The purpose of this study was to determine whether treatment with granulocyte colony-stimulating factor (G-CSF), which mobilizes endothelial progenitor cells from bone marrow, can safely improve the clinical outcomes of patients with atherosclerotic peripheral artery disease (PAD).
Thirty-nine patients with intractable PAD were randomly assigned to 3 groups: a negative control group (n=12) treated with conventional drug therapy; a positive control group (n=13) treated with conventional drug therapy plus bone marrow transplantation (BMT); and a G-CSF group (n=14) treated with conventional therapy plus subcutaneous injection of 2-5 microg/kg of recombinant human G-CSF once daily for 10 days. One month after treatment, subjective symptoms improved significantly in the G-CSF and BMT groups. Ankle-brachial pressure index and transcutaneous oxygen pressure increased significantly in the BMT and G-CSF groups, but no such improvements were seen in the group receiving conventional therapy alone.
G-CSF improves the clinical signs and symptoms of patients with intractable PAD to the same degree as BMT does. This noninvasive treatment may thus represent a useful new approach to managing the disease.
"G-CSF monotherapy is one treatment that can avoid the invasiveness of bone marrow transplantation . Thirty-nine patients were randomly assigned to conventional drug therapy, conventional drug therapy plus bone marrow transplantation (BMT), or conventional therapy plus G-CSF. "
[Show abstract][Hide abstract] ABSTRACT: Gene therapy and cell-based therapy have emerged as novel therapies to promote therapeutic angiogenesis in critical limb ischemia (CLI) caused by peripheral artery disease (PAD). Although researchers initially focused on gene therapy using proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factors (HGF), cell therapy using bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (BMMSCs), G-CSF-mobilized peripheral blood mononuclear cells (M-PBMNCs), and endothelial progenitor cells (EPCs) have also been extensively studied. Based on the elaborate studies and favorable results of basic research, some clinical phase I/II trials have been performed, and the results demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI. However, the phase 3 clinical trials have thus far been limited to gene therapy using the HGF gene. Further studies using well-designed larger placebo-controlled and long-term randomized control trials (RCTs) will clarify the effectiveness of gene therapy and cell-based therapy for the treatment of CLI. Furthermore, the development of efficient gene transfer systems and effective methods for keeping transplanted cells healthy will make these novel therapies more effective and ease the symptoms of CLI.
"Thus, interventions that increase circulating progenitor cells may promote angiogenesis and improve walking performance in people with PAD . However, results of studies conducted to date have been mixed   . Therefore, it is currently unclear whether interventions that increase progenitor cell levels improve walking performance in patients with PAD. "
[Show abstract][Hide abstract] ABSTRACT: Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.
"Growth factors that can naturally mobilize bone marrow progenitor cells to peripheral blood have been tested for their ability to treat various atherosclerotic diseases. While favourable results have been reported in peripheral arterial disease, such as improvement in limb perfusion , limited benefits were shown in patients with myocardial infarction  , although men seemed more susceptible to favourable effects . Moreover, doubts remain regarding the functional integrity of EPCs mobilized by those pharmacological agents . "
[Show abstract][Hide abstract] ABSTRACT: Atherosclerotic diseases are responsible for a significant part of morbidity and mortality in western countries. According to the classical views, atherosclerotic lesions develop as the result of an inflammatory process initiated by endothelial damage. The discovery that bone marrow-derived cells participate in endothelial repair and new vessel growth has changed the pathogenetic models of cardiovascular disease. These cells, termed endothelial progenitor cells (EPCs), represent the endogenous endothelial regenerative capacity and the ability to form new collateral vessels. In this review we describe how quantitative and qualitative alterations of EPCs have a significant role in virtually all stages of the atherosclerotic process and in the clinical manifestations of the diseases: starting from the impact of risk factors on EPCs, through the mechanisms that link EPC reduction/dysfunction to plaque formation, and finally to the clinical syndromes. An attempt to diverge our attention from the vessel wall to the bloodstream reveals a central role of EPCs in atherogenesis.
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