The natural history of untreated severe or critical limb ischemia

Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature.

Effects of Nitric Oxide on Cell Proliferation: Novel Insights

After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.

Postischemic Revascularization: From Cellular and Molecular Mechanisms to Clinical Applications

Rationale: Critical limb ischemia is a life-threatening complication of peripheral arterial disease. In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death. Objective: To provide a systematic review of the literature and a meta-analysis of studies evaluating safety and efficacy of autologous cell therapy for intractable peripheral arterial disease/critical limb ischemia. Methods and Results: We retrieved 19 randomized controlled trials (837 patients), 7 nonrandomized trials (338 patients), and 41 noncontrolled studies (1177 patients). The primary outcome was major amputation. Heterogeneity was high, and publication bias could not be excluded. Despite these limitations, the primary analysis (all randomized controlled trials) showed that cell therapy reduced the risk of amputation by 37%, improved amputation-free survival by 18%, and improved wound healing by 59%, without affecting mortality. Cell therapy significantly increased ankle brachial index, increased transcutaneous oxygen tension, and reduced rest pain. The secondary analysis (all controlled trials; n=1175 patients) shows that there may be potential to avoid ≈1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2332 patients) precisely estimated the changes in ankle brachial index, transcutaneous oxygen tension, rest pain, and walking capacity after cell therapy. Intramuscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear cells may outperform bone marrow–mononuclear cells and mesenchymal stem cells. Amputation rate was improved more in trials wherein the prevalence of diabetes mellitus was high. Cell therapy was not associated with severe adverse events. Remarkably, efficacy of cell therapy on all end points was no longer significant in placebo-controlled randomized controlled trials and disappeared in randomized controlled trials with a low risk of bias. Conclusions: Although this meta-analysis highlights the need for more high-quality placebo-controlled trials, equipoise may no longer be guaranteed because autologous cell therapy has the potential to modify the natural history of intractable critical limb ischemia.

Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies

BackgroundShort-term (within 6 weeks follow-up) clinical studies indicate that implantation of bone marrow cells (BMCs) into ischemic limbs may improve peripheral ischemia. Here, the long-term safe...

Beneficial effects of autologous bone marrow cell infusion and antioxidants/L-arginine in patients with chronic critical limb ischemia.

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Beneficial effects of autologous bone marrow cell infusion and antioxidants/L-arginine in patients with chronic critical limb ischemia.