase in ankle pressure index of more than 0.1 was observed in five out of five patients. The long diameter of eight out of 11 ischemic ulcers in four patients was reduced by more than 25%. Intramuscular injection of naked hepatocyte growth factor plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Although the present data were obtained to demonstrate safety in a Phase I/early Phase II trial, the initial clinical outcome with hepatocyte growth factor gene transfer seems to indicate its usefulness as sole therapy for critical limb ischemia. Randomized placebo-controlled clinical trials of alternative dosing regimens of gene therapy will be required to define the efficiency of this therapy.     

The latest review of therapeutic angiogenesis using angiogenic growth factors to peripheral arterial diseases

Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment of patients with severe ischemic diseases. Indeed, human gene therapy for peripheral arterial disease(PAD) using VEGF gene demonstrated the beneficial effects. In contrast, we have reported the potent angiogenic activity of hepatocyte growth factor (HGF) in animal study and we planned gene therapy for ASO and Buerger disease using HGF gene (TREAT-HGF). In a prospective, open-labeled clinical trial, we investigated the safety and biological efficiency of this gene therapy in patients with peripheral arterial disease(PAD) who had failed conventional therapy.     

跨膝关节腘动脉闭塞治疗发展趋势及面临的主要问题

对于慢性下肢动脉缺血患者,血管腔内治疗具有微创,围手术期并发症少,技术成功率高等特点。与传统开放手术相比,血管腔内治疗具有创伤小,围手术期并发症少的特点。但易发生血管再狭窄,这也是影响其推广的重要原因。腘动脉置入支架可因为关节活动导致支架变形,甚至折断,从而导致支架内再狭窄。近来随着支架的改良及斑块旋切术等新技术,通过血管腔内技术治疗腘动脉病变的成功率得到不断改善,但远期效果还有待进一步论证。     

Cardiovascular safety of lumiracoxib: a meta-analysis of all randomized controlled trials > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis

BACKGROUND: The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate. OBJECTIVE: The objective of this study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. METHODS: The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of > or =1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published. RESULTS: For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46-1.51; versus naproxen: RR 1.49, 95% CI, 0.94-2.36; versus placebo: RR 1.08, 95% CI, 0.41-2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28-2.25; versus naproxen: RR 1.69, 95% CI, 0.82-3.48; versus placebo: RR 1.27, 95% CI, 0.25-6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35-2.35; versus naproxen: RR 1.42, 95% CI, 0.70-2.91; versus placebo: RR 0.59, 95% CI, 0.13-2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone. CONCLUSION: This meta-analysis of 34,668 patients receiving > or =1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).     

Gene-therapy for peripheral vascular diseases

The prognosis for patients with chronic critical leg ischemic is often poor. The treatment of peripheral vascular disease, although greatly improved over recent decades by drug medication, surgical and minimally-invasive techniques, remains limited by vascular proliferative lesions and by our inability to modulate the progression of native disease. The therapeutic angiogenesis is now the most expected therapy for peripheral vascular diseases. This review explores some of concepts and methods of therapeutic angiogenesis including gene therapy using angiogenic growth factor such as VEGF and basic FGF and an implantation of bone marrow derived endothelial progenitor cells.     

Platelet microparticles and soluble P selectin in peripheral artery disease: relationship to extent of disease and platelet activation markers

BACKGROUND: There is increased platelet activation in many cardiovascular diseases. This observation may explain the presence of increased levels of platelet microparticles (PMP) in these diseases. However, whether or not levels of PMPs inter-relate with other markers of platelet activation, such as soluble P-selectin, or with disease severity, is unknown. We therefore hypothesized raised PMP levels in stable peripheral artery disease (PAD) intermittent claudication (IC), with an additional increase in severe PAD critical limb ischaemia (CLI). Furthermore, we tested the hypothesis that PMP levels are correlated with other markers of platelet activation, such as soluble P-selectin, membrane bound P-selectin (CD62P) and 63. METHODS: Patients with PAD were recruited from the vascular outpatient and inpatient facilities at a teaching hospital. Age- and sex-matched controls were also recruited from healthy volunteers. Venous blood was obtained from 23 patients with severe disease (CLI), 36 with moderate disease (IC), and from 30 healthy controls. The percentage of platelets positive for CD62P and CD63, as well as the numbers of PMPs were defined by flow cytometry. Plasma soluble P selectin was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: PMPs were increased relative to healthy controls in patients with IC, with a further increase in CLI (P<0.001). Soluble P selectin and CD62+ve platelets were raised in both patient groups, but there was no difference amongst the two patient groups. CD63+ve cells were raised only in CLI compared to healthy controls. In multivariate analysis, only PMP and soluble P selectin independently predicted disease severity, and the two markers correlated modestly (r=0.345, P<0.001). CONCLUSION: Increased PMP and soluble P selectin are both related to the severity of symptomatic PAD. However, it is uncertain if this relationship is a cause or effect of atherosclerosis. This finding may have clinical implications as PMPs have the potential to influence the progression of atheroma as well as promote thrombosis.     

腔内血管成形术治疗糖尿病膝下动脉长段闭塞病变的价值

目的探讨经皮腔内血管成形术治疗糖尿病膝下动脉长段闭塞病变的临床疗效及价值。方法本组56例糖尿病膝下动脉长段闭塞病变患者,男34例,女22例,年龄48～76岁,中位年龄62岁。Fontaine分期,Ⅱb期(中至重度间歇跛行)19例,Ⅲ期(缺血性静息痛)21例,Ⅳ期(不同程度的溃疡和坏疽)16例。所有患者术前均行患肢CT血管造影及数字减影血管造影检查;术后定期门诊随访12个月,观察记录临床症状和体征变化;并于术前和术后1、3、6和12个月行患肢跛行距离、足趾皮温、踝肱指数(ABI)、趾肱指数(TBI)、CT血管成像(CTA)或彩色多普勒显像检查。结果 56例患者的103条病变肢体共有膝下动脉长段闭塞血管127支,平均闭塞长度(14.51±5.62)cm;其中106支长段闭塞动脉通过球囊扩张成形得以再通,经皮腔内血管成形术成功率为83.5%。术后所有开通成功的患肢皮温改善明显,术后患者的疼痛症状明显缓解或消失。跛行距离、足趾皮温、ABI、TBI等在术后1、3、6、12个月均较术前有显著性改善,P<0.05。共38条肢体(40.9%)发生了再狭窄,12个月的肢体保全率高达92.2%(95/103)。结论经皮腔内血管成形术治疗糖尿病膝下动脉长段闭塞病变,近期疗效确切,安全性较高,虽然其远期再狭窄率较高,但能有效控制病情的发展和缓解临床症状,有助于提高缺血肢体的肢体保全率。