Critical limb ischemia: current challenges and future prospects

Luigi Uccioli, Marco Meloni, Valentina Izzo, Laura Giurato, Stefano Merolla, Roberto Gandini, Luigi Uccioli, Marco Meloni, Valentina Izzo, Laura Giurato, Stefano Merolla, Roberto Gandini

Abstract

Critical limb ischemia (CLI) is considered the most severe pattern of peripheral artery disease. It is defined by the presence of chronic ischemic rest pain, ulceration or gangrene attributable to the occlusion of peripheral arterial vessels. It is associated with a high risk of major amputation, cardiovascular events and death. In this review, we presented a complete overview about physiopathology, diagnosis and holistic management of CLI. Revascularization is the first-line treatment, but several challenging cases are not treatable by conventional techniques. Unconventional techniques for the treatment of complex below-the-knee arterial disease are described. Furthermore, the state-of-the-art on gene and cell therapy for the treatment of no-option patients is reported.

Keywords: cell therapy; critical limb ischemia; medical therapy; peripheral arterial disease; revascularization.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Pedal to plantar technique. Notes: Preprocedural angiography (A). Multiple balloon dilatations performed in a pedal to plantar loop manner (B and C). After the rendezvous in the PTa of the antegrade catheter and the retrograde guidewire advanced from the ATA (D and E), further balloon dilatations have been performed in an antegrade manner from the posterior tibial artery (F and G). Final angiography (H). Abbreviation: PTa, posterior tibial artery.
Figure 2
Figure 2
Trans-collateral technique. Notes: Owing to the chronic occlusion of the ATA, in order to avoid damage to the anterior perforator branch of the peroneal artery, which sustained blood flow to the pedal artery (A and B), a retrograde recanalization of the plantar arch and the ATA through the lateral calcaneal branch of the peroneal artery was performed (CE). After the rendezvous of the antegrade and retrograde guidewires in the ATA, multiple balloon dilatations were done in an antegrade manner (F and G). Patency of the ATA lumen was reestablished at the final angiographic control (H and I). Abbreviation: ATA, anterior tibial artery.
Figure 3
Figure 3
Double approach technique. Notes: Preprocedural angiography showed occlusion of the ATA with patency of the pedal artery via the anterior perforator branch of the peroneal artery (A and B). In order to avoid the dissection of this precious collateral, the subintimal recanalization of the ATA was not extended beyond this level; therefore, a retrograde puncture of the plantar artery was performed (C). After the rendezvous (D) of the guidewires advanced in opposite directions, balloon dilatation (E and F) from the antegrade approach was performed obtaining a direct straight flow to the forefoot (GI). Abbreviation: ATA, anterior tibial artery.
Figure 4
Figure 4
Distal venous arterialization. Notes: Preprocedural angiography showed patency of the ATA and the peroneal artery with absence of the PTa, medial plantar artery and lateral plantar artery (A and B). After a failed intraluminal attempt, a subintimal recanalization of the PTa was performed, but a reentry in the true lumen of the medial plantar artery was not achieved. Therefore, an entry in the distal plantar vein was obtained (C) and then confirmed by a gentle injection of a contrast medium through the balloon catheter (D). After balloon catheter dilatations of the arteriovenous fistula and the occluded arterial segment (EF), postprocedural angiography showed patency of the PTa (G) and a good retrograde filling of the small distal venous channels toward the nonhealing wound area of the heel (H). Abbreviations: ATA, anterior tibial artery; PTa, posterior tibial artery.

References

    1. Murabito JM, Evans JC, Nieto K, Larson MG, Levy D, Wilson PW. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Heart J. 2002;143(6):961–965.
    1. Adam DJ, Beard JD, Cleveland T, et al. BASIL trial participants Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366(9501):1925–1934.
    1. Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. J Vasc Interv Radiol. 2004;15(11):1197–1207.
    1. Steg PG, Bhatt DL, Wilson PW, et al. REACH Registry Investigators One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297(11):1197–1206.
    1. Caro J, Migliaccio-Walle K, Ishak KJ, Proskorovsky I. The morbidity and mortality following a diagnosis of peripheral arterial disease: long-term follow-up of a large database. BMC Cardiovasc Disord. 2005;5:14.
    1. Abu Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 2015;62(6):1642–1651.
    1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Intersociety consensus for the management of peripheral arterial disease (TASC II) J Vasc Surg. 2007;45(suppl S):S5–S67.
    1. Strandness DJ, Sumner D. Hemodynamics for Surgeons. New York: Grune & Stratton; 1975. pp. 278–281.
    1. Criqui MH, Fronek A, Klauber MR, Barret-Connor E, Gabriel S. The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral arterial disease: results from noninvasive testing in a defined population. Circulation. 1985;71(3):516–522.
    1. Orchard J, Strandness DE., Jr Assessment of peripheral vascular disease in diabetes. Report and recommendations of an international workshop sponsored by the American Heart association and the American Diabetes Association. Diabetes Care. 1993;16:1119–1209.
    1. Young MJ, Adams JE, Anderson GF, Boulton AJ, Cavanagh PR. Medial arterial calcification in the feet of diabetic patients and matched non-diabetic control subjects. Diabetologia. 1993;36(7):615–621.
    1. Park SC, Choi CY, Ha YI, Yang HE. Utility of toe-brachial index for diagnosis of peripheral artery disease. Arch Plast Surg. 2012;39(3):227–231.
    1. Ballad JL, Eke CC, Bunt TJ, Killen JD. A prospective evaluation of transcutaneous oxygen measurements in the management of diabetic foot problems. J Vasc Surg. 1995;22(4):485–490.
    1. Bradbury AW, Adam DJ. Diagnosis of peripheral arterial disease of the lower limb. BMJ. 2007;334(7606):1229–1230.
    1. Visser K, Hunink MG. Peripheral arterial disease: gadolinium-enhanced MR angiography versus color color-guided duplex: a meta-analysis. Radiology. 2000;216(1):67–77.
    1. Hingorani A, Ascher E, Marks N. Preprocedural imaging: new options to reduce need for contrast angiography. Semin Vasc Surg. 2007;20(1):15–28.
    1. Prince MR, Zhang H, Morris M, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology. 2008;248(3):807–816.
    1. Rydahl C, Thomsen HS, Marckmann P. High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol. 2008;43(2):141–144.
    1. Wertman R, Altun E, Martin DR, et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American Universities. Radiology. 2008;248(3):799–806.
    1. Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJ. Diagnostic performance of computed tomography angiography in peripheral arterial disease: a systematic review and meta-analysis. JAMA. 2009;301(4):415–424.
    1. Stegemann E, Tegtmeier C, Bimpong-Buta NY, et al. Carbondioxide- aided angiography decreases contrast volume and preserves kidney function in peripheral vascular interventions. Angiology. 2016;67(9):875–881.
    1. Willigendael EM, Teijink JA, Bartelink ML, Peters RJ, Buller HR, Prins MH. Smoking and the patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg. 2005;42(1):67–74.
    1. Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J Vasc Surg. 2014;60(6):1565–1571.
    1. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22.
    1. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA task force on practice guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; Trans-Atlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006;47:1239–1312.
    1. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med. 1999;341(6):410–418.
    1. ESH/ESC 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21(6):1011–1053.
    1. XXXX Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) group. Lancet. 1998;352(9131):837–853.
    1. Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular events): a randomised controlled trial. Lancet. 2005;366(9493):1279–1289.
    1. Giurato L, Vainieri E, Meloni M, et al. Limb salvage in patients with diabetes is not a temporary solution but a life-changing procedure. Diabetes Care. 2015;38(10):e156–e157.
    1. Uccioli L, Gandini R, Giurato L, et al. Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. Diabetes Care. 2010;33(5):977–982.
    1. Owen RJ, Hiremath S, Myers A, Fraser-Hill M, Barrett BJ. Canadian association of radiologists consensus guidelines for the prevention of contrast-induced nephropathy: update 2012. Can Assoc Radiol J. 2014;65(2):96–105.
    1. Antithrombotic Trialists’ Collaboration Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J. 2002;324(7329):71–86.
    1. Aiello A, Anichini R, Brocco E, et al. Treatment of peripheral arterial disease in diabetes: a consensus of the Italian Societies of Diabetes (SID, AMD), Radiology (SIRM) and Vascular Endovascular Surgery (SICVE) Nutr Metab Cardiovasc Dis. 2014;24(4):355–369.
    1. Bradbury AW, Ruckley CV, Fowkes FGR, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2002;366(2005):1925–1934.
    1. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De LN. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008;47(5):975–981.
    1. Albers M, Romiti M, Brochado-Neto FC, Pereira CA. Meta-analysis of alternate autologous vein bypass grafts to infrapopliteal arteries. J Vasc Surg. 2005;42(3):449–455.
    1. Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, Morabito A. Predictive values recorded of transcutaneous oxygen tension for above-the-ankle amputation in diabetic patients with critical limb ischemia. Eur J Vasc Endovasc Surg. 2007;33(6):731–736.
    1. Söderström MI, Arvela EM, Korhonen M, et al. Infrapopliteal percutaneous transluminal angioplasty versus bypass surgery as first-line strategies in critical leg ischemia: a propensity score analysis. Ann Surg. 2010;252(5):765–773.
    1. Schaper NC, Andros G, Apelqvist J, et al. Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report of the International Working Group on the Diabetic Foot. Diabetes Metab Res Rev. 2012;28(suppl 1):236–237.
    1. Hinchliffe RJ, Andros G, Apelqvist J, et al. A systematic review of the effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral arterial disease. Diabetes Metab Res Rev. 2012;28(suppl 1):179–217.
    1. Johnson BL, Glickman MH, Bandyk DF, Esses GE. Failure of foot salvage in patients with end-stage renal disease after surgical revascularization. J Vasc Surg. 1995;22(3):280–285.
    1. Venermo M, Biancari F, Arvela E, et al. The role of chronic kidney disease as a predictor of outcome after revascularisation of the ulcerated diabetic foot. Diabetologia. 2011;54(12):2971–2977.
    1. Meloni M, Giurato L, Izzo V, et al. Long term outcomes of diabetic haemodialysis patients with critical limb ischemia and foot ulcer. Diabetes Res Clin Pract. 2016;116:117–122.
    1. Ferraresi R, Centola M, Ferlini M, et al. Long-term outcomes after angioplasty of isolated, below-the-knee arteries in diabetic patients with critical limb ischaemia. Eur J Vasc Endovasc Surg. 2009;37(3):336–342.
    1. Giurato L, Gandini R, Meloni M, et al. Percutaneous angioplasty in diabetic patients with critical limb ischemia and chronic kidney disease. Open J Endocr Metab Dis. 2013;3(3):208–212.
    1. Caravaggi C, De Giglio R, Pritelli C, et al. Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects. J Intern Med. 2002;252(3):225–232.
    1. Graziani L, Piaggesi A. Indications and clinical outcomes for below knee endovascular therapy: review article. Catheter Cardiovasc Interv. 2010;75(3):433–443.
    1. Faglia E, Clerici G, Clerissi J, et al. Long term prognosis of diabetic patients with critical limb ischemia: a population based cohort study. Diabetes Care. 2009;32(5):822–827.
    1. Weis-Müller BT, Römmler V, Lippelt I, et al. Critical chronic peripheral arterial disease: does outcome justify crural or pedal bypass surgery in patients with advanced age or with comorbidities? Ann Vasc Surg. 2011;25(6):783–795.
    1. Werneck CC, Lindsay Tibial TF. angioplasty for limb salvage in high-risk patients and cost analysis. Ann Vasc Surg. 2009;23(5):554–559.
    1. Pomposelli FB, Kansal N, Hamdan AD, et al. A decade of experience with dorsalis pedis artery by-pass: analysis of outcome in more than 1000 cases. J Vasc Surg. 2003;37(2):307–315.
    1. Pomposelli FB, Jr, Marcaccio EJ, Gibbons GW, et al. Dorsalis pedis arterial bypass: durable limb salvage for foot ischemia in patients with diabetes mellitus. J Vasc Surg. 1995;21(3):375–384.
    1. Meloni M, Izzo V, Giurato L, et al. Risk of contrast induced nephropathy in diabetic patients affected by critical limb ischemia and diabetic foot ulcers treated by percutaneous transluminal angioplasty of lower limbs. Diabetes Metab Res Rev. 2017;33(3)
    1. Faglia E, Clerici G, Clerissi J, et al. Angioplasty for diabetic patients with failing bypass graft or residual critical ischemia after bypass graft. Eur J Vasc Endovasc Surg. 2008;36(3):331–338.
    1. Dick F, Diehm N, Galimanis A, Husmann M, Schmidli J, Baumgartner I. Surgical or endovascular revascularization in patients with critical limb ischemia: influence of diabetes mellitus on clinical outcome. J Vasc Surg. 2007;45(4):751–761.
    1. Gandini R, Chiappa R, Di Primio M, et al. Recanalization of the native artery in patients with bypass failure. Cardiovasc Intervent Radiol. 2009;32(6):1146–1153.
    1. Diehm N, Shang A, Silvestro A, et al. Association of cardiovascular risk factors with pattern of lower limb atherosclerosis in 2659 patients undergoing angioplasty. Eur J Vasc Endovasc Surg. 2006;31(1):59–63.
    1. Ambler GK, Radwan R, Hayes PD, Twine CP. Atherectomy for peripheral arterial disease. Cochrane Database Syst Rev. 2014;3:CD006680.
    1. Schmidt A, Ulrich M, Winkler B, et al. Angiographic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease. Catheter Cardiovasc Interv. 2010;76(7):1047–1054.
    1. Gargiulo M, Giovanetti F, Bianchini Massoni C, et al. Bypass to the ankle and foot in the era of endovascular therapy of tibial disease. Results and factors influencing the outcome. J Cardiovasc Surg (Torino) 2012;55(3):367–374.
    1. Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. Endovascular therapy as the primary approach for limb salvage in patients with critical limb ischemia: experience with 443 infrapopliteal procedures. Vascular. 2006;14(2):63–69.
    1. Papavassiliou VG, Walker SR, Bolia A, Fishwick G, London N. Techniques for the endovascular management of complications following lower limb percutaneous transluminal angioplasty. Eur J Vasc Endovasc Surg. 2003;25(2):125–130.
    1. Soder HK, Manninen HI, Jaakola P, et al. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results. J Vasc Interv Radiol. 2000;11(8):1021–1031.
    1. Gandini R, Pipitone V, Stefanini M, et al. The “Safari” technique to perform difficult subintimal infragenicular vessels. Cardiovasc Intervent Radiol. 2007;30(3):469–473.
    1. Manzi M, Fusaro M, Ceccacci T, et al. Clinical results of below-the knee intervention using pedal-plantar loop technique for the revascularization of foot arteries. J Cardiovasc Surg (Torino) 2009;50(3):331–337.
    1. Fusaro M, Agostoni P, Biondi-Zoccai G. “Trans-collateral” angioplasty for a challenging chronic total occlusion of the tibial vessels: a novel approach to percutaneous revascularization in critical lower limb ischemia. Catheter Cardiovasc Interv. 2008;71(2):268–272.
    1. Palena LM, Manzi M. Extreme below-the-knee interventions: retrograde transmetatarsal or transplantar arch access for foot salvage in challenging cases of critical limb ischemia. J Endovasc Ther. 2012;19(6):805–811.
    1. Gandini R, Uccioli L, Spinelli A, et al. Alternative techniques for treatment of complex below-the knee arterial occlusions in diabetic patients with critical limb ischemia. Cardiovasc Intervent Radiol. 2013;36(1):75–83.
    1. Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg. 1987;40(2):113–141.
    1. Attinger CE, Evans KK, Bulan E, Blume P, Cooper P. Angiosomes of the foot and ankle and clinical implications for limb salvage: reconstruction, incisions, and revascularization. Plast Reconstr Surg. 2006;117(suppl 7):261S–293S.
    1. Fossaceca R, Guzzardi G, Cerini P, et al. Endovascular treatment of diabetic foot in a selected population of patients with below-the-knee disease: is the angiosome model effective? Cardiovasc Intervent Radiol. 2013;36(3):637–644.
    1. Alexandrescu V, Vincent G, Azdad K, et al. A reliable approach to diabetic neuroischemic foot wounds: below-the-knee angiosome-oriented angioplasty. J Endovasc Ther. 2011;18(3):376–387.
    1. Iida O, Soga Y, Hirano K, et al. Long-term results of direct and indirect endovascular revascularization based on the angiosome concept in patients with critical limb ischemia presenting with isolated below-the-knee lesions. J Vasc Surg. 2012;55(2):363–370.e5.
    1. Söderström M, Albäck A, Biancari F, Lappalainen K, Lepäntalo M, Venermo M. Angiosome-targeted infrapopliteal endovascular revascularization for treatment of diabetic foot ulcers. J Vasc Surg. 2013;57(2):427–435.
    1. Lejay A, Georg Y, Tartaglia E, et al. Long-term outcomes of direct and indirect below-the-knee open revascularization based on the angiosome concept in diabetic patients with critical limb ischemia. Ann Vasc Surg. 2013;28(4):983–989.
    1. Izzo V, Meloni M, Fabiano S, et al. Transcutaneous oximetry is a useful tool to highlight ischemia of the heel. Cardiovasc Intervent Radiol. 2017;40(1):120–124.
    1. Brosi P, Baumgartner I, Silvestro A, et al. Below-the-knee angioplasty in patients with end-stage renal disease. J Endovasc Ther. 2005;12(6):704–713.
    1. Edmonds ME, Blundell MP, Morris ME, Thomas EM, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med. 1986;60(232):763–771.
    1. Gandini R, Merolla S, Scaggiante J, et al. Endovascular distal plantar venous arterialization in dialyzed patients with critical limb ischemia and posterior tibial artery occlusion: a technical note of a new frontier of Limb Salvage in a challenging subset of patients. J Endovasc Ther. 2018;25(1):127–132.
    1. Francois-Franck M. Note a propos de la communication de M Raimond Petit sur la susture arterio-veneuse. Compt Rend Hebd Soc Biol. 1896;48:150.
    1. Matolo NM, Cohen SW, Wolfman EF. Use of an arteriovenous fistula for treatment of the severely ischemic extremity: experimental evaluation. Ann Surg. 1976;184(5):622–625.
    1. Uccioli L, Giurato L, Meloni M, et al. Comment on Hoffstad et al. diabetes, lower-extremity amputation, and death. Diabetes Care 2015;38:1852–1857. Diabetes Care. 2016;39(1):e7.
    1. Hoffstad O, Mitra N, Walsh J, Margolis DJ. Diabetes, lower-extremity amputation, and death. Diabetes Care. 2015;38(10):1852–1857.
    1. Rajagopalan S, Mohler ER, 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. Circulation. 2003;108(16):1933–1938.
    1. Powell RJ, Simons M, Mendelsohn FO, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008;118(1):58–65.
    1. Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther. 2008;16(5):972–978.
    1. Ko SH, Bandyk DF. Therapeutic angiogenesis for critical limb ischemia. Semin Vasc Surg. 2014;27(1):23–31.
    1. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis. 2010;209(1):10–17.
    1. Lawall H, Bramlage P, Amann B. Stem cell and progenitor cell therapy in peripheral artery disease. A critical appraisal. Thromb Haemost. 2010;103(4):696–709.
    1. Liu Y, Xu Y, Fang F, Zhang J, Guo L, Weng Z. Therapeutic efficacy of stem cell-based therapy in peripheral arterial disease: a meta-analysis. PLoS One. 2015;10(4):e0125032.
    1. Wang ZX, Li D, Cao JX, et al. Efficacy of autologous bone marrow mononuclear cell therapy in patients with peripheral arterial disease. J Atheroscler Thromb. 2014;21(11):1183–1196.
    1. Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia – microvascular therapies coming of age. Circulation. 2008;118(1):9–16.
    1. Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. Eur J Vasc Endovasc Surg. 2015;50(6):775–783.
    1. Teraa M, Sprengers RW, van der Graaf Y, Peters CE, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013;258(6):922–929.
    1. Gremmels H, Teraa M, Quax PH, den Ouden K, Fledderus JO, Verhaar MC. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther. 2014;22(11):1960–1970.
    1. Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L. Hyperglycemia regulates hypoxia-inducible factor 1-alpha protein stability and function. Diabetes. 2004;53(12):3226–3232.
    1. Uccioli L, Izzo V, Meloni M, Vainieri E, Ruotolo V, Giurato L. Non-healing foot ulcers in diabetic patients: general and local interfering conditions and management options with advanced wound dressings. J Wound Care. 2015;24(4 suppl):35–42.
    1. Buschmann I, Schaper W. Arteriogenesis versus angiogenesis: two mechanisms of vessels growth. News Physiol Sci. 1999;14:121–125.
    1. Halstead AE, Vaughan RT. Arteriovenous anastomosis in the treatment of gangrene of the extremities. Surg Gynecol Obstet. 1912;14:1.

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