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Multicenter Study
. 2022 Nov;25(4):535-546.
doi: 10.1007/s10456-022-09844-7. Epub 2022 Jul 8.

Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial

Yuuki Shimizu  1 , Kazuhisa Kondo  2 , Ryo Hayashida  2 , Ken-Ichiro Sasaki  3 , Masanori Ohtsuka  3 , Yoshihiro Fukumoto  3 , Shinichiro Takashima  4 , Oto Inoue  4 , Soichiro Usui  4 , Masayuki Takamura  4 , Masashi Sakuma  5 , Teruo Inoue  6 , Tokuichiro Nagata  7 , Yoshihiro J Akashi  8 , Yoshihiro Yamada  9 , Tamon Kato  10 , Koichiro Kuwahara  10 , Kaoru Tateno  11 , Yoshio Kobayashi  11 , Rei Shibata  12 , Toyoaki Murohara  13 ; TACT-ADRC multicenter trial Group
Collaborators, Affiliations
Multicenter Study

Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial

Yuuki Shimizu et al. Angiogenesis. 2022 Nov.

Abstract

Background: Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia.

Objectives: We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan.

Methods: The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation.

Results: The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm2 at to 109 mm2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively.

Conclusions: Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015.

Keywords: Adipose-derived regenerative cells; Critical limb ischemia; Multicenter clinical trial; Therapeutic angiogenesis.

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Conflict of interest statement

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Figures

Fig. 1
Fig. 1
Trial profile. TACT: therapeutic angiogenesis by cell transplantation, ADRC: adipose-derived regenerative cell
Fig. 2
Fig. 2
Patients’ characteristics (A) etiologies of critical limb ischemia and (B) target limbs, and (C) breakdown of the Fontaine class in participants
Fig. 3
Fig. 3
Procedural results. Figures indicate the quantity of total adipose tissue collection, the total cell number of ADRCs, and the cell viability rate, respectively, for all individuals
Fig. 4
Fig. 4
Primary outcomes in terms of safety evaluation for the TACT-ADRC procedure. Figures indicate (A) survival rate from all-cause death, (B) evasion rate of major limb amputation, and (C) the composition of survival, the evasion of major limb amputation, and the freedom from MACCE. MACCE: major adverse cardiac and cerebrovascular events
Fig. 5
Fig. 5
Secondary outcomes of the TACT-ADRC procedure. A Pain scale evaluated as per the NRS at the baseline and 6 months after ADRC implantation, (B) ulcer size was calculated as the grand total of major axis length times the minor axis length at the baseline and 6 months after ADRC implantation, (C) walking distance covered in 6-min for the patients with lower limb ischemia at the baseline and 6 months after ADRC implantation, (D) Tissue blood perfusion indicated by ABI, and (E) SPP in all cases, (F) SPP results only in severe cases as less than 40 mmHg at baseline. NRS numerical rating scale, 6 min walking distance: 6MWD, ABI ankle-brachial index, and SPP skin perfusion pressure
Fig. 6
Fig. 6
Time courses after ADRC implantation (A) improvements in non-healing ulcer and blood perfusion recovery in a case of the 63 years’ upper limb ischemia patient. B Laser Doppler blood perfusion analysis and angiography in the 74-years-old CLI patient due to CTD
Fig. 7
Fig. 7
The case of toe necrosis with multiple non-healing operative scars in a patient of TAO. All non-healing scars were completely healed (A), following the recovery of blood perfusion and angiographical improvement (B) at 24 weeks after ADRC implantation
See this image and copyright information in PMC

References

    1. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, Mills JL, Ricco JB, Suresh KR, Murad MH et al: Corrigendum to 'Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia' [European Journal of Vascular & Endovascular Surgery 58/1S (2019) 1–109]. Eur J Vasc Endovasc Surg 2020, 59(3):492–493. - PubMed
    1. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360(9331):427–435. doi: 10.1016/S0140-6736(02)09670-8. - DOI - PubMed
    1. Povsic TJ, Henry TD, Traverse JH, Fortuin FD, Schaer GL, Kereiakes DJ, Schatz RA, Zeiher AM, White CJ, Stewart DJ, et al. The RENEW trial: efficacy and safety of intramyocardial autologous CD34(+) Cell Administration in Patients With Refractory Angina. JACC Cardiovasc Interv. 2016;9(15):1576–1585. doi: 10.1016/j.jcin.2016.05.003. - DOI - PubMed
    1. Mathur A, Fernandez-Aviles F, Bartunek J, Belmans A, Crea F, Dowlut S, Galinanes M, Good MC, Hartikainen J, Hauskeller C, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial. Eur Heart J. 2020;41(38):3702–3710. doi: 10.1093/eurheartj/ehaa651. - DOI - PMC - PubMed
    1. Bolli R, Perin EC, Willerson JT, Yang PC, Traverse JH, Henry TD, Pepine CJ, Mitrani RD, Hare JM, Murphy MP, et al. Allogeneic mesenchymal cell therapy in anthracycline-induced cardiomyopathy heart failure patients: the CCTRN SENECA Trial. JACC CardioOncol. 2020;2(4):581–595. doi: 10.1016/j.jaccao.2020.09.001. - DOI - PMC - PubMed

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