Therapeutic angiogenesis for peripheral artery disease: cytokine therapy

In recent years the importance of circulating bone marrow-derived cells in angiogenesis and collateral growth has been demonstrated in peripheral artery disease (PAD) and other ischaemic diseases. Although the mechanisms by which these cells exert their angiogenetic/arteriogenetic effects are not completely understood, improving the accumulation of bone marrow-derived cells at the site of vascular growth using cytokines has become one aim in some of the regenerative therapies. Interestingly recent data indicate that in addition to effects attributed to such accumulated cells there are also direct effects of cytokines used via their receptors. Several investigations in animal hind limb models of ischaemia have demonstrated the beneficial effect of bone marrow mobilisation using colony-stimulating factors (CSF) on collateral growth and perfusion recovery. Clinical studies in PAD patients, however are still rare and led to inconsistent data, in part due to different application protocols, choice of cytokine and low patient numbers with strong placebo effects. Moreover; the aetiology of the disease in humans differs markedly from the artificial occlusion of the femoral artery in a mostly healthy animal in the preclinical setting. Another approach to enhance arteriogenesis, which has been successful in animal models of hind limb ischaemia, is the local injection of the monocyte chemoattractant protein 1 (MCP-1). This treatment stimulated the invasion of monocytes leading to improved collateral growth and restoration of limb perfusion. Recent reports from animal experiments, in which both treatment strategies were combined (i.e. bone marrow mobilisation and enhancement of cell migration to the site of vascular growth), have shown strong synergistic effects, pointing at the importance to orchestrate the different processes involved in vascular repair in order to achieve maximal therapeutic effects.     

Therapeutic angiogenesis for peripheral artery disease: stem cell therapy

Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis that is associated with a significant limitation in limb function due to ischaemia and high risk of cardiovascular mortality. The lower limb manifestations of PAD principally fall into the categories of chronic stable claudication, critical leg ischaemia, and, rarely, acute limb ischaemia. Lower limb ischaemia induced by PAD is a major health problem. In the absence of effective pharmacological, interventional or surgical treatment, amputation is undertaken at the end-stage as a solution to unbearable symptoms. The concept of "therapeutic angiogenesis" has become widely accepted during the past few years. Bone marrow consists of multiple cell populations, including endothelial progenitor cells, which have been shown to differentiate into endothelial cells and release several angiogenic factors and thereby enhance neovascularisation in animal models of hind limb ischaemia. The promising results from various preclinical studies provide the basis for clinical trials using bone marrow-derived cells or non-bone marrow cells, like cells from the peripheral blood or other tissues. However, the mechanisms by which these cells exert their positive effects are poorly understood until now. This review summarises the data from experimental and clinical studies related to peripheral arterial disease and cellular therapy.     

Therapeutic angiogenesis for coronary artery disease

Opinion statement Angiogenesis is a promising new therapy for the treatment of patients with coronary artery disease who are not candidates for standard revascularization techniques. The concept of therapeutic angiogenesis is based upon improving myocardial function by increasing blood flow to ischemic areas of the heart. Angiogenic growth factors, including fibroblast growth factor and vascular endothelial growth factor, have been shown to induce functionally significant angiogenesis in preclinical studies. Both protein and gene formulations are under investigation; currently, protein-based therapy is considered the more practical form of therapy. The delivery of these growth factors is another aspect of angiogenic therapy under development, with several techniques used in clinical trials. However, the optimal method of delivery with regard to tissue specificity and duration of exposure is not yet defined. Despite encouraging preclinical data, the results of clinical trials so far have shown only, if any, modest improvements in cardiac function and clinical outcome. Further randomized, double-blind, placebo-controlled trials are necessary to support angiogenesis as a therapy for ischemic cardiac disease.     

Therapeutic angiogenesis for coronary artery disease

A large body of evidence in animal models of ischemia shows that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization. Many cytokines have angiogenic activity; those that have been best studied in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger-scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein and have not yet shown significant improvement in exercise time or angina compared with placebo. Larger-scale placebo-controlled studies of gene transfer are in progress. Clinical studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor-cell or stem-cell supplementation, to provide safe and effective therapeutic myocardial angiogenesis. Determination of which growth factors or cells are required to optimize therapeutic neovascularization in an individual patient should be a goal of future research.     

Therapeutic angiogenesis: protein and gene therapy delivery strategies

Angioplasty and surgical bypass, the primary interventional therapies for the treatment of atherosclerosis, are limited by the development over time of native vessel restenoses and graft occlusions. Furthermore, these therapies are not options for a significant number of individuals in whom the extent of vascular pathology is especially severe or widespread. Angiogenesis, the growth of new vasculature, is a critical biological response to ischemia that provides collateralization, or 'biological revascularization' of vascular obstructions. Therapeutic angiogenesis is a strategy whereby one of several known 'angiogens', mediators that induce angiogenesis, can be administered to augment the native angiogenic processes and enhance the formation of collateral vasculature. This report describes the techniques available for providing therapeutic angiogenesis, including acute and sustained-release techniques to deliver protein angiogens and a number of gene therapy strategies to deliver genes coding for the angiogens.     

Therapeutic angiogenesis with vascular endothelial growth factor in peripheral and coronary artery disease: a review

Therapeutic angiogenesis constitutes an alternative treatment for patients with extensive tissue ischaemia in whom primary vascular reconstruction procedures are not feasible or have previously failed. At present vascular endothelial growth factor (VEGF) has been the most widely used angiogenic factor in experimental and human clinical trials. Early clinical data provide evidence that gene transfer of the VEGF gene can achieve beneficial angiogenesis, with minimal side-effects. Ongoing phase III clinical studies will reveal definitive efficacy.     

Arteriogenesis versus angiogenesis in peripheral artery disease

Different forms of vessel growth in the adult organism contribute to the compensation for an occluded artery. We here summarize the major differences between arteriogenesis and angiogenesis and provide evidence in favour of a therapeutic stimulation of collateral growth. In addition, we outline current knowledge about regulatory mechanisms transducing the initial physical stimulus into a cellular response. As an example, the role of nitric oxide during arteriogenesis is discussed, and finally, we propose a mechanism of how an efficient decision is made that makes the larger collaterals larger and the smaller ones smaller.     

Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease

Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.     

Therapeutic angiogenesis for ischemic cardiovascular disease

In animal models of ischemia, a large body of evidence indicates that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization. While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with end-stage coronary artery disease have shown large increases in exercise time and marked reductions in symptoms of angina, as well as objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein, and have not yet shown significant improvement in either exercise time or angina when compared to placebo. Larger scale placebo-controlled studies of gene transfer are in progress. Future clinical studies will be required to determine the optimal dose, formulation, route of administration and combinations of growth factors, as well as the requirement for endothelial progenitor cell or stem cell supplementation, to provide effective and safe therapeutic myocardial angiogenesis.     

Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases.

Recent progress in molecular biology has led to the development of gene therapy as a new strategy to treat a variety of cardiovascular diseases. Targeted diseases range from single gene deficiency diseases to more complex diseases in adults such as restenosis after angioplasty. One obvious major target in the field of gene therapy is ischemic diseases such as myocardial infarction, angina and peripheral arterial diseases (i.e. ASO (arteriosclerosis obliterans)). In a large proportion of such patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for severe ischemic hearts and critical ischemic limbs. Therefore, novel therapies are required to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. The endothelial cell specificity of VEGF has been considered to be an important advantage for therapeutic angiogenesis, as endothelial cells represent the critical cellular element responsible for new vessel formation. Indeed, human gene therapy for ASO and angina has already begun in the USA, with surprising and beneficial effects. We have focused on hepatocyte growth factor (HGF), which is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis in various types of cells. Recently, HGF is also considered to be a powertul growth tactor for endothelial cells. In this review, we described the potential gene therapy for ischemic diseases using HGF.     

Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease

We aim to determine the efficacy and safety of gene and cell angiogenic therapies in the treatment of peripheral arterial disease (PAD) and evaluate them for the first time by a meta-analysis. We include in the formal meta-analysis only the randomized placebo-controlled phase 2 studies with any angiogenic gene or cell therapy modality to treat patients with PAD (intermittent claudication, ulcer or critical ischemia) identified by electronic search in MEDLINE and EMBASE databases (1980 to date). Altogether, 543 patients are analyzed from six randomized, controlled trials that are comparable with regard to patient selection, study design, and endpoints. We perform the meta-analysis regarding clinical improvement (improvement of peak walk time, relief in rest pain, ulcer healing or limb salvage) and rate of adverse events. At the end of treatment, therapeutic angiogenesis shows a significantly clinical improvement as compared to placebo in patients with PAD (odds ratio [OR] = 1.437; 95% confidence interval [CI] = 1.03?2.00; P = 0.033). The response rate (improvement of peak walk time) of the pooled groups according to clinical severity does not significantly differ for gene therapy as compared with placebo in the treatment of claudicating patients (OR = 1.304; 95% CI = 0.90?1.89; P = 0.16). Otherwise, we find significant efficacy of the treatment in critical ischemia (OR = 2.20; 95% CI = 1.01?4.79; P = 0.046). The adverse events rates show a slightly significantly higher risk of potential nonserious adverse events (edema, hypotension, proteinuria) in the treated group (OR = 1.81; 95% CI = 1.01?3.38; P = 0.045). We find no differences in mortality from any cause, malignancy, or retinopathy. The patients with PAD, and particularly those with critical ischemia, improve their symptoms when treated with angiogenic gene and cell therapy with acceptable tolerability.     

老年2型糖尿病性下肢动脉病变的腔内治疗

目的 观察并总结腔内治疗老年2型糖尿病严重下肢动脉病变的临床疗效及技术经验.方法 收集2010年2月-2012年2月55例老年2型糖尿病性下肢动脉疾病患者,采用INVATEC-DEEP长球囊,进行下肢动脉经皮穿刺血管腔内成形术（percutaneous transluminal angioplasty,PTA）治疗,观察治疗前后的临床症状、体征及踝肱指数（ankle brachial index,ABI）的改变,并进行随访.结果 55例患者共55条肢体接受了腔内治疗,技术成功率为74.5％（41/55）,无并发症发生.共随访6m,失访率为0;其中,技术成功组所有患肢血供明显增加,相应节段肢体皮温升高,足背动脉搏动增强,麻木感和痛感显著减轻,生存率为95.1％,肢体存活率97.6％;技术失败组患者生存率为78.6％,肢体存活率71.4％,随访期间ABI为（0.78±0.13）.结论 腔内治疗老年2型糖尿病性下肢动脉疾病技术成功率高,临床疗效显著,但远期效果有待进一步随访.     

冠心病和外周血管疾病患者的抗凝和抗血小板治疗

近年来,冠心病（CHD）和外周血管疾病（PAD）成为威胁人类健康的主要疾病。对CHD和PAD的药物治疗主要在于预防新的动脉粥样硬化的形成及稳定已存在的病变,最常用的药物治疗方法是抗血小板和抗凝治疗。本文通过对比大量临床试验来比较抗血小板和抗凝药物治疗CHD和PAD患者的效果以及安全性,总结了更有效和更安全的方案来预防动脉粥样硬化事件的发生。