Autologous adipose-derived stromal cell treatment for patients with refractory angina (MyStromalCell Trial): 3-years follow-up results

Abbas Ali Qayyum, Anders Bruun Mathiasen, Steffen Helqvist, Erik Jørgensen, Mandana Haack-Sørensen, Annette Ekblond, Jens Kastrup, Abbas Ali Qayyum, Anders Bruun Mathiasen, Steffen Helqvist, Erik Jørgensen, Mandana Haack-Sørensen, Annette Ekblond, Jens Kastrup

Abstract

Background: Stem cell therapy is investigated as a treatment option for patients with ischemic heart disease. In this study, long-term safety and efficacy of autologous intra-myocardial injections of adipose-derived stromal cells (ASCs) was studied in patients with refractory angina.

Methods: Sixty patients with coronary artery stenosis and preserved left ventricular ejection fraction were 2:1 randomised to intramyocardial injections of ASCs or saline and followed for 3 years.

Results: For patients in the ASC group, the bicycle exercise time and the exercise performance in watt were un-changed (383 ± 30 s to 370 ± 44 s, P = 0.052 and 81 ± 6 to 78 ± 10, P = 0.123, respectively), but the performance in METs was reduced significantly (4.2 ± 0.3 to 4.0 ± 0.4, P = 0.027) during the follow-up period. However, in the same period, there was in the placebo group a significant decline in bicycle exercise time (437 ± 53 s to 383 ± 58 s, P = 0.001), the exercise performance measured in watt (87 ± 12 W to 80 ± 12 W, P = 0.019) and in METs (4.5 ± 0.4 to 4.1 ± 0.4, P = 0.002). Moreover, angina measured as CCS class was significantly reduced in the ASC group but not in the placebo group (2.5 ± 0.9 to 1.8 ± 1.2, P = 0.002 and 2.5 ± 0.8 to 2.1 ± 1.3, P = 0.186, respectively). However, no significant change was observed between the two groups.

Conclusions: Patients receiving ASCs had improved cardiac symptoms and unchanged exercise capacity, in opposition to deterioration in the placebo group. Trial registration ClinicalTrials.gov Identifier: NCT01449032. Registered 7 October 2011-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT01449032?term=jens+kastrup&rank=7.

Keywords: Adipose derived stromal cells; Chronic ischemic heart disease; Refractory angina; Regeneration; Stem cell therapy.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Bicycle exercise test. Performance in a time duration, b in watt and c in METs
Fig. 3
Fig. 3
Cardiac symptoms measured as a CCS classification and b NYHA classification

References

    1. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63:1123–1133. doi: 10.1016/j.jacc.2013.11.053.
    1. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A, et al. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129:1493–1501. doi: 10.1161/CIRCULATIONAHA.113.004046.
    1. Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54:132–141. doi: 10.2302/kjm.54.132.
    1. Bochev I, Elmadjian G, Kyurkchiev D, Tzvetanov L, Altankova I, Tivchev P, et al. Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro. Cell Biol Int. 2008;32:384–393. doi: 10.1016/j.cellbi.2007.12.007.
    1. Fraser JK, Schreiber R, Strem B, Zhu M, Alfonso Z, Wulur I, et al. Plasticity of human adipose stem cells toward endothelial cells and cardiomyocytes. Nat Clin Pract Cardiovasc Med. 2006;3(Suppl 1):S33–S37. doi: 10.1038/ncpcardio0444.
    1. Heydarkhan-Hagvall S, Schenke-Layland K, Yang JQ, Heydarkhan S, Xu Y, Zuk PA, et al. Human adipose stem cells: a potential cell source for cardiovascular tissue engineering. Cells Tissues Organs (Print). 2008;187:263–274. doi: 10.1159/000113407.
    1. Helder MN, Knippenberg M, Klein-Nulend J, Wuisman PIJM. Stem cells from adipose tissue allow challenging new concepts for regenerative medicine. Tissue Eng. 2007;13:1799–1808. doi: 10.1089/ten.2006.0165.
    1. Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, et al. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv. 2017;89:169–177. doi: 10.1002/ccd.26601.
    1. Perin EC, Sanz-Ruiz R, Sánchez PL, Lasso J, Pérez-Cano R, Alonso-Farto JC, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE Trial. Am Heart J. 2014;168(88–95):e2.
    1. Houtgraaf JH, den Dekker WK, van Dalen BM, Springeling T, de Jong R, van Geuns RJ, et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:539–540. doi: 10.1016/j.jacc.2011.09.065.
    1. Sadat S, Gehmert S, Song Y-H, Yen Y, Bai X, Gaiser S, et al. The cardioprotective effect of mesenchymal stem cells is mediated by IGF-I and VEGF. Biochem Biophys Res Commun. 2007;363:674–679. doi: 10.1016/j.bbrc.2007.09.058.
    1. Gehmert S, Sadat S, Song Y-H, Yan Y, Alt E. The anti-apoptotic effect of IGF-1 on tissue resident stem cells is mediated via PI3-kinase dependent secreted frizzled related protein 2 (Sfrp2) release. Biochem Biophys Res Commun. 2008;371:752–755. doi: 10.1016/j.bbrc.2008.04.151.
    1. Alt E, Pinkernell K, Scharlau M, Coleman M, Fotuhi P, Nabzdyk C, et al. Effect of freshly isolated autologous tissue resident stromal cells on cardiac function and perfusion following acute myocardial infarction. Int J Cardiol. 2010;144:26–35. doi: 10.1016/j.ijcard.2009.03.124.
    1. Qayyum AA, Haack-Sørensen M, Mathiasen AB, Jørgensen E, Ekblond A, Kastrup J. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regen Med. 2012;7:421–428. doi: 10.2217/rme.12.17.
    1. Qayyum AA, Mathiasen AB, Mygind ND, Kühl JT, Jørgensen E, Helqvist S, et al. Adipose-derived stromal cells for treatment of patients with chronic ischemic heart disease (MyStromalCell Trial): a randomized placebo-controlled study. Stem Cells Int. 2017;2017:5237063. doi: 10.1155/2017/5237063.
    1. Follin B, Tratwal J, Haack-Sørensen M, Elberg JJ, Kastrup J, Ekblond A. Identical effects of VEGF and serum-deprivation on phenotype and function of adipose-derived stromal cells from healthy donors and patients with ischemic heart disease. J Transl Med. 2013;11:219. doi: 10.1186/1479-5876-11-219.
    1. Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007;115:3165–3172. doi: 10.1161/CIRCULATIONAHA.106.687376.
    1. Povsic TJ, Henry TD, Traverse JH, Fortuin FD, Schaer GL, Kereiakes DJ, et al. The RENEW trial: efficacy and safety of intramyocardial autologous CD34(+) cell administration in patients with refractory angina. JACC Cardiovasc Interv. 2016;9:1576–1585. doi: 10.1016/j.jcin.2016.05.003.
    1. Losordo DW, Henry TD, Davidson C, Sup Lee J, Costa MA, Bass T, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109:428–436. doi: 10.1161/CIRCRESAHA.111.245993.
    1. Friis T, Haack-Sørensen M, Mathiasen AB, Ripa RS, Kristoffersen US, Jørgensen E, et al. Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina. Scand Cardiovasc J. 2011;45:161–168. doi: 10.3109/14017431.2011.569571.
    1. Mathiasen AB, Haack-Sørensen M, Jørgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina–final 3-year follow-up. Int J Cardiol. 2013;170:246–251. doi: 10.1016/j.ijcard.2013.10.079.
    1. Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Fischer-Nielsen A, Kofoed KF, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial) Eur Heart J. 2015;36:1744–1753. doi: 10.1093/eurheartj/ehv136.
    1. Haack-Sørensen M, Follin B, Juhl M, Brorsen SK, Søndergaard RH, Kastrup J, et al. Culture expansion of adipose derived stromal cells. A closed automated Quantum Cell Expansion System compared with manual flask-based culture. J Transl Med. 2016;14:319. doi: 10.1186/s12967-016-1080-9.
    1. Kastrup J, Haack-Sørensen M, Juhl M, Harary Søndergaard R, Follin B, Drozd Lund L, et al. Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure—a safety Study. Stem Cells Transl Med. 2017;6:1963–1971. doi: 10.1002/sctm.17-0040.
    1. Kastrup J, Schou M, Gustafsson I, Nielsen OW, Møgelvang R, Kofoed KF, et al. Rationale and design of the first double-blind, placebo-controlled trial with allogeneic adipose tissue-derived stromal cell therapy in patients with ischemic heart failure: a Phase II Danish multicentre study. Stem Cells Int. 2017;2017:8506370. doi: 10.1155/2017/8506370.
    1. Paitazoglou C, Bergmann MW, Vrtovec B, Chamuleau SAJ, van Klarenbosch B, Wojakowski W, et al. Rationale and design of the European multicentre study on stem cell therapy in IschEmic non-treatable Cardiac diseasE (SCIENCE) Eur J Heart Fail. 2019;21:1032–1041. doi: 10.1002/ejhf.1412.
    1. Qayyum AA, Kastrup J. Measuring myocardial perfusion: the role of PET, MRI and CT. Clin Radiol. 2015;70:576–584. doi: 10.1016/j.crad.2014.12.017.
    1. Qayyum AA, Kaur KP, Mathiasen AB, Haack-Sørensen M, Ekblond A, Kastrup J. Influence of patient related factors on number of mesenchymal stromal cells reached after in vitro culture expansion for clinical treatment. Scand J Clin Lab Invest. 2017;77:541–548. doi: 10.1080/00365513.2017.1354258.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel