Critical limb ischemia (CLI) is a severe disease associated with a high risk of amputation and mortality. In patients who cannot be revascularized, several medical options have been tested, including the use of prostanoids, spinal cord stimulation, and lumbar sympathectomy. None of these treatments has demonstrated a benefit on the amputation rates after 6 months of follow-up; these treatments cannot therefore be recommended for CLI treatment in patients forwhom surgery is not an option. In this setting, gene therapy and cell therapy to stimulate angiogenesis have been tested mainly in phase I and II clinical trials and are reviewed in this article. These studies demonstrated the short-term safety and feasibility of these new approaches, but larger randomized studies remain necessary to demonstrate their clinical benefits and longterm safety.
Baumgartner I, Schainfeld R, Graziani L. Management of peripheral vascular disease. Annu Rev Med2005;56:249-272.
2.
Second European Consensus Document on chronic critical leg ischemia. Circulation1991;84:IV1-IV26.
3.
Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. Trans Atlantic Inter-Society Concensus (TASC). J Vasc Surg2000;31:S1-S296.
4.
Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal (outflow lesion) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five-year follow-up. Circulation2001;104:2057-2062.
5.
Kudo T, Chandra FA, Ahn SS. The effectiveness of percutaneous transluminal angioplasty for the treatment of critical limb ischemia: a 10-year experience. J Vasc Surg2005;41:423-435; discussion 435.
6.
Faglia E, Dalla Paola L, Clerici G, et al. Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg2005;29:620-627.
7.
Holden W.Reconstruction of the femoral artery for arteriosclerotic thrombosis. Surgery1950;27:417-417.
8.
Leng GC, Davis M, Baker D. Bypass surgery for chronic lower limb ischaemia. Cochrane Database Syst Rev2000:CD002000.
9.
Schainfeld RM, Isner JM. Critical limb ischemia: nothing to give at the office?Ann Intern Med1999;130:442-444.
10.
Ubbink D, Vermeulen H. Spinal cord stimulation for nonreconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev2005:CD004001.
11.
Klomp HM, Spincemaille GH, Steyerberg EW, Habbema JD, van Urk H.Spinal-cord stimulation in critical limb ischaemia: a randomised trial. ESES Study Group. Lancet1999;353:1040-1044.
12.
Loosemore TM, Chalmers TC, Dormandy JA. A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease. Int Angiol1994;13:133-142.
13.
Prostanoids for chronic critical leg ischemia. A randomized, controlled, open-label trial with prostaglandin E1. The ICAI Study Group. Ischemia Cronica degli Arti Inferiori. Ann Intern Med1999;130:412-421.
14.
Favier J, Germain S, Emmerich J, Corvol P, Gasc JM. Critical overexpression of thrombospondin 1 in chronic leg ischaemia. J Pathol2005. In press.
15.
Nabel EG, Plautz G, Boyce FM, Stanley JC, Nabel GJ. Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science1989;244:1342-1344.
16.
Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of ph VEGF165 in patient with ischaemic limb. Lancet1996;348:370-374.
17.
Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of ph VEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation1998;97:1114-1123.
18.
Makinen K, Manninen H, Hedman M, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, doubleblinded phase II study. Mol Ther2002;6:127-133.
19.
Shyu KG, Chang H, Wang BW, Kuan P.Intramuscular vascular endothelial growth factor gene therapy in patientswith chronic critical leg ischemia. Am J Med2003;114:85-92.
20.
Rajagopalan S, Mohler E 3rd, Lederman RJ, et al. Regional angiogenesis with vascular endothelial growth factor (VEGF) in peripheral arterial disease: design of the RAVE trial. Am Heart J2003;145:1114-1118.
21.
Comerota AJ, Throm RC, Miller KA, et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg2002;35:930-936.
22.
Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science1990;247:1465-1468.
23.
Rajagopalan S, Mohler ER 3rd, Lederman RJ, et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation2003;108:1933-1938.
24.
Labs KH, Dormandy JA, Jaeger KA, Stuerzebecher CS, Hiatt WR. Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group. Circulation1999;100:e75-e81.
25.
Gounis MJ, Spiga MG, Graham RM, et al. Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Ther2005;12:762-771.
26.
Cao R, Brakenhielm E, Pawliuk R, et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med2003;9:604-613.
27.
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science1997;275:964-967.
28.
Gulati R, Jevremovic D, Peterson TE, et al. Diverse origin and function of cells with endothelial phenotype obtained from adult human blood. Circ Res2003;93:1023-1025.
29.
Yoon CH, Hur J, Park KW, et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation2005;112:1618-1627.
30.
Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet2002;360:427-435.
31.
Higashi Y, Kimura M, Hara K, et al. Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation2004;109:1215-1128.
32.
Saigawa T, Kato K, Ozawa T, et al. Clinical application of bone marrow implantation in patientswith arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J2004;68:1189-1193.
33.
Huang PP, Li SZ, Han MZ, et al. Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost2004;91:606-609.
34.
Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care2005;28:2155-2152160.
35.
van Royen N, Schirmer SH, Atasever B, et al. START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. Circulation2005;112:1040-1046.
