Therapeutic Angiogenesis for Patients with Limb Ischaemia by Autologous Transplantation of Bone-Marrow Cells:A Pilot Study and a Randomized Controlled Trial. - TACT (Therapeutic Angiogenesis)
The goal of this study was to investigate the safety and efficacy of autologous bone marrow-mononuclear cell implantation in patients with ischemic limbs due to peripheral arterial disease.
An initial pilot study was performed in which 25 patients (group A) with unilateral ischaemia of the leg were injected with bone marrow-mononuclear cells into the gastrocnemius muscle of the ischamic limb and with saline into the less ischemic limb. They subsequently recruited 22 patients (group B) with bilateral leg ischaemia, who were randomly injected with bone marrow-mononuclear cells in one leg and peripheral blood-mononuclear cells in the other as a control. Primary outcomes of this study were safety and feasibility of treatment, based on ankle-brachial index (ABI) and rest pain.
In group A patients, the ABI in legs injected with bone marrow-mononuclear cells increased from 0.34 (95% CI 0.27-0.40) at baseline to 0.47 (0.41-0.52) at week 4; increases in ABI (>0.1 at week 4) were noted in majority (17 of 25) patients. No improvement in ABI at 4 weeks were observed in legs injected with saline. In group B patients, ABI was significantly improved in legs injected with bone marrow-mononuclear cells compared with those injected with peripheral blood-mononuclear cells (difference 0.09 [95% CI 0.06-0.11]; p<0.0001). similar="" improvements="" were="" seen="" for="" transcutaneous="" oxygen="" pressure,="" rest="" pain,="" and="" pain-free="" walking="" time.="" these="" improvements="" were="" maintained="" at="" 24="" weeks.="" similar="" improvements="" were="" seen="" for="" transcutaneous="" oxygen="" pressure,="" rest="" pain,="" and="" pain-free="" walking="" time.="" these="" improvements="" were="" maintained="" at="" 24="">
Among patients with ischemic limb disease due to peripheral vascular disease, autologous implantation of bone marrow-mononuclear cells was safe and was associated with improvement in ABIs, rest pain, and pain free walking time. These observations are consistent with therapeutic angiogenesis mediated by the ability of bone marrow cells to supply endothelial progenitor cells and to secrete various angiogenic growth factors or cytokines. In this study, bone-marrow implantation was associated with increases in blood flow among patients with critical limb ischemia, as assessed by substantial increases in ABI, TcO2, and pain-free walking time and by formation of new collateral vessel formation on the angiogram. Implantation of bone marrow-mononuclear cells also improved clinical symptoms such as rest pain, and ischemic ulcers or gangrene allowing successful limb salvage. One of the limitations of this study is the relatively short duration of follow-up of 24 weeks, which precludes true assessment of the long-term safety of this approach. The 8 % cardiac mortality in Group A is disconcerting, as angiogenic growth factors may be associated with accelerated atherosclerotic plaque growth. Overall, this small preliminary study is encouraging but requires prospective validation in larger randomized blind trials with a longer duration of follow-up.
Tateishi-Yuyama E, Matsubara H, Murohara T, et al, for the Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic Angiogenesis for Patients with Limb Ischemia by Autologous Transplantation of Bone-Marrow Cells: A Pilot Study and a Randomized Controlled Trial. Lancet 2002; 360:427-35.
Clinical Topics: Diabetes and Cardiometabolic Disease, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and Vascular Medicine, Exercise
Keywords: Follow-Up Studies, Plaque, Atherosclerotic, Gangrene, Muscle, Skeletal, Stem Cells, Cytokines, Ankle Brachial Index, Peripheral Arterial Disease, Pain, Walking, DNA, Antisense, Bone Marrow Cells, Genetic Therapy, Ulcer, Ischemia, Limb Salvage, Oxygen
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