A.A. ZORKIN¹, E.V. DROZZHIN¹, I.I. KATELNITSKIY², K.V. MAZAISHVILI¹

¹Surgut State University, 1 Gubkin Str., Surgut, Russian Federation, 628400

²Rostov State Medical University, 29 Nakhichevanskiy pereulok, Rostov-on-Don, Russian Federation, 344022

Zorkin A.A. ― PhD (medicine), Associate Professor of the Department of Faculty Surgery, tel./fax: (3462) 52-16-00, e-mail: az_99@mail.ru, ORCID ID: 0000-0002-3208-4179

Drozzhin E.V. ― D. Sc. (medicine), Professor, Head of the Department of Faculty Surgery, tel./fax: (3462) 52-16-00, e-mail: fxsurgu@yandex.ru, ORCID ID: 0000-0001-8191-3706

Katelnitskiy I.I. ― D. Sc. (medicine), Professor, Head of the Department of Surgery №1, tel./fax: (8632) 50-40-74, e-mail: rostgmukhb1@yandex.ru, ORCID ID: 0000-0001-9913-740X

Mazaishvili K.V. ― D. Sc. (medicine), Professor of the Department of Faculty Surgery, tel./fax: (3462) 52-16-00, e-mail: fxsurgu@yandex.ru, ORCID ID: 0000-0003-1291-1381

 The inability to perform revascularization interventions in patients with peripheral artery obliterating diseases (PAOD) at the stage of critical limb ischemia (CLI) reaches 30%, which significantly increases the risk of limb loss. One way to solve this problem is to use modern technologies of angiogenesis, based on the use of growth factors and cellular structures capable of proliferation and differentiation into neovascular vessels. In the article, from the standpoint of evidence-based medicine, practical questions of the application of therapeutic angiogenesis in CLI are considered. The effectiveness and safety of various stimulants of angiogenesis have been studied according to the data of the main international and Russian controlled clinical research. The clinical effectiveness of the technologies under consideration in patients with CLI with respect to the parameters of limb and quality of life preservation, as well as the absence of serious side effects, was proved. At the same time, therapeutic angiogenesis at the present stage should be considered as an auxiliary method of treatment or a component of complex therapy. Further research is required to develop optimal therapeutic algorithms and evaluate the long-term results of the technology application.

Key words: critical limb ischemia, obliterating diseases of lower limbs, therapeutic angiogenesis, growth factors, cellular therapy.

(For citation: Zorkin A.A., Drozzhin E.V., Katelnitskiy I.I., Mazaishvili K.V. Therapeutic angiogenesis in patients with peripheral artery obliterating diseases and critical limb ischemia: possibility of therapy from evidence-based medicine positions. Practical Medicine. 2018)

REFERENCES

1. Zudin A.M., Zasorina M.A., Orlova M.A. Epidemiological aspects of chronic critical lower limb ischemia. Khirurgiya, 2014, no. 10, pp. 91-95 (in Russ.).
2. Miyahara T., Suhara M., Nemoto Y. et al. Long-term results of treatment for critical lim bischemia. Ann.Vasc. Dis, 2015, vol. 8, pp. 192-197.
3. Norgren I., Hiatt W.R., Dormandy M.R., et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASK II). J. Vasc. Surg, 2007, 45 Suppl, pp. 5-67.
4. Varu V.N., Hogg M.E., Kibbe M.R. Critical limb ischemia. J. Vasc. Surg, 2010, vol. 51, pp. 230-241.
5. Freisinger E., Reinecke H. High amputation rates and mortality ― is critical limb ischemia still a losing game? Wasa, 2015, vol. 44, p. 325.
6. Davies M.G. Critical limb ischemia: cell and molecular therapies for limb salvage. MDCVJ, 2012, vol. 8 (4), pp. 20-27.
7. Hirschi K., Goodell M. Common origins of blood and blood vessels in adults?. Differentiation, 2001, vol. 68 (4-5), pp. 186-192.
8. Annex B.H. Therapeutic angiogenesis for critical limb ischaemia. Nat. Rev. Cardiol, 2013, vol. 10 (7), pp. 387-396.
9. Iyer S.R., Annex B.H. Therapeutic angiogenesis for peripheral artery disease: lessons learned in translational science. JACC Basic Transl. Sci, 2017, vol. 2 (5), pp. 503-512.
10. Inampudi C., Akintoye E., Ando T., Briasoulis A. Angiogenesis in peripheral arterial disease. Curr. Opin. Pharmacol, 2018, vol. 39, pp. 60-67.
11. Gorenoi V., Brehm M.U., Koch A., Hagen A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst. Rev, 2017, vol. 6, CD011741.
12. Lederman R.J., Mendelsohn F.O., Anderson R.D., et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet, 2002, vol. 359 (9323), pp. 2053-2058.
13. Rajagopalan S., Mohler E.R. 3rd, Lederman R.J., 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, vol. 108 (16), pp. 1933-1938.
14. 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, vol. 16 (5), pp. 972-978.
15. Powell R.J., Simons M., Mendelsohn F.O., 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, vol. 118 (1), pp. 58-65.
16. Powell R.J., Goodney P., Mendelsohn F.O. et al. HGF-0205 Trial Investigators. Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial. J. Vasc. Surg, 2010, vol. 52 (6), pp. 525-530.
17. Creager M.A., Olin J.W., Belch J.J., et al. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation, 2011, vol. 124 (16), pp. 1765-1773.
18. Gu Y., Zhang J., Guo L., et al. A phase I clinical study of naked DNA expressing two isoforms of hepatocyte growth factor to treat patients with critical limb ischemia. J. Gene Med., 2011, vol. 13 (11), pp. 602-610.
19. Shvalʹb P.G., Gavrilenko A.V., Kalinin R.E. et al. Efficacy and safety of using Neovasculgen in the complex therapy of patients with chronic lower limb ischemia (IIB — III phase of clinical trials). Kletochnaya transplantologiya i tkanevaya inzheneriya, 2011, vol. 6, no. 3, pp. 76-83 (in Russ.).
20. Gavrilenko A.V., Voronov D.A. Results of complex treatment of patients with chronic lower limb ischemia using gene technologies of stimulation of angiogenesis (part 1). Angiologiya i sosudistaya khirurgiya, 2015, vol. 21, no. 3, pp. 7-15 (in Russ.).
21. Chervyakov YU.V., Vlasenko O.N. Quality of life in patients with atherosclerosis of the lower extremities using standard treatment and therapeutic angiogenesis. Terapevticheskiy arkhiv, 2017, vol. 89, no. 9, pp. 87-92 (in Russ.).
22. Katelʹnitskiy I.I., Katelʹnitskiy Ig.I., Alekseeva G.A. The first experience of quantitative evaluation of the results of therapeutic angiogenesis. Kletochnaya transplantologiya i tkanevaya inzheneriya, 2012, vol. 7, no. 4, pp. 83-85 (in Russ.).
23. Katelʹnitskiy Ig.I., Muradov A.M. Modern possibilities of revascularization of the popliteal-tibial segment in patients with critical lower limb ischemia. Uspekhi sovremennoy nauki i obrazovaniyayu, 2017, vol. 1, no.1, pp. 19-24 (in Russ.).
24. Kalinin R.E., Suchkov I.A., Deev R.V. et al. Gene induction of angiogenesis in inoperable patients with atherosclerosis and diabetes mellitus. Angiologiya i sosudistaya khirurgiya, 2018, vol. 24, no. 2, pp. 33-40 (in Russ.).
25. Chervyakov YU.V., Staroverov I.N., Vlasenko O.N. et al. Long-term results of treatment of patients with chronic lower limb ischemia by indirect revascularization and gene therapy methods. Angiologiya i sosudistaya khirurgiya, 2016, vol. 22, no. 1, pp. 29-37 (in Russ.).
26. De Haro J., Acin F., Lopez-Quintana A., et al. Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels, 2009, vol. 24 (5), pp. 321-328.
27. Gorenoi V., Brehm M.U., Koch A., Hagen A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst. Rev, 2017, vol. 6, CD011741.
28. Burt R.K., Loh Y., Pearce W., et al. Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA, 2008, vol. 299 (8), pp. 925-936.
29. Liotta F., Annunziato F., Castellani S., et al. Therapeutic efficacy of autologous non-mobilized enriched circulating endothelial progenitors in patients with critical limb ischemia ― The SCELTA Trial. Circ. J, 2018, vol. 82 (6), pp. 1688-1698.
30. Saigawa T., Kato K., Ozawa T. et al. Clinical application of bone marrow implantation in patients with atherosclerosis obliterans, and the associacion between efficacy and the number of implanted bone marrow cells. Circ. J, 2004, vol. 68 (12), pp. 1189-1193.
31. Sukovatykh B.S., Orlova A.Yu. Stimulation of angiogenesis by bone marrow cells during experimental limb ischemia. Angiologiya i sosudistaya khirurgiya, 2017, vol. 23, no. 1, pp. 43-50 (in Russ.).
32. Matoba S., Tatsumi T., Murohara T., et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. Am. Heart J, 2008, vol. 156 (5), pp. 1010-1018.
33. Amann B., Luedemann C., Ratei R., Schmidt-Lucke J.A. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant, 2009, vol. 18 (3), pp. 371-380.
34. Powell R.J., Comerota A.J., Berceli S.A., et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J. Vasc. Surg, 2011, vol. 54 (4), pp. 1032-1041.
35. Iafrati M.D., Hallett J.W., Geils G., et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J. Vasc. Surg, 2011, vol. 54 (6), pp. 1650-1658.
36. Walter D.H., Krankenberg H., Balzer J., et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial PROVASA). Circ. Cardiovasc. Interv, 2011, vol. 4, pp. 26-37.
37. Molavi B., Zafarghandi M.R., Aminizadeh E., et al. Safety and efficacy of repeated bone marrow mononuclear cell therapy in patients with critical limb ischemia in a pilot randomized controlled trial. Arch. Iran Med, 2016, vol. 19 (6), pp. 388-396.
38. Wang S.K., Green L.A., Motaganahalli R.L., et al. Rationale and design of the Marrow Stim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial investigating autologous bone marrow cell therapy for critical limb ischemia. J. Vasc. Surg, 2017, vol. 65 (6), pp. 1850-1857.e2.
39. Darinskas A., Paskevicius M., Apanavicius G., et al. Stromal vascular fraction cells for the treatment of critical limb ischemia: a pilot study. J. Transl. Med, 2017, vol. 15 (1), pp. 143.
40. Wijnand J.G.J., Teraa M., Gremmels H., et al. SAIL Study Group. Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia. J. Vasc. Surg, 2018, vol. 67 (2), pp. 656-661.
41. Samura M., Hosoyama T., Takeuchi Y. et al. Therapeutic strategies for cell-based neovascularization in critical limb ischemia. J. Transl. Med, 2017, vol. 15 (1), p. 49.
42. Moazzami K., Moazzami B., Roohi A. et al. Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst. Rev., 2014, vol. 12, CD008347.
43. Lara-Hernandez R., Lozano-Vilardell P., Blanes P. et al. Safety and efficacy of therapeutic angiogenesis as a novel treatment in patients with critical limb ischemia. Ann. Vasc. Surg., 2010, vol. 24 (2), pp. 287-294.
44. Franz R.W., Parks A., Shah K.J. et al. Use of autologous bone marrow mononuclear cell implantation therapy as a limb salvage procedure in patients with severe peripheral arterial disease. J. Vasc. Surg, 2009, vol. 50 (5), pp. 1378-1390.
45. Van Tongeren R.B., Hamming J.F., Fibbe W.E., et al. Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia. J. Cardiovasc. Surg. (Torino), 2008, vol. 40 (1), pp. 51-58.
46. Bartsch T., Brehm M., Zeus T., et al. Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin. Res. Cardiol, 2007, vol. 96 (12), pp. 891-899.
47. Iyer S.R., Annex B.H. Therapeutic angiogenesis for peripheral artery disease: lessons learned in translational science. JACC Basic Transl. Sci, 2017, vol. 2 (5), pp. 503-512.