Skip to main content
Top
Published in: Heart and Vessels 9/2017

01-09-2017 | Original Article

Clinical features and predictors of patients with critical limb ischemia who responded to autologous mononuclear cell transplantation for therapeutic angiogenesis

Authors: Naoyoshi Aoyama, Makoto Nishinari, Shinichi Ohtani, Akifumi Kanai, Chiharu Noda, Mitsuhiro Hirata, Akira Miyamoto, Masafumi Watanabe, Tohru Minamino, Tohru Izumi, Jyunya Ako

Published in: Heart and Vessels | Issue 9/2017

Login to get access

Abstract

The clinical features of patients with critical limb ischemia (CLI) who responded to angiogenesis using autologous peripheral blood mononuclear cell transplantation (PB-MNC) have not yet been fully characterized, and there are no useful predictors to judge the curative effect in the early period after PB-MNC. This study sought to clarify the clinical features and predictors in patients with CLI who were successfully treated using PB-MNC. 30 consecutive patients [arteriosclerosis obliterans: 24 patients, thromboangiitis obliterans: 6 patients] who were diagnosed with major amputation despite maximal medical therapy were enrolled in this study. The study endpoint was major amputation within 3 months after PB-MNC. The collected data were evaluated for correlation between patients with and without major amputation within 3 months after PB-MNC. Six patients underwent major amputation and 1 patient underwent minor amputation. In the patients with major amputation, transcutaneous oxygen tension before PB-MNC and transplanted CD34-positive cells were lower than those of patients without major amputation. In the patients with amputation, interleukin-6 (IL-6) continued to increase after the first PB-MNC, and basic fibroblast growth factor (bFGF) decreased within 3 days after the first PB-MNC. PB-MNC was useful for the patients who were managed for inflammation and who had revascularization of the upper-popliteal arteries and two of the infra-popliteal arteries by endovascular and/or surgical revascularization. Variation in IL-6 and bFGF in the early period after PB-MNC could be useful predictors for the requirement of amputation within 3 months after PB-MNC.
Literature
1.
go back to reference Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, REACH Registry Investigators (2007) One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 297:1197–1206CrossRefPubMed Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, REACH Registry Investigators (2007) One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 297:1197–1206CrossRefPubMed
2.
go back to reference McKenna M, Wolfson S, Kuller L (1991) The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 87:119–128CrossRefPubMed McKenna M, Wolfson S, Kuller L (1991) The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 87:119–128CrossRefPubMed
3.
go back to reference Amann B, Leudemann C, Ratei R, Schmidt-Lucke JA (2009) Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transpl 18:371–380CrossRef Amann B, Leudemann C, Ratei R, Schmidt-Lucke JA (2009) Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transpl 18:371–380CrossRef
4.
go back to reference Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mono- nuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28:2155–2160CrossRefPubMed Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mono- nuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28:2155–2160CrossRefPubMed
5.
go back to reference Jude EB, Eleftheriadou I, Tentolouris N (2010) Peripheral arterial disease in diabetes—a review. Diabet Med 27:4–14CrossRefPubMed Jude EB, Eleftheriadou I, Tentolouris N (2010) Peripheral arterial disease in diabetes—a review. Diabet Med 27:4–14CrossRefPubMed
6.
go back to reference Takahara M, Kaneto H, Katakami N, Iida O, Matsuoka TA, Shimomura I (2014) Effect of sarpogrelate treatment on the prognosis after endovascular therapy for critical limb ischemia. Heart Vessels 29:563–567CrossRefPubMed Takahara M, Kaneto H, Katakami N, Iida O, Matsuoka TA, Shimomura I (2014) Effect of sarpogrelate treatment on the prognosis after endovascular therapy for critical limb ischemia. Heart Vessels 29:563–567CrossRefPubMed
7.
go back to reference Benoit E, O’Donnell TF, Patel AN (2013) Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transpl 22:545–562CrossRef Benoit E, O’Donnell TF, Patel AN (2013) Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transpl 22:545–562CrossRef
8.
go back to reference De Haro J, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C (2009) Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 24:321–328CrossRefPubMed De Haro J, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C (2009) Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 24:321–328CrossRefPubMed
9.
go back to reference Liew A, Bhattacharya V, Shaw J, Stansby G (2016) Cell therapy for critical limb ischemia: a meta-analysis of randomized controlled trials. Angiology 67:444–455CrossRefPubMed Liew A, Bhattacharya V, Shaw J, Stansby G (2016) Cell therapy for critical limb ischemia: a meta-analysis of randomized controlled trials. Angiology 67:444–455CrossRefPubMed
10.
go back to reference Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M, Saito Y, Uemura S, Suzuki H, Fukumoto S, Yamamoto Y, Onodera R, Teramukai S, Fukushima M, Matsubara H, TACT Follow-up Study Investigators (2008) 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 156:1010–1018.CrossRefPubMed Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M, Saito Y, Uemura S, Suzuki H, Fukumoto S, Yamamoto Y, Onodera R, Teramukai S, Fukushima M, Matsubara H, TACT Follow-up Study Investigators (2008) 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 156:1010–1018.CrossRefPubMed
11.
go back to reference Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda S, Kunieda T, Miyauchi H, Oyama T, Matsuura K, Nishi J, Kobayashi Y, Nagai T, Kuwabara Y, Iwakura Y, Nomura F, Saito Y, Komuro I (2006) Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res 98:1194–1202CrossRefPubMed Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda S, Kunieda T, Miyauchi H, Oyama T, Matsuura K, Nishi J, Kobayashi Y, Nagai T, Kuwabara Y, Iwakura Y, Nomura F, Saito Y, Komuro I (2006) Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res 98:1194–1202CrossRefPubMed
12.
go back to reference Tateno K, Minamino T, Moriya J, Katada A, Yokoyama M, Miura K, Komuro I (2008) Cell therapy for cardiovascular diseases. Ann Vasc Dis 1:66–79CrossRefPubMedCentral Tateno K, Minamino T, Moriya J, Katada A, Yokoyama M, Miura K, Komuro I (2008) Cell therapy for cardiovascular diseases. Ann Vasc Dis 1:66–79CrossRefPubMedCentral
13.
go back to reference Brevetti G, Giugliano G, Brevetti L, Hiatt WR (2010) Inflammation in peripheral artery disease. Circulation 122:1862–1875CrossRefPubMed Brevetti G, Giugliano G, Brevetti L, Hiatt WR (2010) Inflammation in peripheral artery disease. Circulation 122:1862–1875CrossRefPubMed
14.
go back to reference Kobayashi N, Hirano K, Nakano M, Muramatsu T, Tsukahara R, Ito Y, Ishimori H (2014) Wound healing and wound location in critical limb ischemia following endovascular treatment. Circ J 78:1746–1753CrossRefPubMed Kobayashi N, Hirano K, Nakano M, Muramatsu T, Tsukahara R, Ito Y, Ishimori H (2014) Wound healing and wound location in critical limb ischemia following endovascular treatment. Circ J 78:1746–1753CrossRefPubMed
15.
go back to reference Durdu S, Akar AR, Arat M, Sancak T, Eren NT, Ozyurda U (2006) Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. J Vasc Surg 44:732–739CrossRefPubMed Durdu S, Akar AR, Arat M, Sancak T, Eren NT, Ozyurda U (2006) Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. J Vasc Surg 44:732–739CrossRefPubMed
16.
go back to reference Poredos P, Rakovec S, Guzic-Salobir B (2005) Determination of amputation level in ischaemic limbs using tcPO2 measurement. Vasa 34:108–112CrossRefPubMed Poredos P, Rakovec S, Guzic-Salobir B (2005) Determination of amputation level in ischaemic limbs using tcPO2 measurement. Vasa 34:108–112CrossRefPubMed
17.
go back to reference Arsenault KA, Al-Otaib A, Devereaux PJ, Thorlund K, Tittley JG, Whitlock RP (2012) The use of transcutaneous oximetry to predict healing complications of lower limb amputations: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg 43:329–336CrossRefPubMed Arsenault KA, Al-Otaib A, Devereaux PJ, Thorlund K, Tittley JG, Whitlock RP (2012) The use of transcutaneous oximetry to predict healing complications of lower limb amputations: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg 43:329–336CrossRefPubMed
18.
go back to reference Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A (2014) Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 32:1380–1389CrossRefPubMedPubMedCentral Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A (2014) Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 32:1380–1389CrossRefPubMedPubMedCentral
19.
go back to reference Raval Z, Losordo DW (2013) Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res 112:1288–1302CrossRef Raval Z, Losordo DW (2013) Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res 112:1288–1302CrossRef
20.
go back to reference Saigawa T, Kato K, Ozawa T, Toba K, Makiyama Y, Minagawa S, Hashimoto S, Furukawa T, Nakamura Y, Hanawa H, Kodama M, Yoshimura N, Fujiwara H, Namura O, Sogawa M, Hayashi J, Aizawa Y (2004) Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J 68:1189–1193CrossRef Saigawa T, Kato K, Ozawa T, Toba K, Makiyama Y, Minagawa S, Hashimoto S, Furukawa T, Nakamura Y, Hanawa H, Kodama M, Yoshimura N, Fujiwara H, Namura O, Sogawa M, Hayashi J, Aizawa Y (2004) Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J 68:1189–1193CrossRef
21.
go back to reference Iso Y, Soda T, Sato T, Sato R, Kusuyama T, Omori Y, Shoji M, Koba S, Katagiri T, Kobayashi Y, Suzuki H (2010) Impact of implanted bone marrow progenitor cell composition on limb salvage after cell implantation in patients with critical limb ischemia. Atherosclerosis 209:167–172CrossRefPubMed Iso Y, Soda T, Sato T, Sato R, Kusuyama T, Omori Y, Shoji M, Koba S, Katagiri T, Kobayashi Y, Suzuki H (2010) Impact of implanted bone marrow progenitor cell composition on limb salvage after cell implantation in patients with critical limb ischemia. Atherosclerosis 209:167–172CrossRefPubMed
22.
go back to reference Horie T, Onodera R, Akamastu M, Ichikawa Y, Hoshino J, Kaneko E, Iwashita C, Ishida A, Tsukamoto T, Teramukai S, Fukushima M, Kawamura A, Japan Study Group of Peripheral Vascular Regeneration Cell Therapy (JPRCT) (2010) Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells. Atherosclerosis 208:461–466CrossRefPubMed Horie T, Onodera R, Akamastu M, Ichikawa Y, Hoshino J, Kaneko E, Iwashita C, Ishida A, Tsukamoto T, Teramukai S, Fukushima M, Kawamura A, Japan Study Group of Peripheral Vascular Regeneration Cell Therapy (JPRCT) (2010) Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells. Atherosclerosis 208:461–466CrossRefPubMed
23.
go back to reference Moriya J, Minamino T, Tateno K, Shimizu N, Kuwabara Y, Sato Y, Saito Y, Komuro I (2009) Long-term outcome of therapeutic neovascularization using peripheral blood mononuclear cells for limb ischemia. Circ Cardiovasc Interv 2:245–254CrossRefPubMed Moriya J, Minamino T, Tateno K, Shimizu N, Kuwabara Y, Sato Y, Saito Y, Komuro I (2009) Long-term outcome of therapeutic neovascularization using peripheral blood mononuclear cells for limb ischemia. Circ Cardiovasc Interv 2:245–254CrossRefPubMed
24.
go back to reference Saito Y, Sasaki K, Katsuda Y, Murohara T, Takeshita Y, Okazaki T, Arima K, Katsuki Y, Shintani S, Shimada T, Akashi H, Ikeda H, Imaizumi T (2007) Effect of autologous bone-marrow cell transplantation on ischemic ulcer in patients with Buerger’s disease. Circ J 71:1187–1192CrossRefPubMed Saito Y, Sasaki K, Katsuda Y, Murohara T, Takeshita Y, Okazaki T, Arima K, Katsuki Y, Shintani S, Shimada T, Akashi H, Ikeda H, Imaizumi T (2007) Effect of autologous bone-marrow cell transplantation on ischemic ulcer in patients with Buerger’s disease. Circ J 71:1187–1192CrossRefPubMed
25.
go back to reference Motukuru V, Suresh KR, Vivekanand V, Raj S, Girija KR (2008) Therapeutic angiogenesis in Buerger’s disease (thromboangiitis obliterans) patients with critical limb ischemia by autologous transplantation of bone marrow mononuclear cells. J Vasc Surg 48:53S–60SCrossRefPubMed Motukuru V, Suresh KR, Vivekanand V, Raj S, Girija KR (2008) Therapeutic angiogenesis in Buerger’s disease (thromboangiitis obliterans) patients with critical limb ischemia by autologous transplantation of bone marrow mononuclear cells. J Vasc Surg 48:53S–60SCrossRefPubMed
26.
go back to reference Fadini GP, Agostini C, Avogaro A (2010) Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis 209:10–17CrossRef Fadini GP, Agostini C, Avogaro A (2010) Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis 209:10–17CrossRef
Metadata
Title
Clinical features and predictors of patients with critical limb ischemia who responded to autologous mononuclear cell transplantation for therapeutic angiogenesis
Authors
Naoyoshi Aoyama
Makoto Nishinari
Shinichi Ohtani
Akifumi Kanai
Chiharu Noda
Mitsuhiro Hirata
Akira Miyamoto
Masafumi Watanabe
Tohru Minamino
Tohru Izumi
Jyunya Ako
Publication date
01-09-2017
Publisher
Springer Japan
Published in
Heart and Vessels / Issue 9/2017
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-017-0968-5

Other articles of this Issue 9/2017

Heart and Vessels 9/2017 Go to the issue